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PMC5871376_01

Female

A 15-year-old female patient presented with a 4-year history of pustular lesions on the proximal region of the upper limbs with a subsequent impairment of the chest and abdomen. During this period, the lesions showed temporary episodes of improvement that evolved with residual hyperchromic macules. Physical examination revealed pustular lesions with a slightly erythematous base, isolated or grouped in a serpiginous pattern, on the trunk and proximal region of the upper and lower limbs. Hyperchromic macules were observed mingled with pustular lesions. There were no lesions on the face, palms, soles, and mucous membranes (Figures 1 and 2). A complete blood count, serum protein electrophoresis and liver, kidney and thyroid functions showed normal results. Histopathology revealed a subcorneal spongiform pustule (Figure 3). Direct immunofluorescence of the perilesional skin for IgA, IgM, IgG and fibrinogen was negative, thus excluding IgA pemphigus. Considering the clinical and histopathological findings, we confirmed the diagnosis of SPD. The patient was treated with dapsone (100mg/day) with a significant improvement after one month, showing only hyperchromic macules and residual crusts (Figure 4). After treatment was instituted we observed a slight increase of total bilirubin (TB = 1.7, DB = 1.2) and a slight decrease of hemoglobin (Hb = 10.7). There were no alterations on the remaining markers of hemolysis and on G6PD dosage. We chose to maintain the treatment and throughout the patient's follow-up all laboratory results remained stable. After complete clinical improvement, dapsone was tapered to 50mg/day and the patient was followed-up every three months. Nine months after treatment was started no flares had been noticed.

PMC9373126_01

Male

A 12-year-old Saudi Arabian boy of consanguineous parents first presented in 2009 at the age of 7 months with chronic diarrhea, poor weight gain, malnutrition, and an eczematous skin rash. Anti-tissue transglutaminase IgA was slightly elevated [39.3 units, upper limit of normal (ULN) = 0-20] and mucosal biopsy of the duodenum showed mild villous atrophy and nonspecific inflammation [Figure 1(c)]. The patient failed to gain weight normally following a trial of a gluten-free diet, despite partial improvement of diarrhea on lactose-free and amino acid formulas. Skin manifestations were progressive, involving the whole skin surface with areas of localized dermatitis and scaling [Figure 1(a) and (b)]. Skin biopsy revealed mild hyperkeratosis with foci of lymphocytic exocytosis and interstitial chronic inflammatory infiltrate, mainly consisting of lymphocytes, with perivascular and peri-appendiceal aggregation seen mainly in the superficial and deep layers of the dermis [Figure 1(d)]. There was one episode of urinary tract infection with Klebsiella pneumoniae organism, which was treated with antibiotics. Renal ultrasonography showed bilateral miniscule renal stones that were detected on serial imaging studies. At the age of 2 years, hepatomegaly with a moderate increase in liver enzymes was found (gamma-glutamyl transferase = 211 U/l, aspartate amino transferase = 132 U/l, alanine amino transferase = 226 U/l, alkaline phosphatase = 382 U/l, bilirubin = 9 umol/l). Percutaneous liver biopsy was performed, which showed expansion of the portal tracts and distension with chronic inflammatory cells, mainly lymphocytes and occasionally eosinophils, along with an ill-defined granuloma surrounded by dense inflammatory cells (Figure 2). Screening for autoimmune markers, including anti-smooth muscle antibody (SMA), anti-nuclear antibody (ANA), and anti-liver kidney microsomal antibody-1 (LKM-1), was negative as were the immunoglobulin (Ig) levels [IgG 19.5 g/l (5.4-16.1 g/l), IgA 3.87 g/l (0.8-2.8 g/l), IgM 1.35 g/l (0.5-1.9), and IgE 77 kU/l (0-195 kU/l)]. Liver enzymes declined with time, although liver enlargement continued. At 4 years of age, following adenotonsillectomy, the boy developed mild splenomegaly and generalized lymphadenopathy of the cervical, axillary, and inguinal lymph nodes, accompanied by digital clubbing. Test results for tuberculosis (tuberculin skin test and chest X-ray), sarcoidosis, and parasitic infections were negative. At 9 years of age, owing to persistent diarrhea, failure to grow, and a high fecal calprotectin level (6200 mg/kg), upper gastrointestinal endoscopy and colonoscopy were performed. Pancolitis was found during colonoscopy and normal upper gastrointestinal endoscopy. Chronic active inflammation was reported in the biopsy specimens, taken from the esophagus, stomach, duodenum, and colonic mucosa, with marked lymphocytic infiltration. In consideration of a possible diagnosis of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, a screening for possible endocrinopathies was performed, but the thyroid function tests with thyroid antibodies were negative, and there were normal fasting blood sugar and hemoglobin A1c levels. There was no evidence of autoimmune neutropenia, anemia, or thrombocytopenia. The patient continued to have alternating diarrhea and normal bowel motions. Anthropometric measures for his age were always under the third percentile for weight, height, and body mass index. Unfortunately, the patient passed away aged 10 years after developing septic shock. Written informed consent was obtained from the parents for genetic testing and for reporting the case. Under HIPAA (Health Insurance Portability and Accountability Act), ethical approval is not needed for case reports. Figure 3 shows the family pedigree of the patient being studied. The whole exome sequencing of the proband was performed on the Illumina, Hiseq2000 sequencing platform at 30x coverage. The full details of DNA purification, library preparation, sequencing, data filtration, and variation identification strategies we adopted are outlined in our recent publications. From the exome data of the proband, we observed a novel, homozygous, and likely pathogenic c.504 C>A variant located in the exon 4 region of the IL2RA gene, resulting in the substitution of a cysteine codon at amino acid position 168 with a termination codon in the IL2RA protein. Sanger sequencing of the proband and of both parents has confirmed the autosomal recessive mode of inheritance of this variant. This variant is absent from the GnomAD, 1000 Genomes Project, Saudi Human Genome Program, and DALIA databases. The functional characterization of the IL2RA variant was performed by various systems biology methods. First, the 3D model of IL2RA variant protein was constructed using the ab-initio method as described. Then, RNAfold webserver was used to estimate the effect of the IL2RA, c.504 C>A variant on the corresponding RNA structure. Findings from mRNA secondary structure of IL2RA predictions have indicated no significant changes in the thermodynamic stability of the mRNA folding pattern due to c.504 C>A variant (Figure 4). Finally, the NCBI conserved domain database was used to map the IL2RA, c.504 C>A variant on the functional domains of the protein molecule. From the results of functional domain analysis, we identified that the c.504 C>A variant falls into a canonical sushi-like functional domain (complement control protein, CCP), spanning between the 125th and 184th amino acids, and it most likely produces a premature protein (104 amino acids) that is shorter than the native IL2RA protein molecule (272 amino acids).

