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PMC4231816_01

Female

A 62-year-old woman was a close contact of a patient with active sputum positive TB. She had a positive Quantiferon test and no evidence for active disease. She had never taken rifampin before. She had hypertension and hyperlipidemia and took metoprolol 25 mg, atorvastatin 20 mg, calcium and vitamin D, and a multivitamin daily. She began rifampin 600 mg daily. Four days later, she developed mild itching that did not respond to diphenhydramine. Twenty-three days later, her lips and eyelid swelled and she developed a generalized rash. She was admitted to the hospital for angioedema. No abnormality was found in routine laboratory tests. She recovered 2 days after stopping rifampin. Her latent tuberculosis was later treated with isoniazid. In this patient, angioedema developed about a month after starting rifampin and recovered soon after its discontinuance. There was no eosinophilia associated with the reaction. Possible rifampin-associated angioedema was questioned previously, but data have not strongly supported it. The pathogenesis of rifampin-induced angioedema is not clear. It may be a non-immunoglobulin E (IgE) mediated mechanism with an imbalance in the arachidonic acid cascade, increasing of leukotrienes or bradykinin-mediated. We alert readers to this adverse effect of a widely prescribed drug to avoid serious outcomes. Rifampin-induced angioedema is a life threatening side effect; therefore, rifampin should not be readministered.

PMC8425344_02

Male

A thirty-four-year-old man with S/B0 thalassemia was admitted five days following the AstraZeneca vaccine with lower back pain, chest pain, and shoulder pain. He was on Hydroxyurea and had a history of splenic sequestration, tuberculosis of the spine, and cholecystectomy. He had no recent admission for over three years (39 months). While in hospital, he developed fever, tachycardia, and dropped saturation, with right-sided crepitations and chest X-rays showing right-sided infiltrates. He was also noted to have significant anemia at 4.5 g/dl, thrombocytopenia at 60 x 109/l, hyponatremia at 127, and a substantial rise in CRP, bilirubin, and other liver enzymes as outlined in Table 1. SARS-COVID-19 testing by PCR was negative. He received blood transfusions antibiotics and recovered gradually and was discharged home six days later.

chadox1 ncov-19 vaccine, sars-cov2, sickle cell disease, vaccine-induced immune thrombotic thrombocytopenia, vaso-occlusive crisis

PMC5960230_01

Female

A 42-year-old woman presented to the outpatient Pneumology Clinic with a complaint of a persistent cough without fever over a month and the onset of chest pain a week prior to presentation. A chest X-ray revealed a left-sided perihilar opacity (Figure 1A). She reported a negative medical history and was prescribed the antibiotic levofloxacin. Computerized tomography (CT) of the thorax demonstrated a solid mass (10x12 cm in diameter) in the left upper lobe, as well as enlarged superior mediastinal and aorto-pulmonary lymph nodes (Figure 1B). Positron emission tomography demonstrated pulmonary neoplasm with a standardized uptake value of 31 and mediastinal lymphadenopathy. Fibrobronchoscopy and EBUS-TBNA were performed in the outpatient clinic, aimed at diagnosing and staging the probable lung tumor. Using a 21-gauge needle, she underwent a bronchoscopy with EBUS-TBNA of subcarinal lymph node stations (nodal station 7) and suspicious histopathological tissue at the upper left bronchus. The procedure was performed under deep sedation using midazolam and propofol; however, resistant cough was noted. Upon completion of the procedure, she complained of acute chest pain, which regressed immediately, and a physical examination was negative following which she returned home. Cytological results of all biopsies obtained with EBUS-TBNA were negative. CT-guided fine-needle aspiration (FNA) performed 3 days later revealed a right-sided pneumothorax associated with a small pneumomediastinum (Figure 2). The patient was admitted to the Department of Internal Medicine for 4 days of observation and responded to conservative management. Based on extranodal dissemination, the cytological samples obtained via FNA that were positive for non-Hodgkin's diffuse large B-cell lymphoma, were later classified (staged) as samples showing a stage IV tumor. We obtained the patient's consent to publish this case report.

endobronchial ultrasound-guided needle aspiration, mediastinal adenopathy, non-hodgkin’s lymphoma, pneumomediastinum

PMC8183367_01

Male

A 38-year-old man, forest guard, resident of a hilly station of Himalayas, having schizophrenia for the past 15 years, being on antipsychotics: aripiprazole and trihexyphenidyl, presented to the emergency department with high-grade, intermittent fever for 7 days along with myalgia and headache. Following 4 days of fever, he developed multiple painless rashes over the soles of both feet and ankles. The rashes were reddish at the onset and later blackened. There was no gangrene formation or bleeding tendency. He reported breathlessness on exertion and later on in the supine position, but not paroxysmal nocturnal dyspnea. Breathlessness was associated with progressive bilateral leg edema and generalized weakness. He had decreased urine output for 1 day. There was no other history of any localizing symptoms. There was no history of substance use, alcohol intake, smoking, or any other comorbidity except above psychiatry illness. He was evaluated in an outside hospital where dengue NS1 antigen (on day 3 of illness) was positive along with low platelet count (40,000/mm3). On examination, he was thin built but pale and edematous, afebrile, mildly drowsy, and disoriented. Vitals were unstable: heart rate 128 bpm, regular with satisfactory pulse volume; blood pressure 98/60 mm Hg with pulse pressure 48 mmHg; tachypneic (respiratory rate 30/min) with arterial oxygen saturation of 86% on ambient room air and 92%-95% on 4 L of O2 therapy (hypoxemia). Along with bilateral pitting pedal edema, there were multiple palpable but nontender purpuric rashes present on both feet ranging in size from 2 mm to 8 mm, with fine scaling and postinflammatory hyperpigmentation with confluence toward the terminal aspect and impending gangrene [Figure 1a]. All peripheral pulses were felt. Jugular venous pulse was not elevated. Chest examination demonstrated bilateral basal fine crackles and occasional wheezes. S1 and S2 were normal but with equal intensity (Tic-Tac rhythm like), and gallop/murmur was not present. Abdominal examination demonstrated mild tenderness over the right hypochondrium and epigastrium, but no palpable liver and spleen. Other systemic examinations were unremarkable. From day 3 of admission (day 9 of illness), he started experiencing severe pain in both feet, which now showed darkening in color and was tender to touch, suggesting impending dry gangrene superimposed on the purpuric rashes [Figure 1a and b]. All peripheral arterial pulsations were normal, including the toe movements, and there was hyperesthesia of feet. A probable diagnosis of EDS (because of outbreak season) with myocardium, vessels, skin, and kidney involvements was made. Electrocardiography showed sinus tachycardia. Chest X-ray revealed features suggestive of early pulmonary edema [Figure 1d]. Initial arterial blood gas analysis showed compensated respiratory alkalosis. Hemogram on day 8 of the illness revealed anemia (Hb, 9.4 g/dL) with a normal mean corpuscular volume (MCV) and corrected reticulocyte count of 2.8, leukocyte count (7900/mm3), and thrombocytopenia (platelet count, 30,000/mm3) with a peripheral smear showing normochromic normocytic picture and reactive lymphocytes. Serum lactate dehydrogenase concentration was increased (457 U/L; reference normal <248 U/L in males). Erythrocyte sedimentation rate was 44 mm/h, and highly sensitive C-reactive protein fraction was 14.2 mg/L. Fibrin degradation products were 12 mg/L, and D-dimer was <0.5. ADAMTS13 levels, serum complement levels, and immunoglobulin levels could not be tested due to technical constraints and resource-limited setting. Kidney function tests suggested acute kidney injury. Liver function tests showed hyperbilirubinemia, predominantly conjugated (total bilirubin: 2.83 mg/dL/direct: 1.33 mg/dL), with mild transaminitis and hypoalbuminemia. NT pro-BNP levels were highly raised (3114.7 pg/mL; normal range <300 pg/mL); however, transthoracic echocardiogram did not reveal any abnormality. Blood cultures turned out to be sterile, and other infectious markers (malaria, scrub typhus, and chikungunya) were negative, except for dengue serology (ELISA-IgM). Serology for hepatitis B, hepatitis C, and human immunodeficiency virus was negative. Doppler ultrasonography of both lower limbs demonstrated normal flow precluding arterial or venous occlusion. A skin biopsy was obtained from the area of purpuric rashes, which revealed foci in the upper dermis with perivascular infiltration by polymorphonuclear cells with mild edema and nuclear fragmentation, suggestive of leukocytoclastic vasculitis or CSVV [Figure 2a and b]. The final diagnosis of EDS with myocarditis, thrombotic microangiopathy, medium-vessel vasculitis (as impending peripheral gangrene), and CSVV (as purpura) was made. He was given oxygen supplementation, titrated intravenous crystalloids, inotropic support (dobutamine), titrated diuretics, and other supportive measures. Intermittent continuous positive end-expiratory pressure support was given. Antipsychotic medications were withheld as per the advice by the psychiatrist. Antiplatelets were added after platelet counts were in the normal range. Over the course of hospital stay, he improved symptomatically, tachycardia and respiratory distress settled, urine output increased with hydration, platelet counts improved, and features of purpura and impending gangrene improved. At the time of discharge, antipsychotic therapy was added as per the opinion of the psychiatrist. On follow-up visit after 7 days, his impending gangrene was not progressing and sloughing had started [Figure 1c], and he was followed up in the department of plastic surgery. Recently, in a follow-up after 2 months of dengue, he is doing his normal daily activities.

gangrene, leukocytoclastic vasculitis, myocarditis, severe dengue

PMC8480259_01

Male

A 9-month and 3-day-old male infant with a chief complaint of "intermittent vomiting blood for 6 h" was admitted to Wuhan Children's Hospital on February 8, 2019. Without obvious incentives, the child presented hemoptysis after coughing with bright red blood a total of four to five times. Three of them were quite serious, and blood clots could be observed. No fever, rash, hematuria, or syncope was found. The boy was treated with anti-infectious drugs, hemostasis, and fluid supplementation at clinics. Then, he was transferred to our hospital for further treatment. He was hospitalized after hypervolemic treatment in the emergency room. The boy had been in good health, with regular vaccinations and no history of exposure to infectious diseases. On physical examination, the boy's heart rate was 160 beats per minute, blood pressure was 97/34 mmHg, and respiratory rate was 35 breaths per minute. He was conscious but pale in color, with reduced skin elasticity. There were no bleeding points throughout the body, and the capillary filling time was 2 s. The superficial lymph nodes throughout the body were not swollen and enlarged, and the sclera had no yellow staining. The pupils had normal reflection of light. There was no congestion in the pharynx. The bilateral breathing movements were symmetrical. The lungs were clear. His heart rate was regular and strong, without a murmur. His abdomen was tender. A hemangioma was detected in the abdominal wall, ~1.5 x 1.5 cm in size, and there was no organomegaly. There were no abnormalities in the extremities and no restrictions on movement. The hemoglobin level was 104 g/L, the hematocrit was 31.6%, the white-cell count was 7.70 x 109/L, and the platelet count was 177 x 109/L. The results of the coagulation test were as follows: the prothrombin time (PT) was 13.5 s, the activated partial thromboplastin time (APTT) was 28.8 s, the thrombin time (TT) was 22.1 s, and the fibrinogen (FIB) level was 1.02 g/L. Liver function tests showed that the total protein (TP) level was 43.5 g/L, the albumin (ALB) level was 26.4 g/L, the total bilirubin (TBIL) level was 3.8 mumol/L, alanine transaminase (ALT) was 31 U/L, and aspartate aminotransferase (AST) was 22 U/L. The X-ray slide of the chest noted bronchitis. Computerized tomography (CT) of the abdomen detected an abnormal density shadow on the left abdominal wall, indicating the possibility of hemangioma. Chest CT showed poor texture, uneven transmission, and ground-glass opacification (GGO) of both lungs. The GGO was more significant in the right lower lobe. Using the CT coronal scan to simulate bronchoscopy, no obstruction signs in the larynx, trachea, or main bronchi were found (Figure 2). After admission, the infant did not exhibit hematemesis again, although the coughing was still continuous. Black stool was observed once. Methods, such as hemostasis, acid suppression, and other symptomatic treatments, were received. An emergency gastrointestinal examination (Figure 3A) showed that there was patchy erythema near the corner of the stomach with a smooth surface and suspected vascular malformation. A biopsy was taken from the surrounding area. The pathology identified mild chronic inflammation of the mucosal tissue (Figures 3B,C). By conducting a thorough bronchoscopy (Figures 4A-F), we found a smooth mucosal protrusion in the opening of the right lower lobe. It was suspected of being a new formation, and bleeding after contact was obvious (Figure 4F). After spraying epinephrine and thrombin, the bronchoscope was removed until no more bleeding was observed. After bronchoscopy, the infant was transferred to the intensive care unit. The blood test was rechecked. The hemoglobin level was 70 g/L, the hematocrit was 22.6%, the white cell count was 5.79 x 109/L, and the platelet count was 189 x 109/L. Hemoptysis diminished, and the stool turned yellow. After 5 days, he developed recurrent hemoptysis three times after coughing, with ~20-30 ml of blood each time, accompanied by cyanotic lips and shortness of breath, ~60 times per minute. Emergency tracheal intubation, mechanical ventilation, volume expansion, and hemostasis were given. Urgent blood analysis showed that the hemoglobin level was 81 g/L, the hematocrit was 25.6%, the white cell count was 8.06 x 109/L, and the platelet count was 315 x 109/L. Therefore, under general anesthesia, the right femoral artery was punctured using the Seldinger technique, and a 5F Cobra catheter and a microcatheter were superselectively inserted into the bronchial artery. The angiogram showed that the bilateral bronchial arteries showed distortion; the distal end was disordered, blurred, and irregularly stained; and more contrast agents showed signs of spillage (Figure 5A). The 5F Cobra catheter was placed in the opening of the bilateral bronchial arteries; the microcatheter was inserted superselectively to avoid the intercostal artery; PVA (300 mum) and gelatin sponge particles (560-710 mum) + dexamethasone (5 mg) + contrast mixed embolization agent were used for arterial embolization via microcatheter; and the embolization was stopped when the contrast agent slowed down significantly. Re-examination angiography showed satisfactory embolization of the bilateral bronchial arteries (Figure 5B). Bronchoscopy was performed again after the operation. The new formation at the opening of the right lower lobe showed no significant bleeding. After 3 days, the trachea intubation was removed. The infant was discharged after the chest radiograph was found to be normal.

bronchial dieulafoy's disease, critical care, pediatrics, pulmonary, rare disease

CT coronal scan of the lung (A,B).

PMC8480259_01

Male

A 9-month and 3-day-old male infant with a chief complaint of "intermittent vomiting blood for 6 h" was admitted to Wuhan Children's Hospital on February 8, 2019. Without obvious incentives, the child presented hemoptysis after coughing with bright red blood a total of four to five times. Three of them were quite serious, and blood clots could be observed. No fever, rash, hematuria, or syncope was found. The boy was treated with anti-infectious drugs, hemostasis, and fluid supplementation at clinics. Then, he was transferred to our hospital for further treatment. He was hospitalized after hypervolemic treatment in the emergency room. The boy had been in good health, with regular vaccinations and no history of exposure to infectious diseases. On physical examination, the boy's heart rate was 160 beats per minute, blood pressure was 97/34 mmHg, and respiratory rate was 35 breaths per minute. He was conscious but pale in color, with reduced skin elasticity. There were no bleeding points throughout the body, and the capillary filling time was 2 s. The superficial lymph nodes throughout the body were not swollen and enlarged, and the sclera had no yellow staining. The pupils had normal reflection of light. There was no congestion in the pharynx. The bilateral breathing movements were symmetrical. The lungs were clear. His heart rate was regular and strong, without a murmur. His abdomen was tender. A hemangioma was detected in the abdominal wall, ~1.5 x 1.5 cm in size, and there was no organomegaly. There were no abnormalities in the extremities and no restrictions on movement. The hemoglobin level was 104 g/L, the hematocrit was 31.6%, the white-cell count was 7.70 x 109/L, and the platelet count was 177 x 109/L. The results of the coagulation test were as follows: the prothrombin time (PT) was 13.5 s, the activated partial thromboplastin time (APTT) was 28.8 s, the thrombin time (TT) was 22.1 s, and the fibrinogen (FIB) level was 1.02 g/L. Liver function tests showed that the total protein (TP) level was 43.5 g/L, the albumin (ALB) level was 26.4 g/L, the total bilirubin (TBIL) level was 3.8 mumol/L, alanine transaminase (ALT) was 31 U/L, and aspartate aminotransferase (AST) was 22 U/L. The X-ray slide of the chest noted bronchitis. Computerized tomography (CT) of the abdomen detected an abnormal density shadow on the left abdominal wall, indicating the possibility of hemangioma. Chest CT showed poor texture, uneven transmission, and ground-glass opacification (GGO) of both lungs. The GGO was more significant in the right lower lobe. Using the CT coronal scan to simulate bronchoscopy, no obstruction signs in the larynx, trachea, or main bronchi were found (Figure 2). After admission, the infant did not exhibit hematemesis again, although the coughing was still continuous. Black stool was observed once. Methods, such as hemostasis, acid suppression, and other symptomatic treatments, were received. An emergency gastrointestinal examination (Figure 3A) showed that there was patchy erythema near the corner of the stomach with a smooth surface and suspected vascular malformation. A biopsy was taken from the surrounding area. The pathology identified mild chronic inflammation of the mucosal tissue (Figures 3B,C). By conducting a thorough bronchoscopy (Figures 4A-F), we found a smooth mucosal protrusion in the opening of the right lower lobe. It was suspected of being a new formation, and bleeding after contact was obvious (Figure 4F). After spraying epinephrine and thrombin, the bronchoscope was removed until no more bleeding was observed. After bronchoscopy, the infant was transferred to the intensive care unit. The blood test was rechecked. The hemoglobin level was 70 g/L, the hematocrit was 22.6%, the white cell count was 5.79 x 109/L, and the platelet count was 189 x 109/L. Hemoptysis diminished, and the stool turned yellow. After 5 days, he developed recurrent hemoptysis three times after coughing, with ~20-30 ml of blood each time, accompanied by cyanotic lips and shortness of breath, ~60 times per minute. Emergency tracheal intubation, mechanical ventilation, volume expansion, and hemostasis were given. Urgent blood analysis showed that the hemoglobin level was 81 g/L, the hematocrit was 25.6%, the white cell count was 8.06 x 109/L, and the platelet count was 315 x 109/L. Therefore, under general anesthesia, the right femoral artery was punctured using the Seldinger technique, and a 5F Cobra catheter and a microcatheter were superselectively inserted into the bronchial artery. The angiogram showed that the bilateral bronchial arteries showed distortion; the distal end was disordered, blurred, and irregularly stained; and more contrast agents showed signs of spillage (Figure 5A). The 5F Cobra catheter was placed in the opening of the bilateral bronchial arteries; the microcatheter was inserted superselectively to avoid the intercostal artery; PVA (300 mum) and gelatin sponge particles (560-710 mum) + dexamethasone (5 mg) + contrast mixed embolization agent were used for arterial embolization via microcatheter; and the embolization was stopped when the contrast agent slowed down significantly. Re-examination angiography showed satisfactory embolization of the bilateral bronchial arteries (Figure 5B). Bronchoscopy was performed again after the operation. The new formation at the opening of the right lower lobe showed no significant bleeding. After 3 days, the trachea intubation was removed. The infant was discharged after the chest radiograph was found to be normal.

bronchial dieulafoy's disease, critical care, pediatrics, pulmonary, rare disease

CT coronal scan of the lung (A,B).

PMC3568014_01

Male

A 38 years-old moderate hemophiliac A male patient was diagnosed to be co-infected with HIV (Subtype B, CCR5+) and HCV (Subtype 4), both transmitted by a blood transfusion received in 1982 during hip surgery for a fracture. Diagnoses of these infections were respectively ascertained in 1988 and 1998. Since 1989, he received different lines of anti-retroviral treatment (ART) then HAART (Highly Active Anti-Retroviral Therapy) with poor compliance, voluntary interruption until 2008, and correct compliance since then. A 215S mutation of the HIV virus reverse transcriptase, which induces resistance to the anti-retroviral drug azidothymidine was consequently identified. His HCV infection (Metavir score A0A1-F1F2 determined by biopsy and checked regularly by noninvasive markers of hepatitis inflammation/fibrosis) was never treated. Moreover his hepatic assessment, as observed with L-aspartate aminotransferase (ASAT), L-alanine aminotransferase (ALAT) and gammaGT gamma-glutamyltransferase markers is not so much disrupted (Figure 1A). The patient received prosthesis of the left eye in 1996 after a paintball accident and a hip replacement in 2011 for osteo-necrosis known since 1982. None of these surgeries were accompanied by infectious side effects. Indeed, over these 30 years and despite an extremely low number of T lymphocytes, the patient displayed neither opportunistic infections, nor HIV-related cancer, nor HCV-hepatitis damages. In 1989 his initial CD4+ T-cells count was 196/mm3 and since 1995 remains between 5 and 59/mm3 (Figure 1B). HIV viral loads have been mostly undetectable (below 40 copies/mL) or very low (matching deliberate HAART interruptions) since 2008 (Figure 1B). Over the past two years, the immunophenotypic and functional status of his CD3-CD56+ NK-cells were explored by multi-parameter flow cytometry (reagents from Becton Dickinson, MountainView, CA, Figures 2A-D). Surprisingly, an abnormally high percentage of NK-cells has been steadily observed, representing approximatively 40% of peripheral lymphocytes and characterized by an expansion of the CD56bright subset (~30 to 50% of NK-cells) (Figures 2A and 2B). The percentage of CD56bright cells seems to increase when the number of CD4 decreases moreover HIV viral load is below 40 copies/ml when % of CD56bright cells is the more important (Figure 2B). These cells display high levels of natural cytotoxicity receptors NCR1 (NKp46), NCR3 (NKp30) and NKG2D compared to CD56dim cells, and have a low expression of NCR2 (NKp44) and CD69, with no labeling for CD57 nor CD25 (data not shown). The inhibitory CD94/NKG2A receptor is expressed by all CD56bright cells and a majority of CD56dim NK-cells while there is a low expression of CD158b on CD56dim and CD56bright NK-cells and a faint labeling with CD158a (Figure 2C). Surprisingly, the NK degranulation potential (% of CD107a) that correlates with target cytolysis, usually exerted by the CD56dim NK subset, is here mainly performed by CD56bright NK-cells. Strikingly, these cells did not produce IFN-gamma following NK activation by K562 (Figure 2D). In addition, no Th1/Th2 cytokines (TNF-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-10) have been detected in the patient's serum (data not shown).

PMC2990241_01

Male

A 30-year-old man had been suffering from right hypochondriac pain and fever. He had no history of the disease and had not received blood transfusion. Furthermore, there was not family history of liver disease. Physical examination revealed that the liver was palpable 5 cm below the right costal margin. Laboratory data showed the following values: aspartate aminotransferase (AST) 23 IU/L; alanine aminotransferase (ALT) 18 IU/L; total cholesterol 154 mg/dL; negative hepatitis B surface antigen, antihepatitis B antibody, and antihepatitis C antibody; alpha-fetoprotein (AFP) 45 ng/mL and total bilirubina 1,71 mg/dL, PCR 54, 50 mg/L (0-5), VES 55 mm/h (2-25). There was no evidence of liver cirrhosis. Blood cultures and screening for tuberculosis were negative. The patient under went noninvasive diagnostic methods: duplex scanning, Computed tomography (CT) and Magnetic Resonance imaging (MRI). The Duplex scanning showed hepatomegaly (18 cm of longitudinal diameter) with presence of heterogeneous mass in the right lobe. The mass was hyperechoic with some calcifications and few anechoic foci, secondary to haemorrhage and necrotic processes (Figure 1). The color Doppler ultrasonography (US-CD) demonstrated normal patency of sovrahepatic vessels. Subsequently the patient was submitted to Computed Tomography (CT) of abdomen (scanner : Highspeed Advantage; GE Medical System Milwaukee, WI, USA). Images were acquired without and with an intravenously contrast media (a single bolus of 120 cc with a flow rate of 2.5 mL/s of nonionic contrast medium via an antecubital venous access), and scans were obtained with threephases from the injection of contrast media. The CT confirmed a mass that occupied almost the whole right lobe of the liver with lower attenuation than surrounding liver on nonenhanced scan. After the injection of the contrast media, it was assessed that the lesion was predominantly of lower attenuation with some calcifications and small slit like or round and lower density areas, corresponding to haemorrhage or necrosis. Contrast enhancement was low and heterogeneous (Figure 2). Magnetic Resonance imaging (MRI) with contrast media demonstrated a 23 x 14 x 13 cm mass in the right lobe. This mass presented a well-defined capsule. T1-weighted images showed heterogeneous global intensity with areas with intensity signal similar to haemoglobin metabolites, areas with signal intensity similar to calcifications and area with signal intensity similar to fat. On T2-weighted images the lesion was hyperintense but heterogeneous because of hypointense areas corresponding to calcifications and bands corresponding to area of lobulation and fibrosis. Furthermore right kidney was displaced posteriorly by the mass with its vascular pedicle (Figure 3). Compressive effects of the mass on sovrahepatic veins were observed without occlusion, while gallbladder was displaced but not infiltrated. Related to MRI features was supposed a hepatoblastic nature of the lesion. Subsequent diagnostic imaging phase, a bioptic sample was obtained with a CT-guided biopsy with 18 G tru-cut needle. Histopathologic examination revealed the presence of mesenchymal and epithelial cells in bioptic specimen and confirmed the diagnosis of a mixed hepatoblastoma (Figure 4). After results of biopsy, surgical intervention was performed in exploratory to resect the tumour. A right trisegmentectomy was performed with tumour grossly resected with microscopic residual disease. The surgical diagnosis confirmed the diagnosis of a mixed hepatoblastoma. No postprocedural complications were observed. He is receiving the VI cycles of systemic chemotherapy whit adriamycin and cisplatin which results in good health.

PMC7333626_01

Male

A 30-year-old previously healthy male presented to the Emergency Department with a 5-day history of productive cough, fever, shortness of breath, and severe pleuritic chest pain. The fever was associated with chills and decreased appetite and was responding partially to over the counter antipyretics. The patient had traveled to India within 4 weeks prior to the presentation. Upon presentation, the patient appeared acutely ill. Vital signs included tachycardia of 112 beats per minute, respiratory rate of 26 breaths per minute, with an oxygen saturation of 94 % on room air. Laboratory investigations showed leukocytosis of 32,800/mu/L with neutrophilia, high procalcitonin of 16.5 ng/mL, and CRP of >300 mg/L. A chest x-ray revealed a right upper lobe patchy consolidation, with no cavitation, associated with prominent perihilar and infrahilar markings. There was no pleural effusion or pneumothorax (Fig. 1). The patient was initially admitted as a case of community-acquired pneumonia (CAP). Sputum and blood cultures were collected. Since his illness was during the COVID-19 pandemic, nasopharyngeal swabs were taken to rule out COVID-19 infection. The patient was started on piperacillin-tazobactam and Azithromycin as per local empiric antibacterial guidelines for CAP. Within a day of incubation, the blood culture grew gram-negative diplococci in the aerobic bottles. The final culture results identified Neisseria meningitidis which was sensitive to benzylpenicillin, ceftriaxone, ciprofloxacin, and meropenem, but resistant to trimethoprim- sulfamethoxazole. The antibacterials were initially changed to ceftriaxone 2 g every 12 h to cover possible meningitis. However, due to the absence of any risks for meningococcemia and its complications, the antimicrobial dose was decreased to 1 g of ceftriaxone every 12 h. The patient denied any headache or neurologic symptoms and was free of any meningeal signs on multiple physical examinations. The patient had no other end-organ complications. Routine liver and renal function laboratory tests were normal and an abdominal ultrasound was unremarkable. HIV testing was negative. Active pulmonary tuberculosis was ruled out with 3 negative samples of sputum acid-fast bacillus (AFB) smears, negative Mycobacterium tuberculosis PCR, and negative Quantiferon test. Sputum culture isolated light growth of normal upper respiratory flora. COVID-19 PCR was negative. Repeat blood cultures were drawn 48 h after the initial culture and showed no growth. The patient was afebrile within 72 h of admission and remained hemodynamically stable throughout the hospital stay with no complications. The patient completed a 10-day course of ceftriaxone and was discharged home safely and in good health. Adequate infection control precautions were maintained throughout his hospitalization.

invasive meningococcal disease, neisseria meningitidis, pneumonia

PMC9373933_03

Female

The third patient was a non-smoking 69-year-old woman, fully vaccinated against SARS-CoV-2. The disease history started 6 months before her referral, when she complained of coughing and dyspnoea. At disease onset, she was diagnosed with COVID-19 because of CT scan presentation with peribronchovascular and subpleural consolidation, although PCR for SARS-CoV-2 was negative. The symptoms remained, leading to a diagnosis of post-COVID-19 ILD. A few months later, breathlessness increased, and a new CT scan showed extension of GGOs, peribronchovascular consolidation and traction bronchiectasis (Fig. 1D). At her referral, physical examination revealed crackles bilaterally, periungual erythema, and mechanic's hands. Pulmonary function testing revealed a forced vital capacity of 50% of predicted and diffusion capacity of carbon monoxide of 30% of predicted. Blood tests showed lymphopenia and anaemia, and muscle enzymes were normal. Autoimmune tests revealed anti-PL7 and anti-Ro52 positivity. Electromyography showed no muscle involvement. The patient had respiratory failure and received pulses of methylprednisolone, followed by oral prednisolone in combination with i.v. CYC, with partial improvement. We describe three patients with anti-synthetase syndrome, positive for anti-PL7, who were referred for post-COVID-19 ILD. Misdiagnosis between post-COVID-19 ILD and anti-synthetase syndrome is not surprising, because the CT pattern combining GGOs and consolidation is highly suggestive of COVID-19, but can be observed in many other conditions, including myopathies. There are data about myositis-associated lung abnormalities mimicking acute COVID-19. In fact, several pathological features of COVID-19, such as epithelial and endothelial alterations, are common to autoimmune ILD. Apart from the well-known similarity of CT features in CTD-related ILD and COVID-19-related lesions, it has been described how we could differentiate between CTD-related ILD and COVID-19. Consolidations in a round shape and GGOs are proposed to be suggestive of COVID-19 in the absence of typical fibrotic abnormalities. Subpleural sparing, absence of parenchymal consolidation and fibrosis inside GGOs might suggest a diagnosis of CTD-related ILD. New-onset autoimmune disease after COVID-19 has also been described, including nine patients diagnosed with myositis after COVID-19, but none was characterized by anti-PL7 positivity. However, causality between SARS-CoV-2 infection and autoimmune disease development should be attributed with caution. These cases illustrate that even during a pandemic, it is essential to apply rigorous diagnostic algorithms when evaluating patients with ILD. Post-COVID-19 ILD should not be a dustbin diagnosis. Worsening of symptoms should lead to consideration of an alternative diagnosis. Autoimmune screening, including myositis-associated autoantibodies, should be performed in patients with persistent ILD in a post-COVID-19 context. Funding: Eirini Vasarmidi was funded by European Respiratory Society, Fellowship ID number: LTRF202101-00863. Disclosure statement: The authors have declared no conflicts of interest. Consent: Informed patient consent was obtained for the publication of this paper.

PMC6317122_02

Female

A 36-year-old female with diabetes mellitus, hypertension, and hypothyroidism underwent a cesarean section a few weeks prior to admission and a gastric sleeve procedure 1 year before that. Two days before admission to hospital, the patient developed ascending numbness followed by weakness, which progressed over 2 days. It interfered with her movement, making her bed bound. She reported a 1-day history of subjective fever and diarrhea a week before the onset of symptoms, which subsided spontaneously. Weakness was not associated with double vision, shortness of breath, slurred speech, abnormal movement, or confusion. She did not have fever, diarrhea, or abdominal pain and did not have similar attacks previously. She lost approximately 40 kg in 2 months; she did not receive any vitamin supplementation after surgery. The patient reported vomiting three to four times daily postoperatively until a month before her presentation. Examination showed that the cranial nerves were intact with no motor or sensory abnormalities. Her UL and LL tone was normal. There was a symmetrical decrease in power in her ULs both proximally and distally. LL power was also decreased. Her reflexes were diminished but elicitable, but her plantar response was mute with various maneuvers. The sensory examination was unremarkable and her coordination was intact. The patient was admitted to hospital as a case of postbariatric surgery myeloneuropathy or GBS. IVIG was given for a complete course of five continuous days. Thiamine loading and maintenance were given parentally. Vitamin B12 and D levels were within normal limits. She was discharged with persistent weakness to undergo rehabilitation. No MRI or NCS was done at admission. She presented again with the same concern and was admitted to neurology inpatient services. An MRI scan of the entire spine was performed, which showed early dorsal spine spondylitic changes with small anterior osteophytes at the lower dorsal spine. An EMG/NCS was also done, showing pure motor neuropathy and myopathic changes at proximal muscle and a normal sensory picture, suggestive of acute motor axonal neuropathy for early Guillain-Barre syndrome. She continued to receive vitamin supplementation and physiotherapy. Plasma exchange was discussed but declined by the family. She will require ongoing extensive neurorehabilitation at a dedicated center at King Faisal Specialist Hospital and Research Centre or King Fahad Medical City in Riyadh.

PMC2817645_01

Female

A 71-year-old Italian woman presented a 2-month history of numbness and pain involving the left leg. She underwent orthopedic evaluation and articular ankle echography for the diagnostic suspicion of Baker cyst, that were negative. She also underwent lumbosacral MRI that did not show any signs of degenerative or traumatic injuries. One month later she developed radicular pain in both legs with hypoesthesia. She underwent cervico-dorsal MRI with contrast that showed a gadolinium-enhancing lesion within the spinal cord at T5-6 with maximum diameter of 11 mm. In the axial sequences the lesion seemed to be completely intramedullary without any signs of bulging. The neuroradiological aspects of the lesion were interpreted as an intramedullary astrocytoma or ependymoma. Neurologically, she had symmetric tendon reflexes, exaggerated in the legs, Babinsky sign on both legs, moderate paraparesis, hypoesthesia and dysesthesia of the entire left leg and left thorax below the T5 metamer. One month after the first MRI, during recovery, she underwent another dorsal MRI with contrast, which confirmed the presence of this intramedullary gadolinium-enhancing lesion at level T5-T6: this was interpreted as hemangioblastoma or ependymoma but, according to the neuroradiologist, it was impossibile to exclude other diagnostic hypothese (fig.1). As a matter of fact, the worsening of neurological symptomatology, expecially the progression of paraparesis, persuaded us to adopt a decompressive surgical strategy and so the patient underwent surgical treatment. A T5-T6-T7 laminectomy was performed, and the dura was opened. There was no evidence of extramedullary abnormality. Posterior longitudinal myelotomy was performed and a well-circumscribed grayish-red lesion was exposed. A histological sample for the extemporary and definitive examination was taken, which showed a histological pattern of small-cell tumoral lesion. For this reason a complete removal with CUSA was performed. The definitive histological examination of the specimen revealed an inflammatory lesion which was composed of a mixed infiltration of mature B and T lymphocytes, with plasma cells and macrophages. Abundant vascular channels, often with hyperplastic endothelium, and focal fibroblastic reaction were observed. The macrophages were occasionally organized to form granulomas. This mass of non-neoplastic inflammatory cells of unknown origin was also studied using histochemical technique (PAS and Ziehl Neelsen), but no fungal or bacteria were found. Also the non-neoplastic nature of the lesion was demonstrated by immunohistochemical studies, which confirmed the mixed nature of lymphocytes, and by the polyclonality of plasma cells with positivity for kappa and lambda light chains of immunoglobulins (fig 2, 3). Postoperatively, there was a complete regression of radicular pain and paresthesia in the left thorax and leg. Postoperative dorsal MRI with contrast was performed 10 days after surgery and confirmed complete removal of the lesion without any signs of residual disease (fig.4a). Postoperative laboratory and radiological exams was performed, such as Toxotest, BK test and Chest RX for the diagnostic hypothesis of toxoplasmosis, TBC, histiocitosys X, or sarcoidosis, that were all negative. We also performed the liquor level of cerebrospinal fluid angiotensinconverting enzyme (ACE) in suspected neurosarcoidosi, which showed a value of 3.2 nmol/mL/min, non discriminatory. The patient was discharged on the seventh postoperative day. At follow up thoracic MRI with contrast was performed 3 (fig.4b) and 10 months (fig.4c) after surgery, and did not show any signs of disease.

PMC7838494_01

Male

An 11-year-old boy was assessed at the Pediatric Emergency Room because of a 3-day history of abdominal pain and distension. He was correctly vaccinated and had no history of interest, except for a self-limited gastroenteritis, 14 days prior to the beginning of this episode. The patient exhibited regular appearance due to spontaneous pain that intensified with movement, fever (38.3 C) and tachycardia (124 bpm) with normal blood pressure (104/62 mmHg). An increase of 3.5 kg over his usual weight was estimated. Physical examination revealed non-pruritic erythematous plaques on the abdomen, pubis and proximal segments of both lower limbs (Figure 1). The abdominal exam was notable for distension, diffuse pain and tenderness. The lower back was painful upon palpation. He had pitting edema at the abdominal wall, lumbar region, and distal segments of the lower limbs. Auscultation of the lungs showed decreased vesicular breath sounds at the right base. Abdominal radiograph was performed showing a probable mass effect on loops of the transverse and descending colon without signs of obstruction. Chest radiograph revealed right pleural effusion. Abdominal CT with contrast was prioritized over ultrasound to better characterize the suspected abdominal mass. It showed ascites, bilateral pleural effusion, lumbar subcutaneous edema and right lower lobe atelectasis with normal cardiac size (Figure 2). Blood analysis revealed an increased white blood cell count of 37.48 x 109/L (neutrophils 34.30 x 109/L), hemoglobin and platelet count in the normal range and no abnormalities in peripheral blood smear. Increased acute phase reactants (C-Reactive Protein 345 mg/L, procalcitonin 2.77 ng/ml), hypoproteinemia with hypoalbuminemia (4.2 g of total proteins/dL with 1.9 g of albumin/dL) and hypogammaglobulinemia (IgG 137 mg/dL, IgG-1 1,060 mg/L, IgG-2 317 mg/L, IgG-3 139 mg/L, IgA 43 mg/L, other isotypes within normal ranges) were detected. Ions, amylase levels, liver enzymes, renal function parameters were in normal range. Biological parameters of heart function such as troponins and N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), were also tested as workup of ascites and pleural effusion, with normal results. The urine study did not show significant proteinuria or hematuria. With an initial diagnosis of peritonitis and pleural effusion, hospital admission was decided and intravenous antibiotic therapy with cefotaxime was initiated. An exploratory laparoscopy was performed 24 h after admission, exposing purulent peritoneal fluid and ruling out appendicitis or visceral perforations. A routine appendectomy was performed with no abnormal anatomopathological findings. Therefore, secondary peritonitis was excluded. Samples of ascitic fluid were tested for cytobiochemical analyses (562 cells/muL, 57% polymorphonuclear; pH 7.34; glucose 31 mg/dL; protein 0.12 g/dL; LDH 32 U/mL; triglycerides 54 mg/dl) and microbiological studies (Gram and auramine stains, bacterial and mycobacterial cultures, as well as polymerase chain reaction for Mycobacterium tuberculosis DNA were all negative). Due to the prevalence of methicillin-resistant Staphylococcus aureus in our environment (~15%), vancomycin was added, and fluid restriction was prescribed with strict monitoring of fluid balance and daily weight. With the suspicion of PP with hypoproteinemia, complementary examinations dismissed nephrotic syndrome, liver failure, alpha-1-antitrypsin (alpha1-AT) deficiency, diabetes mellitus, lupus erythematosus, giardiasis, celiac disease, tuberculosis and immunodeficiencies. Biochemical stool analysis showed elevated alpha1-AT (1.9 mg/g of stool; reference value < 0.3 mg/g) and increased clearance of alpha1-AT (107.7 mL/24 h; reference value < 27 mL/24 h), compatible with protein-losing enteropathy (PLE). He had a favorable clinical course with a gradual decrease in inflammatory parameters, progressive improvement in serum protein and gamma globulin levels, and total reabsorption of pleural effusion and peritoneal fluid during admission. The patient completed 21 days of antibiotic therapy (14 days of intravenous cefotaxime and 10 days of intravenous vancomycin and, after discharge, 7 days of oral amoxicillin-clavulanic acid). Further studies to identify the cause of this PLE included a normal colonoscopy and a gastroscopy that showed a very erythematous and discretely edematous mucosa and enlarged gastric folds in the body and fundus of the stomach. Gastric mucosal biopsies revealed an extensive and significant hyperplasia of the foveolar mucosecretory epithelium, causing elongated and tortuous foveolar glands with loss of parietal cells, and edematous lamina propia. No signs of lymphoplasmacytic or neutrophilic infiltrate, intraepithelial lymphocytosis, pathogenic microorganisms or intracellular cytomegalovirus (CMV) inclusions were identified. Duodenal mucosa was preserved. These findings were compatible with MD. The histochemical study for Helicobacter pylori and the immunohistochemical study for CMV were negative (Figure 3). CMV serology was also negative. In spite of the initial hypogammaglobulinemia of our patient, no intravenous immunoglobulins were administered to prevent the risk of new pyogenic bacterial infections since he showed a good clinical evolution and his plasmatic gammaglobulin and protein levels spontaneously increased slowly along the next weeks. Analytical controls performed 6 months later showed a complete recovery of total plasma proteins and albumin levels. Immunoglobulin levels normalized 10 months after hospital admission. After 12 months of follow-up, the patient has not presented any recurrence. A summary of his clinical course is showed in Figure 4.

ménétrier's disease, case report, hypertrophic gastropathy, primary peritonitis, protein-losing enteropathy

PMC6529672_01

Female

A 4-month-old female infant, born prematurely at 30 weeks and weighing 1,550 g, was hospitalized after 4 days of cough and fever. Her past history included a controlled premature birth by cesarean section due to placenta previa. She suffered from a brief period of mechanical ventilation and administration of exogenous surfactant after being born. After admitted, mild bilateral lung coarse rales were found on physical examination. Laboratory tests results showed a white blood cell count of 22.9x109 cells/L containing 58.2% neutrophils and a C-reactive protein concentration of 28 mg/L. Chest radiography exhibited patchy shadows localized to the right lung and lower left lung (Figure 1A). Subsequent computed tomography (CT) detected multiple masses and small nodules across both lungs with mediastinal lymph node involvement (Figure 1B and C). The patient was then started on intravenous ceftriaxone. Bronchoscopy revealed minimal overlying airway secretions and airway patency extending from the upper respiratory tract to the lungs; 3-9 acid-fast bacilli organisms/100 high-power fields were found in bronchoalveolar lavage fluid (BALF) and gastric aspirate by Ziehi-Neelsen staining. Thus, the patient was suspected of harboring pulmonary tuberculosis infection and treated with isoniazid, rifampin, and pyrazinamide. Although both tuberculin skin test and interferon gamma (IFN-gamma) release assays were negative, mycobacterial liquid cultures of bronchoalveolar lavage and gastric aspirate were positive at 118 and 86 hrs of culture, respectively. Isolated mycobacteria were identified (with a confidence level of 84%) as MABC using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Vitek MS system, bioMerieux, France), supporting a diagnosis of MABC pulmonary disease. Immunologic evaluation results, including serum immunoglobulin levels and flow cytometric lymphocyte phenotyping were as follows: IgG 4.96 g/L (normal range 1.8-8 g/L), IgM 1.00 g/L (normal range 0.2-1 g/L), IgA 0.225 g/L (normal range 0.08-0.8g/L), IgE <5.00 IU/mL (normal range <=15 IU/mL), CD3+ cells 69.4% (normal range 55-82%), CD4+ cells 53.9% (normal range 55-57%), CD8+ cells 14.9% (normal range 11-25%), B cell 23.2% (normal range 11-45%), which were basically normal. However, natural killer (NK) cell level was 3%, which is below normal range 7-40%. In the review after 3 months, NK cell level raised to 10%. Whole exon sequencing (WES) was then performed and detected no pathogenic mutations, ruling out genetic disorders such as cystic fibrosis and primary immunodeficiency disease as factors contributing to exacerbation of MABC pulmonary disease in our patient. The subject family has no other case of MABC infection or immune-compromised individuals. According to expert consensus regarding diagnosis and treatment of NTM diseases, the therapy was modified to include oral clarithromycin (7.5 mg/kg, q12 h), linezolid (10 mg/kg, q8 h), and intravenous imipenem (15 mg/kg, q6 h). Due to the possibility of other mycobacterial infections, rifampicin (15 mg/kg/day) and ethambutol (15 mg/kg/day) were also administered. Subsequently, the patient's temperature returned to normal after 1 week and her cough gradually reduced, prompting cessation of intravenous imipenem administration. She was discharged after 25 days of hospitalization. After an additional 3 months of outpatient therapy, her chest CT remained unchanged and the patient exhibited recurrence of fever with wheezing. The white blood cell count was 17.6x109 cells/L, of which 47.4% were neutrophils, with a C-reactive protein concentration of 30 mg/L. Bronchoscopy revealed an excrescent obstruction of the sub-branch of the right lower bronchi. Acid-fast staining microscopy and mycobacterial cultures of BALF and gastric aspirate were negative. The isolates that had been preserved during the first hospital stay were sent to the National Tuberculosis Clinical Laboratory of Beijing Chest Hospital for drug susceptibility testing (DST) and further strain identification. DST was carried out according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Final tested drug concentrations were as follows: clarithromycin 0.0625-32 mug/mL, amikacin 0.5-256 mug/mL, moxifloxacin 0.0625-32 mug/mL, cefoxitin 0.5-256 mug/mL, linezolid 0.25-128 mug/mL, imipenem 0.25-128 mug/mL, meropenem 0.25-128 mug/mL, and doxycycline 0.0625-32 mug/mL. The minimum inhibitory concentration (MIC) of each drug was determined using the CLSI-recommended broth microdilution method performed in 96-well plates. DST demonstrated that isolates were susceptible to clarithromycin (MIC 0.25-0.5 mug/mL), amikacin (MIC 1-2 mug/mL), moxifloxacin (MIC 1 mug/mL), cefoxitin (MIC 4-8 mug/mL), and linezolid (MIC 1 mug/mL), with intermediate susceptibility to imipenem (MIC 8 mug/mL) and resistance to meropenem (MIC 64 mug/mL) and doxycycline (MIC >32 mug/mL). The isolates had no inducible resistance to clarithromycin, as they were susceptible to clarithromycin at both days 3 and 14. DNA sequence analysis of the ribosomal gene internal transcribed spacer (ITS) and rpoB, and hsp65 genes was performed to identify the subspecies of causative agent. Bacterial DNA extracted using the boiling method was used as a template for PCR. PCR primer pairs were as follows: 5'-AAGTCGTAACAAGGTARCCG-3' and 5'-TCGCCAAGGCATCCACC-3' for the ribosomal gene ITS region, 5'-GGCAAGGTCACCCCGAAGGG-3' and 5'-AGCGGCTGCTGGGTGATCATC-3' for rpoB, and 5'-ATCGCCAAGGAGATCGAGCT-3' and 5'-AAGGTG-CCGCGGATCTTGTT-3' for hsp65. PCR products were purified and sequenced by TsingKe Biotech Corp. (Beijing, China). Species identification was accomplished using BLAST searching that ultimately identified patient isolates as M. abscessus subsp. massiliense (with sequence identity of 99%). After consultation with physicians specializing in NTM disease from Beijing Chest Hospital, we treated the patient with intravenous cefoxitin (40 mg/kg q8 h), oral azithromycin (10 mg/kg/d), and moxifloxacin (10 mg/kg/d). After 3 months of treatment using this regimen, chest radiography revealed improvement, with white blood cell count (8.65x109 cells/L) and C-reactive protein concentration (<8 mg/L) both returning to normal ranges (4-10x109 cells/L and 0-8 mg/L, respectively). Cefoxitin was discontinued after 4 months of use. Monitoring for adverse drug events was performed monthly. No obvious adverse drug reactions were observed. Blood platelet counts ranged from 152x109 cells/L to 298x109 cells/L (normal range 100-400x109 cells/L). Ranges of aspartate aminotransferase were 12-38 U/L (normal range 5-40 U/L), of alanine aminotransferase were 8-26 U/L (normal range 5-40 U/L), of serum total bile acid were 5-8 micromol/L (normal range 0-10 micromol/L), of urea were 1.8-5.2 mmol/L (normal range 1.7-7.1 mmol/L), and of creatinine were 32.1-52.2 micromol/L (normal range 30-80 micromol/L). The ECG (electrocardiogram) was normal. After 12 months of antibiotic therapy, bronchoscopy revealed no excrescent obstruction or airway patency. Chest CT showed that most lung lesions had been absorbed, with strip shadows visible in both lungs (Figure 2A and B). Moxifloxacin was discontinued; however, based upon the recommendation of NTM disease specialists, the patient continued to receive oral azithromycin and cefprozil for 4 months, with cessation of all treatment after 16 months of antibiotic therapy. Upon examination at 3 and 6 months after completion of therapy, the patient was in good clinical condition. The recent laboratory tests results showed a white blood cell count of 8.2x109 cells/L containing 49.6% neutrophils and a C-reactive protein concentration <8 mg/L. The patient will continue to receive regular follow-up by mycobacterial disease physicians.

azithromycin, drug resistance, nontuberculous mycobacteria, pulmonary, treatment outcome

Chest radiograph and chest HRCT scan on admission. (A) showed patchy shadows in the right lung (arrows) and the lower left lung (arrow).

PMC6529672_01

Female

A 4-month-old female infant, born prematurely at 30 weeks and weighing 1,550 g, was hospitalized after 4 days of cough and fever. Her past history included a controlled premature birth by cesarean section due to placenta previa. She suffered from a brief period of mechanical ventilation and administration of exogenous surfactant after being born. After admitted, mild bilateral lung coarse rales were found on physical examination. Laboratory tests results showed a white blood cell count of 22.9x109 cells/L containing 58.2% neutrophils and a C-reactive protein concentration of 28 mg/L. Chest radiography exhibited patchy shadows localized to the right lung and lower left lung (Figure 1A). Subsequent computed tomography (CT) detected multiple masses and small nodules across both lungs with mediastinal lymph node involvement (Figure 1B and C). The patient was then started on intravenous ceftriaxone. Bronchoscopy revealed minimal overlying airway secretions and airway patency extending from the upper respiratory tract to the lungs; 3-9 acid-fast bacilli organisms/100 high-power fields were found in bronchoalveolar lavage fluid (BALF) and gastric aspirate by Ziehi-Neelsen staining. Thus, the patient was suspected of harboring pulmonary tuberculosis infection and treated with isoniazid, rifampin, and pyrazinamide. Although both tuberculin skin test and interferon gamma (IFN-gamma) release assays were negative, mycobacterial liquid cultures of bronchoalveolar lavage and gastric aspirate were positive at 118 and 86 hrs of culture, respectively. Isolated mycobacteria were identified (with a confidence level of 84%) as MABC using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Vitek MS system, bioMerieux, France), supporting a diagnosis of MABC pulmonary disease. Immunologic evaluation results, including serum immunoglobulin levels and flow cytometric lymphocyte phenotyping were as follows: IgG 4.96 g/L (normal range 1.8-8 g/L), IgM 1.00 g/L (normal range 0.2-1 g/L), IgA 0.225 g/L (normal range 0.08-0.8g/L), IgE <5.00 IU/mL (normal range <=15 IU/mL), CD3+ cells 69.4% (normal range 55-82%), CD4+ cells 53.9% (normal range 55-57%), CD8+ cells 14.9% (normal range 11-25%), B cell 23.2% (normal range 11-45%), which were basically normal. However, natural killer (NK) cell level was 3%, which is below normal range 7-40%. In the review after 3 months, NK cell level raised to 10%. Whole exon sequencing (WES) was then performed and detected no pathogenic mutations, ruling out genetic disorders such as cystic fibrosis and primary immunodeficiency disease as factors contributing to exacerbation of MABC pulmonary disease in our patient. The subject family has no other case of MABC infection or immune-compromised individuals. According to expert consensus regarding diagnosis and treatment of NTM diseases, the therapy was modified to include oral clarithromycin (7.5 mg/kg, q12 h), linezolid (10 mg/kg, q8 h), and intravenous imipenem (15 mg/kg, q6 h). Due to the possibility of other mycobacterial infections, rifampicin (15 mg/kg/day) and ethambutol (15 mg/kg/day) were also administered. Subsequently, the patient's temperature returned to normal after 1 week and her cough gradually reduced, prompting cessation of intravenous imipenem administration. She was discharged after 25 days of hospitalization. After an additional 3 months of outpatient therapy, her chest CT remained unchanged and the patient exhibited recurrence of fever with wheezing. The white blood cell count was 17.6x109 cells/L, of which 47.4% were neutrophils, with a C-reactive protein concentration of 30 mg/L. Bronchoscopy revealed an excrescent obstruction of the sub-branch of the right lower bronchi. Acid-fast staining microscopy and mycobacterial cultures of BALF and gastric aspirate were negative. The isolates that had been preserved during the first hospital stay were sent to the National Tuberculosis Clinical Laboratory of Beijing Chest Hospital for drug susceptibility testing (DST) and further strain identification. DST was carried out according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Final tested drug concentrations were as follows: clarithromycin 0.0625-32 mug/mL, amikacin 0.5-256 mug/mL, moxifloxacin 0.0625-32 mug/mL, cefoxitin 0.5-256 mug/mL, linezolid 0.25-128 mug/mL, imipenem 0.25-128 mug/mL, meropenem 0.25-128 mug/mL, and doxycycline 0.0625-32 mug/mL. The minimum inhibitory concentration (MIC) of each drug was determined using the CLSI-recommended broth microdilution method performed in 96-well plates. DST demonstrated that isolates were susceptible to clarithromycin (MIC 0.25-0.5 mug/mL), amikacin (MIC 1-2 mug/mL), moxifloxacin (MIC 1 mug/mL), cefoxitin (MIC 4-8 mug/mL), and linezolid (MIC 1 mug/mL), with intermediate susceptibility to imipenem (MIC 8 mug/mL) and resistance to meropenem (MIC 64 mug/mL) and doxycycline (MIC >32 mug/mL). The isolates had no inducible resistance to clarithromycin, as they were susceptible to clarithromycin at both days 3 and 14. DNA sequence analysis of the ribosomal gene internal transcribed spacer (ITS) and rpoB, and hsp65 genes was performed to identify the subspecies of causative agent. Bacterial DNA extracted using the boiling method was used as a template for PCR. PCR primer pairs were as follows: 5'-AAGTCGTAACAAGGTARCCG-3' and 5'-TCGCCAAGGCATCCACC-3' for the ribosomal gene ITS region, 5'-GGCAAGGTCACCCCGAAGGG-3' and 5'-AGCGGCTGCTGGGTGATCATC-3' for rpoB, and 5'-ATCGCCAAGGAGATCGAGCT-3' and 5'-AAGGTG-CCGCGGATCTTGTT-3' for hsp65. PCR products were purified and sequenced by TsingKe Biotech Corp. (Beijing, China). Species identification was accomplished using BLAST searching that ultimately identified patient isolates as M. abscessus subsp. massiliense (with sequence identity of 99%). After consultation with physicians specializing in NTM disease from Beijing Chest Hospital, we treated the patient with intravenous cefoxitin (40 mg/kg q8 h), oral azithromycin (10 mg/kg/d), and moxifloxacin (10 mg/kg/d). After 3 months of treatment using this regimen, chest radiography revealed improvement, with white blood cell count (8.65x109 cells/L) and C-reactive protein concentration (<8 mg/L) both returning to normal ranges (4-10x109 cells/L and 0-8 mg/L, respectively). Cefoxitin was discontinued after 4 months of use. Monitoring for adverse drug events was performed monthly. No obvious adverse drug reactions were observed. Blood platelet counts ranged from 152x109 cells/L to 298x109 cells/L (normal range 100-400x109 cells/L). Ranges of aspartate aminotransferase were 12-38 U/L (normal range 5-40 U/L), of alanine aminotransferase were 8-26 U/L (normal range 5-40 U/L), of serum total bile acid were 5-8 micromol/L (normal range 0-10 micromol/L), of urea were 1.8-5.2 mmol/L (normal range 1.7-7.1 mmol/L), and of creatinine were 32.1-52.2 micromol/L (normal range 30-80 micromol/L). The ECG (electrocardiogram) was normal. After 12 months of antibiotic therapy, bronchoscopy revealed no excrescent obstruction or airway patency. Chest CT showed that most lung lesions had been absorbed, with strip shadows visible in both lungs (Figure 2A and B). Moxifloxacin was discontinued; however, based upon the recommendation of NTM disease specialists, the patient continued to receive oral azithromycin and cefprozil for 4 months, with cessation of all treatment after 16 months of antibiotic therapy. Upon examination at 3 and 6 months after completion of therapy, the patient was in good clinical condition. The recent laboratory tests results showed a white blood cell count of 8.2x109 cells/L containing 49.6% neutrophils and a C-reactive protein concentration <8 mg/L. The patient will continue to receive regular follow-up by mycobacterial disease physicians.

azithromycin, drug resistance, nontuberculous mycobacteria, pulmonary, treatment outcome

Chest radiograph and chest HRCT scan on admission. (B and C) Multiple masses and small nodules over both lungs (arrows). . Abbreviation: HRCT, high-resolution computed tomography.