cd25, il2ra, granuloma, hepatitis, immune disease, immunodeficiency

PMC6626469_02

Female

P7: And if you go there, get the (case) paper issued...then wait in line...even then they don't treat properly, don't touch us, they just give the medicine and ask us to go. (Community discussion, Mixed gender group, Location: Far from district head-quarters (>60 km), primary health center in the same village as place of discussion, center more than 10 years old). "Once there was a drunk man...came in demanding I give him IV at once since his hands and legs are paining. Was shouting here -standing right where you are...Gets angry because I gave the IV line to the other patients. I have only limited IV lines- and others are also patients...how can we attend to everyone in a fast way" (Nurse, 25 years, Female, experience-5 years) Out-patient care gets low preference-within target-oriented structures The primary health centers' biggest role is in national program...because of the national program and their targets, there is less focus on the OPD...there are a lot of targets...conduct deliveries...do vaccination...then all new programs have their own targets. (Medical Officer, Male, 39 years, experience-12 years). Risk-averse behaviours and poor referral practices deter its function as a 'link' to higher tiers. Our senior used to tell us 'if you want to take a risk, then you do it elsewhere ....if you want to play, then do it only if you have the guts...if you want to play, do it elsewhere or in your private practice....not in the primary health centre...nothing happens here and don't try to change things... Also, the issue is that if there is some issue...even a tiny issue, at least five journalists will turn up here...and we have to answer them...and they will dramatise the episode.' (Medical Officer, Male, 33 years, experience-9 years). In short, most doctors are not happy at primary health centres; and said that they would prefer private sector jobs, that were regarded as more lucrative, or express a preference for working at higher tiers of the public health system:where the clinical work is perceived as more challenging. In the region, we collected empirical data from, many posts for second doctors at primary health centres are vacant:in a desperate attempt to fill these posts the government has enforced a compulsory 1-year stint at primary health centres for new medical graduates. The graduates we interviewed do not plan to stay on beyond completion of this stint. The community views and evaluates primary health centres like any other curative health facility on the basis of OPD services (and some inpatient services). Community expectations are clearly centred around these centres being good, primary-level curative care facilities:dispensing a variety of free drugs and treatments:and most centres could not live up to these expectations. First, primary health centres, designed under the ethos of 'selective care', offer a very narrow range of curative health services:and have only a few generic drugs available. The community feels that these centres dispensed the 'same medicines for all diseases'; and even those medicines were not given at times due to stock-outs (see box 2). Second, these centres function mostly from a 'rational clinical care' perspective; and do not cater to demands for 'instant relief' by the community. Hence, the treatment offered by primary health centres is often in contrast to those offered by local private practitioners. These practitioners, not bound by the strict regulations that government doctors had to adhere to, cater to 'mass appeal':by administering strong drug combinations that provide instant relief, and intravenous rehydration therapies as per the patients' demand (even when these treatments were clinically irrational). These practices set a different set of expectations in the community about primary-level care:which primary health centres could not address. In addition, strained community-provider relationships (described in the next section) adversely affect people's opinions of these centres. All these factors together make the local private practitioner the first access point to primary-level curative care. Primary health centres today, are, at best, accessed for select services such as immunisation, family planning, for antidotes to animal bites and treatment of certain diseases like tuberculosis and malaria. A common community complaint is the lack of 'attention' given to them at primary health centres. Attention appears to comprise (1) the doctor taking time to understand the issues, (2) doctor using the stethoscope and touching the patient during the interaction, (3) support staff who speak politely and follow doctors' instructions and (4) the prescription of strong medicines. All this, the community feels, does not happen in most primary health centres (see box 2). Doctors' notions of attention are different from those of communities. For one, most doctors do not believe that the type of ailments people came with to primary health centres require more than a quick appraisal. This quick appraisal and the small window of contact with the doctor sometimes has adverse consequences. For instance, one patient we met:who reported throat pain:had not informed the doctor at the centre of her prior visits to a specialist who suspected throat cancer. When asked why she did not share this information, her answer was that the doctor never asked. She also suspected the doctor of pocketing throat-related medication from the centre. This case is also an example of suspicious attitudes of the community towards primary health centre staff. Indeed, the community, in general, has poor views about all public institutions as well as employees who work at these institutions (It must be noted that though people relied on local private practitioners for first access, the community had developed a sense of wariness about these practitioners; people believed that private practitioners were sometimes money-minded, had tie-ups with drug stores and prescribed unnecessary and costly medicines). The wariness of the community towards the staff is not a one-sided phenomenon. Primary health centre doctors express frustration over patients who demanded drugs like cough syrups and intravenous rehydration:despite having no clinical need. Nurses and laboratory technicians report of people fighting with them over the non-arrival of laboratory reports or unwillingness to wait in the line for their turn (see box 2). In summary, mutual wariness between the community and staff at primary health centres deters a trust relationship, essential to the provision of good primary-level care. The biggest contribution of primary health centres within the health system is perceived:by almost all health system staff:to be in operationalising vertical programme and schemes (see box 2). This perception stems from a complex interaction of factors:including strict targets set within the system for vertical programme; and targets which the staff feel compelled to complete because they are held accountable only for these within bureaucratic work environments. Staff express more concerns on how they 'report' the schemes:rather than how they carry out activities under various schemes. Also, activities whose targets (numbers) are checked less frequently by higher level managers get less attention. Within such target-oriented vertical structures, there is little support and encouragement for activities:like the OPD:from the authorities. While two OPDs are mandated in a day, it is an accepted practice to conduct only one. In short, basic curative care at primary health centres has been side lined; this fact, exacerbated by the lack of drugs and equipment, in an environment of mutual wariness between the community and health staff, has made poor quality OPDs a harsh reality at these centres. Doctors perceive themselves as 'professionally isolated' at primary health centres and in practice-feel delinked from the referral tiers. They express concerns about having to deal with consequences of adverse events (such as a death or a mishap) with no peer support. This isolation, combined with drug-stock outs and lack of equipment/diagnostics, has led to 'risk-averse' behaviour among doctors, resulting in an increased number of referrals from primary health centres than necessary from a clinical angle (see box 2). Health staff at primary health centres do not see the referral tiers as 'support' to their work: when cases were referred, they see this as passing on the legitimate clinical work of the higher tiers. This 'referral' is not perceived as making any difference to the goals of the centres:whose work is viewed as that of programme operation. Hence, staff do not think of it as their duty to follow up on referred cases (The exception to this was delivery. In Maharashtra, recent efforts have been made to strengthen ambulance linkages between the primary health centres and the higher tiers- to ensure that referral during delivery was timely. The primary health centre was held accountable for such referrals). Consequently, instead of becoming an integral link in a referral system, primary health centres have become institutes for 'preventive' issues and 'programmes' that refer even primary-level cases. Hence, these are thought of as 'too basic' and places that 'can't really do much'. Disparaging attitudes towards primary health centres are encountered in conversations with almost all health staff, but most explicit among doctors and administrators. A summary of the micro context is presented in table 2.

contextual factors, health policy and systems research, peripheral health clinics, primary health care

PMC7723782_04

Male

This is the case of a 77-year-old man with hypertension, emphysema, and old tuberculosis, who is an ex-smoker and who presented with fever and sore throat. Levofloxacin and ciclesonide were administered on day 8 for bilateral pneumonia with respiratory failure. He was diagnosed with COVID-19 on day 10. He needed IMV due to a rapid progressive respiratory failure on day 11. P/F was 170, which was classified as moderate ARDS at that time. Although favipiravir has been initiated, low-dose steroid (hydrocortisone 250mg/day), intravenous immunoglobulin, sivelestat, and prone position therapy were administered after intubation. The respiratory status improved temporarily, but P/F and consolidation with traction bronchiectasis and volume loss worsened. MP (methyl-prednisolone 1000mg for three days) was initiated from day 14. After this therapy, P/F, LDH, and CT findings were improved (Fig. 1). PSL 30mg (0.5mg/kg/day) was started after the pulse therapy, and the dose was gradually tapered. He was successfully extubated on day 30, negative conversion of RT-PCR was confirmed on day 24, and finally he was discharged without oxygen demand on day 30. PSL was finished on day 33. MP with respiratory failure due to COVID-19 was administered to four patients (three males, one female). The median day of MP administration was day 17 (14-29), the late phase of COVID-19. The median age was 64.5 years (43-77). The comorbidities were hypertension in three cases, history of smoking in two cases, and bronchial asthma, emphysema, and old pulmonary tuberculosis in one case. The median time to diagnosis, respiratory failure, or intubation was 10.5 days (6-11), 9.5 days (8-12), or 12 days (10-23), respectively. The median findings of body temperature, lymphocyte, LDH, and C-reactive protein on intubation were 38.5 Celsius (36.8-38.6), 393.5/mul (219-1227), 442.5IU/l (364-599), and 15.7mg/dl (12.8-35.8), respectively. Lopinavir/ritonavir, hydroxychloroquine, favipiravir, and ciclesonide which were expected to have an antiviral effect were administered on day 10.5 (8-19) (median, range). Intravenous immunoglobulin and antibiotics were administered in all cases. Prone position therapy was performed in three cases. Low-dose corticosteroids were administered in all cases around the timing of intubation. MP improved P/F, LDH, and CT findings in all cases in spite of bimodal worseness after intubation (Figs. 1 and 2). The median duration of systemic corticosteroid, intubation, ICU stay, and negative conversion of RT-PCR was 26 days (13-37), 9.5 days (8-12), 11 days (9-17), and 35 days (24-51), respectively. All cases succeeded in withdrawing from oxygen therapy, but one patient was transferred to a rehabilitation hospital due to disuse symptom. No other adverse events were observed.

covid-19, late phase, steroid, steroid pulse therapy

Computed tomography of the chest during the clinical course in case 1. It showed bilateral peripheral ground glass opacities on day 11 (on admission). These opacities progressed consolidation with traction bronchiectasis and volume loss on day 19 (the day steroid pulse therapy was started). Patient almost recovered from these findings on day 61.