PMC6529672_01

Female

A 4-month-old female infant, born prematurely at 30 weeks and weighing 1,550 g, was hospitalized after 4 days of cough and fever. Her past history included a controlled premature birth by cesarean section due to placenta previa. She suffered from a brief period of mechanical ventilation and administration of exogenous surfactant after being born. After admitted, mild bilateral lung coarse rales were found on physical examination. Laboratory tests results showed a white blood cell count of 22.9x109 cells/L containing 58.2% neutrophils and a C-reactive protein concentration of 28 mg/L. Chest radiography exhibited patchy shadows localized to the right lung and lower left lung (Figure 1A). Subsequent computed tomography (CT) detected multiple masses and small nodules across both lungs with mediastinal lymph node involvement (Figure 1B and C). The patient was then started on intravenous ceftriaxone. Bronchoscopy revealed minimal overlying airway secretions and airway patency extending from the upper respiratory tract to the lungs; 3-9 acid-fast bacilli organisms/100 high-power fields were found in bronchoalveolar lavage fluid (BALF) and gastric aspirate by Ziehi-Neelsen staining. Thus, the patient was suspected of harboring pulmonary tuberculosis infection and treated with isoniazid, rifampin, and pyrazinamide. Although both tuberculin skin test and interferon gamma (IFN-gamma) release assays were negative, mycobacterial liquid cultures of bronchoalveolar lavage and gastric aspirate were positive at 118 and 86 hrs of culture, respectively. Isolated mycobacteria were identified (with a confidence level of 84%) as MABC using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Vitek MS system, bioMerieux, France), supporting a diagnosis of MABC pulmonary disease. Immunologic evaluation results, including serum immunoglobulin levels and flow cytometric lymphocyte phenotyping were as follows: IgG 4.96 g/L (normal range 1.8-8 g/L), IgM 1.00 g/L (normal range 0.2-1 g/L), IgA 0.225 g/L (normal range 0.08-0.8g/L), IgE <5.00 IU/mL (normal range <=15 IU/mL), CD3+ cells 69.4% (normal range 55-82%), CD4+ cells 53.9% (normal range 55-57%), CD8+ cells 14.9% (normal range 11-25%), B cell 23.2% (normal range 11-45%), which were basically normal. However, natural killer (NK) cell level was 3%, which is below normal range 7-40%. In the review after 3 months, NK cell level raised to 10%. Whole exon sequencing (WES) was then performed and detected no pathogenic mutations, ruling out genetic disorders such as cystic fibrosis and primary immunodeficiency disease as factors contributing to exacerbation of MABC pulmonary disease in our patient. The subject family has no other case of MABC infection or immune-compromised individuals. According to expert consensus regarding diagnosis and treatment of NTM diseases, the therapy was modified to include oral clarithromycin (7.5 mg/kg, q12 h), linezolid (10 mg/kg, q8 h), and intravenous imipenem (15 mg/kg, q6 h). Due to the possibility of other mycobacterial infections, rifampicin (15 mg/kg/day) and ethambutol (15 mg/kg/day) were also administered. Subsequently, the patient's temperature returned to normal after 1 week and her cough gradually reduced, prompting cessation of intravenous imipenem administration. She was discharged after 25 days of hospitalization. After an additional 3 months of outpatient therapy, her chest CT remained unchanged and the patient exhibited recurrence of fever with wheezing. The white blood cell count was 17.6x109 cells/L, of which 47.4% were neutrophils, with a C-reactive protein concentration of 30 mg/L. Bronchoscopy revealed an excrescent obstruction of the sub-branch of the right lower bronchi. Acid-fast staining microscopy and mycobacterial cultures of BALF and gastric aspirate were negative. The isolates that had been preserved during the first hospital stay were sent to the National Tuberculosis Clinical Laboratory of Beijing Chest Hospital for drug susceptibility testing (DST) and further strain identification. DST was carried out according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Final tested drug concentrations were as follows: clarithromycin 0.0625-32 mug/mL, amikacin 0.5-256 mug/mL, moxifloxacin 0.0625-32 mug/mL, cefoxitin 0.5-256 mug/mL, linezolid 0.25-128 mug/mL, imipenem 0.25-128 mug/mL, meropenem 0.25-128 mug/mL, and doxycycline 0.0625-32 mug/mL. The minimum inhibitory concentration (MIC) of each drug was determined using the CLSI-recommended broth microdilution method performed in 96-well plates. DST demonstrated that isolates were susceptible to clarithromycin (MIC 0.25-0.5 mug/mL), amikacin (MIC 1-2 mug/mL), moxifloxacin (MIC 1 mug/mL), cefoxitin (MIC 4-8 mug/mL), and linezolid (MIC 1 mug/mL), with intermediate susceptibility to imipenem (MIC 8 mug/mL) and resistance to meropenem (MIC 64 mug/mL) and doxycycline (MIC >32 mug/mL). The isolates had no inducible resistance to clarithromycin, as they were susceptible to clarithromycin at both days 3 and 14. DNA sequence analysis of the ribosomal gene internal transcribed spacer (ITS) and rpoB, and hsp65 genes was performed to identify the subspecies of causative agent. Bacterial DNA extracted using the boiling method was used as a template for PCR. PCR primer pairs were as follows: 5'-AAGTCGTAACAAGGTARCCG-3' and 5'-TCGCCAAGGCATCCACC-3' for the ribosomal gene ITS region, 5'-GGCAAGGTCACCCCGAAGGG-3' and 5'-AGCGGCTGCTGGGTGATCATC-3' for rpoB, and 5'-ATCGCCAAGGAGATCGAGCT-3' and 5'-AAGGTG-CCGCGGATCTTGTT-3' for hsp65. PCR products were purified and sequenced by TsingKe Biotech Corp. (Beijing, China). Species identification was accomplished using BLAST searching that ultimately identified patient isolates as M. abscessus subsp. massiliense (with sequence identity of 99%). After consultation with physicians specializing in NTM disease from Beijing Chest Hospital, we treated the patient with intravenous cefoxitin (40 mg/kg q8 h), oral azithromycin (10 mg/kg/d), and moxifloxacin (10 mg/kg/d). After 3 months of treatment using this regimen, chest radiography revealed improvement, with white blood cell count (8.65x109 cells/L) and C-reactive protein concentration (<8 mg/L) both returning to normal ranges (4-10x109 cells/L and 0-8 mg/L, respectively). Cefoxitin was discontinued after 4 months of use. Monitoring for adverse drug events was performed monthly. No obvious adverse drug reactions were observed. Blood platelet counts ranged from 152x109 cells/L to 298x109 cells/L (normal range 100-400x109 cells/L). Ranges of aspartate aminotransferase were 12-38 U/L (normal range 5-40 U/L), of alanine aminotransferase were 8-26 U/L (normal range 5-40 U/L), of serum total bile acid were 5-8 micromol/L (normal range 0-10 micromol/L), of urea were 1.8-5.2 mmol/L (normal range 1.7-7.1 mmol/L), and of creatinine were 32.1-52.2 micromol/L (normal range 30-80 micromol/L). The ECG (electrocardiogram) was normal. After 12 months of antibiotic therapy, bronchoscopy revealed no excrescent obstruction or airway patency. Chest CT showed that most lung lesions had been absorbed, with strip shadows visible in both lungs (Figure 2A and B). Moxifloxacin was discontinued; however, based upon the recommendation of NTM disease specialists, the patient continued to receive oral azithromycin and cefprozil for 4 months, with cessation of all treatment after 16 months of antibiotic therapy. Upon examination at 3 and 6 months after completion of therapy, the patient was in good clinical condition. The recent laboratory tests results showed a white blood cell count of 8.2x109 cells/L containing 49.6% neutrophils and a C-reactive protein concentration <8 mg/L. The patient will continue to receive regular follow-up by mycobacterial disease physicians.

azithromycin, drug resistance, nontuberculous mycobacteria, pulmonary, treatment outcome

Chest radiograph and chest HRCT scan on admission. (B and C) Multiple masses and small nodules over both lungs (arrows). . Abbreviation: HRCT, high-resolution computed tomography.

PMC6529672_01

Female

A 4-month-old female infant, born prematurely at 30 weeks and weighing 1,550 g, was hospitalized after 4 days of cough and fever. Her past history included a controlled premature birth by cesarean section due to placenta previa. She suffered from a brief period of mechanical ventilation and administration of exogenous surfactant after being born. After admitted, mild bilateral lung coarse rales were found on physical examination. Laboratory tests results showed a white blood cell count of 22.9x109 cells/L containing 58.2% neutrophils and a C-reactive protein concentration of 28 mg/L. Chest radiography exhibited patchy shadows localized to the right lung and lower left lung (Figure 1A). Subsequent computed tomography (CT) detected multiple masses and small nodules across both lungs with mediastinal lymph node involvement (Figure 1B and C). The patient was then started on intravenous ceftriaxone. Bronchoscopy revealed minimal overlying airway secretions and airway patency extending from the upper respiratory tract to the lungs; 3-9 acid-fast bacilli organisms/100 high-power fields were found in bronchoalveolar lavage fluid (BALF) and gastric aspirate by Ziehi-Neelsen staining. Thus, the patient was suspected of harboring pulmonary tuberculosis infection and treated with isoniazid, rifampin, and pyrazinamide. Although both tuberculin skin test and interferon gamma (IFN-gamma) release assays were negative, mycobacterial liquid cultures of bronchoalveolar lavage and gastric aspirate were positive at 118 and 86 hrs of culture, respectively. Isolated mycobacteria were identified (with a confidence level of 84%) as MABC using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Vitek MS system, bioMerieux, France), supporting a diagnosis of MABC pulmonary disease. Immunologic evaluation results, including serum immunoglobulin levels and flow cytometric lymphocyte phenotyping were as follows: IgG 4.96 g/L (normal range 1.8-8 g/L), IgM 1.00 g/L (normal range 0.2-1 g/L), IgA 0.225 g/L (normal range 0.08-0.8g/L), IgE <5.00 IU/mL (normal range <=15 IU/mL), CD3+ cells 69.4% (normal range 55-82%), CD4+ cells 53.9% (normal range 55-57%), CD8+ cells 14.9% (normal range 11-25%), B cell 23.2% (normal range 11-45%), which were basically normal. However, natural killer (NK) cell level was 3%, which is below normal range 7-40%. In the review after 3 months, NK cell level raised to 10%. Whole exon sequencing (WES) was then performed and detected no pathogenic mutations, ruling out genetic disorders such as cystic fibrosis and primary immunodeficiency disease as factors contributing to exacerbation of MABC pulmonary disease in our patient. The subject family has no other case of MABC infection or immune-compromised individuals. According to expert consensus regarding diagnosis and treatment of NTM diseases, the therapy was modified to include oral clarithromycin (7.5 mg/kg, q12 h), linezolid (10 mg/kg, q8 h), and intravenous imipenem (15 mg/kg, q6 h). Due to the possibility of other mycobacterial infections, rifampicin (15 mg/kg/day) and ethambutol (15 mg/kg/day) were also administered. Subsequently, the patient's temperature returned to normal after 1 week and her cough gradually reduced, prompting cessation of intravenous imipenem administration. She was discharged after 25 days of hospitalization. After an additional 3 months of outpatient therapy, her chest CT remained unchanged and the patient exhibited recurrence of fever with wheezing. The white blood cell count was 17.6x109 cells/L, of which 47.4% were neutrophils, with a C-reactive protein concentration of 30 mg/L. Bronchoscopy revealed an excrescent obstruction of the sub-branch of the right lower bronchi. Acid-fast staining microscopy and mycobacterial cultures of BALF and gastric aspirate were negative. The isolates that had been preserved during the first hospital stay were sent to the National Tuberculosis Clinical Laboratory of Beijing Chest Hospital for drug susceptibility testing (DST) and further strain identification. DST was carried out according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Final tested drug concentrations were as follows: clarithromycin 0.0625-32 mug/mL, amikacin 0.5-256 mug/mL, moxifloxacin 0.0625-32 mug/mL, cefoxitin 0.5-256 mug/mL, linezolid 0.25-128 mug/mL, imipenem 0.25-128 mug/mL, meropenem 0.25-128 mug/mL, and doxycycline 0.0625-32 mug/mL. The minimum inhibitory concentration (MIC) of each drug was determined using the CLSI-recommended broth microdilution method performed in 96-well plates. DST demonstrated that isolates were susceptible to clarithromycin (MIC 0.25-0.5 mug/mL), amikacin (MIC 1-2 mug/mL), moxifloxacin (MIC 1 mug/mL), cefoxitin (MIC 4-8 mug/mL), and linezolid (MIC 1 mug/mL), with intermediate susceptibility to imipenem (MIC 8 mug/mL) and resistance to meropenem (MIC 64 mug/mL) and doxycycline (MIC >32 mug/mL). The isolates had no inducible resistance to clarithromycin, as they were susceptible to clarithromycin at both days 3 and 14. DNA sequence analysis of the ribosomal gene internal transcribed spacer (ITS) and rpoB, and hsp65 genes was performed to identify the subspecies of causative agent. Bacterial DNA extracted using the boiling method was used as a template for PCR. PCR primer pairs were as follows: 5'-AAGTCGTAACAAGGTARCCG-3' and 5'-TCGCCAAGGCATCCACC-3' for the ribosomal gene ITS region, 5'-GGCAAGGTCACCCCGAAGGG-3' and 5'-AGCGGCTGCTGGGTGATCATC-3' for rpoB, and 5'-ATCGCCAAGGAGATCGAGCT-3' and 5'-AAGGTG-CCGCGGATCTTGTT-3' for hsp65. PCR products were purified and sequenced by TsingKe Biotech Corp. (Beijing, China). Species identification was accomplished using BLAST searching that ultimately identified patient isolates as M. abscessus subsp. massiliense (with sequence identity of 99%). After consultation with physicians specializing in NTM disease from Beijing Chest Hospital, we treated the patient with intravenous cefoxitin (40 mg/kg q8 h), oral azithromycin (10 mg/kg/d), and moxifloxacin (10 mg/kg/d). After 3 months of treatment using this regimen, chest radiography revealed improvement, with white blood cell count (8.65x109 cells/L) and C-reactive protein concentration (<8 mg/L) both returning to normal ranges (4-10x109 cells/L and 0-8 mg/L, respectively). Cefoxitin was discontinued after 4 months of use. Monitoring for adverse drug events was performed monthly. No obvious adverse drug reactions were observed. Blood platelet counts ranged from 152x109 cells/L to 298x109 cells/L (normal range 100-400x109 cells/L). Ranges of aspartate aminotransferase were 12-38 U/L (normal range 5-40 U/L), of alanine aminotransferase were 8-26 U/L (normal range 5-40 U/L), of serum total bile acid were 5-8 micromol/L (normal range 0-10 micromol/L), of urea were 1.8-5.2 mmol/L (normal range 1.7-7.1 mmol/L), and of creatinine were 32.1-52.2 micromol/L (normal range 30-80 micromol/L). The ECG (electrocardiogram) was normal. After 12 months of antibiotic therapy, bronchoscopy revealed no excrescent obstruction or airway patency. Chest CT showed that most lung lesions had been absorbed, with strip shadows visible in both lungs (Figure 2A and B). Moxifloxacin was discontinued; however, based upon the recommendation of NTM disease specialists, the patient continued to receive oral azithromycin and cefprozil for 4 months, with cessation of all treatment after 16 months of antibiotic therapy. Upon examination at 3 and 6 months after completion of therapy, the patient was in good clinical condition. The recent laboratory tests results showed a white blood cell count of 8.2x109 cells/L containing 49.6% neutrophils and a C-reactive protein concentration <8 mg/L. The patient will continue to receive regular follow-up by mycobacterial disease physicians.

azithromycin, drug resistance, nontuberculous mycobacteria, pulmonary, treatment outcome

Chest HRCT scan after 12 months of antibiotic therapy. (A and B) Most of the lung lesions are absorbed, but there were still some strip shadows in both lungs (arrows). . Abbreviation: HRCT, high-resolution computed tomography.

PMC6529672_01

Female

A 4-month-old female infant, born prematurely at 30 weeks and weighing 1,550 g, was hospitalized after 4 days of cough and fever. Her past history included a controlled premature birth by cesarean section due to placenta previa. She suffered from a brief period of mechanical ventilation and administration of exogenous surfactant after being born. After admitted, mild bilateral lung coarse rales were found on physical examination. Laboratory tests results showed a white blood cell count of 22.9x109 cells/L containing 58.2% neutrophils and a C-reactive protein concentration of 28 mg/L. Chest radiography exhibited patchy shadows localized to the right lung and lower left lung (Figure 1A). Subsequent computed tomography (CT) detected multiple masses and small nodules across both lungs with mediastinal lymph node involvement (Figure 1B and C). The patient was then started on intravenous ceftriaxone. Bronchoscopy revealed minimal overlying airway secretions and airway patency extending from the upper respiratory tract to the lungs; 3-9 acid-fast bacilli organisms/100 high-power fields were found in bronchoalveolar lavage fluid (BALF) and gastric aspirate by Ziehi-Neelsen staining. Thus, the patient was suspected of harboring pulmonary tuberculosis infection and treated with isoniazid, rifampin, and pyrazinamide. Although both tuberculin skin test and interferon gamma (IFN-gamma) release assays were negative, mycobacterial liquid cultures of bronchoalveolar lavage and gastric aspirate were positive at 118 and 86 hrs of culture, respectively. Isolated mycobacteria were identified (with a confidence level of 84%) as MABC using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Vitek MS system, bioMerieux, France), supporting a diagnosis of MABC pulmonary disease. Immunologic evaluation results, including serum immunoglobulin levels and flow cytometric lymphocyte phenotyping were as follows: IgG 4.96 g/L (normal range 1.8-8 g/L), IgM 1.00 g/L (normal range 0.2-1 g/L), IgA 0.225 g/L (normal range 0.08-0.8g/L), IgE <5.00 IU/mL (normal range <=15 IU/mL), CD3+ cells 69.4% (normal range 55-82%), CD4+ cells 53.9% (normal range 55-57%), CD8+ cells 14.9% (normal range 11-25%), B cell 23.2% (normal range 11-45%), which were basically normal. However, natural killer (NK) cell level was 3%, which is below normal range 7-40%. In the review after 3 months, NK cell level raised to 10%. Whole exon sequencing (WES) was then performed and detected no pathogenic mutations, ruling out genetic disorders such as cystic fibrosis and primary immunodeficiency disease as factors contributing to exacerbation of MABC pulmonary disease in our patient. The subject family has no other case of MABC infection or immune-compromised individuals. According to expert consensus regarding diagnosis and treatment of NTM diseases, the therapy was modified to include oral clarithromycin (7.5 mg/kg, q12 h), linezolid (10 mg/kg, q8 h), and intravenous imipenem (15 mg/kg, q6 h). Due to the possibility of other mycobacterial infections, rifampicin (15 mg/kg/day) and ethambutol (15 mg/kg/day) were also administered. Subsequently, the patient's temperature returned to normal after 1 week and her cough gradually reduced, prompting cessation of intravenous imipenem administration. She was discharged after 25 days of hospitalization. After an additional 3 months of outpatient therapy, her chest CT remained unchanged and the patient exhibited recurrence of fever with wheezing. The white blood cell count was 17.6x109 cells/L, of which 47.4% were neutrophils, with a C-reactive protein concentration of 30 mg/L. Bronchoscopy revealed an excrescent obstruction of the sub-branch of the right lower bronchi. Acid-fast staining microscopy and mycobacterial cultures of BALF and gastric aspirate were negative. The isolates that had been preserved during the first hospital stay were sent to the National Tuberculosis Clinical Laboratory of Beijing Chest Hospital for drug susceptibility testing (DST) and further strain identification. DST was carried out according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Final tested drug concentrations were as follows: clarithromycin 0.0625-32 mug/mL, amikacin 0.5-256 mug/mL, moxifloxacin 0.0625-32 mug/mL, cefoxitin 0.5-256 mug/mL, linezolid 0.25-128 mug/mL, imipenem 0.25-128 mug/mL, meropenem 0.25-128 mug/mL, and doxycycline 0.0625-32 mug/mL. The minimum inhibitory concentration (MIC) of each drug was determined using the CLSI-recommended broth microdilution method performed in 96-well plates. DST demonstrated that isolates were susceptible to clarithromycin (MIC 0.25-0.5 mug/mL), amikacin (MIC 1-2 mug/mL), moxifloxacin (MIC 1 mug/mL), cefoxitin (MIC 4-8 mug/mL), and linezolid (MIC 1 mug/mL), with intermediate susceptibility to imipenem (MIC 8 mug/mL) and resistance to meropenem (MIC 64 mug/mL) and doxycycline (MIC >32 mug/mL). The isolates had no inducible resistance to clarithromycin, as they were susceptible to clarithromycin at both days 3 and 14. DNA sequence analysis of the ribosomal gene internal transcribed spacer (ITS) and rpoB, and hsp65 genes was performed to identify the subspecies of causative agent. Bacterial DNA extracted using the boiling method was used as a template for PCR. PCR primer pairs were as follows: 5'-AAGTCGTAACAAGGTARCCG-3' and 5'-TCGCCAAGGCATCCACC-3' for the ribosomal gene ITS region, 5'-GGCAAGGTCACCCCGAAGGG-3' and 5'-AGCGGCTGCTGGGTGATCATC-3' for rpoB, and 5'-ATCGCCAAGGAGATCGAGCT-3' and 5'-AAGGTG-CCGCGGATCTTGTT-3' for hsp65. PCR products were purified and sequenced by TsingKe Biotech Corp. (Beijing, China). Species identification was accomplished using BLAST searching that ultimately identified patient isolates as M. abscessus subsp. massiliense (with sequence identity of 99%). After consultation with physicians specializing in NTM disease from Beijing Chest Hospital, we treated the patient with intravenous cefoxitin (40 mg/kg q8 h), oral azithromycin (10 mg/kg/d), and moxifloxacin (10 mg/kg/d). After 3 months of treatment using this regimen, chest radiography revealed improvement, with white blood cell count (8.65x109 cells/L) and C-reactive protein concentration (<8 mg/L) both returning to normal ranges (4-10x109 cells/L and 0-8 mg/L, respectively). Cefoxitin was discontinued after 4 months of use. Monitoring for adverse drug events was performed monthly. No obvious adverse drug reactions were observed. Blood platelet counts ranged from 152x109 cells/L to 298x109 cells/L (normal range 100-400x109 cells/L). Ranges of aspartate aminotransferase were 12-38 U/L (normal range 5-40 U/L), of alanine aminotransferase were 8-26 U/L (normal range 5-40 U/L), of serum total bile acid were 5-8 micromol/L (normal range 0-10 micromol/L), of urea were 1.8-5.2 mmol/L (normal range 1.7-7.1 mmol/L), and of creatinine were 32.1-52.2 micromol/L (normal range 30-80 micromol/L). The ECG (electrocardiogram) was normal. After 12 months of antibiotic therapy, bronchoscopy revealed no excrescent obstruction or airway patency. Chest CT showed that most lung lesions had been absorbed, with strip shadows visible in both lungs (Figure 2A and B). Moxifloxacin was discontinued; however, based upon the recommendation of NTM disease specialists, the patient continued to receive oral azithromycin and cefprozil for 4 months, with cessation of all treatment after 16 months of antibiotic therapy. Upon examination at 3 and 6 months after completion of therapy, the patient was in good clinical condition. The recent laboratory tests results showed a white blood cell count of 8.2x109 cells/L containing 49.6% neutrophils and a C-reactive protein concentration <8 mg/L. The patient will continue to receive regular follow-up by mycobacterial disease physicians.

azithromycin, drug resistance, nontuberculous mycobacteria, pulmonary, treatment outcome

Chest HRCT scan after 12 months of antibiotic therapy. (A and B) Most of the lung lesions are absorbed, but there were still some strip shadows in both lungs (arrows). . Abbreviation: HRCT, high-resolution computed tomography.

PMC10196485_01

Male

A 13-year-old male child was referred to local hospital due to 5 days of dizziness, and 2 days of fever and dyspnea. Except for a history of neurodermatitis cured by antihistamines, the patient had normal nutritional status without other previous underlying diseases, head injury and drug exposures. Additionally, routine childhood vaccines had been implemented in this patient. No local epidemiology of communicable diseases had been reported in the area where the patient resided. On physical examination, the children exhibited nasal flaring with respiratory rates of 31 breaths/minute, in absence of cyanosis, pallor, retractions, crackles, heart murmurs, hepatosplenomegaly, or extremity edema. The chest x-ray revealed streaky opacities in both lungs. Review of the rest documents suggested hypoalbuminemia (2.1 g/dl), along with normal results of cerebrospinal fluid (CSF) analysis, non-enhanced computed tomography (CT) scan of head, aminotransferase, and renal function. As being supposed to be secondary to acute infections, no further effort was directed toward defining the underlying causes of hypoalbuminemia. The patient was initially diagnosed as pneumonia, and antibiotic treatment (oxacillin, 100 mg/kg per day) was administered. His condition deteriorated within 2 days of hospitalization, presenting with a progressive course of breathlessness, lethargy, and hemodynamic instability, along with elevated levels of leukocyte. Thus, the patient was directly transferred to the pediatric intensive care unit (PICU) in our hospital in view of critical illness. On arrival, he exhibited altered mental status, sunken eyes, dehydrated skin, cold extremities, and photoreactive pupil with hypothermia (35.7 C), tachypnea (35 breaths/minute), tachycardia (127 beats/min), hypotension (82/60 mmHg), and percutaneous oxygen saturation of 95% via a nasal cannula. Other than rough respiratory sounds, the rest of his physical examinations were unremarkable. Initial laboratory investigations performed on day 1 of hospitalization had revealed increased leukocyte (21,600/mul) with 84.3% neutrophils and 9.4% lymphocytes, red blood cell (RBC) count (4.14 x 106/mul), hemoglobin (11.3 g/dl), hematocrit (33.9%), procalcitonin (0.8 ng/ml), and C-reactive protein (CRP) (1.89 mg/dl) with normal platelets (39.4 x 104/mul). Results of renal function, electrolytes, and blood gas analysis were within normal ranges. Decreased antithrombin III level (44%) combined with elevation of fibrin degradation products (FDP, 45.8 mug/ml), D-dimer (DDI, 7.9 mug/ml) and fibrinogen (553 mg/dl), were identified. Moreover, Serum albumin was low at 2.4 g/dl (Table 1). Chlamydia/mycoplasma antibody, PPD test, myocardial troponin I, complement level, antistreptolysin O (ASO) titer, RT-PCR for SARS-CoV-2, blood culture, and echocardiography demonstrated normal findings. Urine examination was not performed because of anuria, while subsequent ultrasound did not revealed structural anatomic anomalies, hydronephrosis or obstructive uropathy. Repeat chest x-ray displayed bibasilar nodular opacities with consolidation. The patient was diagnosed as pneumonia combined with shock. Right internal jugular catheterization was placed under ultrasound guidance. The patient was then given intravenous resuscitation via 0.9% sodium chloride (20 ml/kg), and ceftriaxone (80 mg/kg per day). Notably, two samples of sputum cultures at 24 h both confirmed Streptococcus pneumoniae. Delayed urinalysis showed 4+ proteinuria by dipstick. Combined with hypoalbuminemia, an unexpected diagnosis of NS was brought to mind irrespective of its absence in symptoms. Despite being hemodynamically stable and absent from fever, his dyspnea and period of headache became progressively worsening. Respiratory distress with percutaneous oxygen saturation of 88% even via a face mask was noted on hospital day 3. Both meningeal irritation and pathological signs were negative. Based on a high degree of suspicion for NS and increased vigilance of consequent hypercoagulability, the possiblity of thromboembolism was taken into account, which might be attributable to dyspnea and headache. This speculation had been corroborated by subsequent amazing results of targeted tests for disclosing the nature of the pulmonary and neurological lesions. Specifically, a computed tomography angiography (CTA) of chest demonstrated multiple intraluminal filling defects in the branch pulmonary arteries of both lungs, suggestive of PE in bilateral pulmonary arteries (Figures 1A,C,E), whereas no evidence of DVT was identified in bilateral lower limb veins by ultrasound. Meanwhile, the head CT manifested high-density shadows in the tentorium cerebelli and venous sinus, with normal results of repeat CSF analysis. Based on the correlation between headache episode and possible intracranial clot, cranial magnetic resonance imaging (MRI) and MR venography (MRV) were subsequently performed. Notably, multiple signal abnormalities were found in superior sagittal sinus, inferior sagittal sinus, straight sinus, bilateral transversal sinuses, bilateral sigmoid sinuses, vein of Galen, and torcula (Figures 2A-D), consistent with the imaging features of CVST. The patient immediately received treatment with high flow nasal oxygen (HFNO) therapy, subcutaneous injection of low molecular weight heparin calcium (150 U/kg per day), and continuous dripping intravenous infusion of urokinase (an initial bolus of 4 x 103 U/kg for 15 min followed by a maintenance dose of 100 x 103 U/kg per day). Of great concern, it was crucial to further confirm the underlying disease contributing to the pathogenesis of CVST and concurrent PE. It was noteworthy that multiple urinalysis had uniformly displayed massive proteinuria without hematuria. 1+ hyaline casts along with granular casts were detected in the sediment under a microscope at low power field (x10). Increase levels of urine beta2-microglobulin were found with values between 1.64 and 2.20 mug/ml (normal value <0.25 mug/ml). Furthermore, a 24-h urine examination revealed 12.5 g proteinuria with a proteinuria to serum albumin (2.0 g/dl) ratio of 6.25. Meanwhile, dyslipidemia (elevated total cholesterol of 11.3 mmol/L and low density lipoprotein of 9.0 mmol/L), and progressive abnormalities in the coagulation-fibrinolysis system (antithrombin III of 37%, FDP of 57.1 mug/ml and DDI of 19.2 mug/ml), were identified. Given negative history of Henoch-Schonlein purpura along with unremarkable findings of human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus, autoimmune antibody and abdominal CT scan, the diagnosis of primary NS was ultimately confirmed. Given negative findings of T-spot assay, serum glucan/galactomannan tests, and radiographic evaluation suggestive of tuberculosis or fungal infections, additional therapy of oral prednisone (2 mg/kg per day) was administered for the treatment of NS. Despite this, screening for a comprehensive prothrombotic workup was also performed in order to exclude multiple additional risk factors for CVST and PE, including protein C/S, homocysteine, Leiden factor V, antineutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibody, anti-Ro/SSA, anti-La/SSB, antiglomerular basement membrane (GBM) antibody, tumor marker concentrations, and bone marrow biopsy. All the results were within normal limits. Encouragingly, his headache and breathlessness gradually resolved. Radiographic recanalization of the infarcted pulmonary and cerebral vessels was identified on the 6th day (Figures 1B,D,F) and 20th day (Figures 2E-H) of antithrombotic therapy, respectively. Moreover, renal remission was achieved on the 13th day of steroid treatment, associated with complete resolution of the coagulation profile. The patient was discharged on oral prednisone, aspirin and dipyridamole after spending 28 days in hospital. Apart from normal renal function without proteinuria, no thromboembolic complications, neurological sequelae and side effects of drugs developed during follow-up for 6 months. Figure 3 summarized the Timeline with relevant data from the episode of care in this case.

case report, cerebral venous sinus thrombosis, children, nephrotic syndrome, pulmonary embolism

PMC5437806_01

Female

A 6-year-old female child of low socioeconomic status, was referred to Department of Orthopedics with the history of insidious onset stiffness of neck with minimal pain for 1 week. Patient's parent gave a history of tuberculosis contact, but had no history of trauma, evening increase of temperature, decrease appetite, and significant weight loss. Examination showed no motor or sensory deficit with all reflexes intact. Blood investigations showed normal report except mild eosinophilia. Noncontrast MRI of the neck showed a well-defined intramedullary cystic lesion at C4-C6 vertebral levels, which was hypointense on T1 weighted and hyperintense on T2 weighted images with peripheral, spinal cord edema having an intracystic hypointense on T2 weighted "target" like lesion suggestive of scolex. Screening of whole spine and brain did not show any other lesion [Figure 1a-c]. Fundus examination was performed to rule out increased intracranial pressure. Sonography of abdomen and computed tomography (CT) scan of the chest was also unremarkable. Hence, on the basis of this absolute diagnostic criterion, final diagnosis of solitary ICC was made. As the patient had no neurological deficit, conservative treatment was opted for this patient. Before the start of treatment, serum Ag-ELISA was performed to follow the effectiveness of treatment, and it was found positive. The patient was given albendazole 15 mg/kg body weight per day orally for 1 month. Oral prednisolone 1 mg/kg body weight/day, was also started 2 days before the start of albendazole, for 2 weeks. Patient's neck stiffness and pain resolved after 1 week of treatment. Ag-ELISA was repeated after 2 months of completion of treatment, and observed negative suggestive of no residual lesion. The patient was alright at the end of 2 years of follow-up.

albendazole, intramedullary cervical spinal cysticercosis, neurological deficit

PMC8214902_01

Male

A 27-year-old-male was allegedly beaten on the head with a wooden stick, following which he was immediately taken to a local civil hospital. There was no history of loss of consciousness, vomiting, seizure, or bleeding from the ear, nose, or throat. On medicolegal examination, an injury over the forehead's left side was noted, and the patient was discharged after first aid. Approximately 25 days after the alleged assault, the patient was brought to the outpatient department complaining of fever, productive cough, and shortness of breath for the past 15 days, and weakness on the left side of his body. He did not have any ear pain, discharge, or nose block. He denied any history of recurrent diarrhea or respiratory infections since childhood. He was not a smoker or drug abuser and did not have any past respiratory illness. He had been working at a construction site for 3 months before the illness. On examination, his Glasgow Coma Scale (GCS) score was 15, and the central nervous system examination revealed left hemiparesis. Non-contrast brain computed tomography showed hypodensity in the right frontal and parietal region adjacent to the ventricle. A chest x-ray showed bilateral heterogeneous infiltration of the lungs (Figure 1A). A high-resolution chest computed tomography showed bilateral nodules of varying size and multiple cavities. The abnormalities were evident in both lungs, mainly in the bilateral upper lobes. There was no pleural effusion or significant mediastinal lymphadenopathy (Figure 1B). He was managed with broad-spectrum antibiotics. The diagnostic possibility of tuberculosis was considered, and empirical anti-tuberculosis treatment was started. Five days later, his GCS score deteriorated to 7 and he was admitted to the ward. Cerebral spinal fluid analysis showed 2,100 cells (reference range [RR]: 0-5 cells/mm3) with a predominance of lymphocytes, the glucose of 95 mg/dL (RR: 50-80 mg/dL), proteins of 16 mg/dL (RR: 15-40 mg/dL). Serological investigations for HIV, and hepatitis B and C were negative. A hemogram showed a total leucocyte count of 10,300/mm3 and a differential count was within normal limits; the hemoglobin was 14.4 mg/dL (RR; 13-15 g/dL) and the platelet count was 219,000/muL (RR 150,000-450,000/ muL). His liver function tests and renal function tests were within normal limits. On the third day of hospitalization, he succumbed to the illness. The autopsy was performed owing to the legal implications of this patient's case.

autopsy, invasive pulmonary aspergillosis, microscopy, neuroaspergillosis

PMC6985093_01

Female

A 28-year-old female patient (K.) was admitted to N. N. Blokhin National Medical Research Center of Oncology in June 2016 after being referred from another hospital for further diagnosis and being treated for multiple renal cell tumors. Patient K. gave informed consent to undergo diagnostic procedures and treatment, as well as to participate in the study, and for the presentation of relevant clinical and molecular data in this paper. This case report was approved by the local Ethics Committee at Sechenov University. Based on the medical records, the patient had pituitary adenoma with endo-, supra-, infra-, and latero-sellar growth with partial descending optic atrophy on the left in 2012. At that time, the disease was clinically manifested by broadening of the feet and fingers, increased sweating, cysts and diffuse changes in the thyroid gland, and an increase in the level of growth hormone. The pituitary adenoma was partly removed via endoscopic transsphenoidal surgery in 2012, and she was treated with somatostatin analogs. At the time of the follow-up examination in 2016, no pituitary adenoma recurrence was detected; she was recommended to continue taking the somatostatin analog (octreotide depot) 20 mg intramuscularly once every 28 days in combination with bromocriptine 2.5 mg per day. At the same time, multiple neoplasms were detected in both kidneys. Family history was negative. The patient and her immediate family had no oncological diseases at a young age or other signs suggesting any known cancer syndrome. At the time of the hospitalization of patient K. in the N. N. Blokhin National Medical Research Center of Oncology, her parents and the child did not have cancer symptoms. Patient K. was examined at Blokhin National Medical Research Center of Oncology. Computed tomography with intravenous contrast detected three 1-2 cm tumor lesions with the active accumulation of the contrast agent in the right kidney. In the left kidney, there were four tumor lesions: a 3.5 x 3.0-cm mostly cystic tumor with a soft-tissue component, with parietal accumulation of the contrast dye in the middle one-third portion; a tumor with a diameter of 1.3 cm at the upper pole; a tumor with a diameter of 1 cm in a subcapsular location in the middle one-third; and a tumor of 1.3 cm in diameter at the lower pole; these tumors similarly accumulated the contrast dye. Various tests were performed, including skeletal scintigraphy, computed tomography of thoracic organs, and ultrasound of the abdominal and pelvic organs, which showed no sign of distant tumor process. Blood count, chemistry, and clotting tests were carried out prior to surgery and showed no clinically significant abnormalities. Complex renal scintigraphy revealed an insignificant decrease in radionuclide clearance; preoperative creatinine clearance was 84 mL/min. Based on the obtained diagnostic data, a multidisciplinary board was held, with the participation of surgical oncologist, oncologist, pathomorphologist, a specialist in radiation diagnostics and urologist. Taking into account the current recommendations of the European Association of Urology and the current standards of medical care of the Ministry of Health of Russia for patient K. with bilateral localized kidney cancer, the tactics of stepwise tumor resection with preliminary examination using computed tomography with contrast was chosen. Partial nephrectomy was performed in two steps. The right kidney was resected during the first step. Intraoperative findings included four tumors of 0.5-1.3 cm in dimension in the lower one-third, three tumors of 0.5-1.0 cm in the middle one-third, and three tumors of up to 1.5 cm in the upper one-third of the right kidney. Through hilar occlusion, all detectable tumors were consecutively removed with a margin of visually unchanged tissue and adjacent pararenal fat under intraoperative ultrasound guidance. The sides of each resection site were sutured together. The kidney ischemia time was 28 min, total surgery duration was 135 min, and blood loss was 300 mL. Postoperative complications did not occur; serum creatinine increased insignificantly to 118 mumol/L. Patient K. was discharged in satisfactory condition on day 13 after surgery. Two months later, in August 2016, patient K. was again admitted to Blokhin National Medical Research Center of Oncology to undergo a second surgery. Computed tomography scanning of the abdomen with intravenous contrast was performed before surgery and showed a deformed right kidney with two low-density sites that had uneven outlines and were 3.0 x 2.2 cm in total (postoperative changes). At least seven contrast-accumulating nodular masses were detected in the left kidney. Compared to the previous scan, which was performed 2 months earlier, one large mass had increased to 4.0 x 3.2 cm (previously 3.7 x 3.0 cm) at the posterior surface, whereas the other masses remained unchanged (Figure 1). Complex testing showed no findings suggesting metastasis. In surgery, nine tumors were consecutively removed with a margin of visually normal tissue from the left kidney with hilar clamping (ischemia time 28 min). Blood loss was 300 mL, and surgery duration was 150 min. The patient developed a fever (38 C) 9 days after the surgery. Due to the dilation in the collecting system of the right kidney, a JJ ureteric stent was placed. The inflammatory infection worsened, warranting a change in the antibacterial therapy and a nephrostomy tube was placed on the right. Signs of acute pyelonephritis were eliminated. The nephrostomy tube was removed 18 days after the surgery. By the end of the surgical treatment, the creatinine clearance was 32 mL/min, and serum creatinine was 168 mumol/L. Patient K. was discharged in a satisfactory condition. Regular follow-up tests were performed in subsequent years. In February 2019, no sign of relapse or disease progression was detected in control complex testing, which included magnetic resonance imaging of the abdominal organs. All tumor masses were removed from the right kidney during the first surgery. Microscopic examination revealed that they were structurally similar, and the tumors were identified as type I papillary RCC, Fuhrman grade 2 (Figure 2). Tumor cell growth was not detected in the pararenal fat. The nine tumors removed from the left kidney during the second surgery were also structurally consistent with type I papillary RCC, Fuhrman grade 2 by histology. Because multiple type I papillary RCC tumors developed synchronously and bilaterally and affected a young patient, molecular genetic testing was carried out for patient K. in the period between the first and second surgeries. Note that it would be more advisable to do this before the first stage of the surgical intervention, so that in case of a positive test result, there would be an extra argument in favor of organ-preserving treatment, but the organizational peculiarities of the hospital care and the time frame for molecular genetic diagnostics made it possible to conduct a genetic study only during the first stage of treatment. Genomic DNA was isolated from a peripheral blood sample with a DNA-sorb-B kit (NextBio, Moscow, Russia). Fragments of MET exons 15-21 were PCR-amplified using primers with previously published sequences. The reaction mixture contained 50-100 ng of genomic DNA, 2.5 mM MgCl2, 1.5 mM each dNTP, 2 pmol of the forward and reverse primers, 1 unit of thermostable Taq polymerase, and 5 muL of 5x PCR buffer (Interlabservice, Moscow, Russia); the total volume was 25 muL. Amplification was performed as follows: 95 C for 1 min; 35 cycles at 95 C for 45 s, 61 C for 25 s, and 72 C for 30 s; and final elongation at 72 C for 50 s. After amplification, the PCR product was treated with 1 unit of alkaline phosphatase and 4 units of Escherichia coli exonuclease I to eliminate free primers and dNTPs. The product was then subjected to Sanger sequencing using a BigDye Terminator v. 3.1 Cycle Sequencing kit and 24-capillary 3500xl sequencer (Thermo Fisher Scientific, Waltham, MA, USA). The single-nucleotide substitution c.3328G>A was found in exon 16 in a heterozygous state (Figure 3). This substitution causes the missense mutation p.V1110I (Human Genome Mutation Database accession no. CM990852, http://www.hgmd.cf.ac.uk/ac/index.php). The germline mutation has been described as a cause of HPRC, occurs in the ATP-binding site of the HGF receptor, leads to its activation, and exerts a transforming effect in fibroblast cultures in vitro. The somatic p.V1110I mutation has similarly been found in a sporadic type 1 papillary RCC (Catalog of Somatic Mutations in Cancer accession no. COSM3724572, http://cancer.sanger.ac.uk/cosmic) and is considered as a pathological factor associated with activation of the HGF receptor. These results confirmed the diagnosis of type I HPRC (OMIM 605074) in patient K. Following the results of the analysis, genetic counseling was carried out and mutation carriage testing was recommended for family members of the first line of kinship. Patient K. was also advised to consult a geneticist and a urologist once every 6-8 months. At the time of writing, there is no information about a confirmed mutation in any of the relatives of patient K. Together with a negative family cancer history, this suggests that the identified germline mutation can be classified as de novo.

met gene, germline mutation, hereditary cancer syndrome, kidney cancer, papillary renal cell carcinoma

PMC6387709_01

Male

The patient is an 18-year-old boy not known to have any medical illness previously, who was referred to the outpatient department from another hospital after 3 months history of seizures. Seizures started with blurring of vision and proceed to right sided head deviation and tonic posturing of the right upper limp which progress to generalized tonic-clonic seizures. The episodes are followed by loss of consciousness and postictal suboccipital and frontal tension headache. There was no history of fever, loss of weight, trauma, or any sensory/motor neurodificit. Family history was unremarkable, with negative past surgical history. All general and local physical examinations were done and all were within normal range. There were no physical findings or family history in favour of neurofibromatosis. Brain MRI with contrast was done and showed right parieto-occipital cortical and subcortical mass lesion measuring about 1.5 x 1.5 cm that has a low signal intensity on T1 and intermediate signal intensity on T2 and FLAIR with intense enhancement postgadolinium administration mainly peripherally with few small susceptibility artefact on T2 associated with significant vasogenic oedema and mass effect on the adjacent sulci (Figure 1). The radiological impression with the above description was most likely representing granulomatous infection (TB) or metastasis. Although a preoperative diagnosis could not be clearly established, the tumor was surgically removed through a right occipital craniotomy. The dura was incised and small area of discoloration was noted. Cortical dissection was done, with multiple pieces for frozen section, which was diagnosed later as suggestive of schwannoma, differential diagnosis meningioma. The tumor was encountered 2mm in subcortical area, which was firm, fibrous in content, yellowish in colour, and resembling meningioma. Postoperatively, the patient did not have any new neurological deficit, and he was discharged 1 day postoperatively in stable condition to be seen and followed up in the clinic after 2 months. He was kept on phenytoin 100 mg orally three times a day and Paracetamol 650 mg tablets 4 hourly PRN. Microscopic examination of the tissue showed areas of nuclear palisading of bland looking spindle cells with dens cellular area alternating with loosely textured myxoid area, consistent with Antoni type A and Antoni Type B, respectively (Figure 2). Immunohistochemical study was diffusely positive for S100 protein and negative for EMA, confirming the diagnosis of schwannoma (WHO grade1).

PMC6324914_05

Female

The first report of the deliberate transplantation of a liver from an HCV-viremic donor to a nonviremic recipient was published in August 2017. The recipient was a 57-year old woman with a history of Child-Turcotte-Pugh class A HCV cirrhosis, who had been on the liver transplant waiting list for 3 years. She had HCV genotype 1A, which had previously been treated with 12 weeks of sofosbuvir/simeprevir combination therapy as part of an industry-sponsored clinical trial, and a sustained virological response had been achieved. However, 6 months later the patient developed hepatopulmonary syndrome and was granted 22 MELD exception points. The patient agreed to accept an HCV-positive liver, understanding that she would have to be retreated with DAAs. The donor was an 18-year-old man who had died from an IV heroin overdose: the donors' HCV genotype was not known at the time of transplantation, but 3 days after transplantation, the recipient's HCV genotype was reported as 1A. Treatment with ledipasvir/sofosbuvir was commenced on posttransplant day 25, and HCV RNA was undetectable by week 8 posttransplant. Two years postliver transplant, the patient remained HCV-RNA-negative, with excellent graft function. One of the areas, where more evidence is currently required, is with regard to the safe use of DAAs for HCV in patients with impaired kidney function. In most of the trials of DAA-based therapies, patients with severe renal impairment were excluded; in addition, the nucleotide polymerase inhibitor sofosbuvir is eliminated through the kidney and is, therefore, not appropriate for patients with estimated glomerular filtration rate less than 30 mL/min per 1.73 m2. The HCV protease inhibitor asunaprevir and the Ns5A inhibitor daclatasvir are mainly eliminated through the liver, and combination therapy with daclatasivir and asunaprevir has been demonstrated to be highly effective and safe in genotype 1 HCV-infected patients with estimated glomerular filtration rate less than 45 mL/min per 1.73 m2. Other drug protocols, including ombitasvir/paritaprevir/ritonavir without ribavirin, or elbasvir and grazoprevir combination therapy, have also been shown to be safe and effective in genotype 1 HCV-infected patients with chronic kidney disease stages 4 and 5, including hemodialysis patients. Effective DAA therapies for genotype 2 HCV-infected patients with impaired kidney function are lacking, however. A Japanese study of the outcomes of sofosbuvir and ribavirin combination therapy in genotype 2 HCV-infected patients with chronic kidney disease stages 1 to 3 found that patients with stage 3 chronic kidney disease were significantly more likely to not experience a sustained virological response, but that otherwise the regimen was safe for patients with kidney impairment. Other studies have reported serious adverse events of sofosbuvir therapy in patients with kidney impairment. Current TSANZ guidelines allow for transplantation of organs from HCV-positive donors to HCV-negative recipients in exceptional circumstances only; however, this is likely to evolve in the light of successful trials of DAAs in D+/R- pairs. At the present time, if there is a patient who is highly likely to die on the transplant waiting list before receiving another organ offer, transplantation with an HCV-NAT-positive organ may go ahead after discussion with an infectious disease or hepatology specialist. The recipient would be then monitored frequently (eg, twice weekly) by plasma HCV RNA, with initiation of DAA therapy as soon as RNA became positive (personal communication P Boan). Factors affecting the choice of DAA regimen would include HCV genotype, renal function, interaction with immunosuppressant medications (eg, protease inhibitors with calcineurin inhibitors), and any organ-specific protocols. HCV infection itself affects dosing requirements of calcineurin inhibitors, and thus the eradication of HCV requires a corresponding close monitoring of immunosuppression trough levels. Treatment protocols are still being refined at the time of writing:when to introduce DAAs, the optimal duration of treatment, and the full extent of drug interactions are questions that are rapidly being addressed. More data and longer term follow up of clinical trial participants are now required to establish whether HCV-negative recipients transplanted with organs from HCV-positive donors experience any survival detriment. In the case of liver transplantation, chronic HCV infection in the donor may have caused fibrosis of the donated liver, which could still affect graft and patient survival even if HCV is successfully cleared in the recipient posttransplant. Also, little is currently known about the risk of treatment failure, which has implications for the informed consent of D+/R- transplants. In addition, there is a need for data on the cost effectiveness of HCV-positive transplantation that inform the appropriate usage of DAAs in organ transplantation:from expanding the donor pool, to reducing the liver transplant waiting list, to preventing and treating donor-derived HCV transmission. The Human T-cell lymphocytic virus-1 (HTLV-1) is an oncogenic retrovirus that preferentially infects CD4+ T-cells. Transmission may occur as a result of breast feeding, IV drug use, sexual intercourse or blood transfusion. Although infection is usually asymptomatic in most individuals, approximately 2% to 5% of infected individuals will subsequently develop acute T-cell leukemia/lymphoma (ATL) around 20 to 30 years after infection. A smaller proportion (0.25-4%) will develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) soon after the initial infection. The majority of HTLV-1-infected individuals will not develop clinical manifestations of ATL or HAM/TSP in their lifetime. However, infection with HTLV-1 suppresses immune surveillance and increases susceptibility to other infections including parasitic infection with Strongyloides stercoralis and scabies, bacterial infections including Mycobacterium tuberculosis, Mycobacterium leprae, and infectious dermatitis, and viral infections including HIV, HCV, and HBV. Breaches in the skin or intestinal mucosa as a consequence of HTLV-1-associated infections (especially scabies and S. stercoralis) may lead to bloodstream infections with S. aureus, Escherichia coli, Streptococcus pyogenes, or other organisms. In addition, HTLV-1 infection is associated with pulmonary disease, including bronchiectasis. Therefore, in affected individuals, HTLV-1 infection is likely to be associated with an increased risk of morbidity and indirectly with increased mortality risk. HTLV-1 is not a ubiquitous virus, rather, it is present throughout the world in clusters of high endemicity. The main foci of HTLV-1 are southwestern Japan (Kyushu Island and the Okinawa archipelago), sub-Saharan Africa (Guinea-Bissau, Ghana, Nigeria, Zaire), the Caribbean (Martinique, Jamaica, Haiti), parts of South America (French Guyana, Peru), and parts of the Middle East and Australo-Melanesia. It is hypothesized that this highly specific geographical distribution originates from a founder effect in certain population groups with the persistence of a high viral transmission rate. On the other hand, large global regions have not been investigated for HTLV-1 infection and population-based studies to estimate HTLV-1 prevalence at the country level are rare, thus the prevalence remains unknown in many areas of the world. What is clear from the areas that have been studied is that HTLV-1 distribution is not homogenous. In Australia, HTLV-1 is endemic among ATSI populations in Central Australia, where infection with the Australo-Melanesian HTLV-1 subtype C predominates; by contrast, studies conducted among mostly non-Indigenous blood donors living in Australian cities found a very low prevalence of HTLV-1, ranging from 0.001% to 0.032%. A retrospective assessment of serology requests made to the Northern Territory Government Pathology Service between 2008 and 2011 found a gradient of HTLV-1 prevalence from Central Australia (highest) to Northern Australia (lowest), ranging from a regional high of 51.7% in the Anangu Pitjantjatjara Lands in northern South Australia, 50% in Ngaanyatjarraku Shire in Western Australia, and 25.3% in the MacDonnell Shire of the Northern Territory, to less than 1% in the greater Darwin region, East and West Arnhem Shire, Roper Gulf Shire, and Tiwi Islands. In terms of the wider Australo-Melanesian region, estimates of the population prevalence of HTLV-1 in the Solomon Islands range from 1.2% to 3%, and a population-based study in the Vanuatu archipelago reported HTLV-1 prevalence of 0.62%. Studies in Fiji and New Caledonia did not detect HTLV-1 in these populations. Risk factors for HTLV-1 among Indigenous Australians living in Central Australia include older age, male sex, previous STI, and residence in the south or west of Central Australia. Each of the major recognized complications of HTLV-1:ATL, HAM/TSP, infective dermatitis, strongyloidiasis, HTLV-1-associated pulmonary disease, crusted scabies:has been described in the Indigenous residents of this region. Although immunosuppression might theoretically affect the rate of onset of HTLV-1-associated disease, reports regarding outcomes among HTLV-1-infected solid organ recipients have been mixed. Retrospective studies of HTLV-1-infected kidney transplant recipients in Japan found no HTLV-1-associated disease in 2 case series of 10 and 16 recipients followed up for an average of 13 and 8 years, respectively. In contrast, a third case series Japan observed 3 cases of ATL at 6, 9, and 25 months after living donor liver transplantation from 8 HTLV-1-infected recipients. There has also been 1 report of an HTLV-positive recipient developing HAM/TSP after a living donor kidney transplant, and 1 report in which 3 recipients from a single deceased donor rapidly developed HAM/TSP posttransplant. Standard testing for HTLV-1 is performed using a combined serological test for HTLV-1 and HTLV-2. An important issue with serological tests for HTLV-1/2 is the extremely high rate of false-positive results in low HTLV prevalence settings. False-positive rates of up to 100% have been reported for potential organ donors in nonendemic settings. A second issue with serological tests is that, at the current time, available assays are unable to distinguish between HTLV-1 and HTLV-2, which is a relevant limitation as HTLV-2 has not been found to be associated with any human disease and should not preclude transplantation. HTLV-1 and HTLV-2 can be distinguished by confirmatory NAT testing, or by virus-specific Western blot or line immunoassay. Given the high false-positive rate, testing is generally not performed in countries where seroprevalence of HTLV-1 is low, or alternatively it is restricted to donors coming from high-risk subpopulations or endemic areas. OPTN has removed the requirement for pretransplant screening for HLTV-1, and it is left to individual organ procurement agencies to decide whether to perform targeted screening on donors thought to be at increased risk of HTLV-1 infection. OPTN recommends that positive HTLV-1/2 screening test results be confirmed using Genelabs HTLV 2.4 (Western blot) or inn genetics HTLV-1/2 Line Immunoassay. European guidelines recommend screening in endemic areas and for donors coming from endemic populations only, and also stipulate that any initial reactive test must be confirmed as a true-positive for HTLV-1 before decisions are made about organ utilization. France and Portugal currently screen for HTLV-1/2, and Spain recommends HTLV-1/2 screening for donors at higher risk of HTLV-1 including immigrants or sexual partners of immigrants from endemic areas and children at risk of vertical transmission. In the Australian context, HTLV serology should be considered for donors from endemic regions (the Caribbean, South America, Africa, Asia, Iran, Romania) and for ATSI people living in the Northern Territory, Queensland, Kimberley, and northern South Australia. Between 1994 and 2001, the UNOS reported 12 HTLV-positive deceased donors, from whom 5 organs were transplanted. As of 2003, 4 of 5 recipients were alive and without malignancy, and a heart transplant recipient of an HTLV-positive organ had died 1 month posttransplant from multiorgan failure although there was no indication that this was related to HTLV-1 infection. A retrospective analysis of outcomes among liver transplant recipients in the United States who received their transplants before August 2007 found no statistically significant difference in graft or patient survival according to the HTLV status of the donor. However, the authors note that their analysis was limited by the short recipient follow-up period (mean, 1.2 years) and the high false-positive rate for HTLV testing. The first European cases of donor-derived HTLV-1 transmission were reported in Spain in 2001. Three recipients of organs from the same donor (a liver and 2 kidney recipients) presented 2 years posttransplant with clinical manifestations of subacute myelopathy. The donor was retrospectively found to be seropositive for HTLV-1 and, despite having no apparent risk factors for HTLV-1, it was found on further investigation that his mother was originally from Venezuela, where HTLV-1 is endemic. Genetic analysis of the transmitted strain of HTLV-1 in this case showed multiple substitutions in the tax gene characteristic of the taxA subgroup, which is associated with greater risk of HAM/TSP development. The investigators hypothesize that the presence of taxA may at least in part account for the rapid onset of neurological disease in these organ recipients. This cluster of HTLV-1 cases in Spain prompted a survey of HTLV-1 seroprevalence among potential organ donors to inform an appropriate national approach to donor screening. This survey, conducted from January 2002 to December 2003 screened for HTLV-1 antibodies in 1298 organ donors. Not a single seropositive donor was identified. Simultaneously, HTLV screening was conducted in a sample of 1079 immigrants, finding a prevalence of asymptomatic carriers of 0.5% (with carriers predominantly originating from South America or Africa). These findings supported the existing policy in Spain of testing for anti-HTLV antibodies only among organ donors from HTLV-1 endemic areas or among native Spaniards with a high suspicion of HTLV-1 infection. There are currently no treatments for HTLV-1 infection. OPTN guidelines state that if the donor is confirmed to be HTLV-1-positive, the recipient(s) should be screened by HTLV-1-specific NAT and serology at 1, 3, and 12 months posttransplant, and should receive ongoing clinical monitoring for the appearance of unexplained neurological disease and/or T-cell leukemia/lymphoma. Counseling to avoid secondary transmission to sexual partners or breast-fed infants of recipients may also be required. The effect of immunosuppression on the outcomes of HTLV-1 infection is not well characterized. Immunosuppression may promote a rapid increased in HTLV-1 proviral load due to a lack of cytotoxic T lymphocyte response to infection, thus leading to a more rapid onset of neurological disease. However, the immunosuppressed status of the organ recipient is only one of several factors that will potentially affect the outcomes of HLTV-1 infection. Certain HTLV-1 subtypes are more likely to result in HTLV-1-related disease than others (eg, Cosmopolitan A viruses carrying the taxA gene are linked to greater risk of TSP/HAM development), and the proviral load is typically higher in patients with TSP/HAM versus asymptomatic carriers. Host factors, including HLA haplotype, may influence the outcome of infection, with the class I allele HLA-A*02 appearing to confer protection against TSP/HAM. Lastly, the route of transmission is also likely to have a role in patient outcomes: HTLV-1 transmission by organ transplantation or blood transfusion exposes the patient to a much larger viral inoculum than by other transmission routes, and it is hypothesized that this results in a shorter latency period and greater risk of TSP/HAM. These factors are likely to account for the variation in outcomes of HTLV-1 infection in solid organ transplant recipients reported in the published literature: although there have been several cases of ATL and TSP/HAM in HTLV-1-positive organ recipients after transplantation, there have also been multiple studies demonstrating an absence of HTLV-1-related diseases in HTLV-1-infected recipients and recipients of HTLV-positive donor organs over long-term follow-up. Data on the epidemiology of HSV types 1 and 2 (HSV-1 and HSV-2) in Australia come from the baseline AusDiab survey, a population-representative survey of adults 25 years and older conducted between 1999 and 2000. Serum analysis of a stratified random sample of 4000 individuals from the original cohort of 11 000 found a seroprevalence of HSV-1 in the Australian population of 76% and a seroprevalence of HSV-2 of 12%. Seroprevalence of HSV-1 peaked in the 65- to 74-year age groups at 85% compared with a seroprevalence of 67% in the 25- to 34-year age groups. Seroprevalence of HSV-2 peaked in the 35- to 44-year age groups at 16% compared with the lowest seroprevalence of 8% in the 65- to 74-year age groups. Seroprevalence of both HSV-1 and HSV-2 were higher in women than in men (80% vs 71% and 16% vs 8%, respectively). Seroprevalence of HSV-2 was higher in capital cities (14%) and metropolitan areas (13%) compared with rural and remote areas (9%). Estimated seroprevalence of both HSV-1 and HSV-2 was higher in Aboriginal and Torres Straight Islander people than non-Indigenous Australians (100% vs 75% and 18% vs 12%, respectively). Although not analyzed as part of the AusDiab survey, international studies have reported HSV-2 seroprevalence among MSM of 24% to 87%. Since its identification in 1994, Kaposi sarcoma herpes virus (KSHV) has been demonstrated to be associated with all forms of Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, and is the most common malignancy of HIV-1-infected persons. KSHV is homologous with, but distinct from, the gamma herpes viridae, EBV, and herpes virus saimiri, and:unlike most herpes viruses:human infection with KSHV is not ubiquitous but has a wide geographic variation. Seroprevalence is estimated to be less than 10% in North America and northern Europe, and between 20% and 80% in the Mediterranean and parts of Africa. Modes of KSHV transmission vary in different parts of the world: in nonendemic regions, sexual transmission is likely the main route of transmission; in endemic regions, primary KSHV infection also commonly occurs in childhood (probably via salivary transmission), and cases of vertical transmission have also been reported. Multiple cases of KSHV transmission from organ donors to recipients have been reported in the literature. Primary infection with KSHV in immunocompromised persons is characterized by fever, splenomegaly, lymphoid hyperplasia, pancytopenia, and in some cases, rapid onset Kaposi sarcoma. In immunosuppressed transplant recipients, KSHV is more commonly associated with neoplastic disease. International guidelines do not require any specific donor screening for HSV-1 or HSV-2, and no contraindication exists to organ donation from donors with latent herpes family viral infections due to high rates of donor and recipient exposure and routine effective antiviral prophylaxis (acyclovir, valaciclovir, ganciclovir, valganciclovir. Nonetheless, it is important to note the potential for fatal de novo infections in naive recipients from organs recovered from latently infected donors (see Transmission), as well as the potential for reactivation in latently infected recipients. Active infection in the potential donor should also not be disregarded. Some transplant centers perform retrospective additional donor tests for latent HSV in cases of seronegative recipients (usually in the case of pediatric recipients) to decide on specific antiviral prophylaxis or treatments and follow-up, although there is minimal evidence to support this approach. European guidelines state that organs can be accepted from donors with latent herpes family viral infections, except in the case of acute herpes viremia in the donor without effective antiviral treatment. Kaposi sarcoma herpes virus DNA is not detectable in all infected individuals; therefore, KSHV must be detected by serological assay. Given that donor-derived primary KSHV infection can be associated with severe disease, European guidelines recommend screening donors for KSHV antilytic antilatent antibodies in areas of high KSHV prevalence (eg, Mediterranean region). As KSHV serology is generally unavailable before deceased donor organ transplantation, screening for KSHV antibodies may be performed retrospectively in the days immediately after transplantation. In the case of a transplant from a positive donor to negative recipient, European guidelines recommend close monitoring of KSHV DNA in the blood to detect infection early. A case of donor-derived HSV-2 infection affecting 6 solid organ recipients occurred in Victoria in 2014. Lungs, kidneys, pancreas, and liver were retrieved from the original donor and transplanted into 4 recipients. The recipient of the kidney-pancreas had an acute myocardial infarction and cardiac arrest 2 days posttransplant and subsequently deteriorated, with brain death declared on day 9. Serological testing on day 9 was negative for HSV-2 IgG, but subsequent HSV-2 NAT later performed on stored samples was positive. This recipient then became a donor, with his lungs and the recently transplanted kidney from the original donor going to new recipients. The original donor had died of hypoxic brain injury; no clinical evidence of HSV-2 infection was seen and no history of recurrent HSV-2 infection was reported. On retrospective laboratory testing, HSV DNA was not detected; however, the donor's serology was positive for HSV-2 IgG (but not for HSV IgM). Biopsy of the kidney originally transplanted into the kidney-pancreas recipient (biopsy performed before retransplantation) showed histiocytes with enlarged nuclei containing possible viral inclusions, and HSV-2-specific staining confirmed the diagnosis of disseminated HSV-2 infection. Of the other recipients of organs from the original donor, only the recipient of the liver developed HSV viremia and clinical symptoms. Evidence of hepatitis was observed on day 13 posttransplant, and HSV-2 viremia was detected. Valaciclovir treatment was increased to 1 g 8 hourly, but on day 19 a disseminated rash developed suspected to be cutaneous HSV. The patient was admitted and IV acyclovir 600 mg was administered 8 hourly, and eventually, the hepatitis and rash resolved and the patient remained symptom free at 12 months posttransplant. None of the other recipients in this case became symptomatic. The recipient of the lungs from the original donor had received CMV prophylaxis with IV ganciclovir and CMV hyperimmune globulin due to CMV-status mismatch, and there was no evidence of viremia or HSV disease up to 12 months posttransplant. The recipient of the second kidney from the original donor also received anti-CMV prophylaxis (valganciclovir 450 mg 12 hourly) and did not develop viremia or any symptoms of HSV disease. The recipient of the retransplanted kidney was seropositive for HSV-1 IgG and HSV-2 IgG at the time of transplantation but negative for HSV IgM and was commenced on valaciclovir 1 g daily on day 1 posttransplant. HSV-2 viremia was noted on day 5 and treatment switched to IV acyclovir 400 mg; viremia resolved and the patient was asymptomatic at 12 months posttransplant. Finally, the recipient of the bilateral lung transplant from the kidney-pancreas recipient was similarly HSV-1 IgG and HSV-2 IgG-positive at the time of transplantation but negative for HSV IgM and was treated with IV ganciclovir 5 mg/kg on day 1 posttransplant. HSV-2 viremia was detected on day 2 posttransplant, and the patient switched to valaciclovir 1 g every 8 hours. Viremia resolved, and the patient was asymptomatic at 12 months posttransplant. These 2 clusters of cases demonstrate that HSV-2 may be transmitted by HSV DNA-negative donors; however, the impact on the recipient depends on whether they have preexisting immunity and on the prophylaxis regimen used. Symptomatic HSV disease only occurred in the recipients who were serologically negative and did not receive prophylactic antiviral therapy. Studies of the seroprevalence of human herpes virus-8 (HHV-8) in organ donors and recipients pretransplantation and posttransplantation have reported rates of seroconversion in D+/R- pairs of between 12 and 29%. The risk of KSHV seroconversion appears to be higher for liver transplant recipients than for kidney transplant recipients. Although relatively rare, the development of KS or other lethal nonmalignant illnesses after donor-derived transmission of HHV-8 has been reported on multiple occasions. It has also been demonstrated that Kaposi sarcoma progenitor cells may be transmitted through solid organ transplantation, with individual HHV-8-infected neoplastic cells able to seed tumors in the recipient. Table 21 summarizes published cases of donor-derived KSHV transmission and their outcomes.