PMC6886192_01

Male

The 22-year-old male patient presented at age 14 years with epistaxis related to severe thrombocytopenia. Immune thrombocytopenic purpura (ITP) was diagnosed and he was initially treated with high doses of prednisone. Prior to immunosuppression, his immunoglobulins had been measured and were found to be in the normal range (IgG 8.8 g/l, nr 7-14). Following initiation of steroid therapy he became hypogammaglobulinemic (IgG 4.3 g/l). Once the severe hypogammaglobulinemia was identified, he was treated with IVIG (2 g/kg), with the added expectation the immunomodulatory doses of IVIG would reduce his risk of infections as well as potentially benefitting his ITP. He then developed Evans syndrome with autoimmune haemolytic anaemia, in addition to the ITP. When reviewed in 2011, he was Cushingoid from corticosteroids. He responded to this regimen and the prednisone was tapered to 10 mg daily and stopped. He was well until 2013 when his ITP relapsed. On this occasion he did not respond to high dose prednisone, vincristine, cyclosporine, cyclophosphamide or rituximab. Due to ongoing cytopenias he underwent a splenectomy in 2014. Histology revealed the presence of splenic granulomas. Although the splenectomy was not successful, he remitted with eltrombopag in 2014. He remained well until early 2017 when he developed diplopia consequent to bilateral cranial VI nerve palsies. He had headaches, fever and signs of meningism. Lumbar puncture showed an elevated CSF opening pressure but protein and other cellular parameters were normal. CSF bacterial culture, fungal antigen tests and viral PCR studies excluded infection. MRI of the brain showed an ill-defined enhancing area around the anterior pons. He had widespread lymphadenopathy including mediastinal and abdominal lymphadenopathy on MRI scanning. Excision biopsy of a left inguinal lymph node showed the presence of discrete non-caseating granulomas, reactive follicles and overall normal lymph node architecture (Fig. 1a). Plasma cells were present although slightly reduced compared to a normal control (Fig. 1b, c). His serum angiotensin converting enzyme (ACE) level was normal. The following week he developed increasing gait instability and was readmitted to hospital. Repeat CSF examination again showed an increased opening pressure (23 cm) and a raised protein level. The cell count and glucose were again normal. A repeat MRI scan of brain and spine revealed enhancing lesions in the cauda equina roots suggestive of granulomatous inflammation (Fig. 2). The previous pontine lesion had resolved. Given the location of inflammation, a biopsy was not possible. Nerve conduction tests of the lower limbs were consistent with nerve root involvement. Several months after starting steroids, a gallium PET scan showed enhancing lesions of the lacrimal gland. PCR studies of the CSF and blood were negative for toxoplasma and tuberculosis (TB), the two main infectious differential diagnoses for granulomatous infections in New Zealand. He had not recently travelled internationally. He had a good response to IV methylprednisolone (1 g) treatment with resolution of headaches and fever, as well as improvement in gait. He was able walk unaided. The improvement was reflected in the blood tests, with the CRP decreasing from 69 to 7 mg/l within a week, and improving cytopenias. He was placed on low dose oral prednisone and mycophenolate with iv methylprednisolone 1 g every 2 weeks. In mid-2018 when the immunosuppression was lifted, his IgG increased from 3.0 g/l to 8.8 g/l (Fig. 3) and the previously decreased IgA and IgM also normalised. Shortly afterwards he developed progressive renal impairment with a creatinine clearance of 36 ml/min. Renal biopsy showed 18/42 sclerosed glomeruli. No granulomas were identified. He was recommenced on Mycophenolate (MMF) and low dose prednisone. There was insufficient time to undertake vaccine response or detailed immunophenotyping studies before the immunosuppression was urgently recommenced. Over the following 6 months the creatinine clearance increased to 66 ml/min. The family has undergone whole exome sequencing for diagnosis and gene discovery but no causative mutation was identified.

cvid, diagnostic criteria, ivig, neurosarcoidosis, sarcoidosis

PMC5831968_01

Male

A 12-year-old boy a known case of relapsed AML has been admitted with impression of febrile neutropenia after the last course of chemotherapy on 16 April 2016. He received the FLAI regimen including fludarabine, cytarabine, and idarubicin (FLAI). After full sepsis workup, meropenem was started and cotrimoxazole (TMP/SMX) was continued with prophylaxis dosage (200 mg/12 hours by oral route). He received voriconazole as a fungal prophylaxis because of the previous history of proven pulmonary aspergillosis. Total white blood cell count was 200/mm3 (without countable neutrophils), hemoglobin was 10 g/dl, and platelet was 6000/mm3. First blood culture was positive for viridans streptococcus (by BACTEC system, time to detection: 9 hours) which was sensitive to vancomycin. Because high-grade fever continued after 48 hours of treatment and according to blood culture results, systemic vancomycin was added to antibacterial medications. The patient developed acute visual loss on 6th day of admission despite the appropriate type and dose of antibiotics. The neurological exam was normal. Retinal detachment and cancer associated retinopathy have been suggested as differential diagnoses in the first general ophthalmologist examination. The therapeutic dose of liposomal amphotericin B has been replaced with voriconazole. Because high-grade fever was not resolved in 8th day of therapy (24 April), the blood sample was sent for a new culture, polymerase chain reaction (PCR; for aspergillosis, mucormycosis, candida, CMV, and tuberculosis), and enzyme-linked immunosorbent assay (ELIZA; for toxoplasmosis and cytomegalovirus antibody assay). A new chest X-ray has also been requested which revealed no new findings. According to the results, toxoplasmosis IgM level was negative (0.1 IU/ml) and IgG level was at a borderline level (9.8 IU/ml). CMV blood PCR was reported to be 950 copy/mL. Anti-CMV antibody (IgG) was positive. Repeated blood PCR was negative for other fungal or viral pathogens. Due to poor patient condition, spiral chest CT scan was requested on 10th day of admission with normal result. Rifampin has been added to the treatment regimen due to deteriorating patient's condition to achieve additive anti-Gram-positive synergistic effect. As the new blood culture results again revealed viridans streptococcus, which is susceptible to linezolid, linezolid has thus been replaced with vancomycin because of persistent bacteremia on 12th day of admission. Lumbar puncture was performed on 29 April with total cells of 50/mm3 (white blood cells, 40/mm3 (polymorphonuclear leukocytes, 40%); red blood cells, 10/mm3), glucose of 50 mg/dl, protein of 48 mg/dl, and lactate dehydrogenase of 40 IU/L. Cytology report of cerebrospinal fluid (CSF) was positive for blasts, and PCR was negative for all viral and fungal suspicious agents. Along with the patient's general condition, the patient complained of deteriorated visual function in the right eye. Therefore, a second ophthalmologist consult with a vitreoretinal specialist has been performed on 16th day of admission. The consultant ophthalmologist reported fluffy lesions with diffuse retinal hemorrhage and patchy focal necrosis (brush fire pattern) in the right eye and normal left eye (Figure 1). Thus, with first impression of cytomegalovirus (CMV) retinitis, vitreous aspiration was performed under anesthesia, and the sample was sent to the laboratory for PCR analysis. DNA was extracted from 100 microL ocular fluid by using High Pure Viral Nucleic Acid Kit (Roche Diagnostic GmbH, Germany) according to the instruction manual. Cytomegalovirus viral load was determined using a genesig quantitative real-time PCR kit (Primer Design Ltd. TM, Advanced Kit, United Kingdom) according to the manufacturer's instruction. The target sequence (glycoprotein B) has previously been shown to be a good genetic marker for CMV in other real-time PCR-based studies. This quantitative PCR assay was sensitive enough to detect 10 copies of CMV genomic DNA. Real-time PCR was performed using an ABI Step One Plus System (Applied Biosystems, Foster City, CA) with standard reagents (TaqMan Gene Expression Master Mix, Applied Biosystems, UK), which showed positive results for CMV (5000 copy/ml). Upon confirmation, the patient received 2 intravitreal injections of ganciclovir 1 week apart with adjunctive systemic antiviral therapy with ganciclovir 5 mg/kg twice daily on 24th day of admission for 2 weeks as induction. In addition, our plan was to continue for about 4 weeks. On 34th day after admission, a new blood sample was requested for CMV PCR, which was shown 1150 copy/ml of CMV DNA in plasma without significant change in baseline CMV viral load. Because of severe retinal necrosis and hole formation at some retinal areas, barrier argon laser photocoagulation was suggested and performed by the responsible ophthalmologist. The final blood culture became negative, but finally he was died due to refractoriness of leukemia and poor response to chemotherapy 8 weeks after admission.