PMC6324914_07

Male

In the case from Singapore, the recipient was a 48-year-old man with chronic HBV and multifocal hepatocellular carcinoma that was outside of the eligibility criteria for liver transplantation in Singapore. The donor procured a commercial deceased donor liver graft in 2009 (country not reported), and was deeply jaundiced on returning to Singapore 3 weeks later for follow-up. Serology and NAT were positive for EBV and HEV-3, and acyclovir was commenced. Magnetic resonance imaging suggested an anastomotic biliary stricture and a biliary stent were successfully inserted; however, despite regular stent changes and good bile outflow, the patient's liver tests did not improve and he remained jaundiced. A liver biopsy 1 month after transplantation showed moderate acute cellular rejection, which responded well to pulse methylprednisolone, yet his liver function continued to deteriorate and 6 months posttransplant he was admitted to hospital with jaundice, ascites, peripheral edema, and constitutional symptoms, and he died shortly after from graft failure with disseminated bacterial and fungal infection. HEV RNA was still detectable at the time of death. In this case, it is not certain whether HEV was donor-derived, or whether the patient acquired it from eating contaminated meat shortly after transplantation. In June 2017, the British Transplantation Society published guidelines for HEV detection and management in transplantation recipients, prompted by surveillance data from England indicating a recent rise in indigenous G3 HEV infection. Seroprevalence of HEV in the general English population is estimated to be as high as 13%, and data from the NHS Blood and Transplant selective screening program indicated that 1 in 2500 blood donations were HEV RNA-positive as of February 2017. A study of recipients of HEV-containing blood products found that 42% developed HEV infection, thus the approximate risk of transfusion-related HEV infection in England is 1 in 5000. On this basis, universal screening of blood components for HEV is now recommended by the UK Advisory Committee for the Safety of Blood, Tissues and Organs. The recommendations of the British Transplantation Society with regard to donor screening and management of HEV in solid organ transplant recipients are summarized in Table 25. In summary, HAV and HEV pose a threat to transplantation in their acute phase, although outbreaks occur rarely in Australia. HDV is of greater concern, as coinfection/superinfection with HBV may seriously affect the outcome of transplantation and effective treatment is currently unavailable; however, measures to prevent HBV transmission to the recipient will prevent HDV transmission. Accordingly, the European Guide to the Quality and Safety of Organs for Transplantation states that organs from donors with HDV are usually not accepted, whereas organs are accepted regardless of the anti-HAV IgG/anti-HEV IgG status of the donor, except in cases of acute HAV/HEV infection. Other international guidelines do not include specific recommendations with respect to HAV, HDV, or HEV. An algorithm for the treatment of HEV-3 infection in transplant recipients has been developed in the event of donor-derived disease transmission or infection posttransplant (see Table 26). Australia and New Zealand are not endemic areas for HEV; therefore, there is no requirement for routine donor screening. HEV transmission is a risk only in the acute phase, so testing for this virus using NAT needs to occur only in donors with clinical suspicion (eg, acute hepatitis) and epidemiological risk for HEV infection. Arboviruses refer to any viruses transmitted by arthropod vectors (eg, mosquitoes, ticks, sandflies). Arboviruses endemic to Australia include the flaviviruses Murray Valley encephalitis virus, the Kunjin lineage of WNV, and Japanese encephalitis virus, and the alphaviruses Ross River virus and Barmah Forest virus. Rates of infection are seasonal, peaking between approximately January and May when mosquitoes are most active, although seasonal trends vary between and within States and Territories according to differences in local mosquito vectors, hosts and climate. Ross River fever is the most common mosquito-borne disease of humans in Australia (6920 notifications in 2017), followed by Barmah Forest virus (449 notifications in 2017). Symptoms of Ross River virus most commonly include arthralgia, and less commonly rash and fever; however, up to 75% of Ross River virus infections are asymptomatic. Symptoms of Barmah Forest virus similarly include arthralgia, rash, fatigue, and flu-like symptoms, although again many people infected will be asymptomatic. Ross River virus and Barmah Forest virus infections have been reported in all Australian states (including Tasmania), with the highest notification rates occurring in Queensland, tropical Western Australia and the Northern Territory. The number of Ross River virus notifications in each State and Territory from 2007 to 2017 is shown in Figure 10. It should be noted, however, that there are known issues with unreliability of serological tests for Ross River virus and Barmah Forest virus, leading to overdiagnosis particularly in the off-season. There have been no cases of transmission of Ross River virus or Barmah Forest virus infection by organ transplantation reported to date, although the potential for donor-derived transmission presumably exists given the ubiquity of these alphaviruses in Australia and 1 report in the literature of a case of Ross River virus transmission via blood transfusion occurring in Western Australia in 2014. The blood donor developed fatigue and arthralgia 2 days after giving blood and was subsequently diagnosed with Ross River virus infection; however, some of the components had already been transferred to a patient before the recall of the affected donation. The recipient was receiving regular blood transfusions due to myelodysplastic syndrome associated with chronic fatigue and joint pains, and had reported a worsening of symptoms in the months after the transfusion of the infected blood. Serological tests were positive for Ross River virus; however, the recipient experienced no further symptoms or sequelae. The potential outcomes in the event of transmission to an immunosuppressed organ transplant recipient are unknown. In contrast to endemic alphaviruses, notifications of the Kunjin lineage of WNV and Murray Valley encephalitis virus are infrequent and mostly sporadic, with approximately 10 cases in recognized outbreak years, generally affecting residents of and visitors to the Kimberley region of Western Australia or the Northern Territory. However, despite the low notification rate, it is recognized that for every clinical case of there may be hundreds of asymptomatic infections, because the vast majority of Kunjin virus and Murray Valley encephalitis virus infections are asymptomatic. Anecdotal evidence suggests Kunjin virus causes symptomatic disease more often than Murray Valley encephalitis virus, with symptoms of Kunjin including arthralgia, myalgia, fever, headache, and occasionally, a rash. When Murray Valley encephalitis virus does cause clinical disease, symptoms are generally more than severe than for Kunjin virus: an estimated 1 in 1000 infections with Murray Valley encephalitis virus results in clinical encephalitis. Encephalitis is less common in cases of Kunjin virus infection. To date, there have been no cases of Kunjin virus or Murray Valley encephalitis virus transmission via blood transfusion or organ donation; however, precautions may be warranted particularly in regions where there are active outbreaks of disease. Other nonendemic arboviruses of public health importance to Australia include dengue virus, chikungunya virus, and Zika virus. Nonendemic arboviruses are of concern primarily in the case of donors whose recent travel history includes south and southeast Asia, tropical Africa, or the Pacific Islands. Imported cases of dengue fever are relatively common among travellers returning from endemic areas, in particular India, Sri Lanka, southeast Asia, and the Pacific Islands (see Table 26). In New Zealand, virtually all notified cases of arboviral infections to date have occurred in overseas travellers, although a local case of sexual transmission of Zika virus was reported in 2016. Only 1 arbovirus is endemic to New Zealand-the Sindbis-like alphavirus Whataroa virus which is established in bird populations on the West Coast of the South Island; however, human infection has only ever been documented serologically (absent of disease). There are 3 mosquito species established in New Zealand that have the potential to be vectors for human diseases: Culex quinquefasciatus (a potential vector for encephalitis viruses), Aedes notoscriptus (a vector for dengue virus), and Aedes australis (a vector for dengue and Whataroa viruses). All 3 are potential vectors for Ross River virus, by none are particularly effective arboviral vectors are would be unlikely to support endemic transmission of arboviruses in New Zealand. In 2016, there were 191 cases of dengue virus infection (4.1 per 100 000) in New Zealand, 28 cases of chikungunya virus infection (0.6 per 100 000 population), 100 cases of Zika virus infection (2.1 per 100 000 population), and 4 cases of Ross River virus infection. Countries of acquisition included Indonesia (dengue), Fiji (dengue, chikungunya, Ross River, Zika), Tonga (Zika virus), Samoa (dengue, Zika), Thailand (dengue), India (chikungunya), Brazil (chikungunya), and Australia (Ross River virus).

PMC6324914_08

Male

The flaviviruses Zika virus and WNV are discussed separately as pathogens of special interest in sections Zika Virus and West Nile Virus, respectively. The WHO declaration of global public health emergency in relation to the 2015/2016 Zika outbreak in Brazil and Central America prompted international authorities to develop targeted recommendations for the prevention of Zika transmission via organ and tissue transplantation, and these are discussed in detail in section Zika Virus. West Nile virus is also of special interest given its widespread global distribution and the relatively large number of reported cases of transmission via solid organ transplantation, with frequently fatal outcomes. The risks of donor-derived transmission of other arboviruses appear to be relatively low, and there are limited case reports of transmission events in the published literature. One case of possible donor-derived dengue transmission was reported from Singapore in 2005. The recipient was a 23-year-old male with end-stage kidney disease due to lupus nephritis, who received a living donor kidney transplant from his mother, who was known to have had a history of dengue fever 6 months before donation. Five days posttransplant, the recipient developed a high fever and, given the donor history, NAT was performed and returned a positive result for dengue virus serotype 1. Twelve days posttransplant, the recipient developed upper gastrointestinal bleeding, gross hematuria and tachycardia. Three days later, he complained of left flank pain and abdominal distension, and a large retroperitoneal hematoma at the bed of the transplanted kidney was revealed on computed tomography (CT). Emergency surgery to evacuate the hematoma was successful, and repeat NAT was negative for dengue. The recipient then went on to have an uneventful recovery, with resolution of hematemesis and hematuria and excellent graft function. In this case, the clinical presentation of dengue in the transplant recipient was similar to that in immunocompetent persons but with longer duration:19 days versus mean duration of 2 to 7 days. European guidelines recommend ruling out acute infection with arboviral diseases including dengue, chikungunya and WNV for donors living in or coming from endemic regions or areas with ongoing outbreaks. In Australia and New Zealand, a similar approach would be warranted: where the donor is a resident of or has a history of travel to an endemic region or area with an ongoing outbreak of arboviral disease, acute infection should ideally be ruled out before proceeding with transplantation. The lung virome consists of transient infections (influenza, human respiratory virus, etc.) as well as resident viruses that are present in both healthy and disease states. Next-generation sequencing techniques have permitted a new appreciation of the diversity of resident viral species within individuals, a large proportion of which remain uncharacterized. Metagenomic studies of samples from cystic fibrosis patients and lung transplant recipients have found that up to 88% of lung virome sequences were unknown. These studies identified a wide range of bacteriophages, as well as herpes virus, adenovirus, human papillomavirus, and torque teno virus. The complexity of the respiratory virome complicates the diagnosis of the causative agent of disease, because pathogenic viruses may be present among the resident viruses of healthy individuals. In an example of this, a metagenomic study of nasopharyngeal aspirates from febrile versus afebrile children detected rhinovirus in both groups. To date, there has been a single study characterizing the lung virome of lung transplant recipients. Young et al found that the majority (>68%) of reads that could be mapped to reference viruses mapped to various anelloviruses, including torque teno viruses, torque teno midi viruses, torque teno mini viruses and small anelloviruses (each with multiple subtypes). These anellovirus sequences were 56-fold more abundant in bronchoalveolar lavage (BAL) from transplant recipients compared to healthy controls. Anelloviruses are ubiquitous in humans and have not yet been causally linked to human diseases; however, Young et al also observed that high anellovirus loads correlated with dysbiotic bacterial communities in the allograft, that is, the higher the anellovirus titer, the greater the divergence between the corresponding bacterial community and healthy controls. The cause and clinical implications of this observation are not yet clear. Other viruses detected within the lung virome by this study included EBV, human herpesvirus, human papillomavirus, and various bacteriophage genomes (eg, phages of Enterobacteria, Salmonella, Pseudomonas, Streptococcus, and Yersinia). Notably, an average of 81% of reads could not be mapped to reference viruses in the NCBI viral database. The authors speculate that many of these correspond to DNA phage sequences. Currently, there are minimal data available on the impact of transplanting the lung virome; however, longitudinal studies are underway and the potential importance of the respiratory virome to outcomes of lung transplantation should be noted. Although next-generation sequencing may be of use for lung donor screening in the future, currently, for practical purposes, viral testing of the donor before implantation and BAL postimplantation will capture most viruses provided that samples are properly handled (personal communication A Glanville). Donors with undiagnosed meningoencephalitis are an uncommon but potentially lethal source of donor-derived infection. Transmission of rabies, LCMV, WNV, Mycobacterium tuberculosis, Cryptococcus, Coccidiodes immitis, Aspergillums, and Balamuthia have occurred when donors with meningitis or encephalitis of unknown cause have been used as organ donors. For this reason, any meningitis or encephalitis without a proven cause should be an absolute contraindication to transplantation, according to the international guidelines. Recognition of transmissible infections in potential deceased donors with meningoencephalitis is often complicated by the circumstances of brain death, which might not raise the suspicion of the presence of a central nervous system infection, for example, stroke in the case of a patient with amoebic encephalitis, or cocaine use in a patient with intracerebral hemorrhage who had rabies. Distinguishing between such ubiquitous causes of death in potential donors as anoxia, head trauma, or cerebrovascular accident and a potentially transmissible central nervous system infection is extremely difficult. In addition, many of these pathogens are not part of routine donor screening in Australia and New Zealand (or elsewhere) and, therefore, would not be detected as part of a standard donor evaluation. Based on reporting to the United States OPTN Ad Hoc Disease Transmission Advisory Committee, the most common diagnoses for central nervous system infections in deceased donors were tuberculosis, endemic fungi, cryptococcosis, coccidiomycosis, and WNV, followed by syphilis, histoplasmosis, toxoplasmosis, and Chagas disease. In some cases, donors diagnosed with treatable forms of meningoencephalitis might be safely used for organ transplantation after a suitable period of antimicrobial treatment for the donor and the recipient. Donors with meningoencephalitis of viral origin other than HSV or VZV, however, present an extremely high risk for disease transmission. If the pathogen in unknown or if the suspected pathogen is one for which no treatment options are available, transplantation should be avoided or pursued with extreme caution only after weighing the risks of adverse recipient outcomes with the risks of waiting for another organ. Where the cause of the meningoencephalitis is confirmed as a virus that is amenable to treatment, for example, HSV encephalitis, the organs might be used if the donor is not viremic and provided that the recipient is seropositive pretransplant and/or is given appropriate prophylaxis. Meningitis of bacterial origin is discussed in the Bacteremia and Meningitis section, and WNV is discussed as a special case in the West Nile Virus section. Published reports of transmission events from donors with unrecognized central nervous system infections highlight the extreme risks associated with such donors, as well as the challenges of recognizing central nervous system infection. In 2004, 4 recipients of organs from a single donor died of encephalitis of unknown cause shortly after transplantation. The donor in this case had presented to the emergency department with nausea, vomiting and difficulty swallowing. He was subsequently admitted to a second hospital with altered mental status requiring intubation, with a fever and fluctuating blood pressures. His toxicology screen was positive for cocaine and marijuana, and a CT of the brain revealed a subarachnoid hemorrhage, which progressed to brain death 4 days after admission. Standard donor screening did not reveal any infection precluding organ donation, and the donor's kidneys, liver and lungs were retrieved for transplantation. Encephalitis developed in all 4 patients within 30 days of transplantation and was accompanied by rapid neurologic deterioration and death an average of 13 days after the onset of symptoms:rabies was subsequently confirmed in all of the organ recipients. Contact investigations revealed that the donor had been bitten by a bat shortly before becoming ill.

PMC6324914_10

Male

A cluster of fatal donor-derived arenavirus cases was reported in Australia in 2008, in which the infectious agent was a previously unidentified LCMV-related arenavirus. The donor in this cluster was a 57-year-old man who died of cerebral hemorrhage 10 days after returning to Australia from a 3-month visit to the former Yugoslavia, where he had travelled in rural areas. No viral nucleic acids were detected in the donor, and no history of acute infectious disease was reported; however, IgG and IgM antibodies were present. He donated his liver and both kidneys to 3 recipients, all of whom developed febrile illness with varying degrees of encephalopathy and proceeding to death within 4 to 6 weeks of transplantation. Bacterial and viral cultures, NAT, and viral and panmicrobial oligonucleotide microarray assays revealed no candidate pathogens, and therefore, RNA was extracted from the brain, cerebrospinal fluid (CSF), serum, liver, and kidney of one of the kidney recipients, and from the CSF and serum of the liver recipient. High-throughput sequencing of amplified RNA samples and examination of Vero E6 cells inoculated with homogenized fresh-frozen kidney tissue revealed the presence of an arenavirus with an identical but previously uncharacterized genetic sequence in the recipients. The case above highlights the challenges of identifying central nervous system infections particularly in donors dying from CVA and the potential for rare and uncharacterized infectious agents to be transmitted by organ transplantation. To aid decision making in this context, the United States OPTN has formulated a guidance document for recognizing central nervous system infections in potential deceased organ donors. Issues for consideration highlighted by this document are listed in Table 27. The number of tuberculosis notifications in Australia in 2016 was 1217 (5.1 per 100 000 population, National Notifiable Disease Surveillance System 2016 data set). The vast majority (approximately 90%) of these cases occurred in Australia's overseas-born population, among which the incidence of tuberculosis is approximately 20 times that of the Australian-born, non-Indigenous population (18.4 vs 0.7 notifications per 100 000 in 2013 respectively). NSW and Victoria account for more than 50% of all tuberculosis cases in Australia, whereas the Northern Territory has the highest jurisdiction-specific notification rate (17.1 per 100 000 in 2013). Tuberculosis incidence in ATSI peoples was 4.6 cases per 100 000 in 2013. The most frequently reported countries of birth for tuberculosis cases in Australia in 2013 were India, Vietnam, the Philippines, and China. Relative to population size, the highest rates of tuberculosis in 2013 were reported for Australian residents born in Somalia, Nepal, Myanmar, Afghanistan, Papua New Guinea, and Sudan. Of those diagnosed within 4 years of arrival in Australia, international students accounted for 21% of tuberculosis cases in 2013. The contribution of international students and the demographics of the Australian resident migrant population (median age, 37 years; ABS 34120DO001_201415) would account for the bimodal distribution of tuberculosis notifications seen in Figure 11. Major risk factors contributing to notified cases of tuberculosis in Australia in 2013 were past travel or residency in a high-risk country (81% of cases), household, or other close contact with tuberculosis (11% cases), or current or previous employment in the health industry (7%). Other risk factors that were present in a small proportion of cases (5%) included current or prior incarceration, current or prior residence in an aged care facility, current or prior employment at a correctional facility, aged care facility or homeless shelter, current or prior homelessness, parent born in a high-risk country, or being treated with immunosuppression. Australia has had very few cases of multidrug-resistant tuberculosis, and these have occurred almost exclusively in the overseas-born population. Of cases where drug sensitivity testing was performed in 2013, 0.3% had resistance to rifampicin alone, 5.2% to isoniazid alone, and 2.4% to both rifampicin and isoniazid (MDR-TB). Zero cases of extensively drug-resistant tuberculosis were reported in 2013:only 2 cases of XDR-TB have been reported since 1995. Figure 12 shows trends in the proportion of tuberculosis cases that were multidrug-resistant since 1995. The spike in 2010 is accounted for by 10 patients with MDR-TB from Papua New Guinea accessing healthcare services in the outer Torres Strait Protected Zone. Incidence of tuberculosis among solid-organ transplant recipients is much higher than the general population, especially among lung transplant recipients. Tuberculosis most commonly appears in the transplanted population due to reactivation of latent infection:an audit at Westmead Hospital Sydney estimated that 30% of waitlisted patients had latent tuberculosis (personal communication: A Webster):but it may also be acquired as a de novo infection posttransplant, or be transmitted via the donor organ. In the United States, tuberculosis is one of the most common donor-derived bacterial infections. Data from Europe and the United States indicate that 0.4% to 7% of solid-organ recipients develop tuberculosis, and donor-derived transmission accounts for less than 5% of these cases. Risk factors for tuberculosis among potential donors include (1) social factors:country of origin or prior residence in an endemic country, history of homelessness, incarceration or alcoholism, and/or contact with persons infected with tuberculosis; and (2) medical risk factors:history of untreated tuberculosis, radiographic evidence of prior tuberculosis, body mass index less than 18.5, diabetes mellitus, and/or cigarette smoking. A recent matched cohort study comparing the clinical features and outcomes of tuberculosis in transplant recipients versus the Spanish general population found that time from clinical suspicion of tuberculosis to diagnosis (positive acid-fast bacilli smear, histopathological pattern of tuberculosis, positive NAT or M. tuberculosis culture) was longer in transplant recipients than in the general population (median, 14 days vs 0 days) and more often required invasive procedures. This study also found that rates of tuberculosis-related mortality were higher among transplant recipients than the general population (18% vs 6%), as were rates of toxicity associated with antituberculosis treatment (38% vs 10%). Tuberculosis in transplant recipients often resists timely diagnosis and is associated with worse outcomes than observed in the general population. One of the challenges for the detection of donor-derived tuberculosis is that disease in donors and recipients may not present as a primary respiratory infection and, therefore, may not be recognized straight away, contributing to delays in diagnosis and reporting. Pulmonary disease accounts for approximately 60% of cases in the Australian general population, with 40% being extrapulmonary. By comparison, extrapulmonary disease accounts for closer to half of tuberculosis cases in the transplant population, and disseminated tuberculosis is substantially more common. Where the donor was born in, or recently travelled to, an endemic country, or where other tuberculosis risk factors are present, the possibility of extrapulmonary tuberculosis should be considered in recipients presenting with an infection of unknown origin. This is of course dependent on the availability of a detailed, accurate donor history, which will not exist in all circumstances. In living donors, it is possible to perform tuberculosis screening in accordance with recommended guidelines; however, in potential deceased donors, this is problematic because there are no proven methods for screening deceased donors for tuberculosis. Chest X-ray and direct microscopy of BAL for acid-fast bacilli have a low sensitivity, and cultures may take up to 8 weeks to turn positive. Tuberculin skin testing is also impractical in the context of deceased donation given a turnaround time of at least 48 hours. NAT can identify M. tuberculosis in clinical specimens from donors with active infection only. Therefore, when these tests are performed, a negative/normal result does not definitively rule out infection with M. tuberculosis, due to the high rate of false negatives and because organisms can remain dormant in the host without causing disease for decades, without any detectable radiographic abnormality. Conversely, abnormal pulmonary findings from a range of causes are common in deceased donors and may confound donor evaluation. Interferon-gamma release assays (IGRAs) might theoretically be useful given their shorter turnaround time (~24 hours). These assays work by stimulating peripheral blood cells with specific antigens; in response, T cells recognizing these antigens are rapidly activated and secrete a variety of cytokines, of which interferon gamma is measured to indicate the pathogen-specific activation of T cells. Interferon gamma release assays are available commercially as T-SPOT.TB (Oxford Immunotec, UK) and QuantiFERON-TB Gold in-Tube (Cellestis, Australia). Drawbacks of these tests include high cost and indeterminate results in immunosuppressed persons; moreover, IGRAs have not yet been validated for use in deceased donors, and it is not known whether brain death impacts the performance of this assay. Further, false-positive results will be common in low-risk populations, whereas false-negative may occur in cases of miliary or disseminated tuberculosis. Therefore, the results of IGRAs cannot be relied upon to either definitively exclude active disease nor as grounds for rejecting a given donor. Given the limitations of tuberculosis screening tools in deceased donors, it is important to evaluate social and medical risk factors in the potential deceased donor. Country of origin and/or prior residence in a highly endemic country is a key risk factor. Tuberculosis country profiles can be reviewed at www.who.int/tb/data., Although difficult to obtain, patient histories for possible contacts with persons infected with M. tuberculosis are important. Given the global challenges of tuberculosis screening in potential organ donors, an international consensus group was formed to provide expert recommendations on this subject. A summary of the recommendations of this group is provided in Table 28. Current UK and European donor screening guidelines make the following recommendations with respect to tuberculosis and organ donation: SaBTO: Donation of organs, tissues and cells is contraindicated from donors with active disease or within the first 6 months of antituberculosis treatment. However, organs can be considered for transplant if a recipient has received a 6-month course of chemotherapy, unless the isolate is found to be resistant to appropriate antituberculosis drugs. If there is a history of tuberculosis at the site of the organ to be used for donation, use of that organ is contraindicated by the donation of other organs is acceptable. EDQM: Organs from donors with disseminated tuberculosis should not be used. Organs from donors with a history of TB and with successful treatment for at least 6 months may be considered, with prophylaxis and/or empiric treatment considered for the recipient in accordance with international guidelines.

PMC6324914_11

Female

Numerous cases of unexpected tuberculosis transmission from donors to recipients have been reported in the literature (see Table 29). Given the difficulties of detecting tuberculosis in deceased donors, many of these cases involved donors with normal chest x-rays, no microscopic evidence of acid-fast bacilli, and/or negative cultures for M. tuberculosis. For example, in a case of multidrug-resistant tuberculosis in a lung transplant recipient in Hong Kong, the donor:a 51-year-old recent immigrant from China:had no history of tuberculosis, and chest x-ray, microscopy of tracheal aspirate, and cultures showed no evidence of M. tuberculosis infection. Other similar cases of donor-derived tuberculosis in solid organ recipients, in which the donor was negative for tuberculosis based on acid-fast bacilli stain, culture, and chest x-ray, demonstrate the importance of donor history in the assessment of potential tuberculosis risk. Table 29 summarizes the tuberculosis risk factors present in donors who subsequently transmitted M. tuberculosis to 1 or more organ recipients. The most common risk factors among reported cases were recent arrival from or previous residence in an endemic country, followed by donor characteristics such as homelessness, alcoholism, incarceration, and health and hygiene status. Cases of drug-resistant tuberculosis transmission further emphasize the importance of donor history: in a recent Australian case of donor-derived tuberculosis in a lung transplant recipient, further investigation into the donor revealed a history of latent tuberculosis 5 years before death, which had been treated with 9 months of preventive isoniazid therapy despite the index case demonstrating M. tuberculosis resistance to isoniazid. A retrospective Spanish study of deceased donors used between January 1998 and June 2011 found that, of 11 deceased organ donors with active M. tuberculosis infection at the time of transplantation, tuberculosis was transmitted to the recipients in 2 cases (transmission rate of 18.2%). The risk of tuberculosis is greater for lung transplant recipients than for recipients of other organs. Of cases of unexpected donor-derived M. tuberculosis transmission identified from the published literature, 15 (52%) of 29 were in single or bilateral lung transplant recipients. Moreover, in several cases of donor-derived M. tuberculosis transmission to lung recipients, it was reported that none of the same-donor organ recipients developed evidence of tuberculosis after several months of observation. Based on a literature review of donor-derived tuberculosis in lung transplant recipients reported by Mortensen et al in 2014, the median time to tuberculosis diagnosis was 88.5 days (range, 21-153 days). The most common presenting symptoms among reported cases were fever and dyspnea; however, in a large proportion of cases (>30%) M. tuberculosis was detected by protocol acid-fast bacilli smear or culture of respiratory specimens before the onset of symptoms (in these cases the median time to diagnosis was 68.5 days). Of the identified cases of donor-derived tuberculosis in lung transplant recipients, 3 (20%) of 15 were fatal. Another lung recipient died from causes unrelated to tuberculosis. In recipients of nonlung organs, M. tuberculosis infection is more likely to present as extrapulmonary disease that is frequently difficult to diagnose. The most common presenting symptom is fever, though some patients may also experience nausea, cough, headache or a deterioration of renal function (see Table 29). Of the reported cases of donor-derived tuberculosis in kidney transplant recipients, 3 (27%) of 11 were fatal, with 1 additional death from unrelated causes. Table 30 summarizes the 2012 recommendations of the Donor-Derived Infections Consensus Conference on M. tuberculosis with regard to clinical management of solid organ transplant recipients under different deceased donor scenarios. In summary, potential donors with a history of tuberculosis may be considered on a case-by-case basis only if they have received active treatment for at least 6 months. Donors with latent tuberculosis need active tuberculosis to be ruled out as far as possible and may be considered on a case-by-case basis with ongoing surveillance for the appearance of tuberculosis in the recipient and consideration of recipient tuberculosis prophylaxis. Prophylaxis should also be considered where the donor has a history of latent tuberculosis that has not been sufficiently treated or in the circumstance of unexplained pulmonary apical fibrosis in the donor without cavitation and without additional testing. At this time, IGRA testing in donors is not suggested. Active tuberculosis in the donor needs to be considered and investigated based on clinical and epidemiological features and the decision to proceed to organ transplantation based on the likelihood of active tuberculosis, the results of rapid tests (AFB microscopy and NAT testing from donor samples), and the likelihood of the recipient receiving another donor offer. The location of the infection in the donor is also relevant to the decision to proceed with transplantation and subsequent recipient management, as risk of transmission is lower when the donor infection is at a site other than the allograft (ie, pulmonary tuberculosis in a kidney donor). If donation proceeds, there should be ongoing surveillance for tuberculosis in the recipient and consideration of recipient tuberculosis prophylaxis. Treatment protocols are informed by drug susceptibility, local drug resistance patterns, and possible drug interactions with immunosuppressant medications (particularly rifampin/rifampicin and rifabutin). A recent systematic review assessed the benefits and harms of antibiotic prophylaxis to prevent tuberculosis in solid organ transplantation, concluding that prophylactic administration of isoniazid reduced the risk of developing tuberculosis posttransplant by more than half (risk ratio (RR), 0.35; 95% confidence interval [CI], 0.14-0.89). There was, however, no significant on all-cause mortality (RR, 1.39; 95% CI, 0.70-2.78), whereas the risk of liver damage was significantly increased (RR, 2.74; 95% CI, 1.22-6.17). The 3 primary studies included in this systematic review were conducted in India and Pakistan:countries with a high prevalence of tuberculosis:therefore, there remains an absence of evidence regarding the benefits and harms of tuberculosis chemoprophylaxis for transplant recipients in area of low tuberculosis prevalence. When donor-derived, reactivated, or de novo M. tuberculosis infection is suspected in solid organ transplant recipients, clinicians will need to test for disease in the graft as well as other sites, using microscopy, NAT, radiology, pathology (acid-fast bacilli stains), as well as clinical judgment. Notably, the tuberculin skin test and IGRAs have poor sensitivity in immunosuppressed persons after solid-organ transplantation, and in any case are not recommended tests in the diagnosis of active tuberculosis. In cases where bacterial infections are transferred from donor to recipient, these cases frequently involve resistant bacteria:in particular MRSA, VRE, and multidrug-resistant Gram-negative rods:that were not cleared by standard antibiotic prophylaxis. Staphylococcus aureus is common in hospital environments, and potential donors may become infected with a resistant strain while in the intensive care unit (ICU). The Australian Group on Antimicrobial Resistance (AGAR) has conducted antimicrobial resistance surveillance since 1986, and surveillance among hospital inpatients since 2005. Laboratories participating in the surveillance network collect S. aureus isolates from hospital inpatients and test then for antimicrobial susceptibility. Epidemiological typing is then performed for isolates identified as MRSA. These surveys have shown a substantial burden of MRSA in Australian hospitals overall, with significant interstate variation in the proportion S. aureus isolates that were MRSA and in the specific MRSA clones circulating in a given region. In 2011, the proportion of S. aureus isolates that were MRSA was 30.3% nationwide, ranging from 19.9% in Western Australia to 36.8% in New South Wales/ACT. There was wide variation between institutions in the proportion of S. aureus that was MRSA, from 7% to 56%. The overall proportion of S. aureus isolates that were identified as healthcare-associated MRSA was 18.2%, ranging from 4.5% in Western Australia to 28.0% in New South Wales/ACT. In 2011, the predominant hospital-acquired MRSA clone in Australia was ST22-IV [2B] (EMRSA-15), although there was significant interstate variation in the circulating clones and in their susceptibility profile. Based on the 2011 AGAR survey data, resistance to the non-beta-lactam antimicrobials was common in MRSA isolates, with the exception of fusidic acid, rifampicin, mupirocin, daptomycin, vancomycin and linezolid (resistance levels below 4% nationally). Ceftaroline is also expected to be active. More recently, the Staphylococcal Sepsis Outcome Program looked at the proportion of S. aureus bacteremia isolates in Australia that are antimicrobial resistant, reporting that 18.8% of S. aureus bacteremia cases were MRSA:a high relatively high proportion compared with several European countries. Enterococci are among the leading causes of bacteremia, and are intrinsically resistant to a broad range of antimicrobials. Moreover, their ability to acquire resistance through plasmid transfer and transposons has allowed them to rapidly evolve additional resistance in the hospital environment. Although historically enterococcal infections were primarily caused by Enterococcus faecalis, there has been a worldwide increase in nosocomial infections with Enterococcus faecium, which not only is innately resistant to many classes of antibiotics but also extremely good at evolving new antimicrobial resistances. AGAR commenced the Australian Enterococcal Sepsis Outcome Program (AESOP) in 2011 for the surveillance of E. faecalis and E. faecium bacteremia and to monitor evolving patterns of antimicrobial susceptibility. Of the enterococcal bacteremia cases identified by AESOP in 2014, 54.9% of isolates were E. faecalis and 39.9% were E. faecium. Of the E. faecalis bacteremia cases, 36.5% were hospital-acquired; however, of the E. faecium cases, 71.8% were hospital-acquired. For E. faecalis, acquired resistance was rare with the exceptions of erythromycin (87.4%), tetracycline (72.5%), ciprofloxacin (25.6%), and high-level gentamicin (38.2%). In contrast, the majority of E. faecium isolates were nonsusceptible to multiple antimicrobials, including ampicillin (90%), erythromycin (95%), tetracycline (53%), ciprofloxacin (92%), nitrofurantoin (77%), and high-level gentamicin (62%), and 46.1% were nonsusceptible to vancomycin. By comparison, the population-weighted mean percentage of E. faecium resistant to vancomycin in Europe is 9% (ranging from 0% in Sweden, to 43% in Ireland). Thus, not only is E. faecium a frequent cause of bacteremia in Australia, the proportion of E. faecium that is resistant to vancomycin is high by international standards. Vancomycin resistance is usually acquired through the acquisition of either the vanA or vanB operon. The first VRE case detected in Australasia occurred in 1994 in a liver transplant patient at Austin Health in Melbourne. Although this first case was a vanA-positive E. faecium, the majority of VRE subsequently detected between 1994 and 2011 was vanB. In late 2013, however, a shift from vanB to vanA E. faecium occurred across Australia. In contrast to the vanB gene, which usually integrates into the E. faecium chromosome, the vanA gene is often located on a plasmid, permitting easy horizontal transfer of resistance. In certain centers dramatic shifts occurred, with vanA almost entirely replacing vanB between 2013 and 2014. A retrospective molecular epidemiological study of VRE among patients admitted to the ICU of Royal Prince Alfred Hospital, Sydney, between January and November 2014 confirmed an increasing incidence of VRE, attributed to multiple concurrent clonal outbreaks of vanA VRE, with reusable medical equipment demonstrated to be an important source of infection. Of 1729 patients admitted over the study period, 5.3% were colonized with VRE on admission (60% with vanB, 39% with vanA, and 1% with both). VRE acquisition rates in the ICU rose from 3.1 per 1000 patient days in 2013 to 7.0 per 1000 patient days in 2014, driven by an increase in vanA acquisition. Overall, 3.6% of patients acquired VRE during their stay in the ICU: 55% acquired vanA VRE, and 45% acquired vanB. The emergence of vanA VRE in Australian hospitals will likely lead to a larger overall burden of VRE in Australia and New Zealand. Recently, the rapid dissemination of novel clone of vanB VRE (ST796) was also reported, first recognized at Austin Health at the beginning of 2012, then almost simultaneously appearing in Auckland, then appearing in South Australia, Tasmania and then New South Wales. AGAR has been monitoring sepsis due to E. coli and Klebsiella since 1992, with the addition of Enterobacter species to the surveillance program in 2004. The 2014 survey reported moderately high levels of ampicillin/amoxicillin resistance in E. coli isolates (50%), with lower rates of resistance to amoxicillin-clavulanate (8%). Moderate levels of resistance were found in E. coli isolates toward cefazolin (21%) and trimethoprim (29%). Multiresistance is on the rise, particularly in E. coli and E. cloacae isolates, with multiresistance rates of 13% and 12% respectively. Also of concern: approximately 25% of E. coli isolates belonged to the ST131 H30-Rx subclone, which is associated with greater antibiotic resistance and greater virulence. Klebsiella pneumoniae isolates had higher levels of resistance to piperacillin-tazobactam and ceftazidime compared with E. coli, but lower rates of resistance to amoxicillin-clavulanate, ticarcillin-clavulanate, cefazolin, ceftriaxone, ciprofloxacin, gentamicin, and trimethoprim. Among Enterobacter species, resistance was common to ticarcillin-clavulanate, piperacillin-tazobactam, ceftriaxone, ceftazidime and trimethoprim. Cefepime, ciprofloxacin, and gentamicin resistance, however, were all less than 10%. In 2014, a total of 14 isolates from 14 patients in 9 institutions across 5 Australian states and territories were found to have a carbapenemase gene. Thus, carbapenem resistance attributable to acquired carbapenemases currently remains uncommon in Australia, although 5 difference gene variants were detected in 2014 (IMP, KPC, VIM, NDM, and OXA-181-like). Compared with other countries in the region, resistance rates in Gram-negative bacteria in Australia are relatively low, but are similar to those observed in Western Europe. With the rise of multidrug-resistant bacteria in hospital environments, an increasing number of potential donors are being exposed to multidrug-resistant bacteria in the ICU, which may then be transmitted to recipients by organ transplantation. Of particular concern are VRE, multiresistant Pseudomonas aeruginosa, ESBL-producing enterobacteriaceae, carbapenem-resistant Acinetobacter baumannii, K. pneumoniae, and other carbapenem-resistant enterobacteriaceae. Lanini et al have described the incidence of carbapenem-resistant Gram-negative bacteria in Italian transplant recipients, reporting 0.63 isolates of carbapenem-resistant Gram-negative bacteria per 1000 recipient days (49 isolates from 887 recipients), and that carbapenem resistance was most frequent among Klebsiella spp. isolates (49%). Rates of nosocomial carbapenem-resistant bacterial infection are likely to be higher in Italy than in Australia and New Zealand, given that carbapenemase-producing Enterobacteriaceae are endemic in Italy and are regularly isolated from patients in most hospitals. This study also reported that mortality was 10.23 times higher in recipients who had cultures positive for carbapenem-resistant Gram-negative bacteria after solid organ transplantation compared to those who did not. Donor-related risk factors for infection or colonization by multidrug-resistant bacteria include prolonged hospital stay (7 days or longer), vasopressor use, and requirement for cardiopulmonary resuscitation or abdominal packing. However, the absence of these risk factors does not preclude nosocomial infection/colonization with multidrug-resistant bacteria, as was demonstrated in a case of carbapenem-resistant A. baumannii transmission from a donor with a hospital stay of only 2 days. In addition, donor country of origin/prior residence is also a potential risk factor: donors from countries with high rates of gut colonization of multidrug-resistant bacteria such as India pose a higher risk of transmission (personal communication L Grayson). In an Italian study of the incidence and outcomes of transplantation using organs from donors with unknown carbapenem-resistant Gram-negative bacterial infection, 10.5% of organ donors were discovered posttransplant to be infected or colonized with carbapenem-resistant Gram-negative bacteria, with proven transmission to the organ recipient in 13% (4 of 30) of affected transplants. The recipients in whom transmission did occur all received antibiotic therapy that was late, short, or inappropriate. There was also a higher risk of transmission where the donors were bacteremic and the donor organ was culture-positive. The first 2 transmission cases involved a donor who died of cerebrovascular accident after 4 days in the ICU and developed a fever after brain death; the day after organ transplantation the donor's blood cultures became positive for carbapenem-resistant K. pneumoniae. Liver, lungs, and pancreas were donated to 4 recipients. The recipient of an extended right graft of the donor liver received preemptive treatment with meropenem alone for 3 days, starting on day 4 posttransplant. On day 7, samples from abdominal drainage fluid were sent for microbiological testing and cultures were positive for carbapenem-resistant K. pneumoniae. The patient was treated with colistin and tigecycline, and the infection was resolved by day 37 posttransplant. The lung recipient was commenced on meropenem alone on day 2 posttransplant; on day 10, cultures from BAL grew carbapenem-resistant K. pneumonia and colistin was added to the treatment for 14 days. The patient did not develop infection, but was found to be colonized by carbapenem-resistant K pneumoniae initially in the lung and later in the rectum. The third case identified by the Italian study involved a donor who had experienced several episodes of fever while in the ICU and was found to be positive for carbapenem-resistant K. pneumoniae after organ retrieval and transplantation. The kidney recipient, who received a full, targeted antibiotic treatment regimen (gentamicin and meropenem for 8 days), remained negative for carbapenem-resistant K. pneumoniae; however, the liver recipient, who received only 3 days of full antibiotic treatment (gentamicin and meropenem), developed leukocytosis, pleural effusion and an intra-abdominal collection on day 12 posttransplant. On day 24, the liver recipient developed fever and infection of the abdominal wound; cultures from the wound swabs grew carbapenem-resistant K. pneumoniae. The wound infection was treated with a few days of oral antibiotics, and on day 60, abdominal ultrasound revealed a per-hepatic collection that had to be drained, with the fluid culture testing positive for carbapenem-resistant K. pneumoniae. After complete drainage and antibiotic treatment, the infection was resolved, and the patient was alive and well 18 months posttransplant. The forth transmission case in this series involved a donor who had been admitted to the ICU for septic cerebral embolization from a methicillin-susceptible S. aureus driveline infection and bacteremia, who subsequently died from cerebral hemorrhage. Known to be a rectal carrier of carbapenem-resistant K. pneumoniae, urine cultures turned positive 2 days after retrieval; however, this information was not properly communicated. One recipient received both kidneys, and on posttransplant day 15 he was readmitted to hospital due to high-grade fever which was confirmed to be due to carbapenem-resistant K. pneumoniae infection of the graft. The patient was treated with meropenem+colistin+tigecyline but blood cultures remained positive so the antibiotic regimen was changed to ertapenem+meropenem+colistin. Despite an initial response, bacteremia returned, and the patient died 2 months later due to persistent carbapenem-resistant K. pneumoniae infection of the graft. In a case reported from Israel, a donor who was an asymptomatic carrier of carbapenem-resistant K. pneumoniae in the respiratory tract donated kidneys, liver, and lungs to 5 recipients. The donor had been admitted to hospital in a deep coma after a near drowning. After 5 days on mechanical ventilation, he was declared brain dead. Routine BAL taken at the time of organ donation grew carbapenem-resistant K. pneumoniae 2 days after transplantation had taken place, with antibiotic sensitivity limited to gentamicin, colistin, and tigecycline. The recipient of the liver and the 2 kidney recipients did not receive postoperative antibiotic treatment, and none developed infectious complications. The 2 lung recipients both received perioperative antibiotic prophylaxis with piperacillin-tazobactam, and after the donor culture results, both received IV colistin for 5 days. One of the lung recipients developed pneumonia 2 weeks after transplantation; Proteus mirabilis was cultured from sputum samples, and after treatment with IV colistin and ciprofloxacin the patient made a full recovery. The second lung recipient was receiving a second transplant due to cystic fibrosis. On day 19 posttransplant, the patient developed tachypnea and dyspnea, and a new infiltrate in the transplanted lung was revealed by radiography. Given the results of donor cultures, the initial empiric antibiotic therapy with piperacillin-tazobactam was changed to colistin and tigecycline; however, the patient continued to deteriorate. One week later, the patient was hypotensive and oliguric, with decreased consciousness. At this time, blood cultures were positive for carbapenem-resistant K. pneumoniae, with antibiotic sensitivity profile the same as the donor. Treatment was unsuccessful and the patient died 4 weeks later. In a 2007 case of carbapenem-resistant A.baumannii transmission from a donor to a lung recipient in Brazil, the donor had been in the hospital for only 2 days before procurement, with partial pressure of oxygen/fraction of inspired oxygen greater than 300, normal chest x-ray, and no evidence of bronchial aspiration by bronchoscopy. Perioperative antimicrobial prophylaxis consisted of vancomycin plus cefepime. On day 2 posttransplant, the recipient developed fever, arterial hypotension, and respiratory failure, with a chest x-ray revealing an infiltrate in the lower third of the right hemithorax. The patient was reintubated and norepinephrine infusion was started, and meropenem substituted for cefepime. On the same day, the results of the donor's BAL culture became available, yielding A. baumannii susceptible to ampicillin-sulbactam, meropenem, imipenem, and amikacin; the result for carbapenems was, however, incorrect. Although the recipient's lung function improved, she remained febrile and wound site infection was noted. On day 9 posttransplant, carbapenem-resistant A. baumannii was isolated from the recipient's BAL and from the surgical wound specimen, and IV polymyxin B was substituted for meropenem, and tacrolimus dosage was reduced. By day 29 posttransplant, the patient's serum creatinine had risen to 2.1 mg/dL and the decision was made to stop polymyxin B therapy. Serum creatinine level returned to baseline; however, on day 46, the patient presented with pneumonia and recurrence of infection at the surgical wound; a transbronchial lung biopsy showed coexistence of CMV pneumonia. Resumption of polymyxin B together with inhaled amikacin produced transient improvement, but the fever returned and respiratory function progressively worsened. Empiric amphotericin B therapy was started on day 57 and immunosuppression stopped on day 61; however, the patient died on day 65 posttransplant.

PMC6324914_14

Male

Directed antimicrobial prophylaxis in recipients has been shown to be effective in preventing transmission of multidrug-resistant Gram-negative pathogens. In a case report from the United States, Ariza-Heredia et al describe the use of organs from a donor known to be infected with carbapenem-resistant K. pneumoniae before organ procurement. The donor was a 21-year-old man who sustained multiple injuries in a motor vehicle accident and was hospitalized for approximately 3 weeks before being declared brain dead. He developed pneumonia during treatment, an infected subdural hematoma, and meningitis due to carbapenem-resistant K. pneumoniae, although blood cultures remained negative. The donor was treated with IV tigecycline for 9 days and received 3 doses of intrathecal gentamicin at the time of death. As cultures were still positive for carbapenem-resistant K. pneumoniae at the time of death, the transplant teams were informed and specific consent sought from the potential recipients and their families. The liver, kidneys, heart, and a vein graft were retrieved. The recipient of the right kidney received pretransplant doses of IV gentamicin (4 mg/kg) and tigecycline (100 mg), and posttransplant received a 10-day course of IV tigecycline (50 mg every 12 hours). Surveillance cultures of the preservation fluid were negative, and 5 months posttransplant, the recipient was doing well. The heart recipient received perioperative IV cefepime (2 g every 12 hours) and tigecycline (100 mg loading does then 50 mg twice daily). Antimicrobial prophylaxis received posttransplant included valacyclovir, trimethoprim-sulfamethoxazole, and inhaled amphotericin B, and cultures remained negative for carbapenem-resistant K. pneumoniae. The recipient of the liver and kidney in the case reported by Ariza-Heredia developed a postoperative infected hematoma and peritonitis due to carbapenem-resistant K. pneumoniae, despite receiving prophylaxis with IV tigecycline (initial loading dose of 100 mg, followed by 50 mg every 12 hours planned for 2 weeks). On posttransplant day 10, the patient developed severe abdominal pain, tenderness and leukocytosis, and cultures of the ascetic fluid were positive for carbapenem-resistant K. pneumoniae. The patient underwent exploratory laparotomy and washout, and IV amikacin was added to the treatment regimen, along with ciprofloxacin for possible synergy, and fluconazole to treat a concurrent Candida albicans infection. On day 24, cultures were still positive for carbapenem-resistant K. pneumoniae, and the treatment regimen was changed to meropenem (1 g IV every 8 hours), amikacin (500 mg IV every 12 hourly), ampicillin (1 g IV every 6 hours), and fluconazole (200 mg p.o. daily) for 4 weeks. Five months posttransplantation, the recipient showed no recurrence of infection. Source control is the first priority in the treatment of multidrug-resistant bacteria, including drainage of collections and the removal of any infected devices. The choice of antimicrobial treatment and dosage should take into account pathogen susceptibility profile and local resistance patterns, predicted drug levels at the site of the infection, cost, method of administration, side-effect profile, severity of infection, and any know multidrug-resistant colonizers in the recipient. Treatment recommendations for multidrug-resistant gram-negative bacteria infections in solid organ transplant recipients are given in Table 31. The number of cases of infectious syphilis reported in Australia in 2016 was 3367, of which 87% of diagnoses were in males and 16% were in ATSI persons. In the non-Indigenous population, male-to-male sex is the primary transmission route, and over 90% of all notifications of infectious syphilis are in males (see Figure 13). In contrast, only 54% of infectious syphilis notifications in ATSIs in 2006 were in males. The infectious syphilis notification rate in Australia increased 107% from 2012 to 2016 (from 6.9 to 14.3 cases per 100 000), driven largely by increased transmission among MSM and by an ongoing outbreak of infectious syphilis among ATSI people living in northern Australia. This outbreak began in northern Queensland in January 2011, spread to the Northern Territory in July 2013, and to the Kimberley region of Western Australia in June 2014. An outbreak in the western, Eyre and far north regions of South Australia was declared in March 2017. By 2016, the infectious syphilis notification rate in the ATSI population living in remote and very remote areas was 135.4 per 100 000:50.1 times higher than the rate in the non-Indigenous population. Also of note, this outbreak has primarily affected young ATSI people:in 2016, 21% of infectious syphilis notifications in the ATSI population were in the 15- to 19-year age group, compared to only 2% of the non-Indigenous population. In New Zealand there has also been a steady increase in infectious syphilis cases since 2002, with a notable jump in notifications from 2013 to 2014 (from 82 to 140 cases). As in Australia, the vast majority of cases (>90%) are in males, and male-to-male sex is the primary transmission route (approximately 90% of cases). The majority ethnicity reported in MSM cases was NZ European (57% in 2014), followed by Asian (13%), Maori (13%), other (12%), and Pacific Islanders (3%). Cases are concentrated among males aged 20 to 34 years, with the biggest increase in cases since 2011 occurring among males aged 20 to 24 years. The Auckland region reported the highest number of infectious syphilis notifications in 2014 (61% of the total). Historically, syphilis screening has been based on nontreponemal serological tests:either the RPR or Venereal Disease Research Laboratory (VDRL) test:which are sensitive in newly infected individuals but can produce false-positive results due to factors such as other infections (eg, HIV), autoimmune conditions, injecting drug use, or other causes of inflammation or immunological reactivity. In a retrospective study of RPR-positive deceased donors, Theodoropoulos et al demonstrated a false-positive rate of 40.6% for RPR tests. Treponemal-specific tests have greater specificity but continue to yield positive results after successful treatment. The United States Centers for Disease Control specify that a diagnosis of syphilis requires positive results on both a nontreponemal test and a treponemal-specific test. Treponemal-specific tests include FTA-ABS tests, the TP-PA) assay, various EIAs, chemiluminescence immunoassays, immunoblots, or rapid treponemal assays. Test performance characteristics of available syphilis tests, versus TP-PA as the gold standard, are given in Table 32. The conventional approach to screening has been to test first with a nontreponemal test and then confirm positive results with a treponemal-specific test, though more recently there has been a shift to a "reverse-sequence" approach, whereby an initial treponemal-specific test is followed by a nontreponemal test to confirm positive results. Current international guidelines and state-based guidelines in Australia recommend routine screening of deceased donors for syphilis infection using a treponemal-specific EIA, with confirmation by a nontreponemal serological test. If the nontreponemal test is negative, then a second treponemal test based on different antigens to the original test should be performed. This reverse sequence approach has the advantage of being able to distinguish potential donors who have been previously treated for syphilis, those with untreated or incompletely treated syphilis, and those with a false-positive result. Treponemal test results should be interpreted in the context of what is known about the donor's history of treatment for syphilis and their sexual history, because there is always the possibility that previously treated persons may have a new, recently reacquired syphilis infection. A positive syphilis test does not necessarily preclude organ donation; however, newly diagnosed syphilis indicates that the donor is also at increased risk of having recently acquired HIV, HBV, or HCV, and decisions regarding utilization should be made accordingly. If the decision is made to proceed with transplantation, then the recipient will require appropriate treatment. Only 4 cases of syphilis transmission via organ donation have been reported:1 confirmed transmission reported to the United States OPTN, and 3 reports in the published literature. In a 2003 case, a homosexual male with a history of treated syphilis donated kidneys to 2 recipients. Donor syphilis serology, available only after transplantation had taken place, was reactive on TP-PA (titer, 1:1280) and RPR (titer, 1:2), which was interpreted as consistent with a history of treated infection. The 2 recipients were informed and were administered a single dose of 2.4 g IV benzyl penicillin instead of the recommended benzathine penicillin 2.4 MU administered intramuscularly. Recipient serum samples collected on day 5 posttransplant were reactive on treponemal EIA, and both recipients were then treated for early latent syphilis according to the 2002 UK guidelines. After 2 years of follow up, both recipients had excellent kidney function, and 3 monthly RPR tests remained negative.

PMC6324914_16

Female

The fourth reported case of donor-derived syphilis transmission was in a lung transplant recipient whose donor, a 38-year-old woman who died of subarachnoid bleeding, returned serology test results indicating past syphilis infection 1 day after transplantation had occurred. The recipient received penicillin G intravenously 3 times per day for 10 days, starting on day 1 posttransplant. Although immunoblot testing detected T. pallidum-specific newly synthesized IgG antibodies on day 29 posttransplant, the patient developed no clinical signs of syphilis infection, and by 3 months posttransplant, the T. pallidum hemagglutination titer had returned to negative. The recipient recovered well over long-term follow-up and graft function was normal. In addition to these cases, there have been 4 cases of organ transplantation involving a syphilis-positive donor that did not result in transmission to the recipient after appropriate therapy. Transplanted organs included kidney, heart, lung, and liver, and in each case, there was no evidence of infection in the recipients, who had all received treatment with benzathine penicillin G. In the most recent of these cases, the EIA results showing that the donor was seropositive for syphilis were available only after transplantation had occurred. Based on negative results on TP-PA and VDRL confirmatory testing, it was not possible to differentiate between treated syphilis and late syphilis, and the decision was made to treat the recipient. Three doses of benzathine penicillin 2.4 MU were administered intramuscularly weekly for 3 weeks, and repeated serology at regular intervals posttransplant showed that the recipient remained free of syphilis infection at 3 months posttransplant. These case reports suggest that, where the donor is found to have latent syphilis, clinical manifestations of T. pallidum can be successfully prevented with treatment of the recipient. However, a donor with secondary syphilis may be bacteremic with the involvement of many organs; hence, caution should be taken if clinical manifestations of secondary syphilis are present. The treatment regime of the recipient should be discussed with an infectious diseases physician and may include use of benzathine or IV penicillin (P Boan, personal communication). There is substantial evidence that organs from bacteremic donors and donors with proven bacterial meningitis can be safely used for transplantation provided that the bacteria are confirmed to be susceptible to antibiotics and the donor and recipient receive appropriate treatment pretransplantation and posttransplantation. However, it is not uncommon for bacteremia in the donor to be unrecognized until after transplantation has occurred: in 1 study, 60% of bacteremic donors were afebrile in the 24 hours before organ procurement. A retrospective study of organ donors in Spain found that 5% of liver and heart donors had bacteremia at the time of organ donation (including recognized and unrecognized infections). The most common microorganisms isolated from donors with bacteremia in were S. aureus, E. faecalis, A. baumanni, and S. viridans. There were no documented incidents of transmission of the isolated bacteria to recipients in this study nor was there evidence of any negative clinical impact on the outcomes of transplantation. The authors note, however, that bacteremic donors may not be safe in all circumstances, and their findings may in part be attributable to a degree of selection bias, whereby patients with positive blood cultures and evident sepsis were never considered as potential donors. It should also be noted that the risk of transmission varies according to the type of bacteria causing the infection:for example, Gram-negative bacilli (eg, E. coli) pose a greater risk than Gram-positive bacteria. Given the high rates of graft loss, morbidity and mortality associated with transmission of bacteremia:especially in the case of infection caused by Gram-negative bacilli:susceptibility testing in the donor is important. Numerous other studies have demonstrated that transplant outcomes in recipients of organs from bacteremic donors are equivalent to outcomes from nonbacteremic donors, provided that the donor is treated with appropriate antibiotic therapy for at least 24 to 48 hours and shows some degree of clinical response (eg, improved white cell blood count, improved hemodynamics, defervescence), and tailored antibiotic treatment is initiated in the recipient in a timely manner. Recipients should be treated with tailored antibiotic therapy for at least 7 days posttransplant, or longer if the organism is difficult to treat (eg, S. aureus) or if there is the potential for infection to disrupt an anastomosis or seed an endovascular source. Based on existing evidence, no particular organ from a bacteremic donor is more likely to transmit infection to the recipient than another. There are also numerous published studies describing successful transplantation using organs from donors who died from microbiologically proven bacterial meningitis caused by N. meningitidis, S. pneumoniae, Haemophilus influenzae, and E. coli. A contributing factor to the low rate of transmission of infection from donors with bacterial meningitis is that the most common meningeal organisms do not survive at the low temperatures maintained during cold perfusion and storage before transplantation. Before organ acceptance, meningitis should be confirmed as the sole site of infection, and the donor should ideally receive 48 hours of appropriate treatment with evidence of clinical improvement before organ retrieval, although successful outcomes have been reported after only 24 hours of antibiotic therapy where blood cultures were negative on the day of donation. Tailored antibiotic therapy in the recipient is recommended for at least 7 days posttransplant. Exceptions exist; however, for example, meningitis caused by Listeria species may cause disseminated infection that is difficult to treat in the immunosuppressed patient, with a high risk of relapse. Similarly, meningitis caused by disseminated M. tuberculosis infection may be transmitted to the recipient with fatal consequences and is a contraindication to transplantation. Other organisms that are rare causes of meningitis but are notable for establishing metastatic infection, adherence to endothelial surfaces, or for having other markers of virulence:for example, S. aureus, P. aeruginosa, Salmonella spp.:are contraindications to organ donation. Lastly, the time course of infection is relevant: persistent bacteremia caused by any organism increases the risk of metastatic infection, and in such cases, organ transplantation may carry a higher risk of disease transmission. European guidelines recommend that, in general, organs from donors with bacteremia or bacterial meningitis should only be considered for use after 48 hours of targeted and effective antibiotic therapy and with clinical evidence that the infection has been cleared. Utilization of donors with ongoing sepsis and positive blood cultures is not recommended, especially if effective therapy cannot be confirmed. If the results of blood cultures are not available before transplantation but clinical data indicate that antibiotic treatment has been effective, then it is recommended that a transplant infectious disease specialist be consulted before organs are discarded. Any meningitis caused by an unknown pathogen is an absolute contraindication for organ donation. A brain abscess is not a contraindication per se; however, the potential causes of the brain abscess should be evaluated before accepting the organs. Extreme precaution should be used for donors with presumed bacterial meningitis with negative cultures, especially when no pathogen can be identified by culture or PCR:in this case, organs should not be used for transplantation. In the case of a nonreactive culture but where the bacteria are confirmed by PCR as the pathogen causing the meningitis, it can be assumed that after 48 hours of antibiotic treatment, infection will not be transmitted. UK guidelines state that where an organ donor has been diagnosed with bacteremia in the 5 days preceding the donation but there is no visible damage or local infection in the organ at retrieval, donation of an organ is acceptable with appropriate recipient antibiotic prophylaxis. Similarly, if bacterial meningitis has been confirmed, but there is no visible damage or local infection in the organ or tissues required at retrieval, the donation of the organs, tissues, and cells are acceptable. Appropriated antibiotic prophylaxis covering any organism from the donor should be considered for identifiable recipients, especially in the case of organs. However, organs from meningitis cases from whom no organism is cultured should not be used. Summarizing these international guidelines, organs from bacteremic donors may be used provided the organism is readily treatable (not MDR), the donor has received at least 24 hours effective antibiotic therapy with some improvement, and a treatment course is administered to the recipient. Organs may be used from donors with bacterial meningitis with a treatment course given to the recipient, although caution is advised where the pathogen has not been confirmed. Bacterial colonization of donor lungs is common as (1) the lungs are in constant contact with the external environment and the airways are normally colonized with multiple organisms; (2) most donors require emergency intubation, which may result in aspiration and pneumonia; and (3) the rate of bronchopulmonary infections increases in proportion to the length of time spent in the ICU (as does the rate of infection with antibiotic-resistant organisms). Before donation, aspiration and consequent pneumonia must, therefore, be ruled out/treated. In particular, the potential transmission of any MDR pathogens must be ruled out. European guidelines state that, in the case of pneumonia without bacteremia, all other organs can be used safely. After at least 48 hours of effective antibiotic treatment and unimpaired pulmonary function, lungs may be considered for donation. In cases where bacterial infection in the donor lungs is not detected before transplantation, lung recipients should not suffer complications due to donor-derived bacteria as long as the transmitted pathogens are not MDR and provided appropriate prophylaxis is given. A recent significant discovery has been the role of disseminated Ureaplasma infection in hyperammonemia syndrome after lung transplantation. Hyperammonemia syndrome is a fatal complication of immunosuppressed patients in which serum ammonia levels progressively increase, leading to cerebral edema and death. It has been described in bone marrow, lung, heart-lung, kidney, liver, intestinal, and islet cell transplant recipients; however, it has most frequently been reported in lung transplant recipients. A large retrospective case series performed at Barnes-Jewish Hospital in St. Louis, Missouri, between 2000 and 2013 found an incidence of hyperammonemia syndrome after lung transplantation of 1% (n = 8/807), with a mortality rate of 75%. A smaller retrospective cohort study of 145 lung transplant recipients found an incidence of hyperammonemia syndrome of 4%. Hyperammonemia syndrome was first described in 1991 in a recipient of a bone marrow transplant. The cause of the syndrome remained unknown, however, until 2015 when Bharat et al published preliminary evidence that the syndrome may be caused by donor-derived infection with Ureaplasma species. Ureaplasma species are mollicutes that depend on urea hydrolysis to ammonia and carbon for energy production, and are part of the normal microbiome of the urogenital tract. Although the hydrolysis of urea and the generation of ammonia in the urine do not cause harm, disseminated ureaplasma infection might pose a severe threat by releasing free ammonia into the circulation. The released ammonia is then converted back into urea in the liver, which provides more substrate to Ureaplasma, and thus a cycle of urea hydrolysis and hepatic urea production is established. In their initial study, Bharat et al performed microbiologic examination (PCR, specialized culture, and molecular resistance profiling) of specimens taken from 6 lung transplant recipients who developed hyperammonemia syndrome posttransplantation. They found evidence of systemic infection with U. urealyticum or U. parvum in all 6 cases, but they found no evidence of infection in 20 control lung transplant recipients with normal ammonia concentrations. Ureaplasma is not known to colonize normal healthy lungs, and why hyperammonemia is reported more frequently in lung transplant recipients than recipients of other solid organ transplants is not known. One theory relates to aspiration at the time of injury causing death. Ureaplasma is able to colonize the oral cavity, with possible routes of transmission, including sexual transmission from the genitourinary tract of a partner. An aspiration event at the time of injury could then cause the organism to be drawn down into the lungs, and given that Ureaplasma does not grow in routinely performed bacteriological cultures, it would not be detected on standard BAL culture. NAT is the fastest detection method if Ureaplasma is suspected, and culture is also available. Bharat et al reported that Ureaplasma species are susceptible to macrolides, fluoroquinolones, and tetracyclines; however, they also observed the emergence of resistance in their case series of 6 patients. At this time, routine donor testing for Ureaplasma is not suggested. Urinary tract infections (UTIs) and pyelonephritis are common among potential donors due to bacteria ascending along the urethral catheter. Any suspected UTIs in potential donors should be confirmed by urine culture, and potential kidney donors with UTI should be investigated to rule out upper tract infection. In case of a UTI restricted to the lower urinary tract, kidneys may be used as they are not infected. All other organs can be safely used for transplantation. Before organ retrieval, the donor should be treated with antibiotics for 24 to 48 hours or until there is documented resolution of the infection. The final decision about organ utilization should be made at the time of organ recovery. Posttransplant treatment of the recipient may reduce the risk of donor-derived infection. In general, however, there is no need to treat the recipient of a nonkidney organ from a deceased donor with nonbacteremic, localized infection that does not involve the transplanted organ (excluding meningitis cases). European guidelines state that in the case of UTI without bacteremia, all nonkidney organs can be used safely for transplant, and that uncomplicated UTI/bacteruria is in most cases not a contraindication for the utilization of kidneys, provided adequate antibiotic treatment is given to the donor and recipient. Toxoplasma gondii is a protozoan (coccidian) parasite of mammals, which reproduces in cat species but has a wide intermediate host range. It is one of the most common parasitic infections of humans and other warm-blooded animals. Exposure is extremely common in all regions of the world, although there is substantial geographical variation in rates of T. gondii (see Table 33). It is estimated that 16% to 40% of the populations of the United States and United Kingdom are infected, whereas in Central and South America and parts of Europe, infection rates are as high as 80%. A study of pregnant women in Australia found 35% had IgG antibodies to T. gondii. Transmission can occur due to: ingestion of undercooked meat containing Toxoplasma cysts; ingestion of contaminated soil (eg, via unwashed fruit or vegetables) containing cat feces; ingestion of cat feces via cleaning a cat's litter box, gardening, contact with sandpits, and so on; transplacental transfer from mother to fetus. It is believed that the majority of infections that occur globally are due to ingestion of cysts in infected meat, or oocysts in food or water contaminated with cat feces. Geographical variation in T. gondii infection is hypothesized to be due to (i) the relative level of contamination in the environment with oocysts, and (ii) local culinary traditions with respect to meat preparation (eg, a preference for raw or undercooked meat). When ingested, bradyzoites from tissue cysts or sporozoites from fecal oocysts transform into tachyzoites and penetrate intestinal epithelial cells and divide rapidly in the intestine. T. gondii is then spread to organs and tissues by invasion of the lymphatics and blood, and is able to multiply in almost any cell in the body. In immunocompetent hosts, symptoms are usually either absent or mild, such as swollen lymph nodes, headache, fever, and fatigue. The immune response to T. gondii infection involves both humoral and cellular factors; however, immunity does not eradicate infection as cysts can persist for years after acute infection. After proliferating, tachyzoites transform into bradyzoites, which are less susceptible to proteolytic enzymes and form latent intracellular cysts mainly in muscle tissues and the brain (although visceral organs including lungs, liver, and kidneys may also be affected). Intact cysts may persist for the life of the host, and can, therefore, be transmitted directly by solid organ transplantation. Intact cysts are unlikely to cause harm in immunocompetent persons; however, in immunocompromised persons, the rupture of a tissue cyst may result in bradyzoites being transformed into tachyzoites, followed by renewed replication. Alternatively, if the donor has an acute T. gondii infection at the time of donation, then tachyzoites transmitted to the recipient may persist and continue proliferating, resulting in severe symptoms, complications, and death. Organs which contain tissue cysts infected with T. gondii carry the risk of primary infection in a naive and immunosuppressed recipient. Hearts are at higher risk of containing T. gondii cysts compared with other organs, and serological tests for toxoplasma are usually included among standard screening tests for heart donors in most jurisdictions. Although a positive serological test for T. gondii is not a contraindication to donation, it may inform the need for prophylaxis in heart recipients. Numerous serological tests exist for the detection of T. gondii antibodies, including both IgM and IgG. IgM antibodies appear sooner after infection than IgG, and disappear faster after recovery. NAT can be used to diagnose active infection; however, given that active infection is rare and the goal of donor screening is primarily to detect latent toxoplasma in the heart and other organs resulting from past infection, international guidelines recommend serological testing only for pretransplant screening of potential organ donors. Donor and recipient toxoplasma IgG are generally recommended as routine for cardiac transplant recipients, with donor testing for acute toxoplasma (IgM, NAT) used only in an appropriate clinical context (ie, where there is clinical suspicion of acute toxoplasmosis). Toxoplasma gondii transmission by organ transplantation has been reported multiple times in the literature, most commonly by heart transplantation, followed by kidney and liver transplantation. Cases of toxoplasmosis after bowel and pancreas transplantation have also been reported. Presenting symptoms typically are nonspecific, including fever, respiratory distress, neurological manifestations, and bone marrow suppression. Cerebral toxoplasmosis, although a well-known complication in HIV patients, is extremely rare in transplant recipients. The majority of cases are diagnosed within 90 days of transplantation, although the median time to onset of symptoms in cases of donor-acquired primary toxoplasmosis is shorter:approximately 15 to 25 days posttransplant:than for reactivation of latent infection. Primary toxoplasmosis is also significantly more lethal: a review of published cases of primary toxoplasmosis after kidney transplantation found a mortality rate of 50%, with fatal outcomes confined to those patients who developed clinical evidence of toxoplasmosis less than 90 days posttransplant. Mortality from toxoplasmosis posttransplantation is highest in those patients with disseminated disease, or where there is a delay in diagnosis and targeted treatment. In 1 such case of fatal disseminated toxoplasmosis after liver transplantation from a seropositive donor to a seronegative recipient, the recipient developed symptoms 12 days posttransplant and was initially treated for MRSA and then for CMV after this was detected on BAL performed on day 26 posttransplant. The patient's condition did not improve, and on day 40, she developed acute respiratory failure with shock. On admission to the ICU, a second BAL was performed and direct microscopy revealed T. gondii tachyzoites, at which point, therapy with pyrimethamine and sulfadiazine was initiated. The patient, however, died 5 days later. The recipients of the other organs from the same donor (heart, lungs, kidneys and cornea) showed no evidence of T. gondii infection more than 9 months posttransplant: all of these recipients were seropositive for toxoplasmosis before transplantation.

PMC10362300_01

Female

A 59-year-old woman with right breast cancer presented to our department with suspicion of NTM infection based on abnormal lung opacities that had been detected 2 years ago. Because she had no respiratory symptoms and the opacities remained stable, she was initially monitored without medication. She underwent right breast resection, followed by treatment with paclitaxel and human epidermal growth factor receptor 2 monoclonal antibodies for 1 year, as well as radiation therapy (50 Gy) to the right chest. However, during chemotherapy for breast cancer, the lung opacities progressed and a cavitary mass was detected (Fig. 1, Fig. 2). Therefore, she underwent further examinations. Upon examination, she was asymptomatic and had normal vital signs. Staining and culture of three sputum samples, including for acid-fast bacteria, did not reveal evidence of bacterial infection. Additionally, interferon-gamma release assay (T-SPOTR; BML, Tokyo, Japan) yielded negative results. Bronchioalveolar lavage fluid via bronchoscopy and sputum samples were collected. Following a 6-week incubation period in a liquid medium, acid-fast staining and culture of the bronchioalveolar lavage fluid showed bacterial growth. However, polymerase chain reaction testing of the samples showed no growth of M. tuberculosis, M. avium, or Mycobacterium intracellulae. As a result, M. shinjukuense was diagnosed by mass spectrometry (MALDI-Biotyper, Bruker Daltonics, Bremen, Germany). Based on the worsening lung opacities, treatment was initiated for our patient based on 10 previous reports of 16 cases of M. shinjukuense (Table 1). Among these cases, eight were treated with anti-tuberculous drugs, one with erythromycin, one with CLA followed by anti-tuberculous drugs, one with RFP, levofloxacin, and CLA, and three with RFP, EB, and CLA. In our patient, the minimum inhibitory concentrations (MICs) of CLA, RFP, EB (BrothMIC NTM, Kyokuto Pharmaceutical Industrial Co., Ltd., Tokyo, Japan), and INH (Vit spectrum-SR, Kyokuto Pharmaceutical Industrial Co., Ltd.) using the broth microdilution method were <0.03, <0.03, <1, and <0.02 mug/mL, respectively. In our study, the MIC of CLA was similar to that of the cases 5 and 14previously reported (Table 1) (3, 9). We treated our patient with RFP, EB, and CLA instead of RFP, EB, and INH because of the more common side effects with INH than CLA. The initial treatment included 600 mg/day of CLA, 500 mg/day of EB, and 300 mg/day of RFP. The patient weighed 48 kg, and no side effects were observed during the first month of treatment. Therefore, we increased the dose of CLA to 800 mg/day and continued EB and RFP at the same doses. After 6 months of treatment initiation, the sputum culture was negative for acid-fast bacilli. Due to the presence of a cavitary lesion and the absence of an established treatment duration for this regimen, we continued treatment for 2 years, similar to previous cases of M. avium complex, to ensure mycobacterial elimination. After 2 years of treatment, the nodules and fibrocavitary disease significantly improved (Fig. 3).

clarithromycin, mycobacterium shinjukuense, mycobacterium tuberculosis, nontuberculous mycobacterium

PMC9949745_01

Female

We present a case of a 71-year-old woman with a medical history of chronic lymphocytic leukemia (CLL) stage Rai 0 Binet A diagnosed in 1997 (24 years before the hospitalization), previous Pneumocystis jirovecii infection, essential arterial hypertension, and hypothyroidism. She was medicated with levothyroxine 0.1mg, amlodipine 5mg, and olmesartan+hydrochlorothiazide 20mg + 12.5mg. She was not receiving any treatment for CLL. The patient presented with fever, night sweats, exertional dyspnea, and nonproductive cough, which started six months before the hospitalization. Laboratory investigations at admission (Table 1) showed new onset pancytopenia (hemoglobin 7.3g/dL, leukopenia 3550/uL with 42% of lymphocytes and platelets 109000/uL), and elevation of C-reactive protein (CRP) (8.29mg/dL), liver enzymes (aspartate transaminase (AST) 242U/L, alanine transaminase (ALT) 125U/L, gamma-glutamyl transferase (GGT) 282U/L), and total bilirubin (1.3mg/dL). Peripheral blood immunophenotype showed monoclonal lymphocytosis compatible with B cell chronic lymphocytic leukemia (CLL-B). Pleural effusion was documented on the chest radiograph (Figure 1). Further diagnostic tests were performed. Bone marrow biopsy documented moderate leukemic infiltration. A whole-body CT scan showed bilateral pleural effusion (Figure 2), mediastinal and hilar adenopathy, hepatomegaly, and ascites (Figure 3). A positron emission tomography (PET) scan revealed discrete metabolic activity in the bone marrow (Figure 4), compatible with the bone marrow biopsy findings (Figure 5). Pleural fluid analysis was compatible with an exudate: the effusion protein/serum protein ratio was 0.6 and the effusion lactate dehydrogenase (LDH)/serum LDH ratio was 0.71. However, a cytologic exam and immunophenotype of the pleural fluid were not done due to insufficient sample quantity. Paracentesis was also performed, documenting a serum ascites albumin gradient (SAAG) >1.1g/dL, suggestive of portal hypertension, and 250 leukocytes with 54.7% of mononucleated cells on the cytologic exam; no neoplastic cells were observed. In addition, a transjugular liver biopsy was performed, and leukemic infiltration of the liver was documented, confirming the diagnosis of CLL progression (Figure 6). Due to persistent fever, worsening pancytopenia, and progressive liver enzyme elevation, HLH was suspected. Further laboratory investigations (Table 2) revealed hyperferritinemia (13097/uL), hypofibrinogenemia (92mg/dL), natural killer (NK) cell depletion, and elevation of soluble cluster of differentiation (CD)25 (>5000/uL). Therefore, an HScore for reactive hemophagocytic syndrome of 251 points was calculated . Infectious causes (including bacterial infection, tuberculosis, human immunodeficiency virus (HIV), cytomegalovirus (CMV), and Eppstein-Barr virus (EBV) infection), autoimmune and pharmacological causes, were excluded as the potential triggers, and thus CLL progression was assumed as the etiology of the HLH. The patient was started on dexamethasone, etoposide, and rituximab after a hematology consultation, resulting in the resolution of the fever, improvement of cytopenias, as well as normalization of coagulation, and liver enzymes. Nevertheless, the patient developed febrile neutropenia and respiratory sepsis with multiple organ dysfunction. Despite the antibiotic therapy with piperacillin/tazobactam and amikacin, aggravation with septic shock ensued. The patient was transferred to an intensive care unit, where she passed away shortly after due to refractory septic shock.

b-cell chronic lymphocytic leukemia (b-cll), fever, hemophagocytic lymphohistiocytosis (hlh), hepatomegaly, septic shock

PMC8473535_01

Male

53-year-old male truck driver with past medical history of benign prostatic hypertrophy and dyslipidemia, presented with diarrhea, weight loss, abdominal pain and fatigue for 4-5 months. He had multiple ER visits and hospitalizations for diarrhea, weight loss, dehydration, and abdominal pain in a four-month period. He reported fatigue, shortness of breath and dysphagia. No fevers or skin rash. He reported diffuse joint pains which he related to arthritis. He emigrated from Mexico in 1979, the last trip back to Mexico was approximately 7 years ago. He reported no recent travel or any exposure to tuberculosis. Physical exam showed no fever, normal vital signs, no peripheral lymphadenopathy, benign abdominal exam, no organomegaly, no neurological deficits, no joint swellings or skin rash. Lab data showed normal WBC count, mild microcytic anemia (ranging between 9 and 11 mg/dl), mildly elevated ESR, and normal LFTs. GI pathogen panel negative, endomysial antibody negative, tissue transglutaminase (tTG) IgA and IgG negative, antimitochondrial antibody negative, rheumatoid factor negative. CT abdomen pelvis showed low attenuation mesenteric lymphadenopathy, similar to that noted on CT abdomen done a year ago. CT abdomen/pelvis done 1 year ago (after he was involved in a motor vehicle accident) showed enlarged low attenuation lymph nodes in the root of the mesentery and retroperitoneum with surrounding infiltrative changes (Figs. 1 and 2). Low attenuation mediastinal lymphadenopathy was also noted on chest CT. He underwent extensive workup following that for this lymphadenopathy. HIV, hepatitis B, hepatitis C, LDH, CEA, CA 19-9, peripheral flow cytometry was negative. PET-CT demonstrated enlarged low attenuation lymph nodes in the root of the mesentery and retroperitoneum without significant FDG uptake (Figs. 3 and 4). Subsequently, he underwent EGD and colonoscopy. Antral biopsies showed mild inflammation of the gastric mucosa and moderate duodenitis, well preserved villous architecture and no evidence of gluten enteropathy. H. pylori was negative. Colonoscopy did not show any significant finding. Bone marrow biopsy was inconclusive and showed possible low-frequency B cell lymphoproliferative disorder with monoclonal B-cell lymphocytes. Cytogenetics and the fluorescence in situ hybridization (FISH) panel were negative. Repeat PET scan done 3 months later, showed improved findings. He was referred to Gastroenterology and underwent small bowel biopsy that showed extensive infiltration of lamina propria by foamy macrophages with resultant villous blunting, PAS positive diastase resistance within macrophages, negative GMS and acid-fast stain (Figs. 5 and 6). Blood PCR came positive for Tropheryma whipplei, confirming the diagnosis of Whipple's disease. He then had transesophageal echo which was unremarkable and spinal tap was negative for PCR Whipple disease. He was treated with ceftriaxone 2 g IV every 12 h for 2 weeks and then switched to sulfamethoxazole/trimethoprim 800 mg/160 mg twice daily for 1 year. A month later on follow-up outpatient visit, he was feeling much better, abdominal pain and diarrhea resolved, and he had gained more than 10 pounds. He still had some intermittent arthralgia. Of interest, recently his brother also started reporting similar symptoms and is undergoing more work up.

ct abdomen, mesenteric and retroperitoneal lymphadenopathy, pet-ct, tropheryma whipplei, whipple’s disease

PMC3335727_01

Female

A 27 year-old, para 3 lady and her husband presented to our clinic with a one year history of secondary infertility that was labelled as unexplained after confirming normal gonadotrophins levels, hysterosalpingogram, and advanced semen analysis. The couple declined diagnostic laparoscopy and chose to undergo treatment with intrauterine insemination (IUI) after they were counselled about their options of assisted reproductive techniques including IUI and IVF with and without ICSI, and their potential complications including the risk of multiple pregnancy and their potential consequences. Ovarian stimulation was undertaken with gonadotrophin using a recombinant FSH product (Puregon; Organon, Oss, The Netherlands). The patient overresponded and had developed 13 follicles over the size of 15 mm on stimulation day 13. The couple was counselled to cancel the treatment cycle or switch to IVF provided an LH surge did not occur. The couple chose the latter and ovarian stimulation continued with a higher dose of the same recombinant FSH product after starting a GnRH antagonist (Cetrotide; Serono, Baxter Oncology, Germany). When most follicles were in the range of 17 to 22 mm, final oocyte maturation was completed with hCG (Choriomon; IPSA, Lugano, Switzerland). Thirty-six hours later, a vaginal ultrasound-guided oocyte collection was undertaken and a total of 23 oocytes were retrieved. After stripping of the surrounding cumulus oophorus from the oocytes in preparation for ICSI, the embryologist evaluated only 19 oocytes as being mature and each was inseminated by a single sperm. After 18 to 20 hours, 17 oocytes showed pronucleate development and were further evaluated on day 2 and day 3 after oocyte recovery. The remaining 2 unfertilized eggs were discarded. On day 3, of the 17 embryos, 10 had developed to the 8-cell stage, one to the 7-cell stage, and 6 remained at 2-to-4-cell stage. After extensive counselling, the couple chose to have 3 embryos transferred back to the uterus, understanding the risk of multiple pregnancy and its potential consequences. Three very good quality 8-cell embryos (with grade 3.5 to 4 out of 4) were considered most appropriate for embryo transfer and this was undertaken later that day at around 72 hours after oocyte recovery. Embryo transfer was undertaken without difficulty using Sydney IVF embryo transfer catheter (Catalogue number K-JETS-6019-SIVF, Cook, Limerick, Ireland). The remaining 8 good quality embryos (seven 8-cell and one 7-cell embryos with grade 3 to 3.5 out of 4) underwent cryopreservation using vitrification technique. On luteal day 18, the patient had a positive pregnancy test with a BhCG level of 747 IU/mL. An ultrasound was performed on luteal day 49, and four intrauterine sacs with embryos each measuring 7 to 10 mm were seen (appropriate for the equivalent gestational age). A normal heartbeat was noted in all embryos. Not surprisingly, the couple was shocked by this news but further discussion and counselling was carried out that day and repeated a week later outlining the possible causes of what have happened, the risks of high order multiple pregnancy, the possible treatment options open to them at that time including selective reduction, the supervision and management of the pregnancy should they choose to continue and the likely options and the gestational age at which delivery might occur. At 11 weeks of gestation, the couple was seen and underwent an ultrasound study that confirmed the viability of all four foetuses. Chorionicity was examined by looking at the intersac membranes and they appeared to be trichorionic quadramniotic pregnancy as the dividing membrane between two of the foetuses showed a "T" sign as opposed to a "lambda" sign that was seen in the other dividing membranes between the foetuses. This was expected as it was the most likely explanation for the transformation of those 3 embryos to 4 foetuses. The couple was counselled again about all potential complications of such kind of pregnancy and they were also counselled about the pros and cons and controversies of cervical cerclage and nuchal translucency measurement in high-order multiple pregnancies. They chose not to undergo nuchal translucency measurement as they made up their mind that they will continue this pregnancy no matter what the outcome is. The couple chose to have a cervical cerclage only if all four foetuses remained alive in 2 weeks. At 13 weeks of gestation, and after confirming viability of the 4 foetuses, McDonald cervical cerclage was carried out with no complications. The patient was seen every 2 weeks starting at 15 weeks of gestation to rule out the early development of TTTS. A detailed morphology exam (level II ultrasound) showed normal 4 foetuses at 19 weeks of gestation with no major anomalies seen in any of them. At 26 of gestation, the patient had some uterine irritability and two doses of 12 mg betamethasone were given a day a part. Three weeks later, gestational diabetes was ruled out and biophysical profile (BPP) as well as end-diastolic-flow umbilical artery Doppler (EDF-UAD) were started at around 29 weeks of gestation and repeated every 2 weeks. At around 33 weeks of gestation, one of the monochorionic foetuses was relatively smaller than the others, with parameters consistent with intrauterine growth restriction (IUGR); however it remained to have normal and concordant amniotic fluid and EDF-UAD. Foetal assessment started to be done on weekly bases in the form of amniotic fluid assessment and EDF-UAD. At 35 weeks and 2 days of gestation, the small foetus remaind to be IUGR, however all four foetuses showed normal interval growth, amniotic fluid, and EDF-UAD. A week later, the patient was found to have a mildly elevated blood pressure (around 142/90 mmHg), but no proteinuria. She was asymptomatic and her investigations including those for HELLP syndrome were normal. Amniotic fluid assessment as well as EDF-UAD of all foetuses continued to be normal with exception to the small foetus that started to have intermittent absent end diastolic flow. Given the excellent gestational age reached and the development of those multiple mild complications, delivery was advised and was undertaken by semielective caesarean section the following day at a gestational age of 36 weeks and 3 days. At this, she delivered four healthy infants, three girls and one boy. Their weights were 1785, 1890 grams (gm), for the monochorionic twin, and 2035 and 2225 gm for the other girl and boy, respectively. The APGAR scores at 1 and 5 minutes were 8 and 9, respectively, for all four infants. All four infants were admitted to the Neonatal Intensive Care unit (NICU) for monitoring only. Four hours later, 2 infants were discharged to the normal nursery including the smallest one. The other two were on nasal oxygen cannula (blended oxygen) as they had Transient Tachypnea of Newborn (TTN), but both were discharged to the normal nursery in less than 24 hours. Pathological examination of the placentae confirmed the zygosity of trichorionic quadramniotic quadruplet. All four babies were discharged home with their mother on post-operative day 3. The babies were seen at 2 and 6 months of age for their scheduled immunization shot. All babies were well and with developmental assessment corresponding to their age. Permission was sought and obtained from the couple to publish this report.

PMC4276084_01

Female

We report the case of 31 years old female patient with endobronchial hamartoma diagnosed by CT scan after repeated episodes of chest pain and pyrosis. The first admission in March 2013, new mother for three months, the patient comes in pulmonology for the sudden appearance of stabbing chest pain, nocturnal cough and heartburn. A history of GERD treated with antacids as needed, and bronchial asthma onset after an episode of pneumonia arose during the first pregnancy occurred two years earlier. Chest X-ray was performed and reported evidence of a prominent right hilum and a subtle increase in parenchymal density in the middle lung field but a mass could not be clearly identified (Fig. 1). In June 2013, the patient returned to our structure for sudden onset of stabbing chest pain associated with dyspnea and fever. The laboratory tests revealed a mild neutrophilic leukocytosis associated with decreased hematocrit (35%) and slightly increased NSE. A contrast-enhanced MD-CT scan of the chest was performed and revealed a beginning middle lobe pneumonia and presence of a mass within the bronchus intermedius consisting mostly of fat with minimal inclusions of soft tissue density (Fig. 2). Multiplanar reconstruction with axis parallel to the bronchus clearly showed that the lesion determined subtotal obstruction of the bronchus intermedius (Fig. 3). The bronchial wall was very uneven and seemed to have a continuous solution on the outside, making its content not separable from the lesion (Fig. 4). Virtual-bronchoscopy reconstruction from the non-enhanced CT scan displayed the mass within the bronchus intermedius (Fig. 5). Based on the findings and subsequent consultation between radiologist, pulmonologist and thoracic surgeon, the patient underwent wedge resection of the bronchus intermedius by thoracotomy. The macroscopic and microscopic sections of the lesion are shown in Figs. 6 and 7 respectively.

ct scan, endobronchial lipomatous hamartoma, pregnancy, young new mother

Non contrast CT shows the presence of a well demarcated endobronchial (right main bronchus) mass characterized by smooth margins and negative density (-89 HU).

PMC4276084_01

Female

We report the case of 31 years old female patient with endobronchial hamartoma diagnosed by CT scan after repeated episodes of chest pain and pyrosis. The first admission in March 2013, new mother for three months, the patient comes in pulmonology for the sudden appearance of stabbing chest pain, nocturnal cough and heartburn. A history of GERD treated with antacids as needed, and bronchial asthma onset after an episode of pneumonia arose during the first pregnancy occurred two years earlier. Chest X-ray was performed and reported evidence of a prominent right hilum and a subtle increase in parenchymal density in the middle lung field but a mass could not be clearly identified (Fig. 1). In June 2013, the patient returned to our structure for sudden onset of stabbing chest pain associated with dyspnea and fever. The laboratory tests revealed a mild neutrophilic leukocytosis associated with decreased hematocrit (35%) and slightly increased NSE. A contrast-enhanced MD-CT scan of the chest was performed and revealed a beginning middle lobe pneumonia and presence of a mass within the bronchus intermedius consisting mostly of fat with minimal inclusions of soft tissue density (Fig. 2). Multiplanar reconstruction with axis parallel to the bronchus clearly showed that the lesion determined subtotal obstruction of the bronchus intermedius (Fig. 3). The bronchial wall was very uneven and seemed to have a continuous solution on the outside, making its content not separable from the lesion (Fig. 4). Virtual-bronchoscopy reconstruction from the non-enhanced CT scan displayed the mass within the bronchus intermedius (Fig. 5). Based on the findings and subsequent consultation between radiologist, pulmonologist and thoracic surgeon, the patient underwent wedge resection of the bronchus intermedius by thoracotomy. The macroscopic and microscopic sections of the lesion are shown in Figs. 6 and 7 respectively.

ct scan, endobronchial lipomatous hamartoma, pregnancy, young new mother

Oblique multiplanar CT reconstruction (lung window) shows entirely the mass within the right main bronchus lumen just before the bifurcation of the anterior segmental bronchus of the upper lobe and posterior segmental bronchus of the upper lobe.

PMC4276084_01

Female

We report the case of 31 years old female patient with endobronchial hamartoma diagnosed by CT scan after repeated episodes of chest pain and pyrosis. The first admission in March 2013, new mother for three months, the patient comes in pulmonology for the sudden appearance of stabbing chest pain, nocturnal cough and heartburn. A history of GERD treated with antacids as needed, and bronchial asthma onset after an episode of pneumonia arose during the first pregnancy occurred two years earlier. Chest X-ray was performed and reported evidence of a prominent right hilum and a subtle increase in parenchymal density in the middle lung field but a mass could not be clearly identified (Fig. 1). In June 2013, the patient returned to our structure for sudden onset of stabbing chest pain associated with dyspnea and fever. The laboratory tests revealed a mild neutrophilic leukocytosis associated with decreased hematocrit (35%) and slightly increased NSE. A contrast-enhanced MD-CT scan of the chest was performed and revealed a beginning middle lobe pneumonia and presence of a mass within the bronchus intermedius consisting mostly of fat with minimal inclusions of soft tissue density (Fig. 2). Multiplanar reconstruction with axis parallel to the bronchus clearly showed that the lesion determined subtotal obstruction of the bronchus intermedius (Fig. 3). The bronchial wall was very uneven and seemed to have a continuous solution on the outside, making its content not separable from the lesion (Fig. 4). Virtual-bronchoscopy reconstruction from the non-enhanced CT scan displayed the mass within the bronchus intermedius (Fig. 5). Based on the findings and subsequent consultation between radiologist, pulmonologist and thoracic surgeon, the patient underwent wedge resection of the bronchus intermedius by thoracotomy. The macroscopic and microscopic sections of the lesion are shown in Figs. 6 and 7 respectively.

ct scan, endobronchial lipomatous hamartoma, pregnancy, young new mother

Non contrast CT axial section (pulmonary window) shows the endobronchial mass (red arrow) that obstructs the right main bronchus.

PMC9798226_01

Male

The patient was a 20-year-old man of Chinese descent presenting with a painful nodule in the left plantar of the second toe for 1 month. For past history, the patient had surgery twice on the same site of the toe 6 years ago and relapsed 1 month later, and there was no other treatment except surgery. Unfortunately, the pathological data were not available, and the operating margin was not known. For this time, the nodule was subcutaneous and palpable. The third surgical resection was performed, and a diagnosis of "low-grade fibromyxoid sarcoma" was made in a local hospital. For further medical attention, the pathological materials were referred to our department for consultation. The clinical follow-up period was 9 months since the last surgery. The timeline is summarized in Figure 1 . Grossly, the lesion was pale solid, and well-defined measuring 9 x 8 x 9 mm in size. Histological examination revealed a relatively well-defined and nodular tumor without a capsule ( Figure 2A ). The tumor was composed of short fascicles of uniform spindle cells in a collagenous to myxoid stroma. The tumor cells had pale eosinophilic cytoplasm and elongated nuclei with finely dispersed chromatin and small inconspicuous nucleoli ( Figures 2B, C ). Mitotic figures were rare. Immunohistochemical staining was performed on 4-microm formalin-fixed, paraffin-embedded sections, which were immersed in a 10-mM sodium citrate buffer (pH 6) for 20 min at 97 C for antigen retrieval. The following antibodies were used: pankeratin (AE1/AE3, 1:50; Dako, Glostrup, Denmark), epithelial membrane antigen (EMA) (E29, 1:200; Dako), bcl-2 (clone 124, 1:100; Dako), CD34 (QB End 10, 1:100; Dako), alpha-smooth muscle actin (alpha-SMA) (1A4, 1:200; Dako), desmin (clone D33, 1:200; Dako), S100 protein (polyclonal, 1:800; Dako), SOX10 (polyclonal, 1:200; Santa Cruz Biotechnology, Dallas, TX, USA), H3K27me3 (RM175, 1:2,000, RevMAb, South San Francisco, CA, USA), MUC4 (8G7, 1:100; Abcam, Cambridge, UK), ERG (EPR3864, prediluted; Roche, Basel, Switzerland), SATB2 (SATBA4B10, 1:100, ZSGB), and Ki67 (MIB1, 1:150; Dako).The positive, blank, and negative controls were also performed in parallel. By immunohistochemistry, the spindle tumor cells showed diffusely and strongly nuclear positive for ERG ( Figure 2D ), while S100, alpha-SMA, CD34, desmin, SATB2, EMA, MUC4, and other spindle cell tumor and vascular markers were negative. Ki67 index was about 15% in tumors. According to the manufacturer's instructions, fluorescence in situ hybridization (FISH) was performed on formalin-fixed, paraffin-embedded tissue sections. Unstained 4-microm sections were placed on electrostatically charged slides and then evaluated using an EWSR1 (22q12) rearrangement in a dual-color, break-apart probe and an EWSR1 (22q12, green) and SMAD3 (15q22, red) fusion probe (LBP, Guangzhou, China). Under fluorescence microscopy, signals from 200 non-overlapping nuclei were counted. The cutoff level for the score as positive was when at least 20% of the nuclei showed a break-apart signal and/or loss of telomeric part or fusion signal (yellow). The FISH assessment demonstrated an unbalanced rearrangement of EWSR1 with loss of the telomeric part ( Figure 3A ), combined with tumor cells, diffuse nuclear staining for ERG the diagnosis of EWSR1::SMAD3-rearranged fibroblastic tumor was considered. To identify the fusion partner, EWSR1 and SMAD3 fusion was detected by FISH ( Figure 3B ), and the fusion was confirmed by RT-PCR and Sanger sequencing between exon 7 of EWSR1 and exon 6 of SMAD3 ( Figure 3C ). Based on the morphology, immunohistochemistry, and gene analysis, the final diagnosis was EWSR1::SMAD3-rearranged fibroblastic tumor. Treatment of the tumor was wide excision. To date, the patient is disease-free without relapse and metastasis for 9 months after the last surgery.

erg, ewsr1, smad3, case report, fibroblastic tumor

PMC4695514_01

Male

On August 29, 2014, The Minister of Health officially announced the First Ebola virus disease case in Senegal. It was related to a 21-year-old national from Guinea, who had been in contact in Guinea with members of his family who had contracted the disease and eventually passed away. He entered Senegal by road, before the second restricted access of frontiers on August 22. He had used an overnight public transport vehicle from August 13 through 14 in order to reach Dakar. At that time, and all along his trip, he had presented no single fever-type symptom. Three days after his arrival, he started showing signs of fever, vomiting and diarrhea with no bleeding, and then decided to consult in a suburban health centre where he had been taken in charge for three days. Due to persisting symptoms, he approached the infectious diseases service at Fann University Hospital, where he was subsequently hospitalized. During all those consultations, he had never informed practitioners as regards the contacts he likely had with other people affected by the Ebola virus disease. Senegal had been alerted by some WHO authorities based in Guinea that a contact-case had probably travelled to Senegal; the investigation undertaken revealed that it was related to the patient hospitalized at the Fann Hospital Infectious Disease Service. He was then immediately placed in an isolation room and some fluid samples were gathered. On August 28, the test operated on the blood sample by the Dakar Pasteur Institute returned as Zaire-Ebola-virus-positive. The investigations undertaken helped identify 74 individuals who had been in contact with the patient (34 in his family and 40 health workers). The reopening of the interrogation of both the patient and his caretaker, with a focus on their itinerary, facilitated the identification of all the family members and the health centre staff. At the level of the hospital, the patient's record was reviewed, along with the list of all personnel on duty. This helped identify all individuals who had been in contact with the patient or his biological samples. All the contacts were put in quarantine inside their homes and were monitored twice a day by the medical district teams in their respective areas, conducting temperature checks and patient questioning. Senegal, since the declaration of the outbreak in Guinea, had implemented a three-step response plan: pre-epidemic, epidemic and post-epidemic. Since the month of March, the National Committee for Epidemics Administration has held weekly meetings in order to implement the pre-epidemic phase activities. This is a permanent committee meeting anytime a threatening epidemic situation occurs in Senegal. During the pre-epidemic phase, all activities essentially deal with the communication of health workers to populations, the training of healthcare personnel, the capacity-building of healthcare workers and the reinforcement of frontiers surveillance. As soon as the case was signified, the epidemic phase was launched and ten commissions were implemented adding to the National Committee for Epidemics Management. A coordination committee supervised by the Healthcare Executive Director including commission presidents and their reporters, along with some partners would meet every morning. The multi-sectorial approach was used as a guide for the commissions' implementation. Epidemiological Investigation and Surveillance Commission: in charge of the monitoring of the 74 contact cases and alert management; social Intervention and Behavior Commission: in charge of the patient's and contacts' psychosocial care; media and Communication Commission: in charge of all aspects dealing with communication; patients' Clinic Care and Infection Control Commission: in charge of the monitoring of the patient's care and also the supervision of healthcare structures; logistics Commission: in charge of the management of all necessary products, facilities and material; security Commission: in charge of patients and contacts security and frontier surveillance; research and ethical aspects commission: in charge of all research and ethical issues related to the epidemic: hygiene and Sanitation Commission: in charge of the decontamination and sanitation healthcare sites; fund-raising Commission: in charge financial resources management. Mobile Intervention Commission: in charge of the transportation and the sampling of all suspect cases.

ebola, senegal, imported case, managment

PMC9871303_01

Female

A 39-year-old hypertensive, non-diabetic female presented with one year history of moon facies, proximal myopathy, buffalo hump, abdominal striae, easy fatigability and hirsutism. The following laboratories were done and revealed a normal ACTH of 8.5 pg/mL [Reference range: 5-46 pg/mL] and elevated 1 mg Dexamethasone suppression test of 17.96 ug/dl [Reference range: < 1.8 ug/dL]. Whole abdominal CT scan revealed a 3.6 x 2.9 x 2.9 cm well-defined heterogeneously enhancing solid mass on her left adrenal. Patient was then diagnosed with Cushing's syndrome secondary to a cortisol-producing adrenal adenoma and was scheduled for elective laparoscopic adrenalectomy. However, a few days prior to the scheduled operation, the patient suddenly had eight episodes of hematochezia with an estimated cumulative blood loss of 800cc. It was not accompanied with abdominal pain, diarrhea, constipation, vomiting, fever, night sweats, weight loss, or cough. She was then admitted for colonoscopy. On physical examination upon admission, the patient was coherent, not in respiratory distress, with an estimated body mass index of 27 kg/m2. She had pale palpebral conjunctiva, normal blood pressure of 120/80, tachycardic at 105 beats per minute, and afebrile. Abdominal exam revealed normoactive bowel sounds, presence of violaceous striae, and no organomegaly, while rectal examination showed good sphincter tone and fresh blood per examining finger. Colonoscopy showed a semi-circumferential white based ulcer on the terminal ileum (Fig. 1). Biopsies were taken and submitted for histopathology revealing acute on chronic inflammation with suspicious focus of granuloma with no intact ileal mucosa appreciated (Fig. 2). Tissue Gene Xpert revealed positive results for M. tuberculosis with no rifampicin resistance. Patient was then started on isoniazid, rifampicin, pyrazinamide, and ethambutol. On the same admission, laparoscopic adrenalectomy (Fig. 3) of the left adrenal gland was performed showing adrenal cortical adenoma, consisting of a fairly pyramidal, brown to orange, doughy tissue, measuring 4.5 x 3.0 x 2.5 cm and weighing 50.0 g (Fig. 4) Microscopic sections showed features of adrenal cortical adenoma characterized by a well- encapsulated benign tumor composed of sheets of cells in an organoid pattern. The individual cells show relatively monomorphic, centrally located, round, bland nuclei and clear, vacuolated cytoplasm with well-defined borders. No features of malignancy such as atypical mitotic figures, venous invasion, or necrosis were noted (Fig. 5). The final pathologic report was adrenal adenoma.

adrenal adenoma, cushing’s syndrome, hematochezia, mycobacterium tuberculosis infection

PMC6336602_01

Female

The patient was a 27-year-old woman with no relevant medical history or family history. In June 2016, she presented at our hospital for 4 months of intermittent fever with 3 and half months of fatigue and dark-colored urine. The patient developed fever (38.5 C) 4 months ago with no apparent cause. The fever type was irregular; it was accompanied by myalgia and occasional headache. She denied any history of chills, pharyngalgia, cough, and expectoration, abdominal pain, diarrhea, localized joint pain, or rash. The patient was prescribed anti-infection therapy for 4 days in a local hospital because of increased white blood cell (WBC) counts and neutrophils. However, her body temperature persisted in the range of 38.5 C to 39.1 C. About 3 and half months ago, the patient was referred to the superior central hospital owing to development of anorexia, fatigue, and dark-colored urine. Results of lab investigations were as follows: serum alanine aminotransferase (ALT) 1187 U/L; serum aspartate transaminase (AST) 1243.7 U/L; total bilirubin (TBIL) 165.4 mumol/L, direct bilirubin (DBIL) 92.2 mumol/L. She tested negative for antigen and antibody markers of hepatotropic hepatitis A-E virus with the exception of hepatitis B surface antibody, and undetectable for viral nucleic acid. She received glycyrrhizin remedies for hepato-protection and to lower transaminase levels, and cefoperazone-sulbactam antibiotic therapy for about 1 month; however, there was no improvement in clinical manifestations. About 2 and half months ago, the patient was transferred to another local hospital for specialized infectious diseases. Liver biochemistry tests showed ALT 374 U/L, AST 164 U/L, TBIL 84.2 mumol/L, DBIL 57.3 mumol/L. Besides, her anti-streptolysin "O" was 201 U/mL, rheumatoid factor was 156.2 IU/mL, and C-reaction protein (CRP) level was 1.9 mg/L. EBV- capsid antigen (CA)-IgM, cytomegalovirus (CMV)-IgM, rubella virus-IgM, toxoplasmosis-IgM, herpes simplex virus 2-IgM, as well as Widal, Weil-Felix test, and Brucella agglutination test were all negative. The anti-extractable nuclear antigen antibodies were all negative. Liver biopsy was performed and then the diagnosis of DILI was considered based on liver pathology (Fig. 1). The patient received symptomatic treatment along with methylprednisolone (starting at 28 mg/day and reduced by 4 mg per week). The patient's temperature and liver function were restored during treatment. However, there was recurrence of fever after 1 week of methylprednisolone withdrawal. When she came to our hospital, she was still febrile (temperature 39.5 C); however, the general physical examination was unremarkable. At admission, the results of blood tests were: WBC 3.95 x 109/L; platelet 142.00 x 109/L; plasma prothrombin time 13.5 s; and fibrinogen 1.86 g/L. Liver biochemistry tests were: ALT 1577 U/L; AST 2354 U/L; TBIL 80.5 mumol/L; DBIL 51.2 mumol/L; albumin 33 g/L; alkaline phosphatase 468 U/L; gamma-glutamyl transferase 215 U/L; lactate dehydrogenase (LDH) 1032 U/L; triglycerides 2.67 mmol/L; erythrocyte sedimentation rate 27 mm/h; procalcitonin 0.06 ng/mL; and CRP 8.80 mg/L. Tuberculin skin test, anti-tuberculosis (TB) antibody, T-Spot TB test, as well as (1,3)-beta-D-Glucan and Galactomannan tests were all negative. A series of blood, urine, stool, and marrow culture were repeatedly negative. CMV DNA level was <500 copies/mL; Multi-tumor markers were all within normal range. However, EBV DNA level was 2.837 x 104 copies/mL. The EBV antibody spectrum showed EBV-CA-IgG (+), EBV nuclear antigen (EBNA)1-IgG (+), and EBV-early antigen (EA)-IgG (+). T cell subsets: clusters of differentiation (CD)3+ 21.05%, CD3+CD4+ 8.83%, CD3+CD8+ 11.53% and CD4/CD8 0.77. On ultrasound, the size of spleen was 12.0 cm x 5.6 cm; however, there was no hepatomegaly or lymphadenectasis in neck, armpits, mediastinum, or along the abdominal blood vessels. After admission, the patient received symptomatic treatment and antiviral therapy with a combination of acyclovir and Foscarnet Sodium. Thymosin alpha 1 and methylprednisolone were prescribed to regulate immunity and as an adjuvant to antiviral therapy. The patient's liver biochemical profile recovered to normal range while intermittent fever continued to persist. Furthermore, an increase in EBV DNA level was also noted (4 weeks after admission: 3.01 x 104 copies/mL; 6 weeks after admission: 1.32 x 107 copies/mL). Bone marrow immunophenotyping for hematological malignancy by flow cytometry with CD45/side scatter (SSC) gating and normal cells as internal reference showed that: lymphocytes (LYs) accounted for about 31.8% of nucleated cells, of which CD3-CD56+ NK cells accounted for about 79.8% and the cells were CD2, CD38, CD56, CD94 positive, and CD7 negative (Fig. 2). Repeat evaluation of the pathologic section of the liver (borrowed from the local hospital) showed mildly expanded hepatic sinusoids with beaded arrangement of LYs; severe lymphocytic infiltration in portal tracts, mixed with occasional atypical LY with dark cytoplasm, prominent nucleoli, and vacuolar nucleus (Fig. 1). EBER-1 probe in situ hybrids of hepatic pathologic section (+). One month after admission, the patient developed hematochezia but colonoscopy showed no abnormality. At this time, blood tests showed WBC 6.54 x 109/L (neutrophils 2.13 x 109/L; LYs 3.84 x 109/L), red blood cell 3.80 x 1012/L, hemoglobin 106.60 g/L, platelet 234 x 109/L; plasma prothrombin time 12.8 s; prothrombin activity 82.00%; international normalized ratio 1.14; fibrinogen 1.03 g/L; and D-dimer 0.89 mg/L. The bleeding resolved after symptomatic treatment. Two months after admission, the patient passed soy urine. Urine test showed red blood cells 67.3/muL and occult blood (+++). The symptoms improved after hemostatic therapy; laboratory tests showed plasma fibrinogen level of 0.77 g/L and ferritin >1200 mg/L. sCD25 in serum was 20312 pg/mL (Ref 400-2700 pg/mL). Based on the above results, the patient received treatment with etoposide and dexamethasone for diagnosis of EBV associated HLH; subsequently, her temperature, liver biochemical profile and blood lipids were restored to normal range. Repeat flow cytometry of bone marrow showed that 11.01% bone marrow cells exhibited an abnormal phenotype of mature NK cells, which accounted for 17.17% of nucleated cells and 64.13% of LYs; the cells were CD56, CD2, CD7dim, CD8dim, CD161, CD94bri, CD159a positive, and CD3, CD4, CD5, CD16, CD159c, CD158b, CD158a/h, Ki67, CD30, CD57, CD10, T cell receptor (TCR) ab, TCRrd, CD158e, CD117 negative; granzyme B positive rate was 91.51% and perforin positive rate was 93.83%; bone marrow chromosome karyotyping: 46, XX [20]; gene rearrangements of IgH and TCRgamma/delta were negative. Bone marrow cytomorphologic features: 3 cell-lineage of erythrocyte, granulocyte and thrombocyte in bone marrow showed active proliferation with toxic change in some granulocytes. The proportion of LYs was within the normal range; occasionally, atypical LYs characterized by dense chromatin and purple-red particles in cytoplasm. The mononuclear-macrophage showed active proliferation and phagocytic red blood cells, platelet fragments, and coarse particles were scattered within the cytoplasm. Bone marrow pathology showed clusters or cord-shaped cells distributed in hematopoietic tissues, with large cell volume and deep nuclear staining. Reticular fiber staining: myelofibrosis-1 (Fig. 3). According to these results, the patient was eventually diagnosed as a case of EBV associated NK cell lymphoma accompanied by HLH. In September 8, 2016, the patient received the first course of revised EPOCH chemotherapy with etoposide (100 mg/d, d1-5), dexamethasone (7.5 mg/d, d1-5; 5 mg/d, d6-14), cyclophosphamide (0.8 g/d, d1-2), and pegaspargase (3750 u/d, tid, d1-2). Fifteen days later, the patient developed hematochezia again; colonoscopy showed that the location of gastrointestinal hemorrhage was in cecum and ascending colon. Unfortunately, the patient died of gastrointestinal hemorrhage and multiple organ failure.