PMC3700482_01

Male

In October 2011, the authors visited a 46-year-old immigrant Moroccan for the first time. The patient reported having suffered 4-6 months from a relentless hiccup, irregular dyspeptic illness, a lack of appetite, a tense (but not painful) abdomen, and weight loss. He did not report fever or sweating. The examination showed the presence of hard, non-painful, bilaterally enlarged lymph nodes in the inguinal and axillary sites, and abdominal distension that suggested an ascitic fluid collection. No cardiovascular signs or symptoms were present. An abdominal ultrasound examination (Figure 1) confirmed the presence of ascites, but there was no enlargement of the liver or the spleen. In summary, an ascitic fluid collection with no signs of portal hypertension was present. The patient was admitted to the hospital, where further diagnostic procedures were performed including: an esophagogastric-duodenoscopy (OGD-scopy) showing signs of Helicobacter pylori and erosive gastritis, and colonos-copy showing a villous adenoma with low-grade dysplasia. A chest and abdomen CT scan (Figure 2) revealed bilateral apical scarring of the lung parenchyma and absence of hilar and mediastinal lymphoadenomegaly, and confirming the presence of abundant ascitic fluid. No significant alterations were seen in the other organs. Blood tests showed normochromic and normocytic anaemia (Hgb 10.6 gr/dl), low iron, and normal ferritin. Transaminases were slightly high, and indexes of inflammation were consistently high, with CRP values between 3.4 and 4.3 mg/dl, D-Dimer 1187 ng/ml, and ESR 42. A Mantoux intradermal reaction was positive (8 mm), but an HIV test, tumor markers, and serologies for hepatitis were negative. The following test results were normal: rheumatoid test (anti-nuclear antibodies), antimitochondrial antibodies, anti-smooth muscle antibody, liver-kidney-microsome antibodies, and anti-neutrophil cytoplasmatic antibodies), antiphospholipid antibodies, and circulating immunocomplex and complement factors. Examination of the ascitic fluid was positive to alkaline reaction, and the Rivalta test showed a protein content of 65.3 g/l. Microscopic examination of the sediment revealed the presence of erythrocytes, leukocytes with predominantly mature lymphocytes (lymph: 80%), and a total amount of polymorphonuclear leukocytes of 1100 n /mmc. Direct bacterioscopy and cultures for mycobacteria were consistently negative. Cytological analysis for atypical cells was negative. The average albumin in the ascitic fluid was 3.2 g/dL, and the average albumin in the serum was 2.8 g/dl; therefore, the serum ascitic albumin gradient (SAAG) was 0.4 g/dl. M. tuberculosis PCR (Polymerase Chain Reaction), performed in a laboratory at another local hospital, was negative. A biopsy of 2 small lymph nodes in the left inguinal side showed only aspecific reactive inflammation. The patient was discharged from the hospital after 32 days, with a diagnosis of "ascites of uncertain nature and signs of inflammation". Radiographic examination of the small intestine was negative. A laparoscopy with directed peritoneal biopsy, which is thought to be the best diagnostic procedure for tuberculosis peritonitis, was subsequently performed at another hospital. Laparoscopy of the abdomen revealed large macro- and micro-nodular degeneration of the visceral and parietal peritoneum, and the presence of plaques and omental thickening, interpreted macroscopically to be similar to a massive peritoneal carcinomatosis. Histological examination of the peritoneal biopsies showed epithelial granuloma with the presence of Langhans-type giant cells and a wide area of caseous necrosis, but without acid-fast bacilli Figure 3). Cytological examination of the ascitic fluid showed the presence of inflammatory cells, predominantly lymphocytes, monocytes, and a small number of polymorphonuclear cells, similar to Langhans cells (Figure 4). The patient was dismissed with a final diagnosis of massive peritoneal tuberculosis. During the short period (15 days) of hospitalization in the Infectious Disease Department, the patient was started on a 4-drug regimen of isoniazid, rifampicin, pyrazinamide, and streptomycin. During the final stay in the hospital, direct examination and cultures of urine, feces, and sputum for mycobacteria were performed, but all results were negative. After administration of the last treatment with streptomycin, the patient was dismissed in good general condition, with maintenance therapy and a follow-up protocol.

ascitic fluid cytology, diagnostic laparoscopy, hiccup and ascites, tuberculous peritonitis, ultrasound tomography and computed tomography scan