PMC9245433_01

Male

In late August 2020, a 46-year-old male was admitted to our emergency department, with complaints of intermittent fever associated with fatigue and anorexia lasting for a month. He also complained of 30-kg weight loss within 5 months. The patient first visited a local hospital 2 weeks ago. Because of fever and lymphadenopathy, a bone marrow aspiration was performed. The bone marrow smear revealed hemophagocytosis and yeast-like bacteria; fungal infection was considered. However, no fungus was cultured in the bone marrow culture. Therefore, empirical antifungal treatment of Voriconazole was prescribed. After taking the drug, the patient developed insomnia and was replaced by itraconazole, without symptom improvement. He works as a cooker and gets up at 1 a.m. every day. He contacted with a soil-based environment for building and construction around his house. He lived in a rural area in Southeast China for more than 40 years and never traveled to foreign countries. At physical examination, the patient has temperature of 39.7 C, pulse rate of 129/min, respiratory rate of 18/min, and blood pressure of 119/63mm of hg and has normal oxygen saturation. He had pallor and hepatosplenomegaly. Heart and lung auscultation were unremarkable. The laboratory examination indicated pancytopenia at admission: hemoglobin, 63 g/L; platelet, 44 x 109/L; leucocytes, 1.6 x 109/L; neutrophils, 1.3 x 109/L. The C-reactive protein (CRP) level was 44.4 (normal, < 8) mg/L, and procalcitonin (PCT) level was 1.65 (normal, <0.15) ng/ml. Fibrinogen levels was decreased (1.0g/L). Serum ferritin was markedly elevated (2,775.0 ng/ml). The CD4 cell count was 120 cells/mul. He had mild abnormal serum levels of aspartate aminotransferase (AST) with 81U/L, alanine aminotransferase (ALT) with 53 U/L, and glutamyl transpeptidase (GGT) with 118 U/L, respectively. There was a decline in albumin levels, 32.0 g/L. The kidney function markers were within normal ranges. The patient had a detectable level of (1 3)-beta-d-glucan, 212.56 (normal, < 60) pg/ml, and the GM (galactomannan) level was not elevated. Serological results for human immunodeficiency virus (HIV), Epstein-Barr virus, cytomegalovirus, hepatitis virus B and C, COVID-19, and the T-cell spot test for tuberculosis infection (T-SPOT) were negative. His blood culture did not grow any pathogenic organism. Table 1 shows the results of relevant blood investigations. Computed tomography (CT) of the chest was normal but the abdominal CT showed hepatosplenomegaly and posterior peritoneum lymphadenopathy ( Figure 1 ). PET/CT revealed hepatosplenomegaly and posterior peritoneum lymphadenopathy and bone marrow with high FDG uptake, suggesting lymphoma probably. A bone marrow puncture was done at admission which displayed hemophagocytosis and negative result for bacterial culture. Hematoxylin and eosin (HE)-stained bone marrow demonstrated oval or round organisms with amaranth nuclei and capsule-like unstained halos around these organisms observed in the cytoplasm of phagocytes ( Figure 2 ). The fungus culture of bone marrow was also sent to laboratory for further identification. After 8 weeks of initial plating on potato dextrose agar (PDA) medium at 25 C and subsequently sub-cultured at intervals of 2 weeks in Columbia blood agar medium at 25 C. These are shown in Figure 3 , which finally confirmed as Histoplasma capsulatum. The patient received empirical treatment with oral itraconazole from the day of admission (200 mg three times daily for 7 days). At day 2 after admission, the body temperature was back to normal. The laboratory examination were repeated at day 4 after admission: hemoglobin, 69 g/L; platelet, 67 x 109/L; leucocytes, 4.7 x 109/L, neutrophils: 4.2 x 109/L. Serum ferritin declined to 1,264.3 ng/ml. After the results of the bone marrow puncture come out, liposomal amphotericin B was prescribed (1.0 mg/kg daily for 10 days), followed by oral itraconazole (200 mg twice daily for a total of at least 12 months). For HLH, the patient received treatment with prednisone 40 mg daily and intravenous immunoglobulin 20 g daily for 5 days. The blood cell count, CRP, PCT, and serum ferritin improved substantially after a week. The CD4 cell count also recovered normal after a week. In this case, the patient presented with HLH with fever, splenomegaly, elevated ferritin, hypofibrinogenemia, blood cell abnormalities, and hemophagocytosis. Although he had no immunocompromised disease and never went to epidemic area, but he had been short of sleeping time for long time, and there was a lot of dust around his house because of building a road. It is unclear whether this may have been a risk factor for disease.

hiv seronegativity, histoplasma capsulatum, hemophagocytic lymphohistiocytosis, histoplasmosis, immunocompetence, liposomal amphotericin b

PMC7532949_01

Female

Madam A, a 72-year-old lady, was diagnosed with JAK2 V617F mutation polycythemia vera in 2019 and was treated with tablet hydroxyurea 500 mg daily and oral aspirin 75 mg daily. She required therapeutic phlebotomy once a week for the first month as her hematocrit level was persistently more than 50%. Prior to her diagnosis of polycythemia vera, she had a history of ischemic stroke in 2008 with residual left-sided hemiparesis, hemorrhoids with banding done twice, diabetes mellitus, hypertension, and dyslipidemia. In early March 2020, during the COVID-19 outbreak in Malaysia, most of her family members whom she was staying with were infected with COVID-19. Therefore, she was screened for being a close contact and was tested positive for SARS-CoV-2 by qualitative real-time reverse-transcriptase-polymerase-chain-reaction (qRT-PCR) assay. She was admitted to the isolation ward for close observation as per local COVID-19 protocol. Her treatment of aspirin and hydroxyurea for her underlying polycythemia vera was continued. While under observation, she developed a worsening cough with chest radiograph showed worsening bilateral lower zone opacities. However, her oxygen saturation remained stable at 97 to 100% under room air. Due to the severity of her COVID-19 infection, she was commenced on oral hydroxychloroquine for 5 days and oral lopinavir/ritonavir for 2 weeks. Her clinical condition improved with treatment. However, she developed per rectal bleeding which was attributed to her hemorrhoids. Her hemoglobin was 16.6 g/dL, total white cell count was 25 x 103/mul, and platelet count was 1247 x 103/mul at the time the bleeding occurred (Table 1). As a result, her hydroxyurea dosage was increased to 500 mg twice daily but her aspirin was withheld. Her rectal bleeding resolved after that. She was hospitalized for 40 days and was discharged following a negative COVID-19 swab. She was not commenced on any anticoagulant in view of the history of rectal bleeding. One week post discharge, she was readmitted with sudden onset of altered consciousness associated with right-sided body weakness. Her Glasgow Coma Scale (GCS) was 14/15, E3V5M6 on presentation. Computed tomography (CT) brain was performed and revealed cerebral venous thrombosis of the straight sinus, vein of Galen, and bilateral internal cerebral veins with venous infarcts (Fig. 1). She was commenced on subcutaneous (S/C) enoxaparin 40 mg twice a day (weight 42 kg). On day 3 of admission, she had a repeat CT brain and cerebral venography for fluctuating GCS level. The repeat brain scan showed evidence of thrombosis involving the superior sagittal and right sigmoid sinus as well, bilateral vasogenic edema, swollen left basal ganglia, and left thalamic region. She was started on intravenous dexamethasone for 5 days to reduce cerebral edema and oral levetiracetam for seizure prophylaxis. Her GCS started to improve 2 days after the commencement of the above treatment. She had a repeat non-contrasted CT brain a week after her 2nd CT brain and showed unchanged multifocal infarcts, no intracranial hemorrhage, and less swollen left basal ganglia region. At the time of her discharge, her GCS was 15/15 and she was on nasogastric tube feeding and wheel-chaired bound due to incomplete recovery of her motor function. On her clinic follow-up a month later, her D-dimer was normal at 0.24mug/ml, and her S/C enoxaparin 40 mg BD was converted to oral warfarin. She is clinically stable on her last review 3 months later.

covid-19, case report, cerebral venous thrombosis, d-dimer, polycythemia vera

PMC4339947_01

Female

A pregnant women (gravida 2) with a 3-year-old daughter delivered twins (diamniotic dichorionic) at 38 weeks of gestation as normal vaginal delivery. The newborns were normal at the time of birth, but presented with hyperbilirubinemia at 16 h of life. Mother was never transfused previously. Clinically both the newborns were stable hemodynamically with no hepatosplenomegaly, hydrops, hematoma, polycythemia, or twin discordance on examination and were adequately taking breast milk. Blood bank received a requisition for reconstituted whole blood for an exchange transfusion for the twins (T1, T2) as their billirubin [Figure 1] was in exchange zone. Twins did not require exchange transfusion as phototherapy which was given over 4 days showed a reduction in the bilirubin levels. Both the newborns further showed progressive decrease in hematocrit (HCT) and later developed hepatosplenomegaly. Peripheral smears revealed no evidence for hemolysis, low reticulocyte count (T1-4%, T2-3%). The TORCH titers, serology for parvovirus, sepsis screen were all negative. Quantitative G6PD and thyroid profile were within normal range. Bone marrow examination showed predominantly normoblasts with few cells showing dyserythropoiesis. The other cell lines such as megakaryocytes and cells of lymphoid lineage were normal. Further adenosine deaminase levels were also done to rule out Diamond-Blackfan anemia. The mother and father also had normal beta and alpha thalassemia screen. Blood sample of the newborn twins as well as the mother were sent to the blood bank. ABO and D blood typing was performed routinely by both manual tube and column agglutination technology (CAT). Direct antiglobulin test (DAT) was done in CAT cards containing polyspecific antihuman globulin (AHG) (anti-IgG and anti-C3d). Screening of irregular antibody and identification was done using surgiscreen and resolve Panel A, ortho-clinical diagnostics (USA) with polyspecific AHG cards. Rh, MNSs and Kell phenotypes were performed in tubes according to manufacturer's instruction by direct agglutination (Rh, K, M, N, S) and by IAT(s). CAT cards (plain and AHG) and rare antisera used for phenotyping were from ortho-clinical diagnostics (USA). Antibody titration was performed on CAT polyspecific cards and by direct agglutination on tubes. The titer was determined by serial two-fold dilutions in saline, tested against selected M+N- red blood cells (RBCs). The reciprocal of the highest dilution that gave a 1+ reaction is referred to as the titer. Blood group of twins was O RhD positive. DAT was negative for both the twins. Elution of the DAT negative sample was not done. Blood group of mother was O RhD positive. On antibody screening, mother showed a positive reaction with screening red blood cells, the reaction strength being cell I- (2+); cell II- (4+); cell III- (4+) at both room temperature and AHG phase, indicating presence of an alloantibody in maternal sample of both IgM and IgG type, which was duly confirmed on 1,4-dithiothreitol treatment. Further antibody identification panel showed antibody specificity to M antigen, reacting at both room temperature and AHG phase. Similar antibody was identified in the serum of both the twins as well, but reacting at AHG phase only (IgG type). Both antibody screen and identification done on the CAT and manual tube showed similar results. Phenotype of the twins was a heterozygous state of M and N antigen (M+N+). The mother was homozygous for N antigen (M-N+) and father was homozygous for M antigen (M+N-) [Table 1]. The M alloantibody (both IgG and IgM types) showed clear evidence of dosage phenomena with a weaker reaction with the heterozygous cells (M+N+) when compared to a homozygous cell (M+N-). The antibody identification was further enhanced by adding one part (0.1 N) HCl to four parts of the serum before testing (to lower the pH at 6.5). Alloantibody also showed a stronger reaction in albumin than in saline. The antibody titer (using tube and CAT both) during 1st week of life was 16 (IgG) in twin-1 (T1) and 8 (IgG) in twin-2 (T2). The mother had a titer of 16 (IgG) and 8 (IgM) after the delivery. Anti-M was detectable in the twins until 7th weeks of life. The anti-M titer in the mother were constant at 32 (IgG) and 16 (IgM) until 8 weeks of follow-up postbirth [Figure 2]. Both the newborns initially showed rise in bilirubin, which subsided following phototherapy (started on day 1) on day 4 and did not require exchange transfusion. Twin-1 showed a decrease in hematocrit to 16% at day 6 and was transfused with 40 mL of (M-N+) packed RBCs (PRBC). On day 32, HCT dropped again to 16% but without any rise in bilirubin and both newborns were transfused with M-N+ PRBC. Repeatedly both showed decrease in the red cells, with all rest other cell lines normal, without any feature of hemolysis. On day 49, postbirth both the twins again had low HCT (15%) and were again transfused with (M-N+) PRBC. Twins continued to have anemia until 70 days of life after birth, their hematocrits stabilized their after [Figure 1].

anti-m alloimmunization, hemolytic disease of newborn, pure red cell aplasia

PMC8150260_01

Female

An 80-year-old woman presented to an outside hospital with fever and a dry cough. The patient's vital signs were as follows: respiratory rate, 20 breaths/min; blood pressure, 123/57 mmHg; heart rate, 85 beats/min; blood oxygen saturation, 96 %; and body temperature, 38.5 C. Based on her medical history, the patient was diagnosed with hypertension, without diabetes mellitus, and connective tissue disease. She had not taken any medications, except those for hypertension. She was a nonsmoker with no family history of interest. An outside posteroanterior chest radiograph performed 3 weeks before showed multiple consolidations and ground-glass opacities in both the mid and lower lung zones (Fig. 1). A subsequent chest CT scan showed multiple pulmonary nodules and masses with internal cavitation in both lungs (Fig. 2). There was no evidence of pulmonary thromboembolism, mediastinal or hilar lymphadenopathy, or pleural or pericardial effusion. Based on the impression of septic pneumonia or necrotizing pneumonia, empiric antibiotic treatment with vancomycin, tazolactam, and ertapenem was administered. However, she did not respond to antibiotics, and fever persisted. Therefore, the patient was referred to our hospital for further investigation. At our hospital, the patient complained of fever and a cough without any clinically significant comorbidities. Laboratory data showed leukocytosis, (13,360/uL [normal, 4800-10,800 /uL]: 82.6 % neutrophils, 10.4 % lymphocytes, 3.9 % monocytes, and 2.0 % eosinophils), increased C-reactive protein levels (10 mg/dL [normal, <0.5 mg/dL]), an increased erythrocyte sedimentation rate (86 mm/h [normal, 0-20 mm/h]), and an increased procalcitonin levels (0.346 ng/mL [normal, 0-0.100 ng/mL]). Her renal and liver function tests were within the normal range. Considering the ineffectiveness of antibiotics at the outside hospital, our first impressions were of vasculitis, such as granulomatosis with polyangiitis (GPA), fungal pneumonia, pulmonary tuberculosis, or an NTM pulmonary infection. The tests for antinuclear antibodies, myeloperoxidase antibodies, and proteinase-3 antibodies were all negative. Moreover, blood cultures for fungi and bacteria were also negative. Blood, sputum, and bronchoalveolar lavage samples tested negatively for Mycobacterium tuberculosis and acid-fast bacilli on an interferon-gamma release assay and polymerase chain reaction. An ultrasound-guided percutaneous needle biopsy of the mass in the right lower revealed a chronic granulomatous inflammation, inflammatory cell infiltration, and distortion of the lung architecture (Fig. 3). One month later, a sputum culture showed growth of Mycobacterium intracellulare, confirming an NTM pulmonary infection. Following treatment with anti-mycobacterial medications (ethambutol, rifampicin, and azithromycin), her symptoms and radiological findings greatly improved (Fig. 4). However, the previously hidden reticular densities in both lower lung zones were detected on a posteroanterior chest radiograph. Two years after the anti-mycobacterial treatment, a follow-up chest CT showed an improvement of the previously observed multiple masses and ground-glass opacities. Furthermore, it showed a predominant lower lobe pulmonary fibrosis with mild ground-glass opacity, reticulation, and traction bronchiectasis that was not identified on the initial chest CT (Fig. 5). She is now on outpatient follow-up with no clinical symptoms.

computed tomography, nontuberculous mycobacteria, x-ray

PMC5370330_01

Male

A 36-year-old male presented to our hospital in 2006 with low back ache inflammatory type with symmetric joint pains involving large joints such as shoulder joints, hip joints, knee joints, and small joints such as metacarpophalangeal joints, elbow joints, and metatarsophalangeal joints. There was associated early morning stiffness for over an hour. On examination, synovitis was present in peripheral joints with restriction of movement in all joints. Modified Schober's test was positive, and the chest expansion (<3 cm) was restricted. On evaluation, he had anemia and elevated erythrocyte sedimentation rate (ESR) (46 mm/h) and C-reactive protein (CRP) (18 mg/L). Liver function tests and renal function tests were normal. Imaging revealed kyphoscoliosis of thoracic spine, syndesmophytes at multiple levels giving the appearance of bamboo spine [Figure 1]. Diffuse ossification of interspinous and paraspinal ligaments with fusion of thoracic and lower cervical vertebra was present. Human leukocyte antigen-B27 (HLA-B27) was positive. In view of HLA-B27, more than 2 SpA features and typical radiological features, ankylosing spondylitis was considered. He was started on nonsteroidal anti-inflammatory drugs (NSAIDs) and dose escalated for symptomatic relief. In view of persisting symptoms and elevated ESR and CRP in spite of optimal NSAIDs, option of biologics was given. He was initially not willing but later accepted for therapy. Before biologic therapy, TB workup was done. Mantoux test was negative, and chest radiography was normal. Patient was administered infliximab by intravenous infusion. Subsequent doses were planned at 2 and 6 weeks and then every 8 weeks. There was an improvement in symptoms. Following three doses of infliximab and 10 months after initiation of therapy, patient came with complaints of fever and cough for 1 week. On examination, breath sounds were reduced over the right side, and there was dullness on percussion. Chest radiograph showed features suggestive of pleural effusion [Figure 2]. Diagnostic thoracocentesis showed lymphocytic (total leukocyte count - 4800 cells/cumm, lymphocytes - 90%) exudative type of effusion with high adenosine deaminase (ADA) (114 IU/L). According to light's criteria (effusion protein - 6 g/dL, serum protein - 3.37 g/dL, effusion lactate dehydrogenase (LDH) - 575 U/L, and serum LDH - 325 U/L), it is an exudative type of pleural effusion. Pleural fluid showed elevated ADA levels (114 IU/L) indicating tuberculous pleural effusion. Anti-TB therapy was started.

ankylosing spondylitis, antitumor necrosis factor-alpha, infliximab, tuberculosis

PMC9899455_01

Male

An otherwise healthy 34-year-old male presented with a loss of consciousness to the emergency department (ER). A gunshot wound entry was observed on his occiput with the right orbital swelling. His Glasgow Coma Scale (GCS) was 10 (E3, V3, M4), with a left-sided weakness grade of 3 on the Medical Research Council of Canada (MRC) scale. An ophthalmological examination was performed and revealed avulsed damaged globe. A head computed tomography (CT) scan was performed, which revealed a bullet lodged in the right orbit with an entrance point from the right occipital bone [Figure 1]. In addition, the CT scan showed an intraventricular hemorrhage in the lateral ventricle due to the spontaneous migration of the bullet through the brain [Figure 2]. The patient is transferred to the operating room, where an interdisciplinary team of surgeons is prepared. The surgery was focused on three targets (1) hematoma evacuation, (2) scalp debridement, and (3) gentle bullet removal, which was performed successfully. The surgery went unremarkable. Furthermore, the postoperative course featured GCS 12 (E3, V4, M5) and a left-sided weakness MRC grade of 3. In the neurointensive care unit (ICU), measures were taken to decrease the intracranial pressure (ICP), including head elevation and mannitol boluses, according to the follow-up neurological examinations alone, as ICP monitoring is not available. In addition, essential care was performed, which included primary wound care and closure of both inlet and outlet in the neuro ICU. However, the patient died on the 7th day postoperatively, which mainly contributed to the patient's TBI.

cranio-orbital, tbi, traumatic brain injury

PMC9899908_01

Female

A 42-year-old woman presented with a 3-week history of a painless, mobile, firm, 2.5-cm lump in the lower outer quadrant of the left breast without axillary lymphadenopathy. No evidence of nipple retraction or discharge was observed. The physical exam of the contralateral breast was unremarkable. She was already known, having been treated 2 years previously for a left invasive ductal carcinoma (lower outer quadrant, triple negative, grade 3, and Ki-67 70%) without nodal involvement (pT1bN0M0, stage IA). At that time, she underwent lumpectomy and sentinel lymph node biopsy followed by anthracycline/taxane-based adjuvant chemotherapy and radiotherapy (40 Gy in 15 fractions prescribed to ipsilateral whole breast with a 10-Gy boost in four fractions to the tumor bed). At first, the new symptomatic swelling presenting in the same quadrant 2 years after primary treatment was highly suspicious of local recurrence. The mammography and ultrasonography revealed an irregular, bulky mass with a lobulated border in the lateral part of the left breast ( Figures 1A-C ). On MRI, there was a 3-cm mass in the lateral part of the left breast with a high signal intensity at the periphery of the tumor ( Figure 1D ). The diagnosis and treatment timeline are demonstrated in Supplementary Figure S1 . The initial core needle biopsy suggested a spindle-cell malignant tumor with osteoid matrix and necrosis, and therefore, an excisional biopsy was then performed. On gross examination, the specimen was 50 mm x 40 mm x 30 mm and contained a medium-to-firm texture nodular lesion measuring 20 mm in maximum dimension and surrounded by fibro-fatty tissue. Microscopically, the lesion was composed of abundant pleomorphic, spindle, and oval cells with infiltrative growth patterns. The tumor cells revealed eosinophilic cytoplasm, prominent nucleoli, and a high mitotic index. Osteoid matrix and necrosis were frequently seen at the periphery of the tumor ( Figures 2A-C ). No evidence of infiltrating ductal carcinoma or ductal carcinoma in situ was observed. The following immunohistochemistry (IHC) results were obtained: Cytokeratin AE1/AE3 (AE1/AE3) (-), cluster of differentiation 56 (CD56) (focal+), special AT-rich sequence-binding protein (SATB) (+), murine double minute2 (MDM2) (+), smooth muscle actin (SMA) (partial+), Ki-67 (80%), cytokeratin 7 (CK7) (-), estrogen receptor (ER) (-), progesterone receptor (PR) (-), human epidermal growth factor receptor 2 (Her2) (0), cluster of differentiation 34 (CD34) (-), and S-100 (-) ( Figures 2D, E ). The negativity of AE1/AE3, an epithelial marker, reconfirmed the lack of an epithelial component. On the other hand, SATB was proven to be involved in the process of osteoblastic differentiation, which also authenticated our pathological prognosis as PBOS. To validate the pathological diagnosis of PBOS and explore the molecular connections between the PBOS and the previous invasive ductal carcinoma (IDC), a commercially targeted NGS was performed on both primary and secondary tumor slices for somatic mutations and peripheral blood samples for germline gene variants. A total of 421 gene variants related to target therapy, immune therapy, chemotherapy response, and genetic predisposition among breast cancer patients were included in the genomic panel. No germline variations were found for this patient. Several copy number variant (CNV) events were identified in the PBOS sample, including CN gains of FGFR1 and CN loss of CDKN2A and TSC2. Regarding somatic mutations, PIK3CA p.H1047R, PTEN p.V275G, TP53 p.T81Nfs*64, and TSC2 p.C728Lfs*34 were detected, with the highest variant allele frequency (VAF) of 59.22% happening in the PIK3CA mutation. Interestingly, somatic PIK3CA p.H1047R, PTEN p.V275G, and TP53 p.T81Nfs*64 were repeatedly detected in both PBOS and IDC tumor samples. On the other hand, somatic EGFR p.E709K was uniquely found in the IDC sample. A written and signed informed consent was obtained from the patients and presented as supplementary material. A CT of the chest, abdomen, and pelvis did not identify any metastases. An 18F-FDG PET/CT scanning was undertaken, and no evidence of a distant lesion or primary osteosarcoma arising from bone was detected, indicating that the breast lesion was primary osteosarcoma. As per our institute routine, the patient was discussed in a multidisciplinary team (MDT), and a skin-sparing mastectomy followed by immediate breast reconstruction with a deep inferior epigastric perforator (DIEP) flap was achieved for her. According to the MDT's opinion, axillary lymph node sampling was not performed. No residual lesion was identified histologically. No adjuvant treatment was recommended. The patient is under regular follow-up right now. The latest follow-up was done on 25 November 2022, and the patient is still alive.

breast malignancy, extraskeletal osteosarcoma, genomic profile, molecular therapy, primary breast osteosarcoma

PMC4714468_01

Female

Patient information: Female, 51 years old Chief complaint: Eye congestion, foreign body sensation Past history: No remarkable past medical history Smoking history and alcohol history: None Occupational history: Meat cutting (duck parts). Worked since July 1, 2009. Present illness: Stinging eyes and foreign body sensation had occurred from mid-December, 2012; eye congestion had also occurred frequently. Symptoms became worse in the presence of bright light. Ocular symptoms mostly occurred later in the working day and after work. Skin exfoliation and redness was observed around the eyes and on the face. Physical examination: Mild hyperemic conjunctiva (+), erythematous diffuse patches (+), facial reddish papule (+), pruritic and stinging sense (+). Laboratory findings: A peripheral blood examination revealed the following: hemoglobin level 11.9 g/dL, hematocrit 35.9 %, white blood cell count 4,500/mm3, and platelet count 180,000/mm3. According to an immunoassay, IgA was 214.0 mg/dL, IgE was 58.80 IU/ml. All these lab findings were within the normal range. Pulmonary function test findings: A pulmonary function test revealed the following: functional vital capacity (FVC) was 3.68 L (115.4 %), forced expiratory volume in one second (FEV1) was 3.00 L (124.5 %), the ratio of FEV1 to FVC was 81.52 % (108.8 %). All findings were within the normal range. Medical imaging findings: There were no significant findings upon plain chest radiography. Ophthalmology findings: Visual acuity was 0.1 in the right eye and 0.08 in the left. Maintained anterior chamber or anterior chamber cells were not observed in either eye. Intra ocular pressure was 14 mmHg in the right eye and 14 mmHg in the left. Schirmer`s test result was 20 mm in the right eye and 18 mm in the left. Diffuse corneal damage was observed (Figs. 2 and 3). On the basis of these results, keratoepitheliopathy was diagnosed. At the time of medical examination by interview, 26 out of a total of 41 workers (64 %) were complaining of ocular symptoms (stinging eye, teardrops, etc.). Moreover, skin symptoms (skin exfoliation, redness) were found in 4 workers (9 %) upon physical examination. Ocular symptoms mostly occurred immediately after finishing work or after going home, and skin symptoms around the eyes often occurred in workers. None of the workers had an abnormal complete blood cell count, and all Ig A and Ig E tests were normal. In addition, plain chest radiography and pulmonary function tests showed no abnormal findings in any of the workers. An ophthalmic examination yielded normal conjunctival findings in all workers; however, 26 out of 41 workers (63.4 %) were diagnosed with keratoepitheliopathy (Table 2). That is, all of the workers who had complained of the symptoms were diagnosed with keratoepitheliopathy. The abattoir processed chickens and ducks, and process flow involved 4 steps in the following order: mooring, cutting of meat, evisceration and cleaning, and selection. There were no significant differences among the processes with regard to the frequencies of workers who complained of ocular symptoms (p = 0.142) or skin symptoms (p = 0.112) (Table 3). These results confirmed that the symptoms were not caused by any specific process. There were no significant differences among the processes in terms of keratoepitheliopathy patient frequency (p = 0.393) (Table 4). Exposure to chemical substances and UV radiation was measured. Workplace environmental monitoring was conducted, focusing on 3 processes: cleaning, cleaning finish, and evisceration and hooking, wherein chlorine, hydrochloric acid, and sodium hydroxide was measured. The workers were not exposed to all 3 chemical substances in all processes, and even in processes where they were exposed, the exposure was well below the permitted limit (Table 5). Workers had none of respiratory symptoms or mucous membrane irritation symptoms that can manifest after exposure to the above chemical substances. In addition, there were no abnormal findings in the pulmonary function test, so that it was not possible to explain the skin and ocular symptoms in terms of exposure to the above chemical substances. What is more, while chemical substances were only used in the department of cleaning and evisceration, keratoepitheliopathy appeared in all departments. Therefore, it was clear on the basis of these findings that exposure to chemical substances was not the cause of the outbreak. Photokeratitis caused by UV radiation was also suspected - based on the ocular and skin symptoms of the workers. For this reason, the effective radiation dose from the UV disinfection lamp was measured. The apron disinfection lamp at the 1st floor was measured and it was found that it emitted UV-B at 15-30 muW/cm2 and UV-C at 40-160 muW/cm2 with a 5-10 cm measuring distance. The lamp at the 2nd floor emitted UV-B at 7-10 muW/cm2 and UV-C at 40-200 muW/cm2. On both floors, these measurements exceeded the exposure limit (American Conference of Governmental Industrial Hygienists [ACGIH] threshold limit values: 10 min at 5 muW/cm2, 5 min at 10 muW/cm2; Table 6). The apron disinfection lamps and UV lamps, in the factory are set to turn off automatically when the door of the disinfection equipment is opened. However, this setting was found to be malfunctioning, and the UV lamps of the disinfection equipment were remaining on when the door was opened. Since workers in all processes need to wear and remove aprons several times a day, it was determined that each individual may have been exposed to the UV radiation of the apron disinfection lamps from a short distance for at least 10 min a day (Fig. 4). It was therefore possible that all workers had been exposed to UV radiation for a significant amount of time, thus potentially explaining the ocular symptoms and keratoepitheliopathy that had occurred in a broad range of workers regardless of process. Furthermore, this was the likely explanation for the sunburn-like skin lesions on the face by exposure to UV. Further evidence was provided when workers' ocular and skin symptoms improved after removal of the UV disinfection lamps. Taken together, it was highly potential that the mass photokeratitis that had occurred in the poultry abattoir was caused by exposure to UV radiation from the apron disinfection lamps.

photokeratitis, poultry abattoir, south korea, ultraviolet

PMC3914201_01

Male

A 53-year-old man with end-stage renal failure (ESRD) of unknown etiology was on hemodialysis (HD) since 1999. He underwent a first RT in 2000, with cyclosporine (CyA), mycophenolate mofetil (MMF), and prednisolone as immunosuppressive therapy. Renal graft was lost after 3 days, due to renal artery thrombosis. Second deceased kidney transplantation was performed in 2007. Both were from cytomegalovirus (CMV) positive donors and the recipient was CMV positive as well. Initial immunosuppressive therapy was daclizumab, prednisolone, MMF, and tacrolimus (TAC). In the immediate posttransplant period, there were no surgical or infectious complications, delayed graft function, or acute rejection episodes. Five months after RT, the patient had a CMV infection treated with ganciclovir with success. Two years later, obstructive acute kidney injury was diagnosed, requiring a urological approach. Graft function stabilized to a serum creatinine (Cr) 2.3 mg/dL. Five years after RT, in February 2012, he was admitted with mild fever, profuse night sweating, and weight loss of 10% of his body weight, with three months of evolution. In the week prior to admission, he complained of pain in the right iliac fossa. The patient had no diarrhea, urinary symptoms, graft pain or other complaints. He had no recent travel history or known TB exposure. Analytical study revealed an elevated C-reactive protein (CRP = 70 mg/L), no anemia or leukocytosis, acute graft dysfunction, or other abnormalities. Serological study was negative, including viral hepatitis and HIV. Tuberculin skin testing was negative. Chest and abdominal X-ray and abdominal ultrasonography showed no abnormalities. Abdominal tomography (CT) was performed and showed terminal ileitis (Figure 1(a)). Colonoscopy revealed congestion and hyperemia of the ileocecal valve (ICV) with two small erosions (Figure 1(b)). ICV biopsy showed large bowel mucosa with irregularities of the surface epithelium and focal erosions, edema and congestion of the corium with mild to moderate inflammatory infiltrate. No viral inclusions, granulomas, or other morphological changes were identified, and Ziehl-Neelsen was negative. Polymerase chain reaction (PCR) for the diagnosis of TB on the biopsy tissue was positive. Antituberculosis (anti-TB) therapy was started with rifampicin, isoniazid, pyrazinamide, and ethambutol, with clinical improvement. There was a need to increase by 7 times the dose of TAC, after the introduction of Rifampicin, without rejection episodes. Nine months later, the patient is asymptomatic and the examination of the small bowel transit and colonoscopy showed no abnormalities and no evidence of reinfection.

PMC3914201_02

Female

A 53-year-old woman, inactive carrier of hepatitis B and ESRD secondary to membranoproliferative glomerulonephritis, was on HD since 1984. She underwent a deceased kidney transplantation in 2007, (CMV donor+/recipient+). Initial immunosuppressive therapy was daclizumab, prednisolone, MMF, and TAC. There were no delayed graft function, acute rejection episodes, and surgical or infectious complications and renal allograft function remained normal. Three years after RT, in February 2010, an episode of intestinal obstruction was documented and assumed as secondary to adhesions. Laparotomy was performed and showed few small bowel and colon loops with a whitish appearance and nodular structures of 5 mm in diameter along the ICV. Partial resection of the ileum was done. Histological examination revealed nonnecrotizing epithelioid granulomas in the ileum's subserosa (Figures 2(a) and 2(b)) and a mesenteric nodule showed a necrotizing nongranulomatous inflammation, and Ziehl-Neelsen was negative. After a short period of paucity of abdominal complaints, the patient suffered low-grade fever, pain in the lower abdomen, alternating constipation, and no hemorrhagic diarrhea. Two months later, in April 2010, she was readmitted with high fever (38.8 C), anorexia, and diffuse abdominal tenderness, especially at the right iliac fossa. Analytic study revealed leukocytosis (12.750/muL), elevated CRP (58 mg/L), without renal graft dysfunction or other abnormalities. Prior pathologic analysis of the intestine was reviewed and PCR analysis was positive for MT. A quadruple therapy consisting of rifampicin, isoniazid, pyrazinamide and ethambutol was started, with favorable evolution. There was a need to increase dose of TAC by 5 times, with no rejection episodes. Six months after anti-TB therapy, small bowel transit and colonoscopy showed no pathological changes. After anti-TB therapy suspension, the patient is asymptomatic, with no signs of reinfection.

PMC4430640_01

Female

Patient is a 25-year-old woman from Guinea-Bissau, West Africa, and was admitted with an 18-month history of dorsal back pain, asthenia, and significant weight loss followed in the last 8 months by loss of the ability to walk. On her physical examination she presented with three skin lesions (two ulcerated and one nodular) involving the right subclavicle region and other two lesions on her left thigh (one ulcerated and the other in a healing phase) (Figures 1 and 2); her neurological exams exhibited an ASIA A paraplegia with a sensory level at D4. Patient was anaemic with hemoglobin of 11,2 g/dL with an erythrocyte sedimentation rate of 75 mm/h and a C-reactive protein of 5,26 mg/dL. Gamma globulin level was 44 g/dL and blood chemistry evaluation was normal. HIV and primary immunodeficiency testing were negative. A chest X-ray revealed an enlarged mediastinal shadow (Figure 3), and the spinal computed tomographic scan showed a large anterior and paravertebral abscess from D1 to D10 with significant compression and osteolytic lesions of vertebral bodies with a kyphotic deformity (Figure 4). Spinal magnetic resonance revealed significant compression of the spinal cord at the kyphotic apex and angulation of the column, anterior and paravertebral epidural abscess consistent with spondylodiscitis (Figure 5). Bone biopsy revealed granulomatous inflammation with few acid-fast bacilli. Skin biopsy of the lesions (Figure 6) revealed acanthosis and pseudoepitheliomatous, hyperplasia of the epidermis, and necrosis foci surrounded by a histiocytic and lymphocyte infiltrate with giant cells on the dermis, consistent with tuberculosis with negative Ziehl-Neelsen stain. The patient was started on quadruple antituberculosis drug regimen together with pyridoxine and steroids, with a progressive clinical improvement, including healing of the skin lesions. One month later, anterior surgical debridement and posterior arthrodesis of the spine were performed. Blood and urine cultures including cultures for mycobacteria all proved negative. Cultures of the material collected through bone biopsy revealed M. tuberculosis. The patient fulfilled 15 months on antituberculosis medication and a favorable outcome was reported with complete recovery of neurological deficits.

PMC8046554_01

Female

A 4-month-old Hispanic female was admitted with nearly 2-month history of cough, posttussive emesis, gagging while feeding, and failure to thrive. She was born in the United States at 38 weeks estimated gestation via spontaneous vaginal delivery with uncomplicated pregnancy and delivery. The infant had mild left hydronephrosis identified by prenatal ultrasound that resolved spontaneously. After delivery, the infant was discharged home with mother in good health. Baby had two normal newborn screens. Family history was negative for immunodeficiency, tuberculosis, or lung disease. Upon developing cough at 2 months of age, she was evaluated as an outpatient by several providers. Due to chest radiograph findings of bilateral infiltrate, she was treated for presumed community-acquired pneumonia with oral antibiotics including 7 days of cefdinir and then 5 days of azithromycin, followed by 7 days of clindamycin without clinical or radiological improvement. At the time of admission for failure of outpatient therapy, physical examination revealed weight of 4.3 kg (<2%), length 58 cm (<5%), and head circumference 38.5 cm (<10%) with heart rate of 99 beats/min, respiratory rate of 40 breaths/min, and peripheral pulse oximetry of 98% on 5L high-flow nasal cannula supplementation. She was afebrile. Respiratory exam was positive for mild/moderate subcostal and intercostal retractions, nasal flaring, and decreased air entry bilaterally, but no wheezes nor crackles. She had evidence of systemic inflammatory response with elevated white blood cell count (24.5 K/CMM), elevated platelets (429 K/CMM), and inflammatory markers (CRP 5.1 mg/L, erythrocyte sedimentation rate 45 mm/hr.) The Pediatric Pulmonology service was consulted and computed tomography scan of the chest showed large posterior bilateral perihilar opacities with sparing of pulmonary periphery and bases, with subcarinal lymphadenopathy (Figure 1). Purified protein derivative (PPD) skin test and T-SPOT . TB interferon-gamma release assay for tuberculosis were negative. Subsequently, bronchoscopy, bronchoalveolar lavage, and lung biopsy were performed. The patient's lung biopsy demonstrated "pleural and subpleural fibrosis and inflammation, mixed, focal neutrophilic aggregate, interstitial thickening with focal lymphocyte infiltration, and alveolar epithelial hyperplasia." The pathology report also indicated "a few clusters of histiocytes, but well-formed granulomas are not seen." The pathology report concluded that the biopsy showed "no evidence of chronic interstitial lung disease in the background." Staining of the biopsy specimens for acid-fast bacilli (AFB) was negative. Surprisingly, pleural fluid culture isolated Mycobacterium abscessus which was also isolated from 1 gastric aspirate. At this time, Pediatric Infectious Diseases service was consulted. Susceptibility testing was performed in our local microbiology lab and after initiation of therapy for M. abscessus with amikacin (11 mg/kg/dose q24 h), clarithromycin (10 mg/kg/dose q12 h) subsequent AFB smears and cultures from bronchoalveolar lavage were negative. As inducible macrolide resistance for M. abscessus isolates has been reported, imipenem-cilastatin (20 mg/kg/dose q12 h) was initiated despite the isolate's MIC reported to be >32 mug/mL, while awaiting erm(41) gene testing results performed at the Mycobacteria/Nocardia lab at the University of Texas Health Science Center at Tyler. A nonfunctional erm(41) gene was identified by sequencing, confirming clarithromycin susceptibility (Figure 2). Imipenem was discontinued after several weeks as the patient developed transaminitis, which resolved after discontinuation. Due to the microbiology findings and severity of the patient's clinical presentation, further immune system function evaluation was undertaken with Pediatric Immunology consultation. HIV antibody and HIV RNA PCR testing were negative. Neutrophil oxidative index to evaluate for chronic granulomatous disease was normal. Lymphocyte phenotyping and mitogen and antigen proliferation studies were normal. She did demonstrate polyclonal hypergammaglobulinemia. However, she had normal antibody responses to diphtheria, tetanus, and 23-valent pneumococcal polysaccharide vaccine administration. Additionally, sweat chloride testing for cystic fibrosis was normal. At this point, Pediatric Pulmonology concluded that underlying lung pathology was unlikely. Consultants from Pediatric Medical Genetics requested urine organic acid and serum amino acid levels which were normal. She was assessed for aspiration that could contribute to her disease (bronchoscopy, barium swallow, and pH probe), but all studies were normal. Nerve conduction study showed no electrodiagnostic evidence to suggest an underlying neuropathy, myopathy, or neuromuscular junction defect. Despite the normal evaluation to this point, we remained concerned about immunodeficiency or other genetic disease increasing susceptibility to nontuberculous mycobacteria (NTM) infection. Whole blood was sent to Dr. Steve Holland (Division of Intramural Research (DIR) at National Institute of Allergy and Infectious Diseases (NIAID)) to assess for potential Mendelian susceptibility to mycobacterial disease (interferon gamma receptor/STAT 1 gene deficiency). Whole exonic captures and analysis of 3635 regions spanning 342 genes were evaluated, though 874 regions corresponding to 250 genes had "inadequate or incomplete coverage." With these limitations, no obvious causative variants were identified from the captured regions screened. Three "uncommon heterozygous variants of unknown significance" were identified (LRBA, RNASEH2Bm, and LYST) as well as one novel heterozygous variant of unknown significance (TMC8). A second whole-exome sequencing test (ExomeNext , Ambry Genetics , Aliso Viejo, CA) requested by Medical Genetics reported "no clinically relevant alterations detected." Over her 4-month hospitalization (complicated by central-line associated bloodstream infection and respiratory syncytial virus infection), her respiratory support was weaned to continuous positive airway pressure and she was discharged with supplemental oxygen via nasal cannula. Repeat computed tomography imaging of the chest was obtained after 7 months of treatment and showed improvement of the bilateral consolidations. Serial chest radiographs revealed marked improvement with only subsegmental atelectasis in the right lung base at 15 months of age. Ultimately, she completed 14 months of amikacin and clarithromycin, and oxygen supplementation via nasal cannula was discontinued. She has normal weight gain and growth parameters at this time. Her hearing tests have been normal.

PMC7276574_01

Male

In July 2018, a 14-year and 9-month-old Caucasian male patient, in good general health, presented with an onset of acute pain while attempting a kick with his contralateral leg during an amateur football match. He, also, noticed that an ecchymosis in the dorsal aspect of the left thigh formed shortly after the traumatic event. He presumed, with no medical consultation, that the acute event was a muscle tear of the hamstrings and dealt with it as such. In September 2018, he consulted an orthopedic surgeon complaining of pain in the dorsal aspect of the left thigh and buttock for 3 months and difficulty walking, resulting in a slight limp. The pain worsened during exercise and an extended period of walking and radiated to the groin area and toward the dorsal and lateral periphery of the left buttock and thigh during physical activity. During clinical examination, range of motion of the left hip is slightly impaired due to pain with particular exacerbation during flexion. Straight leg rise was about 70 , 15 lower compared to the right hip. Neither neurological and vascular symptoms or signs nor involvement of other musculoskeletal components were detected. The patient underwent frontal radiographic examination of the pelvis and hip (Fig. 1a) that showed irregularity of the inferior margin of the left ischial tuberosity with fragmentation and avulsion of the apophysis and also ultrasonography of the area that was normal. A tumor could not be excluded from the differential diagnosis yet, so follow-up was crucial. After about 9 months, later than the follow-up that was advised, in which the patient was prescribed with rest and painkillers and saw great improvement, he underwent full investigation that included another radiographic examination (Fig. 1b) that was unchanged compared to the previous one, computed tomography (CT) (Fig. 2), MRI (Fig. 3), Technetium99 scintigraphic scan (Fig. 4), and blood analysis. The CT scan (bony window) confirmed the diagnosis as apophysitis of the ischial tuberosity, as it showed enlargement of the left ischial tuberosity with irregularity of its inferior margin and focal sclerosis. The MRI showed apophyseal avulsion with marrow edema and widening of the apophysis and focal edema of the insertion of the hamstrings. Blood analysis had no pathological findings (white blood count 6350 with neutrophil 57%, erythrocyte sedimentation rate 4, and alkaline phosphatase 187 IU/l). Finally, in the bone scintigraphic scan, there was an increased blood flow in the ischial tuberosity, compatible with the diagnosis, and a slight increase of the bone metabolism in the left ischial body (posterior view) and the anterior-lateral aspect of the left femoral diaphysis due to a known non-ossifying fibroma. With the entire investigation concluded, the diagnosis is confirmed as an apophysitis of the ischial tuberosity. The patient is treated with rest, physical therapy, and painkillers.

apophysitis, ischial tuberosity, teenage athlete

PMC8053472_01

Female

Five pediatric patients (including three female and two male) with ages ranged from 2 to 17 years old (average 9-years old). At admission all the patients presented hydrocephalus, and a ventriculoperitoneal shunt (VPS) was subsequently placed. Physical examination revealed low weight in one subject and moderate malnutrition in two cases [Table 1]. All patients showed signs of endocranial hypertension on admission. Sixth nerve palsy was identified in three children and central facial palsy in one case. Seizures were documented in one child, while in another case the patient developed ataxic gait. Three children debuted with hemiparesis; two patients had Parinaud's sign and meningeal signs on admission. Papilledema was found in three patients on fundoscopy. Fever was recorded in only three cases [Table 2]. Preoperative CT scan showed an Evans index greater than postoperative control MRI (average of 0.39, ranges 0.31-0.58, and 0.30, ranges 0.15-0.31, respectively). Three cases presented asymmetric hydrocephalus (AH) [Figure 1] and abnormalities in the fourth ventricle morphology (cases 2, 4-5). Case 2 developed a isolated fourth ventricle (IFV) [Figure 2]. Case 5 developed compression and displacement of the fourth ventricle secondary to tonsillar displacement and Chiari II malformation [Figure 2c]. In control MRI studies, two children presented cerebral vasculitis (case 2-3). Postsurgical control MRI showed leptomeningeal enhancement (5/5) and basal arachnoiditis (4/5) (involving perimesencephalic cisterns and medial portion of the Sylvian cisterns). Serological tests in CSF revealed IgG levels from 0.150 to 0.495 D.0. (mean 0.845 D.0. across subjects) while in serum IgG titers ranged from 0.005 to 2.16 D.0. (mean 0.8344). Children with CM diagnosed by serology presented serum IgG levels against Coccidioides >0.500 D.0 with an upper limit of 2.16 D.0. (case 1, 3-4). In contrast, in patients diagnosed by histopathology (cases two and five) titers were <0.150 D.0. and therefore considered negative for systemic coccidiomycosis. Only two patients, with serological diagnosis of CM, presented positive serum IgM titers for Coccidioides (>=0.150 D.0)*. Mean IgE levels ranged from 25 to 173.UI/ml (mean 0.845 D.0.). Case 5 (patient with Chiari II malformation, who underwent myelomeningocele repair at birth), presented high levels of IgE but did not meet the criteria for Job Syndrome. One patient presented high levels of IgM and in 40% (n = 2) high levels of IgG were observed. The average IgG titers ranged from 1219 to 1858 mg/dl (mean 1522.4 mg/dl). Despite having the highest serum IgG titers, Case 4 antibodies against Coccidioides were not increased (negative test). Hyper or hypogammaglobulinemia was not detected in the rest of cases. T lymphocyte counts were normal in the tested case. No patient presented with eosinophilia or lymphopenia. Serology tests for HIV, hepatitis B and C were negative in all cases. CSF cytology was positive in two children [Figure 3]. All leptomeningeal biopsies showed inflammation signs, but no spherules were identified. CSF analysis revealed no abnormalities in four subjects; only in one case low glucose levels and mild pleocytosis was detected (see Annex I). All CSF cultures were negative for fungi. Case 2 presented growth for on the distal shunt catheter. Fluconazole at doses of 6-12 mg/kg/day was prescribed as life-long antifungal therapy. Corticosteroids were indicated in case of cerebral vasculitis, or signs of serious illness. Case 2 was treated with caspofungin and cephalosporins initially due to a positive culture for Pseudomonas aeruginosa in the distal shunt. The child presented neurological deterioration and poor evolution and MRI showed HA, cerebral vasculitis, and IFV. After a month of hospitalization and multiple shunt replacements, C. immitis was isolated in ventricular CSF [Figure 3a] and treatment with Fluconazole 800 mg/day was started. However, the patient presented cardiorespiratory arrest and evolved to a persistent vegetative state. VPS placement was performed in all subjects. In case of bacterial superinfection, external ventricular drains were also placed (case 2). An average of three surgeries was performed per subject (range 1-9). Case 2 developed IFV and it was therefore decided to place a shunt of the fourth ventricle into the subarachnoid space. Case 2 presented hyponatremia secondary to transient syndrome of inappropriate antidiuretic hormone secretion (SIHAD), with spontaneous resolution. Cases one and three were initially treated as tuberculous meningitis, but CSF PCR was negative for tuberculosis, and CM was later diagnosed by positive IgG serology against Coccidioides in ventricular CSF. These two children developed rash and drug related hepatitis due to the interaction of fluconazole and the initial antifimic therapy. The average follow-up was 8 months after discharge. Serum IgG and IgM titers against Coccidioides and liver function tests were periodically requested. Control serological tests were reported as negative (<0.150 D.0.). Clinical outcomes were satisfactory in four cases, without evidence of long-term neurological compromise. However, one child (case two) developed a persistent vegetative state. One year after discharge none of the subjects died.

coccidioidal meningitis, diagnosis, hydrocephalus, pediatric, serology

PMC6694717_02

Male

A 40-year-old man from hills of Nepal presented to the emergency department of Patan Hospital in August 2018 with complaints of weakness in the right half of the body, deviation of the left side of the face and slurring of speech for 4 days. At 3 weeks prior to this, he had visited another tertiary level hospital in Kathmandu for pain in the lower abdomen and fever, where he was diagnosed as having ileo-cecal tuberculosis based on colonoscopy and biopsy with positive Ziehl-Neelson staining. He was then prescribed with antitubercular therapy (ATT) that included 3 tablets of Fixed dose combination consisting of isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg and ethambutol 275 mg once daily and prednisolone 40 mg once daily. He was advised to take ATT from a health centre near his residence, whereas prednisolone was dispensed from the hospital pharmacy. Unfortunately, he just took prednisolone, but no ATT. As a result, he ended up in emergency with the aforementioned complaints. On evaluation, his chest x-ray showed features of pulmonary tuberculosis. Cerebral spinal Fluid (CSF) analysis was done which showed red blood cells (RBC) 200/microl (normal value, 0/microl), WBC 64/microl (normal range, 0-5/ microl), neutrophil 24%, lymphocytes 64%, protein 294 mg/dl (normal range, 15-45 mg/dl) and sugar 49 mg/dl (normal range, 50-80 mg/dl). Cerebrospinal fluid GeneXpert testing was positive for Mycobacterium tuberculosis. He was then diagnosed as disseminated tuberculosis with meningeal involvement and was admitted to Patan Hospital with ATT (3 tablets of fixed-dose combination consisting of Isoniazid 75mg, Rifampicin 150 mg, Pyrazinamide 400 mg and Ethambutol 275mg once daily) and dexamethasone (6 mg three times a day) for 3 days. He was then discharged with ATT (same dose as above) and prednisolone (40 mg once daily) after proper counselling about the nature of the disease and site of availability of anti-tubercular drugs. He came in for follow-up after 2 weeks with improvement in the symptoms and has been taking all medications properly.

communication, methotrexate, tuberculosis

PMC8110398_01

Female

A 9-year-old generally healthy girl with a history of a small muscular ventricular septal defect presented to the emergency room with chest pain and dyspnea. She had recovered from a recent upper respiratory infection and had also sustained minor trauma to the anterior chest wall in a fall a week prior. At presentation, she appeared well with temperature, 98.6 degrees Fahrenheit; heart rate, 104 beats per minute; respiratory rate, 28 breaths per minute; blood pressure, 113/66 mmHg; pulsus paradoxus, 8 mmHg; and normal pulse oximetry with minimal pulse amplitude variation on plethysmography. Her physical exam was notable only for mild tenderness over the sternum, with normal findings on cardiac auscultation. Chest radiography revealed a mildly enlarged cardiomediastinal silhouette and a focal opacity over the right middle lung possibly representing infection or pulmonary contusion. An electrocardiogram (ECG) was normal (Figure 1(a)). Echocardiography demonstrated a moderate-sized circumferential pericardial effusion, right atrial collapse, normal inflow and outflow variability across valves, normal biventricular systolic function, and no ventricular septal defect. Laboratory findings were notable for a leukocyte count of 12,000 cells/microl with an elevated absolute eosinophil count of 1,570 cells/microl (normal 40-190 cells/microl), elevated C-reactive protein of 1.94 mg/dL (normal <0.5 mg/dL), elevated erythrocyte sedimentation rate of 45 mm/hr (normal 0-30 mm/hr), and elevated cardiac troponin T of 0.25 ng/mL (normal <0.1 ng/mL). CMR (Figure 2) showed an elevated myocardial global T2 value (70 ms), an elevated native myocardial global T1 value (1150 ms), increased left ventricular wall thickness, and a moderate-sized pericardial effusion. There was no myocardial late gadolinium enhancement. The patient was admitted to the cardiology service. The working diagnosis was viral myopericarditis, but the differential diagnosis also included cardiac contusion, pulmonary contusion, and a range of etiologies for peripheral eosinophilia. Although some of the echocardiographic findings were consistent with tamponade physiology, the physical findings were not, and pericardiocentesis was not performed. Treatment was initiated with oral ibuprofen (400 mg every 8 hours) and colchicine (0.1 mg/kg daily) with resolution of chest pain, normalization of troponin and inflammatory markers, persistently normal ECGs, and reduction in the size of the pericardial effusion over three days. However, the peripheral eosinophilia increased (Figure 3). Consultation was obtained from the infectious diseases, allergy/immunology, and rheumatology services. Additional history was elicited, including pica and exposure to two dogs and a cat in the home. Further testing was recommended. Chest computed tomography revealed multiple pulmonary nodules with adjacent ground glass opacities, consistent with vasculitis or infection (Figure 4). In the absence of systemic symptoms, an infectious workup was broadened, and a full rheumatologic evaluation and steroid initiation was postponed until the results of the infectious diseases workup were finalized. Microbiologic testing included negative PCRs for influenza, respiratory syncytial virus, parainfluenza virus, rhinovirus, and adenovirus. Bartonella henselae titers and a T-SPOT tuberculosis test were also negative. Mycoplasma pneumoniae IgM and IgG were elevated, but nasopharyngeal Mycoplasma PCR was negative. Toxocara serology was sent and was pending at discharge on hospital day 3. At a two-week follow-up visit, the patient remained asymptomatic on ibuprofen and colchicine. Diffuse T-wave inversion appeared on serial ECGs, consistent with pericarditis (Figure 1(b)). Her absolute eosinophil count continued to rise to 2,450 cells/microl. Twelve days into her illness, the Toxocara antibody resulted positive. An abdominal ultrasound examination was normal, without signs of liver involvement. A repeat echocardiogram showed a very small residual pericardial effusion. Ibuprofen and colchicine were discontinued, and treatment was initiated with a five-day course of oral albendazole (6 mg/kg/dose twice daily) and prednisolone (0.5 mg/kg/dose twice daily). At late follow-up there was a normal eosinophil count (Figure 3), and on echocardiogram, there was normal ventricular function and no pericardial effusion.

PMC6502708_01

Female

This is a report of a 56-year-old female patient who was admitted at our institution for the clarification of diffuse interstitial infiltrations of the lower lung lobes and hilar and mediastinal lymphadenopathy. A malignancy, in particular a non-Hodgkin lymphoma, was initially suspected and a mediastinoscopy was primarily performed to gain a sufficient amount of material. A bleeding which occurred during this procedure was handled with local compression with a gauge and minimal use of local electrocautery. The procedure was concluded with sampling of the enlarged lymph nodes at the right inferior paratracheal level without complete resection. Radiological control on the first postoperative day excluded hematoma formation or pneumomediastinum and the patient was discharged on the next day. The histological examination of the specimens showed a histiocytic lymphadenitis. Due to the discrepancy between clinical evaluation and histological findings, an EBUS-TBNA was performed 2 weeks after the mediastinoscopy. Probes were attained from lymph nodes at stations 4L, 4R, 11L, 7 as well as from the right main bronchus. One week later the patient was readmitted to the hospital due to fever and fatigue. The mediastinoscopy wound was lightly reddened and a small amount of serous fluid was easily evacuated after applying slight pressure on the wound. A computed tomography scan of the thorax was suspicious of a bronchomediastinal fistula depicting a pneumomediastinum ( Figs. 1 and 2 ), whereas a bronchoscopy confirmed the fistula showing a melting lesion on the right main bronchus ( Fig. 3 ). The patient was then subjected to a right axillary thoracotomy; the pretracheal area until the tracheal bifurcation was partially loose but did not have any sign of an extended infection. Microbiological specimens from the site of the paratracheal tissue obtained during the surgical revision were negative. Specimens taken from the lesion site during the preoperative bronchoscopy were positive for Staphylococcus . The fistula with a size of a baby fingertip was located on the right main bronchus. A local debridement was done and the bronchial defect was directly closed with 4-0 PDS sutures and covered with the mobilized azygous vein. An extended biopsy of the enlarged lymph nodes was also performed. The patient was treated with antibiotics postoperatively. Postoperative bronchoscopy revealed a firm closure of the lesion ( Fig. 4 ). The mediastinoscopy wound healed easily without any further surgical measures. The patient recovered completely and was discharged 1 week later. Histology of the abundant specimens excluded again malignancy, showing anthracotic and histiocytic-altered lymphatic tissue, as well as an extended active perilymphadenitis matching to the local bronchomediastinal fistula.

mediastinal lymph nodes, mediastinum (incl mediastinoscopy), thoracic surgery, ultrasound (all applications)

PMC3540688_01

Female

The case concerns a 40-year-old woman who presented at our outpatient department with 2 years history of low back pain and lower limb weakness for 1 month. She presented to us with bladder incontinence and inability to ambulate. The bladder dysfunction had started 7 days before hospital presentation. On examination, she looked depressed and pale; there was no lymphadenopathy and apparent organomegaly. She had tenderness of lower thoracic spinal processes. Neurological examination of the legs showed reduced tone, and grade 1 paraplegia (MRC Scale). Knee jerks as well as ankle jerks were absent, both plantar reflexes were not elicitable, and there was sensory deficit over both lower limbs below mid-thigh level. No clinically significant past history was present. She was admitted and investigated. Investigations showed normal serum biochemistry apart from a mild increase of alkaline phosphatase, which was 15 KAU/L (normal 2-13). The total white cell count was within normal limit, differential count showed neutrophils 25%, lymphocytes 70%, monocytes 2%, eosinophils 3%, and basophils 0.0%, and no atypical lymphocytes were seen in blood film. The erythrocyte sedimentation rate was 24 mm/1st h. A lumbosacral spine X-ray (Figure 1) examination showed vertebra plana of T10 vertebra with sclerosis and maintained disc space. Abdominal ultrasound was normal; no organomegaly and enlarged lymph nodes were detected. Bone marrow biopsy was done which showed normal bony trabeculae. MRI scan showed (Figure 3) vertebra plana of T10 vertebra with complete marrow replacement of vertebral body and posterior elements with associated homogenously enhanced soft tissue component in adjacent pre- and paravertebral space and in ventral and dorsal epidural spaces leading to severe cord compression and spinal canal stenosis. Although radiological picture was not in favor of tuberculosis, we started antitubercular treatment, as tuberculosis is very common in India and we have seen the cases of spinal tuberculosis with unusual presentation. However, patient did not respond to antitubercular treatment. The patient was operated and anterolateral decompression of spinal cord was done to relieve symptoms of cord compression. Histopathological examination showed malignant small round cells (Figure 2) with some rosette formation. A diagnosis of small round cell tumor was suggested on basis of these findings. Immunohistochemistry examination showed positivity of tumor cells for common leukocyte antigen distinguishing it from round cell tumor. The patient improved remarkably after surgery. Sensory symptoms improved and motor power regained to 4/5 on hip and 5/5 on knee and ankle (MRC Scale). Bladder control could not be gained 30 days after surgery.

PMC5679777_01

Male

A 61-year-old man with a known history of hypertension and gastroesophageal reflux disease presented to the emergency room with worsening abdominal pain, intractable nausea, and 3 days of vomiting. He was experiencing episodes of nonspecific abdominal pain that would last for 4-5 days every month for the previous year. Over-the-counter medications such as ranitidine and magnesium oxide provided minimum relief. Prior to admission, the patient took 4 tablets of 81-mg aspirin and 9 tablets of 250-mg acetaminophen over 3 days. Review of systems was positive for intermittent constipation, heartburn, and anorexia. He denied use of alcohol and herbal medications or supplements. Vital signs at the time of triage were stable. Physical examination was significant for scleral icterus, jaundice, and tenderness in the epigastrium and right lower quadrant of the abdomen. Laboratory data revealed a normal white blood cell count and platelet count, with hemoglobin 16.1 g/dL. The liver enzymes were remarkable for total bilirubin 10.6 mg/dL, conjugated bilirubin 7 mg/dL, alanine aminotransferase (ALT) 371 IU/L, aspartate aminotransferase (AST) 252 IU/L, gamma-glutamyl transpeptidase 301 IU/L, and alkaline phosphatase 199 IU/L. Serological tests for viral hepatitis A, hepatitis B, hepatitis C, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, and herpes virus were negative. Acetaminophen, salicylate, and ethanol levels were undetectable. Autoimmune disease was also ruled out by negative immunological assays. During the course of his admission, his aminotransferases rose gradually, peaking at 512 IU/L AST and 593 IU/L ALT at hospital day 11. Total bilirubin trended down slightly to 7.2 mg/dL. Computed tomography (CT) of the abdomen with contrast performed in the emergency room revealed a 2 cm x 3 cm calcified speculated mass located in the ileocecal valve with associated right lower quadrant mesenteric lymphadenopathy and an unremarkable liver, spleen, and pancreas (Figure 1). Repeat CT of the chest/abdomen/pelvis performed as part of the metastatic work-up at our institute revealed findings similar to the prior CT imaging. Tumor markers carcinoembryonic antigen and alpha-fetoprotein were negative. The patient refused magnetic resonance imaging due to severe claustrophobia. An upper endoscopy revealed a segment of Barrett's esophagus Prague Classification C8M9, with gastroesophageal junction 38 cm from the incisors; biopsies confirmed goblet cell metaplasia consistent with Barrett's esophagus. A colonoscopy revealed evidence of a submucosal mass in the ileocolonic region/terminal ileum, which was obstructing the terminal ileum (Figure 2). The biopsies of the mass were consistent with carcinoid tumor (Figure 3). An octreotide scan revealed focal radiotracer uptake within the partially calcified soft tissue mass that abutted and involved the medial wall of the cecum. There was an additional focus of radiotracer uptake in a soft tissue mass within the mesentery adjacent to the cecal mass, which represented a lymph node. There was a physiologic distribution of radiotracer uptake in the liver but no evidence of metastasis (Figure 4). The ileocecal mass was surgically resected, along with lymph node dissection. Final surgical pathology revealed a low-grade neuroendocrine tumor (carcinoid), 1.5 cm in the largest dimension, infiltrating through the muscularis propria to the subserosal adipose. Seven of the 12 lymph nodes resected were positive for metastatic carcinoma. The margins of the resection were negative. The appendix was negative for neuroendocrine tumor. Tumor cells were positive for chromogranin, synaptophysin, and pan-cytokeratin (AE1/AE3), and negative for CD56 and TTF-1. Ki-67 labeling index was <=2%. The liver abnormalities without a discernable cause called for a liver biopsy, which showed benign liver parenchyma. After the surgical resection of the tumor, the liver enzymes trended down and normalized within 2 weeks. The absence of any definite cause of cholestasis in conjunction with immediate downward trending of liver enzymes after resection of the carcinoid suggests a paraneoplastic phenomenon.

PMC5869061_01

Female

A 29-year-old had previously undergone two caesarean sections, the second five months previously at a district general hospital. The operation and immediate postoperative period were uneventful. Three months later she noticed a purulent discharge from her wound. She was advised to take antibiotics and to dress the wound daily but despite this the discharge continued and she presented to us. She gave a history of primary infertility of 6 years, for which she was never evaluated. On examination her vital signs were within normal limits. Abdominal examination revealed a pus-draining sinus through the Pfannenstiel scar (Fig. 1). As per speculum examination there was mucoid discharge; per vaginally, the uterus was anteverted to 6-8-week size, with restricted mobility and appeared adherent anteriorly. Her haemoglobin was 102 g/l. Other haematological investigations were within normal limits. A cartilage-based nucleic acid amplification test (CBNAAT) of a sample of the wound discharge for diagnosis of tuberculosis, was negative. Transabdominal ultrasonography was suggestive of a pelvic fluid collection with a sinus tract. On fistulogram, the contrast opacified as a blind-ending cavity measuring 8 x 2 cm, with an irregular outline and evidence of contrast in the pelvic cavity adjacent to gut loops. Magnetic resonance imaging revealed a peripherally enhancing collection in the abdominal wall communicating with the uterus and the exterior through the abdominal wall. Laparotomy for excision of the fistulous tract was arranged. Intraoperatively, on excising the scar we found two fistulous tracts with granulation tissue around them. The first tract connected the skin to the uterine cavity, with necrosis of the anterior uterine wall. The second tract commenced in the skin and ended at another point on the skin. The patient gave informed consent for excision of the fistulous tracts and/or total abdominal hysterectomy. However, it was deemed that there was no scope for excision and to avoid the risk of sepsis the decision was made for a total abdominal hysterectomy. Both ovaries were normal. On gross examination, there was evidence of granulation tissue in the endometrial cavity and necrosis in the anterior uterine wall (Fig. 2). A specimen was sent for histopathological examination. The postoperative period was uneventful. The histopathological examination revealed granulomatous inflammation suggestive of tuberculosis. She responded well to anti-tubercular therapy. The patient for discharged on the 10th postoperative day on anti-tubercular drugs. She presented for follow-up after 6 weeks with a well healed scar.

lower-segment caesarean section, tuberculosis, uterocutaneous fistula

PMC7739786_01

Male

The person involved in the case study was a 28-year-old male with a BMI of 20. The program was adapted for Target heart rate (THR) training by High-intensity Interval training-based treadmill running. The training aimed to achieve the THR in peak HR for the maximum time possible, thus improving VO2 max (Tayler et al.,; Thomas et al.,). The device used to track the Heart rate and Program data was a Fitbit Charge 2. The case study divided training into five phases, namely, the initial training phase, training phase, peak phase, weight training/detraining phase, and memory reactivation phase. The maximum aerobic capacity or max heart rate (HR) was calculated by a formula created by Nes et al.: HRmax = 211 - (0.64 x age), which is 193 bpm. The peak zone or maximum THR to peak zone (i.e., 85% and above of the maximum aerobic capacity) is >85% of 193. The training type used was High-Intensity Interval training (HIIT). High-intensity Interval training is built upon alternating between short, high-intensity bursts of energy with slower recovery phases throughout a single workout. Initially starting with steady-state cardio, this method gradually progresses to HIIT. It starts with an initial warm-up phase followed by alternating high-intensity running and slow walking recovery bursts; lastly, there is a cool-down phase. The aerobic detraining phase was achieved by inducing weight training. The weight training work out was low to mid-intensity weight training. The main parameters considered for evolution were the heart rate zone and graph, the number of steps per exercise session, the calories burnt, and the duration of the exercise. The conditions set for training were considered to be the timing of training and the intensity of the treadmill, including speed in km/hr and inclination. The training was done in the morning session. Before training, the subject was regularly exercising/running for 20-30 min a day for 6 months. The average foot stride was of 2.5ft. The average room temperature varied from (22 +- 2) Celsius in winter to (31 +- 3) Celsius in summer. The activity tracker data report consists of the date, time, HR graph, Calorie burn graph, step count, HR zone, etc. This consisted of 5 km running on a treadmill within approximate 40 (+-5) min. The initial warm-up burst was 3 KM/Hr to 6 KM/Hr walk for 5-7 min. The maximum speed of highest intensity per burst was 12 KM/Hr with every burst of 1 min, and the lowest was 6 KM/Hr for a low-intensity bout with every burst of 1 min. Total High- and Low-intensity alternating bursts was on average 25-29 min. The last 2-3 min phase consisted of the cool down. As shown in Figure 1, the average step count was (5,200 +- 400) steps per exercise session, summating to an average of 5 km on the ground running. The average calorie burn was (400 +- 30) calories. The peak heart zone (85 to 100 percent of the maximum HR) maintained was 4 (+-2 min). The maximum maintained zone was the cardio zone (70 to 84 percent of your maximum heart rate). This training was varied to 4-5 days a week for nearly 7 months. The treadmill inclination varied by 2% (+-1). After the initial training, the peak performance stage was reached. As shown in Figure 2, the average step count was 5,600 (+-500) steps per exercise session, resulting in an average of 5.5 (+-0.5) km on the ground running. The average calorie burn was 470/+-30 calories. The enhancement to VO2 Max was seen. The peak heart zone (85 to 100 percent of your maximum heart rate) that was maintained for 15 min (+-4). The maximum maintained zone was the peak heart rate zone. The cardio zone was maintained for an average 15 (+-4) min (70 to 84 percent of your maximum heart rate). All treadmill training parameters were, on average, the same as the initial phase. After the peak performance stage was reached, the subject maintained a regular training schedule for 3-4 days a week, with a reduction in treadmill training parameters concerning the intensity of bursts, number of bursts per exercise, and high burst time duration. The main aim of the schedule was to maintain the peak heart performance achieved during training. As shown in Figure 3, the maintained VO2 Max was seen. The peak heart zone (85-100% of your maximum heart rate) maintained was 14 min (+-4). The maximum maintained zone was the peak heart rate zone. The cardio zone was maintained for an average of 16 (+-4) min (70 to 84% of your maximum heart rate). Following continuous induction of high-intensity aerobic exercise for almost 1.5 years, remarkable weight loss (10 +- 0.5 Kg) and subsequent muscle loss was seen. So, the partial detraining from aerobic exercise and added weight training was achieved. Weight training consisted of 2 days of weight training followed by cardio training for 1 day and a following 2 days of weight training. Weight training was low to mid intensity supplemented by a protein diet with 1-1.2 gm protein per kg in the natural form. No as shown in Figure 4, peak HR zone was maintained. The maximum HR zone maintained was the fat burn zone for an average of 22 (+-10) min. Average exercise lasts for 40 min (+-5). The average step count was 2,100 (+-500) steps per exercise bout, coming to an average of 1.5 (+-0.5) km. The average calorie burned was 250/+-30 calories. This was very important phase to be noted. After 3 months of treadmill activity of regular steady sate jogging/walking was added at a speed of 6 km/Hr for just 10 min (+-3) at the end of weight training without any HIIT or high intensity burst, the heart rate suddenly peaked to the peak HR zone. The place and the time spent on the treadmill were all similar stimuli to that used during peak HR training. There was no high inclination of increment in the speed to reach peak HR. As shown in Figure 5, even the average distance covered after 10 min on the treadmill was not more than the 1.2 km average, and that is despite the total steps taken being close to 3,000 in the whole session. To cross verify whether this was the effect of memory reactivation, i.e., the same stimulus as time, odor, temperature, place, and equipment, four different settings were tested. First, the treadmill session was added to the first part of weight training. Second, we tested the effect of running the whole session outdoors or in a completely different environment. Third, we changed the treadmill environment by changing the complete stimulus other than that previously used. Last, we carried out reverification after a few months under the same stimulus. In the first trial, the result was the same as with the stimulus that was used during training when added at the start of weight training instead of at the end; HR was easily raised to the peak zone. It was tested for an average of 15 min. The heart rate was triggered to reach toward the peak HR zone in just couple of minutes. During the weight training session, it varied in the fat burn zone. As shown in Figure 6, during the second verification trial, the subject was made to run for 38 min (+-2) in an outdoor non-similar stimulus environment with HIIT-type running. Of note was the fact that the heart rate remained in the cardio and fat burn zone and did not reach the peak HR. The distance was 4.6 km, and the step count was 4,870. Looking at distance covered, the step count, and the calorie burn graph, we can see that it was similar to the training or peak phase data, but changes in the environment resulted in different HR zones, and this was after nearly 5 months of aerobic partial detraining. As shown in Figures 7, 8, during the third verification trial, yjr subject was made to run for 12 min (+-2) in a non-similar treadmill stimulus environment with HIIT-type running during his weight training session of an average of 37 min. The location, equipment, and environment (Rasch and Born,) was changed completely. Of note was the fact that the heart rate remained in the cardio and fat burn zone and did not reach the peak HR. In the fourth trial, the subject was weight trained in the same environment (Rasch and Born,; Van Someren et al.,; Schedlbauer et al.,) after a few days of discontinuation with the addition of cardio training at the end of session, i.e., a similar treadmill stimulus environment with slow jogging of 6 km/Hr during the weight training session with the same place, time, equipment, etc, As shown in Figure 9, the heart rate was easily raised to the peak zone. It was tested for 12 min average. Heart rate was triggered to reach the peak HR zone in just a couple of minutes.

thr, aerobic, exercise, memory reactivation, neuronal ensemble, peak heart rate

PMC8574107_01

Female

A 68-year-old man with end-stage renal disease of unknown etiology underwent a KTx from a 32-year old deceased female donor, who died of head trauma (cytomegalovirus D-/R+, Epstein-Barr virus D+/R+). He had a past history of type 2 diabetes, hypertension, coronary artery disease and squamous cell carcinoma of the tibial area resected 8 years before the KTx. His past medical history also included pulmonary tuberculosis. He had been maintained on haemodialysis for the preceding seven years. At the time of KTx he was in a good general condition. HLA mismatching was 0 : 1 : 0 (A, B, DR), respectively. Anesthesia and surgery were uneventful, with good initial kidney perfusion. He underwent basiliximab induction therapy and commenced EVR, cyclosporine (CsA) and prednisone maintenance therapy. EVR was introduced because of the history of squamous cell carcinoma. CsA was chosen over tacrolimus in order to prevent significant deterioration of glycemic control in a patient with type 2 diabetes. The doses of EVR and cyclosporine were adjusted to maintain standard target trough levels. The chest X-ray performed on the day of KTx showed no obvious abnormality. Three months later the patient presented with fever, progressive dyspnea, and a productive cough for two weeks. On general examination, the patient was conscious and well-oriented. He had a pulse rate of 108/min, lood pressure of 100/60 mmHg, respiratory rate of 28 cycles/min and there was evident cyanosis. Room air oxygen saturation was around 90%. Other systemic examinations were normal. Admission chest radiography showed patchy infiltrates suggestive of bacterial pneumonia in the left inferior segments corresponding to crackles, rhonchi and wheezes on auscultation. His laboratory testing revealed a white blood cell (WBC) count of 15.8 x 109/l, hemoglobin 11 g/dl, platelet count 216 x 109/l, absolute neutrophil count 14.9 x 109/l, absolute lymphocyte count 0.32 x 109/l, and C-reactive protein (CRP) 281 mg/l. Kidney function was stable with serum creatinine of 0.92 mg/dl and MDRD eGFR on admission > 60 ml/min/1.73 m2. The EVR level was 7.1 ng/ml and cyclosporine level 150 ng/ml (Table 1). He initially received amoxicillin/clavulanic acid. Bacterial cultures of blood and urine were negative. The symptoms improved, and fever resolved, with a decrease in both WBC and CRP levels over the next few days with empiric antibiotic treatment. There was clinical improvement, but without a radiological resolution. An HRCT scan (Fig. 1A) revealed a disseminated nodular pattern in both lungs, accompanied by peribronchial consolidations and lung parenchyma retraction dominating in the lower lobes. No pleural effusion was seen. Bronchoscopy was unremarkable. A transbronchial biopsy revealed mild nonspecific inflammation with areas of fibrosis in the bronchial walls. Bronchoalveolar lavage was sent for cell count, bacterial and viral culture, and fungal and acid-fast bacillus analysis. Both sputum and bronchoalveolar lavage cultures were positive for Achromobacter denitrificans. After a complete diagnostic workup including repeated bacterial and mycobacterial cultures, QuantiFERON1-TB Gold test, blood CMV-PCR, blood Aspergillus galactomannan and Candida mannan, immunofluorescent staining of bronchoalveolar fluid for Pneumocystis jiroveci, other pulmonary opportunistic infections were ruled out, and a diagnosis of A. denitrificans pneumonia and EVR pulmonary toxicity was made. A 17-day course of piperacillin/tazobactam chosen according to the susceptibility profile (Table 2), and a reduction of the EVR dose to the target trough levels of 2.8-3.2 ng/ml resulted only in partial resolution of radiological abnormalities confirmed by HRCT (Fig. 1B). After three weeks of antibiotic treatment EVR was withheld. EVR discontinuation with no additional antibiotic treatment resulted in complete recovery and a complete resolution of pulmonary infiltrates in an HRCT performed at a further 10-week follow-up (Fig. 1C). The immunosuppressive regimen on discharge was restricted to cyclosporine and glucocorticosteroids. We performed a functional analysis of peripheral blood neutrophils and monocytes using Phagotest and Phagoburst tests (both Glycotope Biotechnology, Germany). Phagotest measures the ability to perform phagocytosis, or specifically the ability of the phagocytes to take up the bacteria, by assessing the level of fluorescence emitted by phagocytes - both monocytes and neutrophils. The fluorescence comes from fluorescently stained bacteria engulfed by the phagocytes. Phagotest was performed in accordance with the manufacturer's protocol and with modifications. The original protocol involves the use of Escherichia coli stained with FITC (fluorescein) only (included in kit). Phagotest was also used for assessing the phagocytosis of A. denitrificans stained with CFDA (carboxyfluorescein diacetate succinimidyl ester). This method was established in our laboratory and described elsewhere. The fluorescence emitted by phagocytes reflects the intensity of the engulfment of bacteria. Apart from using different bacteria, all stages of the manufacturer's manual were performed in the same manner for E. coli and A. denitrificans phagocytosis assessment. Phagoburst measures the ability of phagocytes to effectively kill the bacteria by the oxidative burst. The intensity of oxidative burst is estimated by assessing the conversion of non-fluorescent DHR123 (dihydrorhodamine 123) into green fluorescence-emitting R123 (rhodamine 123) in the presence of reactive oxidants. The higher the fluorescence is, the more intense is the oxidative burst. As in case of Phagotest, the assessment with E. coli (already in the manufacturer's kit) and A. denitrificans isolated from the patient's sputum and bronchoalveolar lavage was performed according to the manufacturer's protocol. The fluorescence intensity was assessed using a FACScan cytometer (BD, USA). Flow cytometry techniques have been extensively used to evaluate phagocyte function. Both Phagotest and Phagoburst have been shown to be useful tests for the evaluation of phagocytosis and oxidative burst activity in different research contexts, providing repeatable and credible results. The ex vivo phagocytic activity (Fig. 2) and intensity of oxidative burst (Fig. 3) measured by the mean fluorescent intensity (MFI) of neutrophils and monocytes against E. coli and A. denitrificans were assessed using patients' cells collected on EVR (2.8 ng/ml) and using patient cells collected 3 weeks after EVR discontinuation, and using cells from a healthy control. The phagocytic activity against A. denitrificans and E. coli of patient neutrophils and monocytes collected during EVR treatment was notably lower compared to neutrophils and monocytes from a healthy control, especially in the case of E. coli. The phagocytic activity of patient neutrophils and monocytes after 3 weeks of EVR absence was higher than patient cell activity in the presence of EVR. The phagocytic activity of patient cells off EVR against A. denitrificans was similar to the activity of healthy controls; however, the activity of patient cells off EVR against E. coli was still below the activity of control cells (Fig. 2). The level of oxidative burst from neutrophils and monocytes, even more so, obtained from the patient on EVR treatment was significantly lower than the oxidative burst from the healthy control cells. After 3 weeks of EVR absence, the oxidative burst of patient neutrophils engulfing E. coli and A. denitrificans was restored to a level similar to the healthy control, even though the patient continued to receive prednisone and CsA. The level of oxidative burst carried out by patient monocytes was also improved with EVR absence, but still lower by half compared to monocytes of a healthy control (Fig. 3). To confirm the aforementioned EVR properties we performed a similar assay in vitro using peripheral blood neutrophils and monocytes from a healthy donor. These cells were exposed to four different concentrations of EVR, ranging from 2 to 15 ng/ml (2 ng/ml, 5 ng/ml, 8 ng/ml and 15 ng/ml). The processes of phagocytosis and oxidative burst generation against both A. denitrificans and E. coli were again significantly affected by increasing doses of EVR in a dose-dependent manner (Figs. 4 and 5).

achromobacter denitrificans, everolimus, kidney transplantation, mtor inhibitors, oxidative burst generation, phagocytosis

Initial computed tomography (CT) of the lungs shows poorly defined bilateral patchy consolidations without pleural effusion,.

PMC9586509_01

Male

A 67-year-old male patient presented with worsening shortness of breath and productive cough with intermittent febrile episodes. He also complained of a 20-pound unintentional weight loss over the last few months. His medical history was positive for emphysema-type chronic obstructive pulmonary disease (COPD) on 3 litres of home oxygen therapy diagnosed 3 years previously with right upper lobe bullous changes, IgM deficiency on replacement therapy that had been diagnosed 4 years previously after recurrent respiratory tract infections, and hypothyroidism. No history of body implants was noted. He had a negative colonoscopy 4 years previously. He also had a history of smoking and a previous diagnosis of idiopathic pulmonary fibrosis diagnosed a few months earlier where extensive work-up for autoimmune disease was unyielding. In the emergency department, examination showed tachypnoea with a respiratory rate of 30 cycles per minute, bilateral diminished breaths sounds, bilateral diffuse crackles and thin build. Examination also showed dystrophic yellowish nails on all extremities (Fig. 1) with no objective fever. Laboratory finding showed only leucocytosis with lymphopenia at 2 (reference 20-53%). A chest x-ray showed worsening bilateral infiltrates and pleural effusion compared with the same study findings 1 month earlier (Fig. 2). The patient was started on high-flow oxygen therapy, systemic steroids and bronchodilators, and empiric antibiotic therapy. Computed tomography (CT) of the chest showed severe rapid cystic, cavitary and bronchiectatic changes mainly in the right upper lobe with extensive peribronchial thickening and persistent left lower lobe mass-like infiltrate (Fig. 3). Infectious work-up was negative. Thoracentesis showed exudative serosanguineous fluid that was negative for malignancy, bacterial and fungal infection, and tuberculosis. Nail clipping and histopathological examination showed no evidence of fungal infection. Mild initial improvement in clinical status was achieved and allowed for bronchoscopy (Fig. 4) which showed copious mucoid secretions. Bronchoalveolar lavage (BAL) with transbronchial biopsies were obtained during the procedure. Biopsy was negative but likely inadequate given the lack of observed alveolar macrophages. BAL bacterial culture, silver stain, acid fast bacilli culture and stain were negative. However, fungal culture was positive for Candida albicans. BAL analysis showed predominant inflammatory cells, mainly macrophages. Despite escalation of supportive care, the patient's respiratory status continued to worsen with increased incremental oxygen requirements over 2 weeks of hospitalization. The patient refused aggressive medical intervention. Palliative care discussion prompted consideration of comfort care.

yellow nail syndrome, bronchiectasis, lymphoedema, pulmonary fibrosis

PMC7586149_01

Female

A 53-year-old lady from Kathmandu presented with complaints of pain and swelling over the left arm following fall on the ground. She also complained of on and off productive mucoid cough since last six months. There is no history of chronic obstructive pulmonary disease, pulmonary tuberculosis, hypertension, diabetes mellitus, or any other illness. She also had swelling over the left chest which was diagnosed based on tissue biopsy as small round-cell tumor of the chest wall. She had also undergone chemotherapy with dexamethasone one month prior to injury. She had a history of on and off backache in the thoracolumbar area, nonradiating, intermittent, relieved by analgesics, and aggravated by mild exercise but with no history of trauma. She was also a known case of somatoform disorder under clonazepam. On examination, her vitals were stable, and other systemic examination was within normal limit. Airway examination showed short neck and Mallampati of grade III. Local examination revealed swelling and tenderness over the left midarm. Her initial laboratory investigations showed increased total count with neutrophilic predominance and thrombophilia. Serum calcium was normal, but serum phosphorous was low (1.5 mg/dl). Her serum creatinine was raised to 7.5 mg/dl with blood urea of 106 mg/dl. Urinary Bence Jones protein was positive. Immunochemistry revealed high beta 2 microglobulin (13616 ng/ml), high alpha 1 and 2 globulin (0.56 g/dl and 1.08 g/dl, respectively), and low serum albumin (3.09 gm/dl). Noncontrast computed tomography showed multiple lytic lesions in the body of thoracic vertebra with a collapse of D8 vertebra. She was hence diagnosed as multiple myeloma, admitted to the hospital, and optimized. On preanesthesia evaluation, the total count was high (16,400/mm3); hemoglobin, 8.3 gm%; thrombophilia, 5,98,000/mm3; and prothrombin time 12.4 seconds with international normalized ratio of 1.00. Her acute kidney injury (blood urea 50 mg/dl and creatinine 1.6 mg/dl) was resolving few days after admission. Serum sodium was 137 meq/L, and potassium was low (2.4 meq/L). SPO2 was 86-90% with PO2 of 66.2 mm Hg in room air. Liver functions were normal except for high lactate dehydrogenase (427 IU/L). Echocardiography revealed normal cardiac function with no underlying structural abnormality and ejection fraction of 60%. X-ray revealed fracture shaft of humerus with multiple lytic lesions (Figure 1). Preliminary diagnosis of American Society of Anesthesiologist (ASA) Physical Status Grade III with left pathological humerus fracture with multiple myeloma with chest wall metastasis with resolving acute kidney injury with somatoform disorder with probable difficult airway was made. She was then planned for open reduction and internal fixation with PHILOS plating. Challenges of increased risk for perioperative bleeding, chest infections, postoperative mechanical ventilation, deep vein thrombosis, and local anesthesia toxicity were anticipated. Therefore, we planned her under regional anesthesia with IBPB under ultrasound guidance with sedation. Even with IBPB, the risk of neurological sequelae particularly phrenic nerve blockade leading to respiratory compromise in the patient was possible. Possibility of requirement of general anesthesia (GA) and postoperative mechanical ventilation was also discussed. Written informed consent with the patient party was taken. On the day of surgery, in the operation theatre, a monitor was attached, and baseline vitals were taken. Ceftriaxone 1 g injection was given intravenously as prophylactic antibiotic. Preliminary scan was done to visualize brachial plexus in the interscalene groove (Figure 2) with ultrasound (Samsung My SONO U6) with linear probe. Location of the phrenic nerve was scanned between the anterior scalene and sternocleidomastoid muscle. Using the in-plane technique and taking care of asepsis, ultrasound compatible needle (PAJUNK, SONOPLEX STIM, 20G x 150 mm) was used to infiltrate the three trunks, mostly superior and middle trunk and lower trunk the least (Figure 3), with total 20 ml local anesthetic (Two 10 ml syringe each containing 5 ml of 1% lignocaine with adrenaline (1 : 100000) and 5 ml of 0.25% bupivacaine plain after dilution). At the time of injection and spread of local anesthetics, caution was taken to visualize the tip of the needle below the superior trunk in the interscalene groove and away from the plane of anterior scalene and sternocleidomastoid to avoid phrenic nerve blockade (Figure 3). At the same time, extra care was taken to use as minimum injection pressure as possible while injecting 5 ml aliquots of local anesthesia. Sensory block was ensured with the pinprick method in the related dermatome. Motor block for radial, ulnar, and median was also present, with minimum handgrip. Clinically, respiratory movement was symmetrical bilaterally and adequate to maintain the oxygen saturation. However we did not measure the diaphragmatic excursion on the blockade side or did any pre- and postspirometry tests to notice the changes. Dyspnea, hoarseness of voice, hiccups, or features of Horner's syndrome were not noted. The patient was sedated using propofol injection at a rate of 50 mcg/kg/min via an infusion pump, and supplemental oxygen was given via facemask at 5 L/min. Fentanyl 50 mcg injection was also given intravenously prior to block to ensure proper pain management. Her vitals remained stable throughout the intraoperative period of 3 hours, and her urine output was maintained 1 ml/h (total 150 ml). Postoperative pain catheter was not placed due to lack of equipment, inadequate training, untrained nursing staff, and risk of high dose of local anesthetics aggravating kidney injury in the postoperative period due to prolonged infusion. In the postoperative ward, pain was managed using multimodal approach with paracetamol 1 g injection every 6 hours and fentanyl infusion at 20 mcg/h. Supplemental oxygen was continued for another 6 h postoperatively at the rate of 2 L/min via nasal prongs, and incentive spirometry was advised. Her Numeric Rating Pain (NRS) scale remained less than 4 out of total 10 mm throughout the first operative day. Complaints of dyspnea, hoarseness, hiccups, and signs of Horner's Syndrome were also not present during the same period. On the second postoperative day, paracetamol was continued with fentanyl as per required basis. Her NRS rating was 2 to 3 and was ambulating comfortably. She had early enteral feeding, mobilization with good compliance on incentive spirometry on the first postoperative day with no issues of postoperative nausea and vomiting. She was discharged on the 5th postoperative day with no issues of wound infections, and her renal function stayed with the normal limits.

PMC9816960_01

Male

A 44-year-old obese black male patient with autosomal dominant polycystic kidney disease was hospitalized in August 2021 to explore pulmonary nodules incidentally discovered on a computed tomography performed while the patient was hospitalized for a renal cyst infection. The patient was born in Mali but had lived in France for the past 43 years. He received a kidney transplant in February 2018. He had no pre-existing lung disease and declared a ten pack-year smoking history. The immunosuppressive regimen consisted of prednisone, mycophenolate mofetil and cyclosporine. Cotrimoxazole prophylaxis against Pneumocystis jirovecii pneumonia was started after transplantation. Pre-transplant screening for latent tuberculosis infection was not performed. The post transplantation period was marked by a recurrent lymphocele treated by laparoscopic marsupialization. In June 2021, the patient presented with fever and a renal cyst infection was suspected. Despite no bacteriological confirmation, he received a 4-week course of ceftriaxone. Thoracoabdominal CT-scan showed pulmonary nodules that led to subsequent pulmonary explorations. Physical examination including lung auscultation was unremarkable. The body mass index reached 34 kg/m2. White blood cell count was 4,14 G/L and C-reactive protein level was 7 mg/l. Serum fungal biomarkers (galactomannan and B-D-glucan), as well as blood aspergillus PCR assay were negative. Glomerular filtration rate measured by 51Cr-EDTA clearance was 54 ml/min. Computed tomography revealed multiple nodules in both lungs, without interstitial infiltrates (Fig. 1A and 1B). The bronchoalveolar lavage (BAL) fluid contained many cells with macrophage predominance (960,000 cells/ml, 94 % macrophages, 5 % lymphocytes, 1 % neutrophils). Standard bacteriological and fungal cultures were negative and auramine staining did not show any acid-fast bacilli. Whole-body positron emission tomography (PET) depicted moderated hypermetabolism of pulmonary nodules (SUVmax: 3.5) without any other abnormal fixation (Fig. 1C). Trans-thoracic lung biopsy was performed and evidenced non-caseating epithelioid and giant cellular granulomas with a negative Ziehl-Neelsen staining. After 49 days, Mycobacterium xenopi grew in the bronchial aspiration culture. No antimicrobial susceptibility testing was performed considering the limited relevance of this test to guide antibiotic treatment. Blood and urine cultures were negative for mycobacteria. Pulmonary nodules increased in size at one-month follow-up CT scan, despite the patient remaining afebrile without any respiratory symptoms. Mycophenolate mofetil dosing was lowered and an antimycobacterial treatment containing rifabutin, ethambutol and azithromycin was initiated. Immunosuppressive drugs were carefully monitored, and doses were adapted for interaction with rifabutin: prednisone and cyclosporine doses were increased by 50 % and 100 % respectively. Several days later, the patient discontinued treatment because of asthenia, fever and myalgias. Adverse events related to rifabutin were suspected and the treatment was switched off for moxifloxacin. The patient's condition improved, and he quickly became afebrile after rifabutin discontinuation. Two months later, computed tomography showed that pulmonary nodules decreased in size. Graft function remained stable. A 12-month treatment was planned.

kidney transplantation, mycobacterium xenopi, non-tuberculous mycobacteria

PMC2734930_01

Female

A 54-year-old Caucasian female presented to the clinic with epigastric pain and bloating after meals. Seven months ago she underwent a laparoscopic Nissen fundoplication for refractory gastroesophageal reflux disease in her native country. Her reflux symptoms started 2 years ago which included severe heartburn, retrosternal crampy pains as well globus sensation. She was initially treated with PPIs for a period of 4 months with only minimal improvement of her symptoms. She underwent laparoscopic Nissen Fundoplication with unremarkable hospital course and was discharged home in the stable condition on the third postoperative day. Shortly after her surgery she left her country and traveled to Los Angeles, only to find herself in an urgent care clinic few days later where she was evaluated for her daily bloating episodes lasting 2-3 hours, inability to belch, and intermittent nausea. After thorough evaluation, which included laboratory work and abdominal X-ray, it was concluded that her complaints were most likely related to a normal post-Nissen fundopication symptoms. She was reassured and subsequently discharged home. However, she continued to have similar symptoms and several weeks later she represented to a local hospital with severe abdominal pain and fevers of 101 F. Her laboratory work revealed elevated WBC 18 000 cells/muL (normal, 4500-10 500 cells/muL). She had sinus tachycardia with the systolic blood pressure of 90 and abdominal examination consisting of generalized peritonitis. She was taken emergently to the operating room for exploratory laparotomy. Intraoperative findings revealed an acute gastric linear tear on the anterior portion of the body of the stomach, 10 centimeters distal to the intact fundoplication wrap. The gastric tear appeared traumatic in origin without any other gastric pathology. Two-layer primary closure of the defect was performed. She remained stable during her hospital stay and was discharged home on 5th postoperative day tolerating regular diet. Two months after her second surgery, she represented again to the emergency department with severe epigastric pain radiating to the back. She was diagnosed with acute pancreatitis on the basis of her symptoms and laboratory values of amylase and lipase 800 UL (normal 60-180 U/L) and 1200 U/L (normal <190 U/L), respectively. Ultrasound and endoscopic retrograde cholangiopancreatography on the admission revealed no evidence of gallstones or choledocholithiasis. Her pancreatitis responded to conservative treatment and she was subsequently discharged home 6 days after her admission with complete resolution of symptoms. During her surgical follow-up visit she continued to complain of postprandial pain with an early satiety and episodic nausea. She appeared weak and malnourished. She noted a 20 lbs weight loss since her initial antireflux procedure. Her abdomen was slightly distended with hyperactive bowel sounds. She had moderate epigastric pain during palpation. She was admitted to the hospital for a work-up of her ongoing symptoms and as well as for poor nutritional status. Her work-up included plain abdominal films, which demonstrated air in a dilated stomach and duodenum with an abrupt vertical cut off and no evidence of air in the small intestine distal to the 3rd portion of the duodenum (Figure 1). Upper Gastrointestinal series obtained subsequently revealed contrast in the dilated duodenum with an abrupt cut off at the level of the superior mesenteric artery pedicle in a supine position (Figure 2). Obstruction was relieved once patient was placed in the prone position (Figure 3). Based on her clinical signs as well as classic radiological findings, a diagnosis of superior mesenteric artery syndrome was made. Patient was taken to the operating room where she underwent duodenojejunostomy. Her postoperative hospital course was uneventful. She was tolerating regular diet and was subsequently discharged home on the 5th postoperative day. Patient remains asymptomatic at one year followup.

PMC7252885_01

Male

The patient was a 16-year-old male with hypertrophic cardiomyopathy (HCM) who initially presented to his primary cardiologist after two episodes of syncope while playing competitive basketball. He had a muscular build including weight 86.9 kg (92nd percentile), stature 185.5 cm (92nd percentile), and body mass index 29 (96th percentile). His baseline electrocardiogram showed a sinus bradycardia at 51 bpm with massive left-ventricular hypertrophy and T-wave inversion in the lateral precordial leads V4-V6 as well as II, III, and aVF. An echocardiogram showed asymmetric hypertrophy of the posterior free wall and apex and normal diastolic intraventricular wall thickness of 15 mm. He was initiated on metoprolol XL and restricted from activities. Further evaluation included a Holter monitor, exercise treadmill test and cardiac magnetic resonance imaging, which demonstrated non-specific atrial and ventricular ectopy, normal blood pressure response, and no myocardial late gadolinium enhancement, respectively. Genetic testing was similarly negative for Class I and Class II mutations, although a Class III mutation was present in the GLA gene. Despite the mixed diagnostic studies, in the presence of unexplained syncope and adequate clinical criteria for HCM, he was referred for placement of a primary prevention ICD. Upon referral to our office, we reviewed the clinical indication for device placement and described the treatment options including a transvenous single-chamber single-coil ICD system and S-ICD system. Given the patient and family's interest in the S-ICD system, he underwent electrode screening supine, sitting, standing and while using a stationary bicycle. He was determined to be an appropriate candidate for the S-ICD system. The procedure was performed under general anesthesia in the pediatric electrophysiology laboratory. Given the patient's large and muscular build, we elected to perform a three-incision technique rather than a two-incision to provide additional lead support. Therefore, a 6-cm incision was made just inferior to the subpectoral groove to the anterior axillary line. A pocket was formed from the incision cranially and laterally, reaching the leftmid-axillary line. A vertical 3-cm incision was made at the left parasternal border at the level of the xiphoid process, exposing the fascia overlying the sternal periostium. The tunneling tool was used to connect this incision to the generator pocket. The lead was then connected to the tunneling tool with a silk tie and pulled from the generator pocket to the xiphoid pocket. The lead was secured to the chest wall fascia with a suture sleeve and a horizontal 3-cm incision was then made at the left upper sternal border to expose the fascia overlying the sternal periostium. The tunneling tool was then used to connect the inferior pocket to the lead tip pocket and the lead was pulled through to the superior position. The lead pockets were sutured closed, and the lead was connected to the generator. Sensing vectors were tested and the configuration was set at the alternate vector. Defibrillation testing was successful on the first treatment of 65 J. The device was programmed with a conditional shock zone 220 bpm and shock zone 240 bpm, and skin closures were then completed. The patient was moved to the postanesthesia care unit in stable condition. A post-surgical anterior-posterior (AP) projection chest X-ray was completed, which showed stable positioning of the device and lead. The following morning, a repeat (posterior-anterior) PA chest X-ray showed the tip of the lead at roughly the seventh rib consistent with the fluoroscopic positioning from the prior day (Figure 1). The patient was evaluated in the emergency department (ED) for a non-specific fever approximately 10 days after the procedure. The work-up was unremarkable, with eventual resolution of the fever and a non-concerning surgical site. An X-ray obtained during this visit showed stable location of the device and leads. The patient was discharged with a routine follow-up schedule ordered. The patient was seen six weeks later for routine follow-up, where he reported an ongoing feeling of contact between the device and his left scapula upon upward stretching of his left arm, as well as a specific episode of stretching during which he felt a tug from his sternum to the left axilla and then relief of the pulling sensation. This episode had occurred some time after he was evaluated in the ED for fever. A chest X-ray performed at this time showed that the lead had migrated from a purely vertical position to a hockey stick right contour with a displacement of approximately 4.5 cm with the tip overlying rib 9 (Figure 2). Evaluation of the patient's device demonstrated adequate sensing, though with a change in the optimal vector from alternate to secondary. The sensing configuration was changed to the secondary vector and the decision was made to obtain a chest X-ray in four weeks for evidence of any continued lead migration. Owing to social developments, the chest radiograph was not completed at that time. Follow-up after an additional 2 months showed further regression of the lead with the lead tip sitting at approximately 6.5 cm below its original position with an increased L-shaped configuration of the high voltage coil (Figure 3). Again, vector analysis showed adequate sensing with no change in lead impedance. Despite a continued lack of symptoms and arrhythmias, based on the continued movement of the lead, there was a growing question of progressive failure to sense. Moreover, no data regarding defibrillation success was available with the new position. As such, the decision was made to reposition the lead. The patient was taken back into the operating room for lead revision approximately 5 months following the initial system placement. We incised the inferior and superior sternal scars and dissected down to the fascia overlying the periosteum. The tip of the lead was not present at the upper incision, nor was the suture sleeve present at the lower. Retained non-absorbable suture material tied to the fascia was present at both sites. The tip of the lead was withdrawn to the lower incision and fully extended. The suture sleeve was not visible and presumably retained proximal to the lower incision site. At this time, the tip of the lead was secured to a new tunneling tool and extended to the superior incision. Its placement was verified with fluoroscopy and the lead tip was then secured at the superior incision site with two non-absorbable stay sutures and the proximal electrode secured with a new suture sleeve and two non-absorbable stay sutures as well. The pockets were then closed in the usual fashion. The sensing vector of choice returned to the alternative vector. Defibrillation testing was not repeated given the prior success of leads and device in the same positions as confirmed by radiography. The patient tolerated the procedure without difficulty and recovered without any fever, pain, swelling, or induration. He limited his activities overall per standard HCM precautions as well as with specific emphasis to avoid activities of the upper extremity to avoid further dislodgement of the lead until adequate healing had taken place. The patient returned for a routine follow-up visit approximately five weeks after the lead revision. An examination showed healing incisions at the manubrium and xiphoid process. The lateral incision was also wellhealed and the subcutaneous ICD lead and device were palpated and in place. Interrogation of the device showed no treated or untreated episodes of ventricular tachycardia. A chest X-ray showed stable placement of both the lead and generator.

lead migration, pediatric, subcutaneous intracardiac defibrillator

PMC5749451_01

Male

In January 2016, a 40-year-old man sought care at a hospital in Alameda County, California, USA, with a 2-week history of progressive cough, dyspnea, pleuritic chest pain, and headache associated with fevers, chills, and night sweats. He had lost 45 kg during the past month. He had a history of inconsistently treated HIV infection and a 10-pack-per-year smoking history. He had emigrated from Mexico 10 years earlier, lived in the East Bay, and had traveled to the Central Valley of California. On examination, he was cachectic, afebrile, hypoxic, and tachypneic. He had oral thrush, bilateral lower lobe crackles, and decreased breath sounds. The rest of the examination, including neurologic and skin assessments, was unremarkable. Chest radiograph and computerized tomographic scan showed diffuse micronodularities with cavitary lesions in both lungs (Figure, panels A, B). Magnetic resonance imaging of the brain revealed a 6-mm ring-enhancing cerebellar lesion (Figure, panel C). Laboratory results revealed a CD4 count and viral load of 5 cells/muL and 15,000 copies/mL, respectively. Blood leukocyte count was 14.9 x 109 cells/muL (reference 4.5-11 x 109 cells/muL), and hemoglobin was 11 g/dL (reference 13.5-17.5 g/dL). Lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transferase were 284 units/L (reference 125-243 U/L), 148 units/L (reference 38-126 U/L), and 242 units/L (reference 3-95 U/L), respectively. Cerebrospinal fluid analyses, including cell count, protein, and glucose measurements, showed standard results. Molecular testing of bronchoalveolar lavage (BAL) fluid for respiratory viruses showed negative results. Serologic test results for blood and urine for coccidioidomycosis, cryptococcosis, toxoplasmosis, and tuberculosis were negative, but the Histoplasma galactomannan urine antigen test (MiraVista, Indianapolis, IN, USA) result was positive at >25 ng/mL (reference <0.5 ng/mL). Examination of cerebrospinal fluid with Gram, acid-fast, and India ink stains and aerobic, mycobacterial, and fungal cultures were negative for organisms. Cytopathologic examination of BAL fluid and lung biopsy samples showed nonnecrotizing granulomas with hematoxylin and eosin stain and both hyphal and yeast forms with fungal stains. The yeasts exhibited multiple budding with broad bases (Figure, panel D). No organisms were seen with an acid-fast stain. Multiple sputum cultures were negative for mycobacteria. Empiric treatment was initiated for coccidioidomycosis, Pneumocystis jirovecii pneumonia, tuberculosis, and bacterial sepsis with intravenous fluconazole; trimethoprim-sulfamethoxazole with steroids; rifampin, isoniazid, pyrazinamide, and ethambutol; and broad-spectrum antimicrobial drugs. On hospital day 2, the patient had hypoxic respiratory arrest and was intubated. Antifungal drugs were changed to micafungin on day 3 and then to liposomal amphotericin B (5 mg/kg/day) on day 6, and he was extubated later that day. Tuberculosis therapy was discontinued on day 15. Antiretroviral therapy was held because of concern that immune reconstitution might worsen the patient's cerebellar lesion. A spontaneous pneumothorax and respiratory failure developed that required reintubation on day 31. His family chose comfort care, and antifungal therapy was stopped on day 41. He died on day 43; autopsy was declined. We sent a mold grown from BAL to a mycology reference laboratory for identification. On microscopic examination of the mold phase, conidia were absent in all subcultures. DNA sequences of the D1/D2 region of the large subunit and internal transcribed spacer region of the ribosomal RNA gene were compared with GenBank nBLAST database (https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE_TYPE=BlastSearch); sequence similarities of 100% and 99%, respectively, were demonstrated for Emmonsia helica strains (including UAMH 3398, UAMH 10539, and UAMH 10593; UAMH Centre for Global Microfungal Biodiversity, University of Toronto, Toronto, Ontario, Canada). We conducted antifungal susceptibility testing of the mold phase. MICs (mug/mL) to fluconazole, itraconazole, posaconazole, voriconazole, and amphotericin B were 8, 0.125, 0.125, <0.03, and 0.06, respectively. Emmonsia-like fungi are an emerging group of pathogens reported globally, which predominantly cause disseminated disease of immunocompromised persons. One of these, E. helica, was originally recored from North America. The first reported case occurred in Alberta, Canada, in 1970 in a farmer with a fatal pneumonia and encephalitis syndrome. A fungal pathogen isolated postmortem from brain and lung tissue was initially identified as Blastomyces dermatitidis on the basis of serologic and histopathologic findings, but its features in culture were atypical. In 2015, Sigler determined that this isolate belonged to a new Emmonsia-like species, which she described as E. helica. Another fatal case of Emmonsia infection was reported from California in a patient after an orthotopic liver transplant. An isolate from that patient also was confirmed as E. helica (I. Schwartz et al., unpub. data). Although the travel history for the second case-patient was not reported and the patient in this report had resided in Mexico, these cases suggest that the area of endemicity of E. helica may include California. This finding is further supported by 2 other fatal cases of atypical mycoses reported in HIV-infected men from California; histopathologic findings of hyphae and multiple budding yeasts were consistent with E. helica (I. Schwartz et al., unpub. data). Investigations are under way to characterize the geographic and host range of E. helica and to clarify the phylogenetic relationships among members of the family Ajellomycetaceae comprising the genera Emmonsia, Blastomyces, Histoplasma and others because recent studies have uncovered far greater complexity than previously supposed.

aids, california, hiv, emmonsiosis, endemic dimorphic fungi, mycosis, opportunistic infection, viruses

PMC9932527_01

Male

A 49-year-old male patient who came to our hospital for three weeks of lung shadow found on physical examination had no cough and sputum, no dyspnea, no appetite or weight loss, no fever, chest pain or hemoptysis, no previous diabetes, no history of trauma or radiation exposure. He had surgery for a fracture of the left clavicle five years ago, the pre-operative chest X-ray have not showed any siderosis changes, and postoperative recovery is satisfactory. When he came to our hospital for examination, the patient performed well in all aspects of his body, body temperature: 36.6 C, pulse: 69 times/min, breathing: 20 times/min, blood pressure: 122/82 mmHg. The patient was mind and spirit, with clear breath sounds in both lungs and no obvious rales of dry and wet, and the remaining physical examination revealed no obvious anomalies. There were no significant abnormalities in common laboratory tests. No significant abnormalities were seen in the routine Electrocardiogram (ECG). Examination of epigastric ultrasonography did not suggest abnormalities associated with this disorder. Pulmonary ventilation function measurement: mild obstructive pulmonary ventilation dysfunction, normal lung diffusion function, negative drug relaxation test. The patient has been working as an "electric welder" for more than thirty years and had a history of smoking for well over twenty years, ten cigarettes per day. He quit smoking after lung shadow was revealed in physical examination. Chest CT done three weeks ago suggested diffuse lesions and localized emphysema, thick-walled cavities and multiple nodules seen in both pulmonary and mediastinal windows ( Figures 1A, B ). The diffuse ground-glass changes in two lungs were considered as diffuse alveolar exudation, at the same time under the two pulmonary interstitial changes, combined with occupational history, considering pneumoconiosis may. Although welding-associated pulmonary fibrosis was the most likely diagnosis for this patient, for further differential diagnosis, we communicate with the patient and his family and inform them of the necessity and risks, and after having their consent, we perform a fiberoptic bronchoscopy. We performed fiber bronchoscopy for differential diagnosis and obtained bronchoalveolar lavage fluid from the posterior segment of the right upper lobe and lingual segment of the left upper lobe. Thecell counts and leukocyte classification results: the posterior upper lobe lavage fluid of the right lung had a bloody turbid appearance, a nucleated cell count of 510/mul and neutrophils accounted for 60%, and the appearance of the lingual segment of the left upper lobe is colorless and micro-muted, with a nucleated cell count of 63/mul, neutrophils 6%. The St. Regis staining of Bronohoalveolarlavage (BAL) fluid showed macrophages engulfing a large number of brown-black particles of varying sizes ( Figure 2A ). Positive Prussian blue staining ( Figure 2B ), alveolar lavage fluid pathological fluid base, and lung biopsy ( Figures 2C-E ), is composed of substantial iron particles. Under the electron microscope visible macrophage cytoplasm containing large size, structure, irregular iron particles ( Figure 2F ), which are brown-yellow or brown-black with different sizes, metallic luster, and strong refraction. The patient's macrophage iron particles differ significantly from those in cases of pulmonary hemorrhage, in which the hemosiderin-containing particles are bluish-black, uneven in size, metallic, and non-refractive. According to pneumoconiosis diagnostic criteria, the patient was diagnosed with pneumoconiosis; also chest CT showed wall cavities with mural nodules, multiple nodules around them, and some nodules with calcification, considering the possibility of old TB. Further acid-fast staining of bronchoscopic brush smears and alveolar lavage fluid showed that acid-fast bacilli were positive (6 in 300 fields) ( Figure 2G ). Acid-fast bacilli were also detected by electron microscopy ( Figure 2H ), biopsy of the posterior right upper lobe of the lung is granulomatous inflammation with necrosis, and the patient was diagnosed with siderosis and TB. The diagnosis of TB in this patient was clear. No obvious abnormalities in Cryptococcus antigen detection, Mycobacterium TB identification, and for rifampicin resistance testing. Mycobacterium tuberculosis and RIF resistance gene testing is detected by the export kit, as long as the sample is added to the kit, and after a period of time, the instrument can display the results. We contacted the patient, learned that he had no family history of TB, and recommended that he go to the local TB hospital for regular chest CT check-ups. The patient also followed our advice to change jobs to avoid further lung damage.

case report, morphology, siderosis, tuberculosis, welder

PMC4443886_01

Female

A 9-year-old girl presented to the Outpatient Otolaryngology Department with swelling under the right jaw that had slowly increased in size for the past two years. There was no associated fever, pain, voice changes, breathing difficulty, dysphagia, odynophagia, weight loss, and/or history of exposure to tuberculosis. There was a history of exposure to cats. Exposure to cats with the onset of symptoms in the patient led to cat scratch disease and fungal infections being included in the differential diagnosis. These were ruled out with a negative cat scratch titer and negative toxoplasma IgG. Physical exam showed the presence of two distinct swellings in the submental and right submandibular (SM) area. The swelling in the right SM area was about 2 x 2 inches and the submental area swelling measured approximately 1.5 x 1.5 inches. The swellings felt firm and nodular and were not freely mobile. The remaining of the ear, nose, and throat and general physical exam was normal. Laboratory tests were negative. Ultrasound (US) of the neck showed the presence of two calcified masses with heterogeneous echotexture. A computerized tomography (CT) scan of the head and neck area with contrast was obtained. A nonenhancing, multilobulated mass with peripheral rim calcification was noted in the SM region mostly on the right side but crossing the midline. The peripheral rim calcifications could signify precursor to bone development within the mass or local necrosis due to mass effect. It measured 4.88 x 3.55 cm (Figure 1). The right SM gland was distinct from the swelling. The remaining salivary glands were normal. The cervical vascular structures were also normal. CT scan characterization of the mass was suggestive of a benign mesenchymal lesion. Other possible differentials included calcified lymph node, calcified plunging ranula without any intraoral component, or liposarcoma. Surgical excision of the mass was performed through a routine right SM approach. The entire mass was removed along with a surrounding cuff of normal tissue. Since the right submandibular gland was distinct from the swelling and did not seem to be involved at the time of surgery, it was not removed. The mass was a well circumscribed and encapsulated soft tissue lesion with adipose tissue, fibrosis, smooth and skeletal muscle, cartilage, and bone fragments. A thin outer rim was calcified, but the rest of the cut surface was mostly yellowish white with a whorled pattern. The findings were consistent with those of a benign mesenchymoma. The child did well at one- and 6-month follow-up periods without any recurrence of the lesion.