PMC9773131_02

Male

Past medical history was significant for a "birthmark" extending over his abdomen and lower back, for which multiple excision/grafting procedures were performed at 6 years of age. He denied any itching, bleeding, or noticeable changes in the lesion's size, texture, color, or appearance for the last 20 years. The patient did not recall a specific diagnosis but reported consistent follow-up and mole mapping with a dermatologist outside the US. Despite being born in the UK, he lived in South Africa from early childhood until his 23 years of age and then returned to his home country, where he stayed until moving to the US a few months before presentation. When he was 10 years old, his father was treated for pulmonary tuberculosis. No other relevant family history was reported. He denied excess alcohol intake, current/former smoking, illicit drug use, overexposure to UV radiation, or known occupational hazards. During bedside evaluation, the patient was found to have heterogeneous brown-to-black patches/plaques scattered on his torso, buttocks, and lower abdomen with satellite lesions, areas of hypertrichosis, and irregular borders, consistent with partially-excised giant CMN of bathing trunk distribution (Figure 1). The skin lesions were mostly flat except for a nodular border where grafting was previously done. In addition, a 2-cm mobile, firm, non-tender and non-erythematous subcutaneous nodule was palpated in the right axillary region. His physical exam was otherwise unremarkable. On initial workup, blood counts, basic chemistries, liver function tests, troponin levels, urinalysis, and electrocardiogram were within normal limits. Conversely, serum D-dimer was elevated (2.42 mcg/mL) and chest radiography showed a left lower lobe (LLL) density of approximately 3 cm, leading to the acquisition of thoracic computed tomography (CT) angiography. Despite a lack of pulmonary emboli, significant findings included two LLL nodules (2.7 and 1.0 cm), a left posterior pleural-based nodule (0.8 cm), and a right lower lobe nodule (0.3 cm). The patient was admitted to the hospital for further diagnostic evaluation. While serum lactate dehydrogenase (LDH) was elevated (350 U/L), other laboratory tests resulted negative (including traditional tumor markers, hepatitis/HIV testing, QuantiFERON-TB Gold, and three sputum acid-fast bacillus smears). Contrast-enhanced CT (CECT) of the abdomen demonstrated hypodense lesions in the left and right adrenal glands (4.7 x 4.1 and 3.7 x 3.5 cm, respectively), between liver segments 2/3 (2.8 x 2.4 cm), and in the left inferior renal pole (1.4 x 1.1 cm). Brain magnetic resonance imaging (MRI) showed multiple enhancing parenchymal nodules of 0.4-1.2 cm, some of them with surrounding edema. Meanwhile, a whole spine MRI found no additional disease in the central nervous system (CNS) or vertebral bodies. The high suspicion of metastatic cancer prompted an incisional biopsy of the right mid-back nodular area. Histopathological evaluation lacked evidence of malignancy and was consistent with reactive melanocytic proliferation to an underlying scar. As a result, the patient underwent an incisional biopsy of the right axillary nodule, with formalin-fixed paraffin-embedded (FFPE) samples revealing malignant cells within fibroadipose tissue (Figure 2). Immunohistochemistry (IHC) showed positivity for preferentially expressed antigen in melanoma (PRAME), S100, melan-A, and tyrosinase:a pattern consistent with melanoma:and negativity for BRAF V600E and NRAS Q61R. A hybridization capture-based next-generation sequencing assay (MSK-IMPACT) was also applied to the FFPE specimens. Although no microsatellite instability or structural variants were found, the tumor was positive for somatic mutations in NRAS exon 3 (c.181C>A, p.Q61K), EP300 exon 31 (c.5992G>A, p.G1998R), and MSH2 exon 12 (c.1996A>G, p.I666V). Additional findings included an estimated tumor mutation burden of 2.5 mutations/megabase and MDM2/GLI1/ERBB3/CDK4/IGF1/TERT/SDHA/EP300/MSH2 amplification. On account of his elevated serum LDH levels and CNS metastases, M1d(1) melanoma was ultimately diagnosed. As surgical metastasectomy was not appropriate, upfront treatment consisted of ipilimumab/nivolumab (3 mg/kg and 1 mg/kg, respectively, administered intravenously once every 3 weeks) and multifraction stereotactic radiosurgery of the brain (27 Gy divided into 3 daily fractions). Low-grade adverse events (hepatitis, thyroiditis, and oral mucositis) occurred after the first cycle of ipilimumab/nivolumab, but did not require immunotherapy discontinuation. Following 6 weeks of treatment, brain MRI showed interval contraction of CNS lesions and chest CTCE demonstrated stable pulmonary lesions. On the other hand, abdominopelvic imaging revealed new mesenteric/inguinal adenopathy and increased metastatic involvement of liver, kidneys, and adrenals. The patient's rapid disease progression led to subsequent-line treatment with CVT (cisplatin 20 mg/m2 IV on days 1-4, vinblastine 1.6 mg/m2 IV on days 1-4, and temozolomide 150 mg/m2 orally on days 1-5 administered every 21 days). Following 3 cycles of cytotoxic chemotherapy, CECT disclosed nonobstructing transient small bowel intussusceptions secondary to intra- and extraluminal metastatic lesions. As a result, the patient was transitioned to nivolumab/relatlimab (480 mg/160 mg IV once every 4 weeks). A few days after the second combination dose, he presented to the ED complaining of intractable abdominal pain. Repeat abdominal CECT showed an edematous, hypoattenuating closed-loop small bowel obstruction with twisting of the mesentery. Given the evidence of significant ischemia, exploratory laparotomy with partial small bowel resection and reanastomosis was performed. The patient recovered well, albeit with considerable weight loss related to continued anorexia and abdominal pain. Stable disease (<20% growth of target lesions) was observed after three nivolumab/relatlimab doses. However, interval imaging after the fourth dose showed progression of the thoracic and abdominopelvic masses. Figure 3 showcases a timeline with relevant data from the patient's clinical course.

mdm2 amplification, nras mutation, congenital melanocytic nevi, giant nevus, metastatic melanoma

PMC9998481_01

Female

Thirty-one patients were included in the case series: 14 females (14/31; 45%) and 17 males (17/31; 55%), with a mean age of 78-years-old (SD +- 9 years) (Table 2). Patients had a variety of comorbidities and 13 were on blood thinners, as indicated in Table 2. The average width of the tumor excision (recipient site pre-excision) was 18.8 mm (SD +- 3.0), ranging from 15 to 27 mm. The average donor site width pre-excision was 11.5 mm (SD +- 1.1 mm), ranging from 9 to 13 mm, and approximately 8-10 mm in height (Table 1). For very large recipient sites in 3 cases, a mini temporal rotation flap was also performed to help fill in the defect. A cantholysis was performed at the recipient site when the lid was under too much tension in an additional 3 cases. Two patients required a canalicular stent based on the location of their tumors. The upper eyelid was used for the ipsilateral lower lid most commonly, but also grafted to the contralateral lower or upper lid. The lower eyelid was grafted to the contralateral lower lid for one patient. In the surgical center's region, it is not protocol for dermatopathologists to provide histopathological margin measurements for BCC. However, the reports stated that the peripheral and deep margins were negative for all patients. The case with MIS had 5 mm margins on histopathology. Radical excision was achieved in all cases. The FBA procedure results demonstrated success with respect to structural integrity, appearance, and viability of the full-thickness composite graft. No complications occurred during the procedure. The sutures did not have to be removed and never caused friction between the lid and cornea. All patients were satisfied with the functional and cosmetic result of their surgery. In general, complications were more common in patients who had a recipient site larger than 17 mm (Table 1). A chalazion developed in the autograft of two eyelids post-surgery, demonstrating that its Meibomian glands likely remained functional. Three patients developed mild ectropion, two of which required repair. There was initial ptosis in many patients due to shortening of the donor eyelid's horizontal length; however, this resolved over weeks. Lashes were generally lost or reduced in number on the grafted eyelid. Two patients developed cysts within or adjacent to the autograft that were inconsequential. Six patients developed minor dehiscence of the autograft, three of which were traumatic in nature due to rubbing the eye, wearing swimming goggles, and using a shield with a string post-operatively. Approximation sutures were required in five of these patients. One patient had a recurrence of BCC at the recipient site many years after excision (Table 1). A different patient had a second primary BCC develop lateral to the excision site. One patient experienced superficial necrosis in the middle inferior aspect of the graft, after developing frostbite of the face. The graft ultimately healed but led to a mild ectropion. The patient required a temporary tarsorrhaphy due to exposure keratitis. No patients developed postoperative entropion, eyelid notching, distichiasis, trichiasis, lanugo hair irritation, donor lid contraction, dry eyes, or other complications (Table 1). The FBA procedure heals in three observable phases: the white phase, the blue phase, and the pink phase (Figure 3). Using the pictures taken at each follow up appointment and patient feedback, it was approximated that the white phase lasted from the time of operation to between 24 and 48 h post-operation, the blue phase lasted from 24 to 48 h and 7-12 days post-surgery, and the pink stage started around day 7-12 post-surgery with visible blood vessels in the autograft. The pink colour slowly faded over weeks to months.