PMC8077407_01

Male

A young farmer (21-year-old male) presented with parietooccipital headache and lower back pain. He had no further neurological deficits. A year previously, he had presented with an epileptic seizure, and cranial MRI had shown a frontal tumor, typical for a low-grade astrocytoma. A biopsy had been indicated, but the patient had refused further examinations at that time. At this presentation, cerebrospinal fluid (CSF) analysis revealed a pleocytosis (49/muL) with massive elevation of protein (>4 g/L) and lactate (9.6 mmol/L) levels. A tuberculous meningitis was suspected and tuberculostatic therapy initiated. MRI showed contrast enhancement in the perimedullary, cerebellar and cauda equina regions. Granulomatous inflammation, possibly due to tuberculosis or carcinomatosis, was presumed. All further diagnostics to exclude bacterial, viral, fungal or autoimmune disease, as well as a CSF cytology with FACS (fluorescence-activated cell sorting) analysis, showed no pathological results. The patient developed a progressive brain stem syndrome with fluctuating left arm palsy and delirium. A biopsy of the tumor and the leptomeninx revealed edematous brain tissue with small fresh hemorrhages and slight, most likely reactive, astrogliosis with focal chronic inflammatory changes in the overlying leptomeninx. There was no immunohistochemical detection of an isocitrate dehydrogenase 1 (IDH1) mutation. It was only on the third biopsy of brain tissue that leptomeningeal cell proliferation with singular mitoses suspicious for a leptomeningeal neoplastic process was revealed. The condition of the patient worsened, and he was subsequently resuscitated and intubated as a result of cardiopulmonary insufficiency and cardiac arrest. The patient died 3 months after admission. The autopsy revealed atypical astrocytic differentiated cell clusters with moderate cell and nuclear polymorphism and with a low proliferation rate in the region of the suspected frontal tumor, corresponding to a low-level malignant diffuse astrocytoma (WHO grade II). A diffuse, malignant, astrocytically differentiated leptomeningeal glioma was found in the overlying meninges, compatible with a primary leptomeningeal glioblastoma of a diffuse type (WHO grade IV, IDH wild type) with tumor infiltration of the cerebral parenchyma and the cerebellar cortex (Fig. 1).

glioblastoma, leptomeningeal spread, meningitis, primary brain tumor

PMC9288144_01

Male

Patient information: the patient, Mr. S was 50 years old, lived in Tambak Asri, was married, self-employed, with high school education, Javanese, Muslim. He had been treated at the Dr. Soetomo Hospital on November 21, 2018. The patient presented to the hospital complaining of a swelling on the right leg which occurred 5 days before hospital admission. The swelling had become more prominent over time and was accompanied by pain in the right leg which occurred 2 days before admission. Pain affected the entire right leg, and was intermittent. In addition, the patient also complained of intermittent shortness of breath which occurred one month before. However, the patient did not have shortness of breath when he was admitted to the hospital. Fever, cough, weight loss, decreased appetite, and night sweats were not reported. The amount of urine produced in a day was 200-300 ml and no defecation problem was reported. The patient had a history of pulmonary tuberculosis (TB) successfully treated in 2015. Clinical findings: the patient had a history of hospitalization at the Dr. Soetomo Hospital 1 week before due to chronic kidney disease (CKD) stage V + refractory hyperkalemia + left solitary kidney + left kidney stone + left ureteral stone + bladder stone + community acquired pneumonia (CAP) + stage II hypertension + obstruction syndrome post TB. He had undergone lumen catheter insertion in the right femoral vein (previous treatment) and removed when re-hospitalized. He underwent hemodialysis during the previous treatment (10th November 2018). A family history of diabetes, hypertension, heart disease, liver, and kidney disease was not reported. During the previous treatment, the patient was scheduled for vesicolithotripsy+ ureteroscopy (URS), but the patient refused it. On physical examination, he was compos mentis, blood pressure was 100/70 mmHg, pulse rate was 98 beats per minute, respiration rate 24 breaths per minute, body temperature 36.9 C, SpO296% (free air), body mass index (BMI) 22.9 kg/m2 and Wong-Baker pain scale was 3. He had pebral conjunctiva (-/-), icterus (-), cyanosis (-), dyspnea (-); single S1S2, murmur (-), gallop (-); inspection (left lung), increased palpation in the right upper lung, dullness in the right upper lung, vesicular/vesicular breath sound, rhonchi (-/-), wheezing (+) in the right lower lung. There were soepel, normal bowel sounds on abdominal examination, liver and spleen were not palpable, shifting dullness (-), muscular defense (-). On examination of the right lower extremity, there was edema (+), redness (+), it was warm (+), and Wells' score was 3. Supporting examination results showed that haemoglobin was 11.4 g/dl, erythrocytes were 4.01 x 106/ul, leukocytes 27.99 x 103/ul, platelets 317 x 103/ul, BUN 60 mg/dl, serum creatinine was 9.93 mg/dl, albumin 3.27 gram/dl, random blood glucose 125 mg/dl, sodium 136 mmol/L, potassium 6 mmol/l, chloride 95 mmol/l, HbSAg rapid test is (-), serum glutamic-oxaloacetic transaminase (SGOT) 28 U/l, SGPT 34 U/l, PPT 10.0 seconds, activated activated partial thromboplastin time (APTT) 30.5 seconds. Urinalysis: glucose (-), ketones (-), bilirubin (-), SG 1.005, blood +4, pH 7, protein (-), urobilinogen (-), nitrite (-), leukocytes +3, erythrocytes 25-50/lp, leukocytes 15-20/hpf. Blood gas analysis: pH 7.32, pCO245 mmHg, pO267.2 mmHg, HCO320 mmol/L, BEecf -4.4 mmol/L, oxygen saturation (SO2) 96%. Sputum examination on November 3, 2018 did not revealed any acid resistant bacteria, and electrocardiography (ECG) examination detected sinus tachycardia. Radiological examinations were based on: 1) Anteroposterior (AP) chest X-ray which showed upper lobe atelectasis and right lung fibrosis, pulmonary TB sequelae, right pleural effusion, and no abnormalities were seen; 2) AP/lateral pedis and cruris right position photo with no abnormal results; 3) AP and lateral radiographs of the right femur showed no abnormality, ultrasound objectified solitary kidney on the left, mild hydronephrosis and left hydroureter which could be caused by left renal pelvis stones, bladder stones; 4) multislice computed tomography (MSCT) stonography showed left solitary kidney, left renal pelvis stone and left medial 1/3 stone causing left 1/3 proximal hydroureter and left mild hydronephrosis, bladder stone. Second day of treatment: complaints of swelling with intermittent right leg pain, shortness of breath (-). Physical examination: compost mentis, blood pressure 110/70 mmHg, pulse rate 98 beats per minute, respiration rate 24 breaths per minute, temperature 36.7 C, SpO298% free air, urine production 650 ml/24 hours (drinking 600 ml + correction fluid 60 ml), lower extremity dextraedema (+), redness (+), and warm (+). Laboratory tests: BUN 52 mg/dl, serum creatinine 7.01 mg/dl, sodium 132 mmol/l, potassium 6.8 mmol/l, chloride 91 mmol/l. Assessment: acute on CKD + sepsis et cause urinary tract infection (UTI) + suspected DVT in the right lower extremity associated with differential leucocyte count (DLC) + hyperkalemia (6.8 mmol/l) + left mild hydronephrosis with medial 1/3 left hydroureter et causa left renal stone and ureteral stone + bladder stones + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Therapy planning: three-step treatment of hyperkalemia (ca gluconate 1 ampoule IV injection followed by D40 + 2 units of insulin as part every 30 minutes for 3 times), nebulization of salbutamol 2.5 mg + ipratropium bromide every 8 hours, fluid restriction (maximum drink of 600 ml), other therapy remains. Planning diagnosis: complete blood count (CBC) evaluation, potassium serum post-correction (5.2 mmol/l), serial renal function test (RFT), and D-dimer. Monitoring included: clinical examination, vital signs, and urine production. Third-day of treatment: complaints of swelling with intermittent right leg pain, shortness of breath (-). Physical examination: compost mentis, blood pressure 110/70 mmHg, pulse rate 93 beats per minute, respiration rate 20 breaths per minute, temperature 36.7 C, SpO298% free air, urine production 1000 ml/24 hours (drinking 600 ml + correction fluid 85 ml), right lower extremity edema (+), redness (+), and warm (+). Laboratory tests: BUN 50 mg/dl, serum creatinine 6.89 mg/dl, sodium 135 mmol/l, potassium 6.2 mmol/l, and chloride 87 mmol/l. Assessment: acute on CKD + sepsis et causa UTI + suspected DVT in the right lower extremity associated with DLC + hyperkalemia (6.2 mmol/l) + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stones + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Therapy planning: two-step treatment of hyperkalemia (ca gluconate 1 ampoule iv injection followed by D40 + 2 units of insulin as part every 30 minutes for 2 times), IVFD D5 + 10 units of insulin as part 7 drops per minute, fluid restriction (drinking a maximum of 1000 ml), other therapies. Planning diagnosis: CBC evaluation, potassium serum post correction (5.0 mmol/l), serial RFT, and D-dimer. Monitoring: clinical examination, vital signs, and urine production. Fourth-day of treatment: complaints: swelling accompanied by intermittent pain in the right leg, shortness of breath (-). Physical examination: compost mentis, blood pressure 120/90 mmHg, pulse rate 96 beats per minute, respiration rate 20 breaths per minute, temperature 36.1 C, SpO298% free air, urine production 1400 ml/24 hours (drink 1000 ml + infusion 500 ml + 60 ml correction fluid), lower extremity dextraedema (+), redness (+), and warm (+). Laboratory tests showed hemoglobin 10.4 g/dl, erythrocytes 4.12 x 106/ul, leukocytes 23.25 x 103/ul, platelets 378 x103/ul, BUN 44 mg/dl, serum creatinine 6.51 mg/dl, sodium 135 mmol/l, potassium 4.8 mmol/l, chloride 95 mmol/l, D-dimer >4 g/ml (normal <0.5 microg/ml). Assessment: acute on CKD + sepsis et cause UTI + suspected DVT right lower extremity associated with DLC + corrected hyperkalemia (4.8) + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stone + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Diagnosis: complete blood count, serial RFT, Doppler ultrasound of the right lower extremity (scheduled in 28th November 2018), and vascular duplex ultrasound scanning (DUS) echo (scheduled in 30th November 2018). Therapy planning and monitoring were the same. Sixth-day of treatment: complaints of swelling accompanied by intermittent pain in the right leg, and shortness of breath (-). On physical examination, the patient was compost mentis, blood pressure 130/90 mmHg, pulse rate 98 beats per minute, respiration rate 20 breaths per minute, temperature 36.2 C, SpO297% free air, urine production 1500 ml/24 hours (infusion 500 ml + 1000 ml drink), lower extremity dextraedema (+), redness (+), and warm (+). Assessment, diagnosis, therapy, and monitoring were the same. Seventh-day of treatment: complaints of swelling accompanied by intermittent pain in the right leg. Physical examination, the patient was compost mentis, blood pressure 130/90 mmHg, pulse rate 97 beats per minute, respiration rate 20 breaths per minute, temperature 36.7 C, SpO299% free air, urine production 2000 ml/24 hours (infusion 500 ml + 1500 ml drink), right lower extremity edema (+), redness (+), and warm (+). Laboratory tests showed hemoglobin 11.3 g/dl, erythrocytes 4.48 x 106/ul, leukocytes 15.38 x 103/ul, platelets 375 x 103/ul, BUN 20 mg/dl, serum creatinine 1.52 mg/dl, sodium 137 mmol/l, potassium 4.8 mmol/l, and chloride 91 mmol/l. Assessment: acute on CKD + sepsis et cause UTI + suspected DVT in the right lower extremity associated with DLC + corrected hyperkalemia (4.8) + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stone + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Diagnosis, therapy, and monitoring were the same. Eigth-day of treatment: complaints of swelling accompanied by intermittent pain in the right leg. On physical examination, the patient was compost mentis, blood pressure 130/80 mmHg, pulse rate 89 beats per minute, respiration rate 20 breaths per minute, temperature 37.0 C, SpO299% free air, urine production 2000 ml/24 hours (infusion 500 ml + 1500 ml drink), right lower extremity edema (+), redness (+), and warm (+). Assessment: acute on CKD + sepsis et causa UTI + DVT in the right lower limb associated with DLC + corrected hyperkalemia (4.8) + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stone + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Diagnosis: Doppler ultrasound of right lower extremity (today), while others were the same. Therapy: venflon, other therapies were same. Monitoring was constant. Ninth-day of treatment: complaints of swelling accompanied by intermittent pain in the right leg. On physical examination, the patient was compost mentis, blood pressure 130/80 mmHg, pulse rate 89 beats per minute, respiration rate 20 breaths per minute, temperature 36.7 C, SpO298% free air, urine production 1500 ml/24 hours (drinking of 1500 ml), lower extremity dextraedema (+), redness (+), and warm (+). Patient assessment: acute on CKD + sepsis and cause UTI + suspected deep vein thrombosis (DVT) in the right lower extremity associated with DLC + corrected hyperkalemia (4.8) + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stone + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Diagnosis: waiting for result of Doppler ultrasound of the right lower extremity. Therapy and monitoring were the same. Tenth-day of treatment: complaints of swelling accompanied by intermittent pain in the right leg. Physical examination: compost mentis, blood pressure 130/80 mmHg, pulse rate 89 beats per minute, respiration rate 20 breaths per minute, temperature 36.8 C, SpO298% free air, urine production 1200 ml/24 hours (drinking 1200 ml), lower extremity dextraedema (+), redness (+), and warm (+). Laboratory tests showed hemoglobin 10.3 g/dl, hematocrit 32.8%, erythrocytes 3.65 x 106/ul, leukocytes 10.23 x 103/ul, platelets 168 x 103/ul, BUN 12 mg/ul. Dl, serum creatinine 0.89 mg/dl, sodium 133 mmol/l, potassium 3.6 mmol/l, chloride 99 mmol/l. Patient assessment: acute on CKD + post sepsis + suspected deep vein thrombosis (DVT) in the right lower extremity associated with DLC + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stone + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Planning diagnosis: waiting for the right lower extremity Doppler ultrasound results, vascular DUS echo (today), others tests were the same. Therapy planning and constant monitoring were the same. Thirteenth day of treatment: complaints of swelling accompanied by intermittent pain in the right leg. Physical examination: compost mentis, blood pressure 130/80 mmHg, pulse rate 90 beats per minute, respiration rate 20 breaths per minute, temperature 36.7 C, urine production 1200 ml/24 hours (drinking 1200 ml/24 hours), lower extremities dextraedema (+), redness (+), and warm (+). Doppler ultrasound of the right lower extremity showed: 1) Diffuse deep vein thrombosis from the common femoral vein, great saphenous vein (GSV), common femoral, superficial, popliteal vein, into right distal posterior tibial vein with subcutaneous edema at the level of the femoral artery to the right dorsalis pedis; 2) no stenosis/occlusion/vascular malformation of the arterial system was seen. Vascular ultrasound (DUS) showed deep vein thrombosis in the right lower extremity. Laboratory results: INR 0.93. Assessment: acute on CKD + post sepsis + deep vein thrombosis (DVT) in the right lower extremity associated with DLC + left mild hydronephrosis with medial 1/3 left hydroureter and cause left renal stone and ureteral stone + bladder stone + left solitary kidney + controlled hypertension + pulmonary tuberculosis sequelae. Planning diagnosis: INR evaluation. Treatment: fondaparinux injection 7.5 mg every 24 hours im (first day). Fourteenth day of treatment: complaints: swelling accompanied by intermittent pain in the right leg. Physical examination showed compos mentis, blood pressure 130/80 mmHg, pulse rate 92 beats per minute, respiration rate 20 breaths per minute, temperature 36.0 C, urine production 1200 ml/24 hours (1200 ml drinking), lower extremity dextraedema (+), redness (+), and warm (+). The assessment was the same. Diagnosis: INR evaluation. Therapy: fondaparinux 7.5 mg injection for 24 hours (second day), the other therapy was the same. Fifteenth day of treatment: complaints: reduced swelling with pain in the right leg. Physical examination showed compos mentis, blood pressure 130/80 mmHg, pulse rate 90 beats per minute, respiration rate 20 breaths per minute, temperature 36.7 C, urine production 1200 ml/24 hours (1200 ml drinking), reduced lower extremity dextraedema. The assessment was the same. Diagnosis: INR evaluation. Therapy: fondaparinux 7.5 mg injection in 24 hours im (third day), warfarin 2 mg/24 hours (first day), the other therapy was the same. Sixteenth day of treatment: complaints: reduced swelling and pain in the right leg. Physical examination showed compos mentis, blood pressure 130/80 mmHg, pulse rate 90 beats per minute, respiration rate 20 breaths per minute, temperature 37.2 C, urine production 1500 ml/24 hours (drinking 1500 ml), reduced dextra edema in lower extremities. Laboratory test results: INR 1. Diagnosis: INR evaluation. Therapy: fondaparinux injection 7.5 mg/24 hours im (fourth day), warfarin 2 mg/24 hours (second day), other therapy. Eighteenth day of treatment: complaints: swelling and pain in the right leg is reduced. Physical examination showed compos mentis, blood pressure 130/80 mmHg, pulse rate 92 beats per minute, respiration rate 20 breaths per minute, temperature 37.0 C, reduced dextra lower extremity edema. Laboratory: INR evaluation. Patient assessments were the same. Diagnosis: RFT evaluation, INR evaluation. Treatment: fondaparinux injection 7.5 mg/24 hours im (sixth day), warfarin 2 mg/24 hours (fourth day), other therapy. Twenty-first day of treatment: complaints: swelling and pain in the right leg is reduced. Physical examination showed compos mentis, blood pressure 130/80 mmHg, and rate of 92 beats per minute, respiration rate of 20 breaths per minute, temperature 37.0 C, reduced dextraedema in lower extremities. Laboratory: INR 2.5. The patient assessment was the same. Diagnosis: none. Therapy: injection of fondaparinux 7.5 mg/24 hours im (stop), warfarin 2 mg/24 hours (seventh day), other therapy. Diagnostic assessment: assessment: atelectasis, right pulmonary fibrosis, TB sequelae and right pleural effusion. There were no signs of active pulmonary tuberculosis on clinical, radiological, and microscopic assessment. Diagnosis: spirometry when the patient was stable. Treatment planning: O2nasal cannula 3-4 liters per minute (lpm) prn, nebulized salbutamol 2.5 mg + ipratropium bromide every 8 hours. Thoracic-cardiovascular surgery consultation: Doppler ultrasound of the right lower extremity and elastic bandage. Heart consultation: DVT in the right lower extremity has not been ruled out. Diagnosis: echo vascular duplex ultrasound (DUS). Treatment: right lower extremity compression splinting. Diagnosis: initial assessment showed acute CKD + sepsis et cause UTI + suspected deep vein thrombosis (DVT) in the right lower limb associated with DLC + hyperkalemia (6.0 mmol/l) + left mild hydronephrosis with left medial 1/3 hydroureter and cause left renal stone and ureteral stone + bladder stones + left solitary kidneys + controlled hypertension + pulmonary tuberculosis sequelae. Initial therapy planning included high-calorie diet (2100 calories per day) low in protein and salt, no fruit, vegetables, broth; venflon/syringe only, 2-step treatment of hyperkalemia (ca gluconate 1 ampoule iv injection, followed by D40 + 2 units of insulin as part twice every 30 minutes), injection of ceftriaxone 1 gram every 12 hours iv, injection of ranitidine 50 mg every 24 hours iv, paracetamol 500 mg every 8 hours prn, amlodipine 10 mg every 24 hours, and fluid restriction (drink maximum 600 ml/24 hours). Diagnosis was based on complete blood count, repeated RFT l, post-corrected serum potassium (5.3 mmol/l), blood culture, urine culture, and D-dimer. Monitoring was based on clinical examination, vital signs, and urine production. Informed consent: the informed consent is provided by the Dr. Soetomo Hospital and given to the patient. The patient agreed to the informed consent on November 21, 2018 at 12.00 pm for examination in Pandan I Room, Class III.

deep vein thrombosis, case report, double lumen catheter, hemodialysis

PMC7984901_01

Male

A 13-year-old male presented in the emergency department with his little finger of the nondominant hand injured while playing basketball. An axial compression with an excessive hyperextension was applied to the tip of his finger while he tried to steal the ball during the game. On physical examination, the finger was found to be deformed, swollen and very painful in performing any movement. There were no signs of neurovascular damage or skin lesion. Initial plain radiographs demonstrated a dorsal dislocation of PIP and DIP joints of his little finger in a step-ladder deformity (Figure 1). Anatomical reduction was easily obtained with a simple and gentle longitudinal traction. Following reduction, both joints were stable and confirmed on plain radiographs with no apparent any bony avulsion fragment or fracture (Figure 1). After that, buddy taping with the ring finger was applied for two weeks, and the patient was advised to mobilize the PIP and DIP joints as long as the discomfort allowed him. At 3 weeks of follow-up, the buddy taping was removed, and he had full extension of both joints, with flexion of the DIP joint to 50 and the PIP joint to 90 . At 6 weeks of follow-up, the patient had full active range of motion. Within 3 months after the reduction, the patient returned to previous level of musical activities (piano playing) without limitation of motion.

PMC7984901_02

Male

A 16-year-old male sustained a hyperextension injury in his index finger of the dominant had while playing football (goalkeeper). The ball had hit to the tip of his finger while he tried to get the ball away from his goal post. On physical examination, the finger was markedly deformed with swelling and difficulty on moving the finger. Neurovascular examination was normal. Initial plain radiographs demonstrated a dorsal dislocation of both the distal and proximal interphalangeal joints (Figure 2). Without the use of local anesthesia, reduction of both the dislocations was easily achieved, by longitudinal traction and pressure on the dorsal aspect of the distal phalanx. Plain radiographs confirmed successful reduction without any bony avulsion fracture (Figure 2). Both joints were stable, and the index finger was immobilized with the middle finger for two weeks. At 3 weeks of follow-up, the flexion of the DIP and PIP joints was 45 and 75 , respectively, while extension was normal in both joints. At 6 weeks of follow-up, the patient had almost full painless active range of motion. 5 months after reduction, he returned to previous level of sports activities.

PMC8627974_01

Male

A 46-year-old man presented to the Emergency Department complaining of acute onset diplopia for one day, as well as worsening intermittent occipital headaches over the past 3 months. His medical history was significant for HIV/AIDS with most recent CD4 count 100 cells/muL and viral load 38,541 copies/mL, with poor adherence to his antiretroviral therapy regimen for the past 6 months. He also described occasional subjective fevers and drenching night sweats but denied dyspnea, cough, chest pain, or other respiratory symptoms. He denied known drug allergies, and his current medications were abacavir, dolutegravir, and lamivudine. He denied tobacco smoking or drug use and reported drinking 1-2 beers during the weekends. He worked as a truck driver and had trips across the Midwest and Southern regions of the US. Six days prior to admission he was discharged from another hospital, where he was hospitalized for chronic headaches. During that hospitalization, a lumbar puncture revealed a CSF with mild pleocytosis of monocytic predominance, normal CSF protein and glucose and negative Gram stain. He was treated with ampicillin, ceftriaxone and acyclovir empirically. CSF Herpes Simplex PCR was negative. Neuroimaging, including magnetic resonance imaging (MRI) and MR angiography of the brain were reported as unremarkable. His symptoms were attributed to an aseptic meningitis of probable viral etiology and he was discharged home off antimicrobials. On arrival to our hospital, the patient was afebrile and hemodynamically stable and in no acute distress, with oxygen saturation 100% on room air. Cardiopulmonary and abdominal exam were unremarkable. Neurological examination revealed binocular diplopia with left ptosis, exotropia and inability to adduct the left eye. Laboratory exams were remarkable for mild leukopenia with white blood cell (WBC) count of 2.6 x 103/muL, absolute neutrophil count of 1.4 x 103/muL, and normocytic anemia. Transaminases were mildly elevated at ALT 63, AST 45. Initial computed tomography (CT) scan of the head without contrast was unremarkable. Despite concern for ischemic stroke, the patient was not a candidate for thrombolysis due to onset of symptoms being 24 h prior. A transthoracic echocardiogram was negative for thrombi or vegetations. Given the history of headaches, subjective fevers, and AIDS, a lumbar puncture was performed on day 1, to assess for chronic meningitis. CSF study showed WBC of 8/muL and 13/muL red blood cells, with 88% lymphocytes and 10% monocytes. CSF protein was 45 gm/dL and glucose was 52 mg/dL. Gram stain was negative for any organisms. Also on day 1, a brain MRI revealed an acute lacunar infarct with restricted diffusion in the left paramidline midbrain, in the expected position of the oculomotor nerve nucleus (Fig. 2). At this point, studies were sent on serum and CSF to evaluate the suspected conditions in the differential diagnosis, including tuberculosis, endemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis), and syphilis. On further testing, a chest CT scan with contrast revealed bilateral numerous tiny miliary nodules of apical predominance, concerning for miliary tuberculosis versus fungal or malignant etiologies (Fig. 3). A bronchoscopy showed normal airways and the bronchoalveolar lavage (BAL) Gram stain revealed rare budding yeasts. The oculomotor nerve palsy resolved spontaneously over the next 4 days only with supportive therapy. Consecutive acid-fast bacillary sputum and BAL smears were negative. Eventually the results of serum, urine and CSF Histoplasma antigens returned as positive. Intravenous liposomal amphotericin B was initiated for disseminated histoplasmosis with CNS involvement for 6 weeks and the patient was then transitioned to oral itraconazole. He continued to have regular follow-ups at the infectious disease clinic after a year of treatment and had no relapses to date.

acquired immunodeficiency syndrome, central nervous system, fungal lung diseases, hiv, lacunar stroke, mycoses, stroke, vasculitis

Chest CT scan with contrast revealing bilateral micronodules predominantly in the upper lung fields in a "miliary pattern" (coronal view).

PMC8114242_01

Male

A 36-year-old African American male with a past medical history of HIV (diagnosed in 2005) presented to the emergency department for generalized weakness, fever, and dizziness on ambulation. The patient has not been taking his anti-HIV medications for past 3 years. Review of system positive for non-bloody diarrhea, 40 pounds weight loss over several months, chills, night sweats, and productive cough. Vital signs on presentation revealed blood pressure of 118/62 mm Hg, heart rate of 136 beats/minute, respiratory rate of 14 breaths/minute, temperature of 38.5 C, and oxygen saturation of 99% on room air. On examination, there were palpable bilateral axillary lymphadenopathy. On initial laboratory evaluation, the following values were noted: total leucocyte count 9.4 x 103/microL (4.5-11 x 103/microL), hemoglobin 9.2 g/dL (12-15.5 g/dL), platelets 112 x 103/microL (140-440 x 103/microL), absolute neutrophil count 6.47 x 103/microL (1.7-7 x 103/microL), absolute lymphocyte count 0.50 x 103/microL (0.9-2.9x 103/microL), blood urea nitrogen 16 mg/dL (8.6-10.3 mg/dL), serum creatinine 1.07 mg/dL (0.60-1.30 mg/dL), troponin 0.045 ng/mL (<0.03 ng/mL), creatinine kinase 86 U/L (30-223 U/L), prothrombin time 13.7 seconds (9.9-13 seconds), international normalized ratio 1.0 (0.9-1.1), partial thromboplastin time 44.7 seconds (25.2-37.4 seconds), HIV viral load 1 423 440 copies/mL, CD4 helper cells 5/microL (359-1519/microL), CD4/CD8 ratio 0.03 (0.92-3.72), lactate dehydrogenase 359 U/L (140-271 U/L), ferritin level 4412.0 ng/mL (16.4-294 ng/mL), and lactic acid was 1.3 mmol/L (0.5-2.2 mmol/L). Electrocardiogram showed sinus tachycardia of 111 beats/minute. Computed tomography (CT) of the head without contrast was negative. Chest X-ray showed no active disease. Noncontrast CT of the chest, abdomen, and pelvis showed left supraclavicular adenopathy (Figure 1), multiple enlarged mesenteric lymph nodes (Figure 2), mildly enlarged retroperitoneal lymph node, and hepatosplenomegaly. An excisional biopsy of the left axillary lymph node revealed epithelioid histiocytic aggregates without caseating necrosis and acid-fast bacilli within the epithelioid histiocytes (Figures 3 and 4). Immunohistochemistry analysis was positive for CD68 (Figure 5) and negative for S100, CD21, CD1a, and CD35. These results were consistent with mycobacterial spindle cell pseudotumor. Blood, stool, and sputum cultures were positive for Mycobacterium avium. Polymerase chain reaction of the biopsy tissue was negative for Mycobacterium tuberculosis complex. The patient was started on ethambutol, azithromycin, and rifabutin. His symptoms including dizziness improved over the course of his hospital stay. Fever resolved after day 9 of initiation of antimycobacterial drugs. Antiretroviral therapy was started on day 10 post commencement of antimycobacterial drugs. He was seen in infectious disease outpatient clinic a month after the diagnosis and was improving clinically.

hiv, mtb, mycobacterium avium, mycobacterium tuberculosis, acquired immunodeficiency syndrome, immunosuppression, mycobacterial spindle cell pseudotumor, spindle cell tumor

PMC8320547_01

Female

A 15-year-old female from the Macanao municipality on the Margarita's Island in Venezuela presented to the local health center with a 6-month history of intermittent fever predominantly occurring at night, malaise, 6 kg weight loss, arthralgias, loss of appetite, dizziness, and amenorrhea. The patient lives in a rural area close to a landfill in a house built with cement ground, brick walls, and a metal roof without running water. She has one dog (unknown Leishmania infection status) and various turtles as pets. She has no history of traveling outside Venezuela. On physical examination, she was pale, with increased respiratory and heart rate, and fever of 39 C. Her weight was 49 kg (percentile 36% according to age and gender), height of 1.57 m (percentile 22.3% according to age and gender), and an abdominal circumference of 76 cm. She had cervical, axillary, and inguinal adenopathy. Cardiac and lung examination were normal. Abdominal examination revealed right upper quadrant tenderness to palpation, and hepatosplenomegaly (liver was palpable at right flank 9.5 cm from the midclavicular line, and spleen with Hackett's system grade V) (Figure 1). Laboratory values on admission demonstrated pancytopenia (Table 1). Abdominal ultrasound and computed tomography confirmed the presence of hepatosplenomegaly. The initial clinical suspicion was that of a lymphoproliferative or myeloproliferative disorder. From an infectious disease perspective, the possibility of VL, a systemic mycosis, or tuberculosis were entertained. We performed a bone marrow biopsy to rule out a hematologic malignancy but also to assess the possibility of histoplasmosis or VL by Giemsa staining. Cultures were negative, but the K-39 ELISA Leishmania titers were positive at 1:100. Immuno-phenotyping of bone marrow cells demonstrated a heterogeneous population of leukocytes with arrest and anomalies in the myeloid line's antigenic maturation, and 1% of blasts compatible with a secondary myelodysplastic syndrome. Bone marrow biopsy showed hypocellularity, discrete collagen fibrosis, and increased macrophages with severe intracellular colonization of Leishmania donovani (Figure 2). Tuberculin skin testing and serologies for human immunodeficiency virus (HIV), syphilis, cytomegalovirus, and Epstein-Barr virus were all negative. The patient received treatment with meglumine antimoniate at 20 mg/kg/day for 30 days and tolerated this therapy without any significant side effects. The patient experienced significant improvement after completion of the treatment, becoming afebrile, and with increased appetite and gradual regression of her hepatosplenomegaly, and was discharged on stable clinical condition. Follow up laboratories after completion of antiparasitic therapy showed a hemoglobin of 10 g/dl, hematocrit of 29%, leukocytes of 5800 U/l, and platelets of 231,000 U/l.

caribbean, margarita island, venezuela, amastigote, endemic, visceral leishmaniasis

PMC9745302_02

Male

A 58-year-old man presented with chest tightness, cough, and asthma without fever in late October 2020. The patient took aminophylline and inhaled budesonide, but without obvious effect. His condition began to worsen gradually and he was admitted to a local hospital on 4 November, 2020. Electrocardiogram showed an elevated ST segment in leads II, III, and arteriovenous fistula (AVF). Echocardiography showed segmental wall motion abnormalities, and the LVEF was decreased (36%). Laboratory examinations showed elevated cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Thus, the patient was transferred to a cardiology care unit (CCU) for acute inferior myocardial infarction and heart failure. Coronary computed tomography (CT) angiography results showed only mild stenosis in the coronary arteries. The patient's symptoms improved insignificantly after the administration of medications that improved cardiac function. During hospitalization, he had fever with temperature of 39.5 C. Blood work showed a white blood cell (WBC) count of 9.7 x 109/L, hemoglobin level of 117 g/L, platelet count of 186 x 109/L, and high levels (2.2 x 109/L) and percentage (22.8%) of eosinophils. As the patient presented with cough and asthma, he was administered anti-infective and antipyretic treatment. Four days later, the patient's body temperature decreased to normal, and the fever symptoms were relieved. He was discharged from the hospital on 19 November, 2020. Two weeks later, the symptoms including fever, cough, and asthma recurred. Upon revisiting the local hospital, the patient's chest CT showed bronchiectasis with infection. He was administered antibiotics for 7 days but with poor effect and had fever with a temperature of 38 C. With no significant relief from symptoms, he revisited our hospital and was admitted to the respiratory department with bronchiectasis. Physical examinations revealed a body temperature of 37.6 C, pulse rate of 111 times/min, respiration rate of 20 breaths/min, and blood pressure of 130/80 mmHg. The laboratory examination showed the following test results: eosinophil count 3.36 x 109/L, percentage of eosinophils 32.10%, cTnI level of 1.032 ng/mL, and BNP level of 1,073 pg/mL. The patient had 1-year history of bronchial asthma and allergic rhinitis. He had a 30-year smoking history, smoking approximately 7 cigarettes per day and quitting smoking for 1 year. The patient did not show any history of hypertension, coronary heart disease, diabetes mellitus, food or drug allergies, infectious diseases, or parasitic infections. Echocardiography showed an enlarged heart and decreased LVEF (47%). It also showed that there were masses in both ventricular apexes with a small amount of pericardial effusion (Figure 2A). Contrast echocardiography showed no perfusion in either of the ventricular apical masses (Figure 2B). Hence, we considered the masses to be thrombi. Eosinophilia and Loeffler endocarditis with thrombus in the RV was considered a probable diagnosis. The patient was administered low-molecular-weight heparin (subcutaneous injection, 5,000 IU (international units), twice daily) and oral prednisone (60 mg, once daily). Nine days later, a routine blood work showed that eosinophils had decreased to within the normal range (0.37 x 109/L); however, frequent syncope persisted. The patient then underwent thrombectomy and tricuspid valve replacement. Pathological results showed an RV thrombus, endocardial fibroplasia, and eosinophilic infiltration. The symptoms relieved significantly after the operation, and he was discharged with oral prednisone (60 mg, once daily) and warfarin (3.75 mg, once daily). Six months later, prednisone was gradually tapered down to 10 mg daily. The patient continued to feel well for 2 years following surgery when he stopped taking prednisone and warfarin on his own. However, 6 months later, the patient experienced edema in both legs and was readmitted. Blood work showed elevated eosinophils once again (5.13 x 109/L). Echocardiography revealed a hypoechoic mass attached to the RVIT (Figure 1C), and contrast echocardiography showed no perfusion in the mass. Thus, the patient was diagnosed to have a recurrence of thrombus . He was once again prescribed oral prednisone (60 mg, once daily) and warfarin (4.5 mg, once daily). At the 3-month follow-up, no edema was noticed in the patient's legs. The eosinophils had restored to normal conditions, and the RV thrombus had dissolved. Thus, the medication was changed to long-term low-dose prednisone (10 mg, once daily) maintenance therapy. The patient remained in good health at later follow-up visits. A probable diagnosis of Loeffler endocarditis was considered. The patient was advised to undergo an endomyocardial biopsy but he refused invasive testing. He also refused to undergo cardiac magnetic resonance (CMR) due to noise intolerance. A bone marrow puncture showed eosinophilia. Genetic FIP1L1/PDGFRA, platelet-derived growth factor receptor-beta (PDGFRB), FGFR1/d8z2 (8p11), and parasite testing were negative. Other abnormal examination results included immunoglobulin G (IgG) 24.9 g/L , immunoglobulin E (IgE) 1,890 IU /mL , and urinary microalbumin 122.74 mg/L . Combined with clinical symptoms and examinations, the final diagnosis was eosinophilic granulomatosis polyangiitis (EGPA) involving multiple organs, including the heart (Loeffler endocarditis), lungs, kidneys, and nasal sinuses. This diagnosis was made according to the Classification Criteria of the American College of Rheumatology for eosinophilic granulomatosis polyangiitis (EGPA). The therapeutic medications included prednisone and mycophenolate mofetil for anti-immunotherapy, warfarin for anticoagulation, sacubitril valsartan, metoprolol, spironolactone, and dapagliflozin for heart failure. The patient's temperature returned to normal, and symptoms of tightness in chest, shortness of breath, and asthma alleviated substantially. During the regular outpatient follow-up visits, eosinophil count, IgG, and IgE levels returned to the normal range, electrocardiogram returned to a normal pattern, LVEF was improved to above 50%, and mural thrombi in both ventricles disappeared in echocardiography (Figure 2C). The patient's exercise tolerance improved significantly and he reported the ability to play basketball for up to an hour. Prednisone and mycophenolate mofetil were gradually tapered down to a maintenance dose. Because the patient had no uncomfortable symptoms and was in a good condition, he requested discontinuation of the medications for heart failure. A recent follow-up reported normal immunoglobulin levels, normal cardiac function, and no mural thrombus in the heart.

loeffler endocarditis, anticoagulant, corticosteroid, eosinophilia, thrombus

PMC6038329_01

Male

A 21-year-old male was admitted with the acute onset of hemoptysis. The night prior to admission he had smoked several (>5) marijuana joints and subsequently developed blood streaked sputum that became bloodier over time. He presented to ER found to have in no distress but was coughing up blood. Vital signs: Blood pressure 122/84 mmHg, Pulse 92 bpm, respiratory rate 20/ minute, with an oxygen saturation of 98% in ambient air. He was alert and oriented without any evidence of oronasal bleeding. His respiratory exam revealed diffuse rhonchi, remainder of his exam was unremarkable. Additional history was significant for 2 days of nasal congestion and headaches but no fever, chills, sweats, myalgia, sore throat, skin rashes, or joint pain/ swelling. He reported smoking 2-5 non-synthetic marijuana joints per day (though denied use of any inhalant aid, i.e. bongs), and had no significant occupational exposures or other illicit drug use. Initial evaluation included a hemoglobin of 16.4 g/dl, leukocytosis of 30.1 k/muL (83% neutrophils, normalized within 24 hours) and normal platelets. Serum chemistries, renal function, liver function, and coagulation studies were all normal. Urinalysis showed 0-2 RBC/ hpf and urine toxicology screen was positive only for tetrahydrocannabinol and negative for cocaine or any other illicit drugs. A Chest x-ray revealed diffuse patchy infiltrates, verified by a Chest CT showing extensive bilateral ground glass infiltrates with upper lobe predominance (Fig. 1) and (Fig. 2). The patient was started on empiric antibiotics (piperacillin/tazobactum, vancomycin and ciprofloxacin). Infectious work up, including blood and sputum cultures, legionella urinary antigen, quantiferon TB test, and HIV antibodies were all negative. A respiratory viral panel was positive for rhinovirus. Echocardiogram was completely normal. Flexible bronchoscopy was performed and revealed blood-streaked secretions diffusely. Successive bronchoalveolar lavage (BAL) was performed in the right and left upper lobes (RUL, LUL), and both appeared consistent with DAH (Fig. 3, Fig. 4). Cell counts were remarkable for a RBC of 44000 cells/mul with 380 white cells /mul (79% macrophages) from the RUL, and RBC of 37000 cells/mul with 363 white cells (74% macrophages) from the LUL. BAL stains and cultures were all negative, and cytology revealed only erythrophages and hemosiderinophages. An extensive rheumatological serologic evaluation including (ESR, CRP, C-ANCA, P-ANCA, Anti-GBM, rheumatoid factor, complement levels, and ENA panel) were negative. Urine cytology did not show any dysmorphic RBCs. The patient's condition improved with resolution of the hemoptysis, and he was discharged in stable condition. Outpatient pulmonary function testing was normal and a repeat Chest imaging had normalized. He was counseled to avoid smoking marijuana and remained symptom-free at his follow up visit.

PMC7364806_01

Male

A 44-year-old male patient complaining of dyspnea, severe pain, and progressive swelling in his jaw and neck for the last 14 days came to our emergency unit. Due to the rapidly extending swelling, he was hospitalized for 5 days in a private hospital, where a chest X-ray, neck, and soft tissue X-ray (Figure 1) and blood examinations were performed. The patient also received intravenous antibiotics (ceftriaxone, metronidazole, levofloxacin, omeprazole, and ketorolac; dosage unknown), yet, as there was no improvement to the size of the swelling, the patient was referred to our hospital. Physical examination revealed that swelling on the right submandibular region extended to the sublingual region, submental region, and the left submandibular region (with a size of 10 x 6 x 2 cm), reddish, febrile, fluctuated, and tender. The patient was febrile (38.8 C), had trismus, 102 beats per minute (bpm) pulse rate, respiratory rate is 26 breaths/minute, SpO2 was 98.2%, and 100/60 mm Hg blood pressure. No history of asthma or allergy was reported. The HIV and tuberculosis results came back negative, and the patient had no history of a dental visit. Therefore, past medical history was considered as non-contributory. Intraoral findings revealed a gangrene pulp of the #47 tooth and pericoronitis around the #48 impacted tooth. No other cavities were detected, regardless of the poor oral hygiene. Supporting clinical and laboratory examination included sequential organ failure assessment (SOFA), complete blood count, blood gas analysis, chest AP Lateral X-ray, and neck and soft tissue X-ray. The Erythrocyte Sedimentation Rate (ESR) test was not performed. Once the laboratory results were obtained (Table 1), a diagnosis of Ludwig's angina and septic shock was confirmed. In regard to the septic shock management, the patient received an infusion of norepinephrine. The patient was taken to the operating room immediately. A tracheostomy, emergency drainage, and tooth extraction (47, 48) were performed. Culture and sensitivity tests of blood and pus were performed but yielded a negative outcome. To allow further drainage, a Penrose drain was placed at the submandibular area, submental area, and (posterior) sublingual area (Figure 2). The patient was admitted for 10 days and received intravenous meropenem (1 g, three times per day), cefotaxime (1 g, three times per day), and metronidazole (500 mg, three times per day) as his antibiotics regimen. Another blood test was performed on the 5th and 10th day after the surgery, while another thorax X-ray was performed on the 10th day. The tracheostomy tube was removed on the eighth day. The patient was discharged on the 10th day following clinical improvement (significant reduction of the swellings in all regions: submandibular, sublingual, and submental), pus production was less than 5 cc/day, mouth opening was more than 3 cm, the patient no longer experienced swallowing difficulty, and vital signs were normal. The blood test results (except for the white blood count that was slightly higher than normal value: 14.930/mm3) and thorax photo results were in favor of this decision.

ludwig’s angina, ludwig’s angina management, septic shock

PMC3085480_01

Male

A 27-year-old Somalian man, who had immigrated to the Netherlands in 1998, was referred in March 2005 with persistent bilateral otitis media, progressive hearing loss, and tinnitus since eight months, which had been unresponsive to several courses of antibiotics. Other complaints were malaise, fever, anorexia, and weight loss for two weeks accompanied by dizziness and unsteady gait, one week later followed by diplopia and drooping mouth. His sister had been diagnosed with TB during screening on immigration in 1998. At that time, the patient's chest radiography showed abnormalities consistent with past healed TB infection. On physical examination, a malnourished man was seen with complete deafness of both ears. Neurological examination confirmed a right facial palsy and left abducens palsy. Otoscopy showed an extensive polypous inflammatory mass in both external ear canals. During fiber endoscopy a similar mass with purulence was seen in the left middle nasal passage extending up to the left Eustachian tube. The remainder of the examination was unremarkable. Laboratory investigation showed a hemoglobin level of 7.2 mmol/L after hydration, an ESR of 56 mm/first h, and mild elevation of serum transaminases. HIV serology was negative. Tone audiometry showed symmetric mixed hearing loss of 80 to 120 dB. On chest radiography, fibrosis in the apex of the left inferior lobe was seen, unchanged compared to 1998. An MRI showed an inflammatory process of both mastoid and petrous bones with abscess formation on the left extending downwards into the parapharyngeal space resulting in a bulge of the contour of the nasopharynx (Figure 1). An extensive bilateral temporal pachymeningitis was observed as well as bilateral involvement of the inner ear. A low-grade infectious disease process such as TB was suggested. Awaiting further test results, empirical treatment with corticosteroids was started. Histology of biopsies from the external ear canals as well as from the mass extending from the nasopharynx and skull base to the nose showed necrotizing granulomatous inflammation with giant cells. Auramine staining was positive with one acid-fast rod in the nasopharyngeal biopsy, and Ziehl-Neelsen staining and PCR of all biopsies were negative. The Quantiferon TB Gold in-tube assay (Cellestis, Carnegie, Australia), performed three days after starting prednisone, was positive (>10 IU/mL interferon-gamma, cut-off value 0.35 IU/mL). Hence, the patient was diagnosed with tuberculous otitis media with petrositis extending via the skull base to the nasopharynx. Treatment with four antituberculous drugs (rifampicin, isoniazide, pyrazinamide, and ethambutol) and pyridoxine was initiated. Within several weeks there was clinical improvement with functional recovery of the nervus facialis and abducens. However, severe hearing loss persisted (>90 dB in both ears at all frequencies), requiring a hearing aid. Culture of the nasopharyngeal biopsy yielded susceptible M. tuberculosis. Isoniazide and rifampin were continued for a total duration of 12 months. In 2005, a 35-y-old man from Sudan, who resided as a refugee in the Netherlands since 3 years, presented with pain in the neck since several months, a sore throat, problems with swallowing, and torticollis to the right. He reported weight loss of five kg in two months. Three months earlier he had been analyzed for unproductive cough, but chest radiography was without abnormalities, and no specific diagnosis was made. On physical examination an ill, transpiring man without a fever was seen. There was a repositionable torticollis to the right shoulder and deviation of the uvula to the right due to paresis of the right N. IX and N. XI. On nasendoscopy, an asymmetric mass with a glazed aspect was seen on the right side of the nasopharynx. The remainder of the examination and the routine laboratorium examination were unremarkable. HIV serology was negative. The Quantiferon TB Gold in-tube assay was positive (>10 IU/mL interferon-gamma; cut-off value 0.35 IU/mL). Chest radiography showed no abnormalities. CT and MRI showed abscess formation and surrounding edema in the retropharyngeal space and prevertebral muscles on the right, accompanied by usurpation of the clivus and C0-C1 joint (Figure 2). The differential diagnosis included TB. Biopsies of the nasopharyngeal mass obtained during nasendoscopy were not diagnostic. Next, a CT-guided biopsy of the prevertebral mass was obtained under complete anesthesia, showing necrotic material with chronic active inflammation. Auramine and Ziehl-Neelsen staining and PCR for M. tuberculosis were negative. Based on the positive Quantiferon test result in the absence of an alternative diagnosis, treatment with four anti-TB drugs was started followed by rapid clinical and radiological improvement with recovery of cranial nerve function. The culture yielded fully susceptible M. tuberculosis. Isoniazide and rifampicin were continued for a total of 12 months. At the end of treatment, only partial destruction of the right C0-C1 joint persisted.

PMC5804607_01

Female

An 81-year-old woman (160 cm, 60 kg) was transferred from a district general hospital to our hospital for treatment of congestive heart failure. At admission, the patient presented with a nonproductive cough, dyspnea, edema in both lower extremities, orthopnea, fever, and occult blood in the stool, all of which began to about 10 days prior to admission. Past medical history included atrial fibrillation (AF). She had a no drinking and smoking history, and activities of daily living were in the normal range. Her temperature was 37.3 C, pulse rate was 133 beats per min with AF, respiratory rate was 24 breaths per min, and blood pressure was 115/58 mmHg. Laboratory findings were as follows: WBC count, 11,040 cells/mm3 without a left shift; hematocrit, 34.7%; platelets, 145,000/mm3; creatinine, 0.8 mg/dL; alanine aminotransferase, 69 U/mL; aspartate aminotransferase, 56 IU/mL; total bilirubin, 1.4 mg/dL; and respiratory alkalosis. A chest radiograph indicated bilateral pleural effusion and pulmonary congestion (Fig. 1). We performed transthoracic echocardiography (TTE). TTE showed an ejection fraction of 50%; verrucas were not detected. Intravenous ampicillin/sulbactam (6 g/day) therapy was initiated to treat a potential bacterial infection (Fig. 2). After diuretic therapy and chest drainage, bilateral pleural effusion and pulmonary congestion improved. On day 2, she experienced severe respiratory distress, with diminished breath sounds, bilateral pulmonary crackles, and an oxygen saturation of 98% while receiving 100% oxygen through a nonrebreather 4-L mask. B. cereus was isolated from two blood sample cultures (arterial blood and venous blood) collected at admission (Fig. 3), and intravenous levofloxacin (250-500 mg/day) therapy was initiated instead of ampicillin/sulbactam therapy (Fig. 2). No pathogenic organisms were identified by sputum and pleural effusion of chest drain cultures. On day 3, clindamycin (1200 mg/day) was combined with levofloxacin (Fig. 2). On day 4, her condition progressed to severe respiratory distress (PaO2/FiO2 ratio = 108). A chest radiograph (Fig. 4) and computed tomography (CT) (Fig. 5) indicated extensive bilateral infiltrates. Her temperature was 37.5 C, pulse rate was 139 beats per min with AF, blood pressure was 78/47 mmHg, and oxygen saturation was 93% while receiving 100% oxygen by a rebreather 15-L mask. She was transferred to the intensive care unit (ICU) and intubated. She had pulmonary coarse crackles, and moderate amounts of frothy pale pink respiratory secretions were collected from the endotracheal tube. Dopamine, dobutamine, and noradrenaline were administered for hypotension. Laboratory findings were as follows: WBC count, 9860 cells/mm3 without a left shift; hematocrit, 37.0%; platelets, 147,000/mm3; creatinine, 1.47 mg/dL; alanine aminotransferase, 98 IU/mL; aspartate aminotransferase, 54 IU/mL; total bilirubin, 1.5 mg/dL; and respiratory alkalosis. The patient was unable to mount an adequate leukocyte count in light of her clinical condition. B. cereus was isolated from five blood sample cultures (four arterial blood cultures and one venous blood culture), but stool cultures were negative at that time. On day 4, intravenous imipenem (750 mg/day) therapy was initiated instead of levofloxacin and clindamycin therapy (Fig. 2). On day 5, levofloxacin (250-500 mg) was combined with imipenem (Fig. 2). She had no history of immunodeficiency, surgery, ill close contacts, risk factors for HIV or tuberculosis, recent central venous catheter insertion, or anthrax vaccination. On day 7, a chest radiograph and CT indicated a reduction in the size of bilateral infiltrates, suggesting that respiratory therapy and antibiotic therapy were effective. The patient was extubated and, on day 9, discharged from the ICU. No further remarkable changes were noted, and she was discharged from the hospital. The present case was unusual, given that the patient was not immunocompromised but succumbed to lung infiltrates associated with B. cereus. B. cereus is a well-known pathogen in food poisoning. It causes toxin-mediated, self-limited illness characterized by emetic or diarrheal syndromes. It is also known to cause bacteremia, endocarditis, meningitis, and pneumonia. Previously reported cases of B. cereus pneumonia in adults are rare and usually associated with significant risk factors which are summarized in Table 1. Immunocompromised patients with B. cereus pneumonia frequently have septicemia and fatal illness. Most previously reported cases of infection occurred in patients with hematological disorders or alcohol abuse. However, four lethal cases of B. cereus pneumonia in immunocompetent welders and metalworkers have been reported. Our patient had no history of immunodeficiency, surgery, ill close contacts, risk factors for HIV or tuberculosis, recent central venous catheter insertion, or anthrax vaccination. It is interesting that our patient, who had none of the known risk factors for severe respiratory illness, survived the episode. However, the patient's age (81 years) may have been a contributing factor. As age advances, the immune system undergoes profound remodeling and decline. This immune senescence predisposes older adults to a higher risk of acute viral and bacterial infections. Compared to previously reported episodes of B. cereus pneumonia in adults (Table 1), our patient was much older and thus may have been more susceptible to B. cereus infection. Non-anthracis Bacillus species might be dismissed as contaminants when isolated from clinical samples. Therefore, detection of the microorganism in multiple samples is usually necessary to make a definitive diagnosis of B. cereus pneumonia. In the present case, the pathogenic role of B. cereus in pneumonia was confirmed by seven different specimens of blood that were sampled aseptically. However, we did not perform a bronchoscopic assessment of lung infiltrates, and B. cereus was not confirmed from bronchial lavage fluid and transbronchial lung biopsy specimens. There were no episodes of infectious disease other than severe pneumonia during hospitalization. Respiratory symptoms such as cough and dyspnea, and gastrointestinal symptoms (occult blood in the stool) were present. Therefore, in the present case, B. cereus pulmonary infection may have resulted from transient bacteremia from a gastrointestinal infection. Indeed, we had suspected as such at a relatively early stage (on day 2). B. cereus produces beta-lactamase and is therefore resistant to penicillin and cephalosporins. B. cereus is usually susceptible to clindamycin, vancomycin, fluoroquinolones, carbapenems, and aminoglycosides. After isolating B. cereus, we switched antibiotics to a combination of imipenem and levofloxacin, which were effective.

bacillus cereus, immunocompetent patient, pneumonia

PMC5836235_01

Female

A 50-year-old woman has suffered from repeated abdominal pain for 6 years. She had had a history of lung tuberculosis 10 years ago; consequently, she had received standard anti-tuberculosis chemotherapy for 9 months. The patient presented with acute lower right abdominal pain for 1 day due to intestinal obstruction proved with plain abdominal radiography. She had no fever, no cough, and no weight loss. Physical examination revealed mild tenderness of the right lower quadrant abdomen. Barium enema showed filling defects of the ileum (Fig. 1). Blood analysis showed a white blood cell count of 7.5x109/L and her C-reactive protein level was 8 mg/L. Chest X-ray revealed pulmonary scars. Bowel thickening (approximately 8.5 mm), distal bowel dilation, and comb sign were seen on small bowel CT (Fig. 2). Colonoscopy was performed and returned without ulcers or nodularities. A purified protein derivative test revealed 15 mm of induration, and T-SPOT was positive. Furthermore, her HIV antibody test was negative. Chest contrast-enhanced CT showed pulmonary scar proliferation without active findings. Her intestinal obstruction was worsening with exclusive nutritional support treatment. We held a multiple-discipline workshop involving a senior surgeon, gastroenterologist, radiologist, and pathologist. Fibrosis of the local small bowel was observed, and all experts reached the consensus that laparoscopic resection was indicated in this patient due to poor outcome of conservative therapy. Informed consent for surgical resection was obtained from the patient. The surgical specimen showed severe fibrosis and stenosis of 6 cm in length, the maximum depth of the lesion was 1.8 cm, additional to multiple cobblestone appearances (Fig. 3). Microscopically, these lesions consisted of granuloma and numerous macrophages. Hematoxylin and eosin staining and immunohistochemistry with periodic acid-Schiff revealed budding forms of histoplasma capsulatum within the macrophages (Fig. 4). Ileum histoplasmosis was diagnosed by the senior pathologist. No postoperative complications were seen.

crohn's disease, ileum histoplasmosis, intestinal tuberculosis

PMC5965317_01

Female

A 22-year-old woman was referred by the critical care team of a district general hospital (DGH) to our regional burns unit with 100% TBSA involvement following toxic epidermal necrolysis (TEN) on the background of GPA. The patient initially presented to the DGH with a fever, shortness of breath and feeling generally unwell. A chest X-ray demonstrated multiple opacities and on computerised tomography (CT) of the chest and abdomen, she was found to have multiple cavitations, a pulmonary embolism and a femoral thrombosis. Granulomatosis with polyangiitis (GPA) was confirmed and the patient was commenced on warfarin, rituximab, methylprednisolone, Immunoglobulins (IgG) and fluconazole, to which she responded well. As part of this regime she had a second and third infusion of rituximab and prophylactic co-trimoxazole. Three days following co-trimoxazole, she presented back to the DGH with angioedema and had developed a rash with an estimated 90% total body surface area (TBSA), involving the oral and ophthalmic mucosa. Fluconazole and co-trimoxazole were immediately stopped and the steroids increased with the initial suspicion of Stevens-Johnson syndrome (SJS). The patient deteriorated, progressing to 100% TBSA, and required significant support from the critical care team. TEN was suspected and subsequently confirmed by skin biopsy. She had an initial SCORTEN (SCORe of Toxic Epidermal Necrosis) score of 3, predicting a 35.3% mortality risk, and was accordingly referred and transferred to our specialist burns centre for management of her extensive wounds. Figure 1a and b show the large extent of the TBSA involved in this patient. Piperacillin/Tazobactam (Tazocin) and Vancomycin antibiotics were commenced following sputum and wound swab sensitivities. One week following admission, prednisolone was reduced to 40 mg daily. After 10 days of treatment, there was good re-epithelisation of the skin. The patient was discharged at 3 weeks following a period of physiotherapy.

toxic epidermal necrolysis, wegener’s granulomatosis, burns unit, concurrent, granulomatosis with polyangiitis, treatment

PMC8720442_01

Female

A 3-year-old girl was brought by her parents to the neurosurgery department with complaints of difficulty walking for 4 months. The patient had a backward bending posture while walking. She swayed to one side and dragged her right lower limb. She also had difficulty wearing her slippers. She was not able to bend forward or sit for a long duration of time. Ten months ago, she had a history of headaches that lasted for a week. The patient also had urinary incontinence for 4 months. The patient had one episode of seizures post which she developed lower limb weakness. There was no history of trauma to the spine and no history of coming in contact with a patient who had TB. The patient was vaccinated according to the World Health Organization schedule. The patient had a history of pneumonia at the age of 1 month, following which she was admitted to the intensive care unit for 1 week. On examination, vitals were stable. Neurological examination showed that the tone of both lower limbs was increased. Plantar reflexes were extensor bilaterally. A magnetic resonance imaging (MRI) from an outside clinic showed a hyperintense intramedullary lesion, on T2W imaging, from T6 to T9 [Figure 1]. On sagittal T1W imaging, with contrast, there was a fusiform dilation of the cord at the same levels with no enhancement. A similar finding was present on the axial cuts [Figure 2]. The scan also showed hydrocephalus. However, on examination, there were no signs of raised intracranial pressure (ICP). The child underwent a T6 to T9 laminoplasty with intramedullary lesion decompression under neuromonitoring. Intraoperatively, the lesion was yellowish, fibrous, and densely adherent to underlying cord and nerve roots. Hence, only debulking of the lesion was performed. Postoperatively, mild deterioration of motor power in both lower limbs was noted. Histopathological examination of the lesion showed features suggestive of tuberculous granulomatous inflammation [Figure 3]. The diagnosis was then established. A pulmonology consultation for initiation of antitubercular treatment (ATT) was taken. The child was started on ATT and was subsequently discharged after being symptomatically better. The patient was reviewed 8 months after her initial visit while still on ATT, and she showed improvement in her gait abnormalities and is walking with support. The review scans [Figure 4] showed complete resolution of the lower lesion but now showed evidence of chronic arachnoid adhesions at the T3 level. A CT brain performed at the same time showed evidence of hydrocephalus, most likely noncommunicating in nature [Figure 5]. This may be due to tubercular meningitis or arachnoiditis. The patient was advised to continue her ATT and was discharged.

antitubercular treatment, pediatric spine, spinal intramedullary lesion, tuberculoma

PMC8761856_01

Female

This is a Chinese case of a 69-year-old female who noticed distention of the hypogastrium accompanied by constipation 20 days ago. No pain, nausea, vomiting, fever, oppression in the chest, jaundice, and bloody stool were found during the period, and she went to the local hospital and received enema treatment. However, distention of the hypogastrium still existed. There were no liver palms, spider-burst, superficial lymph node enlargement, tenderness, rebound tenderness, masses, fluid thrill, shifting dullness, hepatojugular reflux, and pathological reflex on relevant physical examination. The patient denied familial genetic, alcohol abuse, hepatitis, hepatic cirrhosis, psychosocial and exposure to radiation, and toxin history. Furthermore, she was examined in line with the care checklist, as shown in Supplementary Figure 1 . Laboratory tests of the tumor biomarkers (alpha-fetoprotein (AFP), CEA, CA125, CA199, CA153), liver function (ALT, AST, TP, ALB, GLB, TBIL, DBIL, IBIL), and lipid index (TG, TC, HDL-C, LDL-C) of serum were normal. She was admitted and underwent abdominal computed tomography (CT), which demonstrated a 3.3-4-cm soft tissue mass shadow in the neck of the gallbladder which was significantly enhanced on enhanced scan with an unclear boundary to the duodenum and head of pancreas ( Figures 1A, B ). Unclear cystic duct, dilation of the common bile duct, and bile ducts inside and outside the liver were shown. No dilation of the pancreatic duct or definite abnormality of the liver was detected. Porta hepatis lymph node enlargement was also observed ( Figure 1C ). Magnetic resonance imaging (MRI) also showed gallbladder neck mass ( Figure 1D ). Therefore, a gallbladder carcinoma was suspected and laparoscope cholecystectomy was performed. The mass was about 3.8 x 3.5 x 1 cm3 in size on the gallbladder wall ( Figure 2A ). The primary lesions consisted of two components: high-grade intraepithelial neoplasia of glands ( Figure 2B ) and hepatoid glands ( Figure 2C ). The tumor cells were cuboidal or polygonal with abundant eosinophilic granular hepatocyte-like neoplastic cells, and the nucleus was large and ovoid; moreover, one to two nucleoli were also shown in the area of the hepatoid component. The lymph node around the gallbladder had been invaded by the hepatoid tumor cells ( Figure 2D ). Immunohistochemical staining shows positiveness of glypican-3 and MUC-1 of high-grade intraepithelial neoplasia of glands, but negativeness or weak positiveness in the hepatoid glands ( Figures 3A, B ). Hepatocyte paraffin 1 (Hep par-1) showed contrasting results ( Figure 3C ). AFP, arginase-1, and Sall-4 were all negative ( Figures 3D-F ), and P53 was strongly positive ( Figure 3G ). The Ki-67 index in hepatoid glands was much stronger than that of other areas ( Figure 3H ). Besides, positiveness of CK-pan, CK7, CK8, CK18, and CK19 and negativeness of CK20 were also detected. TMB of 688 genes detected by MGISEQ-2000 of Beijing Genomics Institute (BGI, Shenzhen, China) was used in the case. The MB21D2 gene showed Exon 2E p.Q311E (c.931C > G) mutation, and abundance of mutation was 10.5%. The GALNT12 gene revealed Exon 1 p.L133Q (c.338T > A) mutation, and abundance of mutation was 13.56%. The ARID2 gene indicated Exon 10 p.L381V (c.1141C > G) mutation, and abundance of mutation was 11.47% ( Table 1 ). No microsatellite instability (MSI) and germline mutation were detected. Finally, we made the diagnosis of primary hepatoid adenocarcinoma of the gallbladder with MB21D2, GALNT12, and ARID2 mutations. The patient remained under careful observation by radiological and ultrasonic examination, and there was no visceral metastasis in the 5-month follow-up. The patient got an appropriate perspective including the assessment and the episode of care in every month, such as ultrasound examination, rehabilitation training, dietary guidance, regular physical examination, and mental status assessment. The patient healed well, and the distention of hypogastrium disappeared. No adverse or unanticipated events and symptoms in physical examination happened during the period.

tmb, case report, gallbladder, hepatoid adenocarcinoma, immunocytochemistry

PMC3327677_01

Unknown

This study is a retrospective review of clinical and laboratory records from hospital databases. Case files for children 0-14 years old admitted to any of the ICUs with a suspicion of malaria between January 2004 to December 2009 were reviewed for: (1) ICU logbooks (in which demographic data from each admitted patient, a presumptive diagnosis at admission and a final diagnosis at discharge are systematically registered), (2) hospital laboratory logbooks (in which the semi-quantitative results of TBSs performed in each hospital are systematically registered), and (3) SIVEP-Malaria (the National Malaria Information System available on-line, which registers results of TBSs performed in each reporting unit such as the hospitals of interest). Cases were included if there was evidence of malaria diagnosis by microscopy in any of the three information systems searched. The study enrolled only patients after 2004 because of better reliability of the National Malaria Information System (SIVEP-Malaria) and access to the clinical files, avoiding retrieval bias. As comparators, clinical and laboratory data from children of the same age group admitted between January 2009 and July 2010 to the Fundacao de Medicina Tropical Dr. Heitor Vieira Dourado with a diagnosis of malaria were retrieved electronically from the computerized hospital records system (iDoctor ) and reviewed. With the exception of automated full blood count, routinely requested for all these hospitalized children, more specific laboratory tests (such as biochemistry and arterial gas analysis) were requested only if clinical symptoms were suggestive of complications. As part of routine follow-up, all malaria admitted children were reassessed in the Outpatient Clinics seven days after discharge to guarantee adequate clinical and parasitological follow-up. TBSs are routinely performed for the diagnosis of malaria in Brazil, prepared as recommended by the Walker technique and evaluated by a local microscopist. The results of peripheral parasitemia are given using the following semi-quantitative system: 1/2+ (200-300 parasites/mm3); 1+ (301-500 parasites/mm3); 2+ (501-10,000 parasites/mm3); 3+ (10,001-100,000 parasites/mm3); and 4+ (>100,001 parasites/mm3). The cut-off to define high parasitemia (in the final analysis) was based on the distribution of semi-quantitative parasitemia results. All positive slides and 10% of negative slides are routinely reviewed in a reference unit with experienced microscopists. In case of divergence, the reviewed result is updated in the on-line system. PCR diagnosis for malaria was not routinely performed in these patients. Only children with a positive TBS for Plasmodium spp. are treated according to the Brazilian Anti-Malarial Treatment Guidelines, which recommends chloroquine (25 mg/kg over 3 days)+primaquine (0.5 mg/kg/day over 7 days) for P. vivax infection and artemether/lumefantrine for 3 days for non-severe P. falciparum infection. Severe P. falciparum infections are treated with parenteral artemether or artesunate for 7 days. Data for each admitted individual was systematically retrieved from the medical charts by the same member of the study team, and included the following variables: sex, age, malarial species, semi-quantitative parasitemia, duration of disease (in days) prior to the admission to the ICU or ward, outcome, presence of a given acute co-morbidity other than malaria or a chronic disease confirmed through a reliable diagnostic method, and presence of any WHO-defined severe malaria criteria. Briefly, WHO criteria for severe falciparum malaria validated for adults and children include: (1) impaired consciousness or unrousable coma (Blantyre coma scale <=2 or Glasgow coma scale <=10); (2) prostration, i.e. generalized weakness such that the patient is unable to walk or sit up without assistance; (3) failure to feed; (4) multiple convulsions (greater than two episodes in 24 h); (5) respiratory distress defined as the presence of deep (acidotic) breathing or retractions; (6) circulatory collapse or shock, systolic blood pressure <50 mmHg (algid malaria) and/or need for vasopressor support; (7) clinical jaundice or total bilirubin >3 mg/dL; (8) hemoglobinuria (blackwater fever); (9) abnormal spontaneous bleeding (disseminated intravascular coagulation); (10) pulmonary edema (radiological); (11) hypoglycemia (blood glucose <40 mg/dL); (12) metabolic acidosis (plasma bicarbonate <15 mmol/L); (13) severe anemia (Hb<5 g/dL); (14) hyperlactatemia (lactate >5 mmol/L); or (15) acute renal failure (serum creatinine >3 mg/dL). Acute respiratory distress syndrome (ARDS) was defined as acute bilateral lung infiltrates in chest X-rays, and a PaO2:FiO2<200 mmHg. The data retrieved were reviewed by another member of the study team and discrepancies resolved by a third member if necessary. In all ICUs, collection of venous blood samples for aerobic culture and arterial blood for gas analysis was routinely carried out on admission prior to administration of antibiotics. From all the patients hospitalized in the ICU, the Pediatric Index of Mortality (PIM) score was calculated with data from the first hour of admission, based on the systolic blood pressure, pupillary reactions to bright light, PaO2, FiO2, base excess in arterial blood, need for mechanical ventilation at any time during the first hour in ICU, elective admission, and presence of concomitant diagnoses. Severity was defined in the presence of at least one of the aforementioned WHO severity criteria. As blood gas analysis samples were not systematically collected for patients not admitted to the ICU, hyperlactatemia and metabolic acidosis were not used to classify severity nor assessed as a risk factor associated with ICU admission. The disease was classified as being directly caused by plasmodial infection if no other cause was identified and no concurrent acute or chronic diseases were confirmed. Data were analyzed using SPSS version 16.0 for Windows (SPSS Inc. Chicago, IL, USA). Proportions of fatality were compared by Fisher exact test (corrected by Yates' test if necessary); differences were considered statistically significant for p<0.05. The crude Odds Ratio (OR) with its respective 95% Confidence Interval (95% CI) was determined considering the admission to ICU as the dependent variable. Logistic regression was used for the multivariate analyses and the adjusted Odds Ratios with 95% CI were also calculated. A multivariate logistic regression was performed with admission to the ICU as the outcome, using an automated backward and forward stepwise estimation. All variables that were associated with admission to the ICU at a significance level of p<0.10 in the univariate analysis were included in the multivariate analysis. Statistical significance was considered if p<0.05 in the Hosmer-Lemeshow goodness-of-fit test.

PMC4532054_01

Female

A 21-year-old Korean woman had suffered from dyspnea and cough for the past 3 months. She was healthy until 2 years ago, when she first noticed both knee joints to swell and subside spontaneously. She also experienced intermittent both lower leg pain. Two months ago, chest P-A showed heterogenous, hazy, streaky densities on both lower lung fields and a well-marginated homogenous squared shape of mass-like density on the right middle lung (Fig. 1). She was treated with isoniazid, rifampin and pyrazinamide under the diagnosis of pulmonary tuberculosis, which was not confirmed by microbiologic study, at a private clinic. After 2 months of anti-tuberculous drugs, the chest X-ray revealed much improved infiltrations on both lower lung fields and right middle lung, but with newly developed lobulated, round homogenous density, with 4x4 cm in diameter, at the left hilar region (Fig. 2). She was transferred to our hospital for the evaluation of the left hilar lung mass. The patient was single, non-smoker and non-drinker. There was no history of pulmonary tuberculosis. She denied fever, sweats, hemoptysis, headache, otalgia and otorrhea, and bladder or bowel dysfunction. The temperature was 36.8 C, the pulse was 68 and the respiration was 18. The blood pressure was 130/80 mmHg. On physical examination, she appeared pale and chronically ill. She had multiple ulcerations on lower lip and oral cavity near right premolar teeth, but not on genital area. The ophthalmologic study showed no abnormal findings. The lung, heart and abdomen were normal. The skin examination revealed erythematous, tender nodules on wrist and both pretibial areas, which were pathologically proven as erythema nodosum. A gynecologist notified the aphthous ulceration of labia minora. The remaining physical examination was normal. The urine was normal. The hematocrit was 27 percent; the white-cell count was 9,000/mm3, with 68 percent neutrophils, 29 percent lymphocytes, 2 percent monocytes and 1 percent eosinophils. The ESR was 28 mm/hour. The shape of RBC was microcytic and hypochromic. The urea nitrogen was 18 mg%, the glucose 80 mg%, the serum alanine aminotransferase 20 IU, the alkaline phosphatase 56 U. The VDRL was negative. The arterial blood gas analysis showed PH; 7.40, PaCO2; 41 mmHg, PaO2; 96 mmHg. An electrocardiogram was normal. The perfusion scan showed lobar perfusion defect of left lower lobe and focal segmental perfusion defect of right lower lobe. The ventilation scan showed round single defect in left hilar area. The computerized tomogram of thorax revealed 5x5cm-sized, round, mass with surrounding low density, suggesting PAA with thrombosis in left lung (Fig. 3). Ascending venogram of lower leg showed diffuse obstruction of right femoral vein. The digital subtraction pulmonary angiogram revealed huge dilatation of left main pulmonary artery, proximal to the obstructed pulmonary artery (Fig. 4). Ten days after admission, blood-tinged sputum occurred abruptly at early morning. The patient was treated with steroids for 14 days without improvement of hemoptysis. During the next 6 weeks, although she was given steroids persistently, the left hilar lesions grew to large mass with diameter of 5 cm. We decided to excise the aneurysmal mass. Macroscopic examination of the excised lobe showed saccular dilation of pulmonary artery surrounded by the underventilated pulmonary parenchyma. On section, the aneurysmal dilatation was 5 cm in diameter and lined with laminated old blood clots. The main histopathological findings were located in the arterial walls. The arterial wall was markedly destructed with minimal fibrous thickening, medial destruction, marked infiltration of inflammatory cells, predominantly neutrophils. A large area of aneurysmal wall was necrotic, ulcerated and attached by thrombus. On special stain, elastic lamina was marked destructed, fragmented and frequently lost. There were multifocal infarctions, both in parenchymal and subpleural portion. She was treated with maintenance prednisolone during 1 year after lobectomy, but she noted sudden massive hemoptysis and eventually died.

The computerized tomogram of thorax reveals 5x5 cm-sized, round, mass with surrounding low density suggesting pulmonary artery aneurysm with thrombosis in left lung.

PMC9673929_01

Male

A 35-year-old male previously healthy surgeon sustained a needlestick injury while performing thoracentesis on a patient with smear-positive pulmonary tuberculosis (PTB) and was suspected of tuberculous pleurisy on November 9, 2012. The source patient was admitted to the local hospital because of respiratory failure, because his sputum detected acid-fast bacilli quickly, PTB was considered and was treated with isoniazid, rifampicin, ethambutol, and pyrazinamide. But his condition deteriorated rapidly and had acute hemopneumothorax. The surgeon in our study gave him an emergency chest puncture and drainage, and he collected the pleural effusion for tuberculosis culture. But he unfortunately sustained a needlestick injury while performing thoracentesis. He immediately disinfected the wound with povidone-iodine and washed it with water and soap. The source patient died the next day because of respiratory failure, it was less than a week before he was admitted to the hospital. Mtb were found in the source patient's hydrothorax culture; however, a susceptibility test was not performed. The surgeon had no history of TB infection or any other health problems. He was vaccinated with Bacillus Calmette-Guerin during childhood. The injury healed normally; however, after 3 weeks, redness, edema erythematous papule, and pain in his thumb at the previously injured site occurred, and then, the papule enlarged and subsequently resulted in abscess formation, which was drained using a needle, Ziehl-Neelsen stain, detecting acid-fast bacilli (AFB). The diagnosis of primary inoculation cutaneous TB was made based on the positive result of Ziehl-Neelsen staining and the source patient's hydrothorax culture. Then, he was treated with isoniazid, rifampicin, ethambutol, and pyrazinamide. After 10 days of treatment, the patient had a mild fever with chest tightness and noted multiple enlarged lymph nodes (LN) in his right axillary region. Then, he was transferred to our hospital. Physical examination revealed an indurated erythematous plaque at the middle of the thumb, a few clear liquids can be observed when pressed (Figure 1A), and tender multiple right axillary LN. Mild movement limitation of the affected finger's mobility was caused by the presence of a lesion. Laboratory testing revealed an elevated C-reactive protein level and a white blood cell count of 21.6 mg/L and 8800 cells/muL, respectively, with 76.7% neutrophils. Human immunodeficiency virus (HIV) types 1/2 and hepatitis viral panels were negative. A chest computed tomography (CT) scan showed multiple enlarged LN in the right axilla and right pleural effusion (white arrows) (Figure 2A). Magnetic resonance imaging (MRI) of the right hand (conducted 50 days after the needlestick) showed tenosynovitis involvement of the entire flexor tendon of the thumb (Figure 2B). The patient underwent thoracic puncture and drainage in our hospital, the pleural effusion was exudative, and the pleural fluid protein was 37.83 g/L. However, acid-fast staining of the pleural fluid was negative, and the general bacterial culture and TB culture were negative. The puncture fluid from the skin lesion was cultured, and Mtb was observed thereafter. Susceptibility was demonstrated against isoniazid and rifampicin. Therefore, the regimen was changed to moxifloxacin (400 mg daily), amikacin (400 mg daily), pyrazinamide (1500 mg daily), prothionamide (600 mg daily), and aminosalicylate (10 g, daily). However, amikacin was discontinued at 5.5 months because the patient complained of tinnitus and aural fullness, then the remaining drugs were continuously administered for 16 months without any other adverse effects. After 4 weeks of treatment, the finger lesion had disappeared (Figure 1B). Axillary adenopathy disappeared approximately 6 months post-treatment. The surgeon completed recovery by the end of the 22-month course of anti-MDR-TB therapy and returned to work afterward and gained normal thumb functions. The patient was maintained in the 8-year follow-up without any relapse.

cutaneous tuberculosis, inoculation tuberculosis, occupational exposure, tubercular tenosynovitis

PMC4779352_01

Female

A middle-aged female clinical doctor with no previous data of serious ill conditions had got over the chicken pox in early childhood (when she was five years old). She had no feeling of any health disorder but these days in the beginning of November of 2015 year she had too much work in her workplace in the hospital: in a short time several nights on duty with big number of seriously ill patients. In her private life she had a very big emotional stress-some financial problems of buying new apartment with neglecting proper nutrition in that period. Around 10th of November she began to feel fatigue, anorexia, general weakness, irritability, mild depression, which she explained that she was overworked. On the 12th of November when she went to sleep she felt the discomfort and mild pain beside the spine in the level of right scapula. She had difficulties in falling asleep with a number of awakenings during the night with feeling of discomfort and mild pain in the right shoulder, upper arm and right elbow. In the morning 13th of November she noticed the red skin indurated papules the size of a few millimeters to half a centimeter in diameter in the palmar side in the root of ring finger. During the day a few indurated papules appeared in the border between the palmary and dorsal side of the right hand in the area of innervations of the ulnar nerve. On the 14th of November a couple of the same indurations appeared in the palmary side of right hand in the root of forearm, and in the region of pinkie finger. In the next few days (4 to 5 days) skin of the ulnary side of the palm of the right hand became erythematous and grouped herpetiform vesicles developed hour by hour, day after day and almost complete clinical picture was developed on the 17th of November. The vesicles were cloudy, some of them with red border, some of them merged in blisters more than 2 centimeters in diameter. That day she went to doctor dermatologist who characterized the appearance as hemorrhagic form of herpes zoster and therapy was prescribed: Acyclovir tbl 5x 800mg two days and 5x600 mg 4 days four days, broad-spectrum antibiotic, vitamins B12 and B1, B6, analgesics and Acyclovir cream locally several times on day. The entire time patient felt fatigue, general weakness, discomfort and pain in most expressed in elbow and in ulnar side of forearm, ulnaro-carpal joint and in the palmary and dorsal side of the right hand all in projection of the branching of ulnar nerve. The vesicles were staggered and grouped also in the projection of ulnar nerve innervations. The pain may be described as burning but no narcotics were needed. It might be reduced by no steroidal anti-inflammatory drugs (ibuprofen) 3 to 4 tablets per day. During the first three days of therapy some new vesicles erupted. About 10 days after first eruption some vesicles started converting into crusts with no new vesicle eruption. After vesicular involution, there was slow resolution of the remaining erythematous plaques, but with visible squeals. On the control examination (10 day after first examination) the dermatologist characterized illness as gangrenous form of herpes zoster with recommendation to patient to examine her immune system and to use panthenol ointment-for epithelialization and skin regeneration long time and eozine (antiseptics) locally for five to six days. She has done blood testing (ESR-erythrocyte sedimentation rate, FBC-whole blood count, liver and kidney laboratory tests, rheumatic tests, OraQUICK HIV test, urine examinations, chest x- ray, ultrasound examination of abdomen and pelvis. All examinations were in normal rate. From day to day she felt better and better but 30 days after the begging of illness she still have crusts in the places of vesicles, the largest one on the ulnar side of the palm of right hand with mild pain in involved area. Two months after first vesicular eruption there are sequels in the form of the pink stains in the places of previous vesicles with mild hyperesthesia in involved area and very mild occasional pain in there especially in the evening. The appearance of skin manifestations in first seven days is presented in the figures 1, 2, 3.

herpes zoster, ulnar localization

PMC9429994_01

Female

Only four persons interviewed had personal memories of the outbreak that occurred in the early 1950's. Two of them had been involved as veterinarians in the 1950's. Now 82 years old a zootechnician (who worked in the 1950's) recalled that people wondered at the time how the disease suddenly came to Estonia and why. There had never been such a disease in Estonia before according their knowledge. Since most of the respondents had directly or indirectly experienced the outbreak, in general, their recollections were similar in several respects, such as the procedure for quarantine, farm lockdowns, disinfection mats on roads, militia guards at farm gates and so on. A zootechnician (aged 82) recalled the control of the disease as follows: "When I studied to be a zootechnic at vocational school in the 1950's, all the students were taken to the dairy farms. There we had to wash the mouths of the animals with a solution of potassium permanganate. The animals were kept for as little time as possible in the barns during the summer. The reason was because the cows' hooves become more damaged inside in the wet manure. The barns were disinfected with lime and ash water. Ash was gathered from the people by the village." There are no reports or news stories in the newspapers about the FMD outbreak in 1982/1983. The first announcement about the FMD appeared in a national newspaper in November and December. Again, it was not written that there was any disease in Estonia at all, but information was given as to how to recognize and control the disease. People were warned that the disease could also be transmitted to humans, yet it was said that processed meat (canned and sausages) from sick animals could be eaten and pasteurized milk could be drunk. Due to the FMD epidemic in England in 2001, the topic of FMD became very popular in the media. In 2001, detailed recollections of the 1982 outbreak also appeared in the press. In one of them, a worker of the Vandra Kolkhoz recalled his experiences and comments were taken by Endel Aaver and an interview with Chief Inspector Mati Loit at the Veterinary Government of the Estonian SSR. The topic was also covered a few years later where the manager of the cattle unit of the Laatre Sovkhoz recalled his experiences. The harsh control techniques in the UK were similar to those in Estonia in 1982. People were locked in barns such in Laatre dairy farm (South Estonia), nearly 30 workers were enclosed for 42 days. Also, in Vandra cattle farm 10 workers were isolated for more than 30 days. Employees were not told they had to stay in the barn for weeks so at first, they did not take their personal belongings with them. The gate doors of the cattle farms were guarded by militia 24-h a day. There were also strict rules inside the farm, men and women slept in separate rooms and drinking alcohol was forbidden. Also, vaccination of the animals started immediately. The milk from diseased cows was first added to dung for disposal, later it was pasteurized on site and fed to calves and vaccinated cows (in some cases to pigs). Hundreds of sick animals were moved to a meat processing plant after the end of the quarantine period. The abattoir was then subsequently disinfected. Everything had to be kept secret. For example, a veterinarian who accidentally mentioned the disease on the radio was punished. Rumors spread that it was an experiment and that the animals were intentionally infected. The reasons for the rumors were: the disease spread among the most advanced and hygienic farms (disinfection mats at the farm entrance, warning signs at the gates), previous secret searches on the farm, unknown people with large sums of money. The manager of the cattle unit of the Laatre Sovkhoz remembered that the situation on the disease had to be reported every day to unknown anonymous Russian-speaking officials. Disease control specialists were also brought to Estonia from other parts of USSR. Aaver and Mati Loit said that in 1982 a total of eight outbreaks occurred in Estonia. According to Aaver, the FMD arrived in Estonia from Belarus through Lithuania and Latvia and reached the sea in the Western part of Estonia. However, there is not much information about the outbreaks in Lithuanian and Latvian SSR in 1982, but in years 1986 and 1987. In addition, Aaver pointed out that more than 30 people from Moscow, who had seen FMD in USSR almost every year, came to aid Estonian specialists at that time. Analysing the wind directions at that time, it has been concluded by researchers that the disease could be spread by the wind. It was found that when the direction of the prevailing wind changed, the infection also decreased. The 1982 outbreak reached the foreign media very quickly. During World War II, almost 80,000 Estonians fled abroad for fear of repression by the Soviet authorities. The largest diaspora was formed in Sweden. Estonians abroad maintained active communication with relatives who remained in their homeland. Thus, the first warnings of the disease in November in the national newspaper of the Estonian SSR reached numerous foreign Estonian newspapers in December 4: in Sweden, Canada, the USA, and Australia. However, in addition to official sources, foreign Estonian newspapers also relied on direct sources, which were letters from Estonia. Thus, the actual extent of the disease and the control measures were known abroad quite quickly and in detail. The disease spread from Russia to Lithuania and Latvia in the spring, and from there to Estonia in the autumn. The letters from Estonia SSR, also show that there was a great shortage of food in Estonia and ideological pressure was increasing. It is noted that, due to FMD, foodstuffs were no longer transported (exported) from Estonia SSR to the domestic market of the USSR and therefore more goods were available in the shops in Estonia. The few tourists that visited the Estonian SSR also reported on the control and spread of the disease. It was repeatedly emphasized that the Soviet Union denied any outbreak of the disease. However, Sweden suspended imports of reindeer, elk and bear meat from the USSR and Finland suspended the ferry service. However, the foreign press did not know the whole truth at the beginning. It was initially thought that infected animals would be killed in Estonia and then burned or buried. However, this was not done. As early as March 1983, a report appeared in US infectious disease reports mentioning an outbreak in the Baltic Soviet republics. However, there was no overview of the actual situation as reported. "However, detailed information is not forthcoming from this region" but the June issue states that "The USSR has denied any outbreaks occurring in its Baltic regions / : /". Two respondents (a zootechnian aged 69 and a veterinarian aged 71) who worked at the country's first large farm in South Estonia highlighted that the dairy farm had been closed for 43 days, from November to the end of December, including Christmas. One of them believes that the disease was brought to the farm intentionally, in other words for training purposes. Respondents added that the disease was noticed when two cows began to exhibit the symptoms of the disease: bite their mouths, producing foam in mouth and intensive saliva flow. One reason for intentional outbreak was that the farm was the production farm of the state animal science research institute, which had modern furnishings and living rooms for the employees (sauna, kitchen, rest rooms), which were not available on other collective farms. This played an important role in combatting FMD on the farm, and about 14-16 people were trapped in the barn. In addition to treating and feeding the animals, staff and clothing and other supplies had to be disinfected on a regular basis. The workload was several times higher than usual because the staff could not leave the farm. After the closure of the farm, beds and mattresses were brought to the staff. Food was provided on a daily basis, and one milking lady began to work as a chef. At that time there was a very strict order on the territory of the farm, there was no access for strangers either. There was a 24-h militia guard at the gate. Those trapped on the farm did not see their family members, children or other relatives. This was very difficult psychologically for all the staff in addition to the physical load. Another reason of intentional outbreak given by respondents was that somebody called every day at 9 o'clock and asked in Russian about the number of animals that were sick and if there were any dead animals. This raised doubts as they were not told who it was who called every morning and asked for these details. It is important to highlight that it was very common in the Soviet Union to conduct training exercises to practice actions for major accidents, including outbreaks of animal diseases, as part of civil protection exercises. Although there are several indications in the respondents' answers that the animals were intentionally infected with FMD, it should not be forgotten that the disease had been detected in the neighboring republic a few months earlier. In the north of Latvia SSR; Tallinn Zoo was closed in 1982 for about 6 months. As the zoo was visited by a significant number of Latvian visitors each year, the zoo had to be closed to avoid FMD. One of the interviewees mentioned that Tallinn Zoo had one of the most representative collections of Bovines and mountain goats in the world. The 1982 FMD outbreak also meant for the zoo that animal feed (such as hay) had to be purchased from Western Estonia instead of the usual southern regions, as there was no imminent threat of FMD from the west. Another major issue that emerges from the survey is the various restrictions, such as road closures and the restrictions on people in the farm and the resulting trauma. One of the respondents (agronomist, aged 76) "people had fear because everyone had animals in their household." A former veterinarian (aged 84) reported: "People knew about the outbreak in southern Estonia. People were very afraid. The authorities also vaccinated one-cow farmers (the authors:cows were kept in virtually every household in rural areas)." A zootechnician (aged 74) narrated: "Cabbages and turnips remained in the field in the affected area because movement in that area was prohibited." A former farm manager (aged 69), remembered: "14-16 people were locked in on the farm. There was a lot of work. There were militia at the gate. The children could only be seen through the fence, as many as the spouse could hold." Several respondents also stated: "The restrictions were very strict at the time. In some places, roads were even dug up to distract traffic." "At the border of the districts there were disinfection mats, the driver had to come out of the cab, and walk across the mats. The shoes smelled afterwards. There was constant guarding of those mats. Almost half a year, but it varied by region; in general, restrictions lasted almost half a year" (agronomist, aged 76). A veterinarian (aged 66) stated that "veterinary students were taught at the university model-based disease control: blocking of roads, bridges and farms during potential animal disease outbreaks. Control instructions were described in detail. Informative posters near farms were common. Barriers at farms and on roads too." It was also mentioned on a few occasions that the manure of the sick cows had to be stored separately, which could not be used as organic fertilizer for years. In some places, dead calves were also burned on bonfires near the cattle unit. When the udders had sores, the milkers protected their hands with rubber gloves while milking. Udder wounds were smeared with zinc ointment, but also udders smeared with ointments. Outside the kolkhoz, people were only allowed to have one cow at home, so the animals were kept in barns at home very carefully. During the period of FMD the milker was detained on the farm, and food was brought into the barn. Some cleaned the barns during the outbreak with juniper smoke and the Russian Orthodox believers near Lake Peipus also brought water consecrated from the church and watered the animals with this. Folk medicine was no longer used in the kolkhozes, but there are some indications of this being used by single cow owners. A former veterinary scientist (aged 74) said: "The cow was still being treated by a veterinarian, folk medicine was not used at the time." FMD vaccine was thought to have been available in the early 1980's as the disease spread across the Soviet Union. This was confirmed by several respondents, one (zootechnician, aged 69) stated that: "Vaccination started immediately in cases of the disease. No animals were killed as a result." This involved a great deal of effort. The cows that were caught were heavily blistered and could not eat normally and it was necessary to prepare a mixture of boiled milk (which could not be sold for human consumption) and grain meal, as it was not possible to feed hay because of the sharp stems irritating the blistered mouths of the cow. A zootechnician (aged 69): "It was painful for the cow to eat hay. They ate a little silage as it was softer." This meant that sick animals had to be fed several times a day to avoid loss of body condition. A veterinarian (aged 71) added: "The cows' mouths were rinsed with a copper preparation. Blisters and sores were also present on the hooves, which were smeared with ointments." It was also mentioned on several occasions that, because the animal was in pain, it led to thinness. It also meant a significant decline in milk yield, even after the cows had recovered. A zootechnician (aged 69) said: "The cows' milk yields did not recover after the end of the quarantine. However, the animals themselves recovered, their body weight returned to normal and the cows were alive." Interviews revealed that one large farm in South Estonia was able to prevent deaths due to huge efforts by the farm personnel, but another farm in the same region had more serious cases, resulting even in dead animals. One veterinarian described the activities during high risk of FMD at a dairy farm in Central Estonia. The story of one veterinarian (aged 85) was as follows: One day in year 1982, at 4 pm, the head of the Tartu District Veterinary Service convened the chief veterinarians of all the farms in Tartu district and distributed vaccines. By the evening of the same day at 11.30 pm, more than 3,000 cattle from our state farm, including 980 cows, had been vaccinated. Everything happened at lightning speed. This prevented the greatest danger. Tartu district is one of the few where there was no foot-and-mouth disease. In any case, the Chief Veterinary Officer of Tartu District later received a letter of honor and/or a letter of thanks from the Veterinary Government of the Ministry of Agriculture. The veterinarian added: "We were given information about foot-and-mouth disease at the monthly meetings of the chief veterinarians, and this was discussed at several meetings. As mentioned above, there were 3,000 cattle in the state farm, and about 12,000 piglets were produced each year. I had a total of 110 livestock workers, including three veterinarians and one assistant veterinarian. Stockpersons, together with the respective regional department heads, made every effort to prevent the spread of the disease. There were disinfection mats in front of both the large farm and each of the smaller barns, as well as a very large and long disinfection bath, where the long semi-trailers bringing concentrate feed could completely wet the wheel tires with disinfectant. These lorries were also disinfected by a trained specialist. A separate topic was the protective clothing of stockpersons and others, to which we paid more attention than before. The fact that many workers had cattle and pigs at home was alarming. The infection could potentially have started there as well. The FMD of 1982 passed our state farm, but the older milking ladies and workers remembered the beginning of the collective farm foot-and-mouth disease in 1952, when the children could not see their parents and the livestock workers had to live and sleep in the stable for weeks." A zootechnician (aged 69) mentioned that "many animals suffered but recovered, while milk yields declined remarkably." The milk was not allowed to be transported out of the farm, it had to be fed either to youngstock or to cows. For this reason, a boiler was brought to the farm to pasteurize the milk. However, the affected animals sooner or later had to be culled. The interviewee added: A total of 92 animals were taken to the slaughterhouse, but in fact worse and thinner cows were sent there at first. However, a year after the disease outbreak, a large number of the animals had to be taken to a meat processing plant, a total of 1,400 animals. This was required by the veterinary regulations. The meat of the affected animals was made into canned food, i.e., the meat had to be heat-treated. And a stockperson (aged 82) remembered: "Animals who were weakened by the disease were transferred to a meat processing plant. The meat was kept there for a day in a bath with a solution of potassium permanganate before it was processed." The outbreak of the disease meant that foodstuffs of animal origin could no longer be placed on the domestic market of the USSR and more of these goods were sold in the shops of the Estonian SSR. For example, one respondent (researcher, aged 83) mentioned: "Foot-and-mouth disease closed the borders of Soviet Estonia. The butter came back for sale in food stores because it was no longer allowed to send parcels with food products to other Soviet republics. At that time, it was common that people of Russian speaking nationalities (e.g., workers at large factories) sent a monthly package of food products to their relatives to other republics."

soviet union veterinary system, collective farms, distortion of the truth, foot-and-mouth disease, veterinary treatment of cattle

PMC4720548_01

Female

We report a 9 year-old Chinese girl, born full term with no family history of recurrent infections or immunodeficiency. She had received hepatitis B and BCG vaccinations at birth without complications. She had multiple infections in infancy including Klebsiella pneumoniae urinary tract infection at 1 month and another two episodes of Klebsiella pneumoniae bacteremia at 2 and 10 months of age, all treated with intravenous ceftriaxone with good recovery and documented clearance. However at 10 months, after presenting with fever and a macular rash hepatosplenomegaly, she was diagnosed with extensive abdominal lymphadenopathy on CT scan. The abdominal lymph node biopsy showed granulomatous formation and sensitive Mycobacterium tuberculosis complex was cultured. The intestinal tuberculosis was treated with rifampicin, isoniazid and pyrazinamide for 12 months with resolution of abdominal lymphadenopathy. At this time, the skin biopsy was clear of mycobacterial species. Immunophenotyping and immunoglobulins levels were normal at the time (Supplementary table 1). The patient's blood was tested for IFN-gamma and IL-12 production after stimulation with BCG, BCG+IL-12 and BCG+IFN-gamma, respectively and showed a diminished production of both IFN-gamma and IL-12 after BCG+IL-12 and BCG+IFN-gamma, respectively as compared to the travel control (Supplementary table 2). Six months after stopping anti-tuberculosis therapy, the patient had tuberculosis infection of the skin manifesting as a painful erythematous plaque with scabbed nodules over the face (lupus vulgaris) (Figure 1), elbows, shins and calves, and the skin biopsy demonstrated acid-fast bacilli, though no specific organism was cultured. Lupus vulgaris in children is very rare, and is almost exclusively due to infections by Mycobacterium tuberculosis or Mycobacterium bovis. She was commenced on isoniazid, rifampicin, pyrazinamide and clarithromycin for 15 months to cover for atypical mycobacterial organisms as well. Subcutaneous recombinant IFN-gamma (rIFN-gamma) was trialled at 20 mcg/m2 twice per week with good response. When anti-tuberculosis medications were changed to dual therapy after 12 months, there was recurrence of intestinal tuberculosis based on CT findings and granulomatous formation on lymph node biopsy (no organism cultured). Ethambutol and moxifloxacin were added to her treatment regimen with good response. These four anti-tuberculosis medications were continued for 3 years together with subcutaneous rIFN-gamma injection. Despite weaning to a very low, likely suboptimal dose of rIFN-gamma, she was free from both mycobacterial and interestingly, pyogenic infections for more than 3 years. It was at this point when a mutation in IkappaBalpha (S36Y) was diagnosed by whole exome sequencing (WES), and stem cell transplantation was offered, but declined by parents in view of stability.

PMC4720548_02

Female

At 8 years old, when anti-tuberculosis medications had already been stopped, and 4 months after stopping subcutaneous rIFN-gamma there was recurrence of infections including Pseudomonas aeruginosa pansinusitis and notable complications of bronchiectasis diagnosed on high resolution CT. Subcutaneous rIFN-gamma was recommenced at 50 mcg/m2 three times per week, however one month after she developed Mycobacterium abscessus left knee septic arthritis and tibial osteomyelitis for which she was treated with intravenous amikacin, cefoxitin and oral clarithromycin based on sensitivities. She has had no further infections on anti-tuberculosis therapy, rIFN-gamma, anti-microbial prophylaxis with Bactrim (after desensitization for challenge-proven allergy) and intravenous immunoglobulin replacement (due to poor pneumococcal antibody responses) and will continue until stem cell transplantation. Physical examination revealed an intellectually normal child with failure to thrive (height and weight less than 3rd percentile) and scarring over the face (a consequence of facial lupus vulgaris which she had at age 3). Respiratory examination reveals bilateral crepitations and wheezes in keeping with bilateral bronchiectasis. There were no features of anhidrotic ectodermal dysplasia (EDA) such as hypohidrosis, sparse hair, dental abnormalities, coarse skin or osteopetrosis. The immunological results (Supplementary tables 1 and 2) show that the patient does not display an overt functional T cell defect and a specific defect in the IL-12/IFN-gamma loop was not identified. WES was thus performed on gDNA from the patient. We identified a heterozygous nucleotide substitution (c.107C>A) in exon 1 of NFKBIA (encoding IkappaBalpha), leading at the protein level to a missense mutation, replacing a Serine at position 36 by a Tyrosine (S36Y). The mutation was confirmed by Sanger sequencing, on PCR fragment amplified from gDNA extracted from granulocytes and dermal fibroblasts (Figure 1). The mutant and WT allele in the patient were of same amplitude, suggesting equal amount of both alleles. The mutation was not found in any public database (1,000G, ExAc, dbSNP). Familial segregation analysis (Figure 1) showed that both parents are wild-type for the substitution; the mutation thus appeared de novo in the patient (Figure 1). This mutation leads to a gain-of-function of IkappaBalpha and was reported in a patient with mild AD-EDA-ID and non-infectious systemic inflammation. We analyzed the IkappaBalpha phosphorylation and subsequent degradation in primary fibroblasts from the patient, a healthy control and a NEMO-deficient cell line after TNF-alpha (20 ng/ml) and IL-1beta (10 ng/ml) stimulation. We found that IkappaBalpha was phosphorylated on Serine 32 after TNF-alpha stimulation in control and in patient's cells, as compared with a NEMO-deficient patient. However, we observe an impaired, but not abolished IkappaBalpha degradation in the patient's cells compared to the healthy control (positive control) and the NEMO-deficient cells (negative control). The same results were obtained after stimulation with IL-1beta. Altogether, we have identified a de novo heterozygous gain-of-function mutation in NFKBIA, affecting the serine at position 36. The mutation does not impair the phosphorylation of IkappaBalpha on Serine 32, but affect partially its degradation, leading to impaired NF-kappaB signaling (Figure 1). This is the first reported case of a female child with absolutely no features of EDA who was found to have a heterozygous missense variation mutation in IkappaBalpha (S36Y) resulting in significant immunodeficiency only. Immune cells as well as dermal fibroblasts from the patient carry the heterozygous missense mutation, apparently at the same level. Out of the eight patients previously reported (Supplementary Table 3), all, except a patient with mosaicism and our own, had at least mild features of EDA. The patient we report does not display any clinical signs of EDA. For reasons still unknown, there is a considerable variability in the extent of the severity of the EDA clinical signs in IkappaBalpha-mutated patient (Supplementary Table 3). In addition, variability in terms of EDA clinical signs is also observed in patients with mutation in another component of the NF-kappaB signaling pathway, IKBKB, as well as in NEMO. Recurrent mycobacterial diseases (tuberculous and non-tuberculous mycobacteria) is observed in our patient. Surprisingly, the other patient described with the exact same mutation (S36Y) by Yoshioka et al, display only mild EDA and had an episode of mycobacterial disease. All the other GOF-IkappaBalpha patients displayed EDA and were free of mycobacterial disease (Supplementary table 3). It is also interesting to note that our patient was free of all infections during three years (not only mycobacterial) when she was under IFN-gamma treatment. Altogether, IkappaBalpha mutations should be suspected in children with bacterial and mycobacterial infections even without EDA clinical presentation. In addition, treatment with rIFN-gamma injection may be proposed to prevent all infections.

PMC10267541_01

Female

In 2014, a 34-year-old woman from Ivory Coast visited our clinic with signs of pelvic inflammatory disease (PID) and a positive chlamydia antibody test. Ultrasound imaging revealed large abscesses, and blood tests showed elevated infection parameters. She underwent laparoscopic surgery; during which, the left obstructed tube was drained and the right tube was removed due to pyosalpinx. A purulent fluid was drained from the pyosalpinx and sent for microbiologic examination. A general culture was negative, and PCR for Chlamydia was also negative. Recent cervical swabs were also negative for sexually-transmitted infections. The removed tube was send for pathology, and the histology sample showed fibrotic tissue with small granuloma's and mild necrosis. Further investigation with Ziehl-Neelsen, Periodic Acid Shift (PAS), and Grocott was performed and no signs of yeast, actinomyces, or tuberculosis could be found. After the operation, the patient was referred to our fertility clinic for a full work-up, but did not follow through with the appointment until 2018. History revealed that she had one child with another partner, fourteen years prior. Hormonal status was normal, and ultrasound showed a normal uterus with a 3.5 mm endometrial thickness and a left ovary with a small cyst (33 x 26 mm) containing cloudy fluid, which was considered to be an endometriosis cyst. The patient and her partner underwent in vitro fertilization (IVF). IVF with embryo-transfer was the choice of treatment. Four embryos could be grown and two embryos of, however, low quality, were transferred into the uterus. Unfortunately, the patient did not become pregnant. Due to COVID-19, further treatment was postponed until 2022, when the patient and partner started an intracytoplasmic sperm injection (ICSI) procedure and the patient became pregnant.

female genital tuberculosis, multi-drug resistant tuberculosis, pregnancy loss, subfertility issues, transplacental exposure

PMC10267541_02

Female

At the time of pregnancy, she was 38 years old. At 10 weeks gestation, a normal ultrasound was performed without any anomalies. However, at 18 weeks gestation, the patient experienced vaginal bleeding, and an extensive ultrasound revealed a sub-placental hematoma. The fetus did not have any structural abnormalities, and the cervical length was 27 mm. Cervical swabs for gonorrhea, chlamydia, bacterial vaginosis, and yeast infections, as well as a PAP smear showed no anomalies. Unfortunately, she returned to the hospital after a new episode of bleeding and cramps and delivered immaturely at 22 weeks gestation. The delivery was complicated by a retained placenta, which was evacuated via vacuum curettage. Afterwards, the placenta was sent to the pathologist for further examination. The pathology report showed a necrotic granulomatous inflammation among others (Fig. 1). During a routine postpartum check-up, the patient reported continuous irregular blood loss and lower abdominal pain. The ultrasound showed an intrauterine homogeneous structure of 13 mm, suspicious for a retained placental tissue. We scheduled her for a hysteroscopy to remove the suspected placental rest. During this procedure, a large amount of thick, yellow, fibrotic tissue was visualized, which could only be partially resected. The procedure was ended due to reaching maximum fluid loss. The pathology report revealed the same granulomatous inflammation, without signs of placental tissue. After consultation with the pathologist, microbiologist, and internal medicine-interstitial lung disease specialist, the following differential diagnosis was drawn up; TB, actinomyces species, auto-immune vasculitis, and auto-immune diseases. A diagnostic work-up was planned accordingly. More tissue was collected by endometrium aspiration technique, which was send for pathology and culture purposes to examine for actinomyces and TB. The Ziehl-Neelsen (ZN) and auramine testing results were negative. In addition, blood was taken for IGRA (QuantiFERON-TB) and a wider panel of tests on IL2-R, ANCAs, ENA, and antibodies. A recent X-ray of the lungs taken because of shortness of breath by the general practitioner showed no signs of lung diseases. The QFT-TB was positive and culture results of the extracted tissue came back positive for Mycobacterium tuberculosis and rifampicin resistant. Accordingly, the patient was referred to an internal medicine infectious disease specialist for further diagnosis, treatment, and follow-up. An extended history was taken with the patient, but she could not recall any periods of coughing, shortness of breath, or night sweats. A CT scan was performed, which showed a suspected tuberculosis granuloma in the left kidney, this was confirmed by a PET-CT and a biopsy. No other sources containing TB were found. The Mycobacterium tuberculosis turned out to be isoniazid and rifampicin resistant. Therefore, we referred the patient to University Medical Center Groningen (UMCG), one of the two tertiary specialized centers in the Netherlands. She was discharged after she started with her treatment for multi-drug resistant tuberculosis for a total duration of 15 months, which is partly teratogenic. For this reason, she had to postpone her pregnancy wish. The patient conceived again in 2023, but unfortunately, this pregnancy resulted in a miscarriage at eight weeks gestation. This case report shows the difficulty of diagnosing extrapulmonary TB in a woman without history of and/or symptoms of tuberculosis in a western country where TB is uncommon.

female genital tuberculosis, multi-drug resistant tuberculosis, pregnancy loss, subfertility issues, transplacental exposure

PMC3336251_01

Female

A 75-year-old woman was seen at a local hospital with a chief complaint of febrile illness and myalgia. She had a heart rate of 145 bpm and a systolic blood pressure of 140 mmHg (Figure 1). Past medical history was unremarkable. She reported no known drug allergies and no current medications. There was no recent travel history. She reported no known tick bites. No unusual dietary exposure was noted. Within 30 minutes of admission, she complained of muscle cramps and had clammy skin and diarrhea. She appeared dehydrated and was started on saline intravenously for clinical dehydration and diagnosed with a likely viral illness and possible sepsis. A urinalysis revealed 3+ leukocyte esterase, 2+ protein, 95 white blood cells/hpf, and many bacteria. A comprehensive metabolic panel showed elevated renal (urea nitrogen = 10.5 mmol/L, creatinine = 114.9 mumol/L) and liver enzymes (AST = 114 U/L, ALT = 163 U/L), high glucose (8.56 mmol/L), and normal electrolytes. The patient was nonreactive for Hepatitis A IgM, Hepatitis B core IgM and surface IgG antibodies, and Hepatitis B surface antigen and HIV. A baseline troponin I was 0.03 mug/L. A complete blood count showed white blood cells (WBC) of 10.0 x 109/L and a hematocrit of 0.404. She was thrombocytopenic with a platelet count of 92 x 109/L. Microscopic examination of the peripheral blood smear revealed numerous loosely-coiled spirochetes consistent with Borrelia sp. infection (Figure 2). A working diagnosis of tick-borne relapsing fever (TBRF) was made. The patient was started on pantoprazole, levofloxin, and acetaminophen. Within 4 hours of antibiotic administration there was a clinical worsening of symptoms complicated by Jarisch-Herxheimer reaction (J-HR). The patient's temperature, blood pressure, and platelet count decreased rapidly (Figure 1). A urine culture was positive for E. coli, and antimicrobial therapy was changed to ertapenem and ciprofloxin based on susceptibility testing results. At 12 hours, spirochetes were no longer visible on the peripheral, and the patient became afebrile. At the time of 36 hours of admission, the patient complained of chest and low-back pain. A repeat troponin was 0.28 mug/L. She was started on metoprolol and transferred to the cardiovascular unit for observation. At the time of 48 hrs, a repeat troponin was 0.96 mug/L. During the next 12 hours of supportive treatment, the thrombocytopenia improved (112 x 109/L), and angina and febrile illness resolved. She was discharged with instructions to follow up with her primary care provider within 10 days. Fourteen days after onset of the illness, the patient's platelet count had normalized to 235 x 109/L. Serological testing for Borrelia sp. was performed on specimens collected on day 1 (acute) and on day 120 (convalescent). The acute specimen was negative whereas the convalescent specimen was positive for antibodies to B. hermsi.

PMC5309401_01

Male

A comatose, circulatory stable, but hypoventilating patient was intubated at the scene and brought in to the emergency department by ambulance. The past medical history, which was provided by his grandmother, revealed that this 39-year-old man had lived with her for many years. The previous weeks prior to presentation he complained of fatigue and recurrent nose bleeds, and he was eating irregularly. At the age of 3 he had been operated on a benign cerebral gangliocytoma and had been on antiepileptic medication because of generalized seizures for some years. The patient had not seen a doctor for many years. Physical examination revealed a patient in a dishevelled condition with bilateral vesicular breathing and distant but regular heart sounds without any murmur, rare bowel sounds, no tenderness to deep palpation, and nonpitting oedema of the legs. His body temperature was slightly elevated (38.5 C). The neurologic examination showed equal pupils reactive to light symmetric muscle tone and absence of plantar reflexes. On admission, laboratory data showed significantly decreased levels of sodium and potassium (sodium: 120 mmol/L, potassium: 2.9 mmol/L) as well as increased levels of creatine kinase (overall-CK: 967 U/L, CK MB 6.7 microg/L (norm CK MB < 7.7 g/L in males)) and glutamate- oxalacetate-transaminase (AST: 62 U/L). The coagulation panel demonstrated a slightly increased international normalised ratio (INR: 1.4) and partial prothrombin time (PTT: 37 s). The complete blood count showed a normochromic normocytic anaemia (haemoglobin: 114 g/L), with normal platelets and leucocytes. The arterial blood gas on admission showed an alkalosis (pH 7.43) with an increased bicarbonate of 31.8 mmol/L (base excess of +7), but as well increased pCO2 of 6.4 kPa. The remaining results were unremarkable including normal liver function tests, glucose levels, and creatinine and urea. A urinary toxicological screening showed no signs of intoxication with benzodiazepines, opiates, amphetamines, tricyclic antidepressants, acetaminophen, or salicylate. The electrocardiogram (ECG) showed a sinus rhythm (85 bpm), normal axis, and an incomplete right bundle branch block (RBBB). The QTc time was within normal range. A computer tomography with angiography of the cerebral arteries (Angio-CT) showed a frontobasal intracerebral bleeding with irruption into the ventricles. A cerebral aneurysm and skull fracture were excluded (Figure 1). A chest X-ray (CXR) showed impressive cardiomegaly without any signs of chest infection or congestive heart failure (Figure 2). An echocardiogram showed a large pericardial effusion with swinging heart but without compromise of right ventricular function and a normal variation of mitral inflow (Figure 3). Significant valve dysfunction was excluded and normal systolic and diastolic left ventricular function and size of heart chambers confirmed. The patient was transferred to the intensive care unit (ICU). Analgosedation with propofol and fentanyl and Continuous Positive Airway Pressure (CPAP) ventilation was continued (positive end expiratory pressure (PEEP): 5 and pressure support (ASB): 5-10 mmHg, inspiratory oxygen concentration FiO2: 40%). To maintain a MEAN blood pressure of 65 mmHg low-dose support with noradrenaline was needed. A supplementation of potassium and sodium was performed. An electric encephalogram (EEG) showed a left frontopolar epileptic focus, so that therapy with levetiracetam was started. Further, diagnostic needle pericardiocentesis was performed and 1300 mL of slightly haemorrhagic pericardial fluid evacuated (glucose 11.5 mmol/L, protein 73 g/L, albumin 44 g/L, lactate dehydrogenase (LDH) 173 U/L, red blood cells: few, and white blood cells 0,21 x 109 (25% neutrophils, 2% lymphocytes)), Gram stain and bacterial cultures were negative, cytology was negative for malignant cells, and polymerase chain reaction (PCR) for tuberculosis was negative. About four hours after this procedure the patient went into cardiac arrest (pulseless electrical activity, PEA) caused by cardiac tamponade. Though the pericardial tube was still in place it was obstructed by coagulated blood. A second needle pericardiocentesis was performed and a significant amount of deeply red haemorrhagic cardiac effusion could be removed, which resolved the patient's deterioration immediately. Further work-up of the hyponatremia (120 mmol/L) could exclude pseudohyponatremia (serum osmolality: 267 (normal range: 280-300 mmol/kg)) and adrenal insufficiency by an adrenocorticotropin hormone (ACTH) stimulation test (cortisol basal: 919 nmol/L, 30 min after stimulation with 250 mug ACTH: 1137 nmol/L, and 60 min: 1235 nml/L). Urine osmolality was 610 mmol/kg and urine sodium content was 39 mmol/kg. Additionally, the thyrotropin level was significantly increased at 112 (normal range 0.33-4.49 mlU/L) accompanying T4 and T3 levels of 1.2 (normal range: 66-181 pmol/L) and 0.4 (normal range: 1.1-3.2 pmol/L), respectively. Thyroid peroxidase (TPO) antibodies could be shown to be significantly increased to 294 IU/mL (normal range: 100-200 U/L). As Hashimoto thyroiditis was found as underlying pathomechanism, the patient was treated with 100 mug levothyroxine once daily and the patient could be extubated five days after admission. Fortunately he was only slightly neurologically impaired (GCS 14, with no signs of cerebral nerve paralysis but decreased muscular strength in all four extremities (M3/4)). Due to recurrence of the pericardial effusion in echocardiographic follow-up, a thoracoscopic pericardial fenestration was performed about 3 months after the ICU stay.

PMC4258348_01

Male

A 15-year-old male presented with complaints of moderate grade fever for 4 months and generalized body swelling with facial puffiness for 2 months. There was no history of cough, weight loss, joint pain, oral ulcerations, skin rash, photosensitivity, loss of hair, pain abdomen, jaundice, or any significant illness in the past. There was no past history of tuberculosis in the patient or in any other family member. General examination revealed moderate pallor and bilateral cervical and axillary lymph nodes, with the largest being of size 1 cm x 1 cm mobile, nontender, and firm. Systemic examination was insignificant except for the presence of palpable spleen, 2 cm below the costal margin. Hemogram was suggestive of bicytopenia (Hb 6.9 g/dL (normal: 12-14 g/dL), TLC 2700/mm3 (normal: 4000-11000/mm3), and total platelet count 2,10,000/mm3 (normal: 150000-400000/mm3)). Serum amino transferases and alkaline phosphatase were raised (SGOT 316 U/L (normal: 20-40 U/L), SGPT 109 U/L (normal: 20-50 U/L), and S. ALP 2750 IU/L (normal: 44 to 147 IU/L)). Total serum protein (5.1 g/dL, normal: 6.0-8.3 g/dL) and albumin (2.3 g/dL, normal: 3.5-5.5 g/dL) were low. Renal function tests were normal. Mantoux test was negative and ESR was slightly raised. Urine routine and microscopy showed 4-5 RBCs and 8-10 pus cells per high power field and 4+ albuminuria. 24-hour urinary protein was 2.1 gm. Kidney biopsy was done. Chest roentgenogram was normal. Ultrasonography of abdomen revealed mild splenomegaly with a tiny hypoechoic mass in spleen suggestive of splenic granuloma, along with a few subcentimetric retroperitoneal lymph nodes. Bone marrow studies were suggestive of nutritional anemia. Cervical lymph node biopsy showed reactive lymphoid hyperplasia. Barium meal follow through showed jejunoileitis. IgM antibody for Epstein-Barr virus was negative. Serum angiotensin converting enzyme levels were also normal. Based on the clinical picture, the high prevalence of tuberculosis in this part of the world and the investigations, a provisional diagnosis of disseminated tuberculosis was kept. The patient was started on a trial of antituberculous treatment and was asked for review with renal biopsy report. He turned up early with high grade fever, swelling of upper lips, and oral ulceration. On further investigations, his antinuclear and antidouble stranded DNA titers were significantly raised (ANA 7.3 IU/mL, N < 1, and anti-dsDNA 680 IU/mL, N < 40). Histopathological report of kidney biopsy was suggestive of membranoproliferative (Type) lupus nephritis. Contrast enhanced computerized tomography of the abdomen revealed hypodense lesions in both liver and spleen (without contrast enhancement), suggestive of granulomas along with few retroperitoneal and mesenteric lymph nodes. Consequently, a revised diagnosis of SLE with lupus nephritis and granulomatous hepatitis was now evident, and the child was put on pulse methylprednisolone 500 mg for 3 days. He showed dramatic improvement clinically.

PMC5633160_01

Male

A 75-year old man with hypertension, but otherwise healthy, was referred to our Cardiology department for a tentative diagnosis of congestive heart failure. Symptoms included fatigue, progressive dyspnea, position-dependent chest pain and pitting edema of the lower extremities. The symptoms had developed over a two-month period with worsening of symptoms seven days prior to admission. On admission his blood pressure was 136/65 mmHg, heart rate 90/min and a core temperature of 37.8 Celsius. Electrocardiography showed low voltage in the extremity leads, but no signs of arrhythmia or ischemia. Chest radiograph revealed ectasia cordis and left sided pleural effusion. Blood chemistry showed C-reactive protein 51 mg/L with a normal white blood cell count. Transthoracic echocardiography revealed concentric pericardial effusion measuring 16 mm, elevated central venous pressure, normal chamber dimensions and wall thickness, no valve disease and normal left ventricular systolic and diastolic function (Fig. 1A). The patient was tentatively diagnosed with viral pericarditis and parapneumonic effusion and received oral amoxicillin/clavulanic acid, furosemide and ibuprofen as an outpatient. However the patient's condition deteriorated over the following months. Throughout the clinical course, the predominant symptoms remained: asthenia, intermittent chest pain and symptoms of heart failure with dyspnea and pitting edema of the lower limbs. Diagnostic approach for evaluation of pericarditis included testing for tuberculosis as well as other infectious causes and rheumatic and autoimmune diseases. Intensified diuretic therapy and pleurocentesis resulted in only transient alleviation of the symptoms. The patient showed signs of progressive heart failure with increasing dyspnoea, excessive edema of the lower extremities and he developed drug resistant atrial fibrillation. Repeat echocardiography showed thickening of the pericardium at four millimeters, pericardial effusion, and signs of the heart being incased in a non-pliable pericardium. Computed tomography (CT) scan revealed thickening of the pericardium, pericardial - and pleural effusions, but no other abnormalities (Fig. 1B, C). Invasive evaluation with simultaneous right - and left-heart catheterization showed an equalization of the end-diastolic pressures at 18 mmHg and pressure tracings showed the classic "Dip-plateau" or "Square-root" filling pattern. Both measurements are distinctive hallmarks of constrictive pericarditis. Subtotal pericardiectomy through a median sternotomy was performed. Both the parietal and visceral pericardium showed significant thickening and fibrosis, and the visceral pericardium adhered completely to the myocardium. Postoperatively, the patient recovered rapidly with relief of symptoms. Bilateral cardiac catheterization revealed normalization of end-diastolic pressures and a marked improvement in cardiac output and cardiac index. Gross examination of the pericardium showed severe fibrosis and thickening, approximately nine millimeters. Microscopic examination showed chronic inflammation and intense pericardial fibrosis. Tissue samples from both the parietal and visceral pericardium were cultured; C. acnes was recovered from two samples. No other infectious agents were recovered. Polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative. Antimicrobial susceptibility testing revealed that is was susceptible to penicillin. The patient was treated with intravenous penicillin G for four weeks, followed by 12 weeks with oral amoxicillin/clavulanic acid. Six months after surgery the patient remained free of infection, showing continued improvement in overall cardiac function, and a complete remission of both pericardial - and pleural effusions as well as atrial fibrillation.

constrictive, cutibacterium, pericardiectomy, pericarditis, propionibacterium