eyelid graft, eyelid reconstruction, eyelid surgery, free bilamellar autograft, full thickness eyelid defect, large eyelid defect

PMC8864130_01

Female

A 16-year-old female was admitted to Kyungpook National University Children's Hospital with complaints of diarrhea, hematochezia, and weight loss for a year. She had been diagnosed with latent TB 1 month before her visit, and a latent TB treatment regimen with isoniazid (INH) for 9 months had been started. She had completed Bacillus Calmette-Guerin (BCG) vaccination. Family history revealed that her father had a history of pulmonary TB, which was treated 3 years ago. On admission, vital signs were within normal range. On physical examination, a perianal fistula with the discharge was observed in the perianal area. Initial laboratory tests showed a white blood cell count of 5,130/muL, a hemoglobin level of 11.6 g/dl, a platelet count of 462,000/muL, an albumin level of 3.5 g/dl, an erythrocyte sedimentation rate (ESR) of 99 mm/h, and a C-reactive protein (CRP) of 3.51 mg/dl. The fecal immunochemical test was positive and fecal calprotectin was 589.9 mg/kg. No pathogens were detected in stool culture and stool polymerase chain reaction (PCR). Chest x-ray showed no abnormal findings in the lungs. However, the interferon-gamma release assay was positive. Ileocolonoscopy showed multifocal ulcers throughout the terminal ileum and colon (Figures 1A,B). Histology revealed cryptitis, crypt abscesses, and noncaseating granulomas; however, the acid-fast bacillus smear, culture, and PCR for TB were negative. Magnetic resonance enterography showed multifocal wall thickening in the colon, ileum, and jejunum and two intersphincteric perianal fistulas (Figures 1C,D). Upper GI endoscopy was unremarkable. The patient was diagnosed with CD with a phenotype of A1b, L3+L4b, B1p, G0 according to the Paris classification. Her pediatric CD activity index (PCDAI) score was 50 and the Simple Endoscopic Score for CD (SES-CD) was 26. Treatment was begun with exclusive enteral nutrition (EEN), mesalazine, and azathioprine, which were effective. Two weeks after the diagnosis, she underwent seton placement. However, 1 month after finishing her 8-week treatment with EEN, her disease relapsed. Azathioprine was changed to methotrexate (MTX). However, symptoms did not improve, and infliximab (IFX) was started 1 month later, considering that she had taken sufficient latent TB treatment with INH for 5 months. The patient chose to take IFX as her biologic agent between IFX and adalimumab, which are the only biologic agents currently approved for the treatment of moderate-to-severe CD. Chest x-ray before starting IFX showed no abnormal findings in the lungs. After starting IFX, INH therapy for latent TB treatment was extended for a total of 12 months. Ileocolonoscopy at 1-year follow-up after IFX treatment revealed endoscopic healing. PCR for TB was negative again from specimens of the ileum and cecum. However, ESR and CRP gradually increased 1 month after the ileocolonoscopy, and she developed diarrhea. IFX trough level was 2.4 mug/mL, and IFX antibody was negative. Considering the suboptimal trough level and negative anti-drug antibody status of the patient, secondary loss of response due to nonimmunogenic pharmacokinetic failure was suspected. Therefore, the IFX interval was shortened from every 8 weeks to every 4 weeks. However, 1 month later, she newly developed symptoms of fever, cough, and sputum. Chest x-ray and chest computed tomography (CT) showed multiple small nodules in both lungs indicating miliary TB (Figure 2A). Bronchoscopy was conducted, and TB was confirmed by a positive TB PCR test of the tracheal biopsy specimen and bronchial washing fluid. IFX treatment was discontinued and the standard TB treatment regimen with INH, ethambutol, rifampin, and pyrazinamide for 2 months followed by INH, ethambutol, and rifampin for 4 months was started. MTX and mesalazine were maintained to treat CD. Miliary TB was completely cured after 6 months of TB treatment (Figure 2B). Three months later, an abdominal CT was performed to evaluate her CD after failed ileocolonoscopy due to poor bowel preparation. No active CD involvement was observed in the bowel, whereas a newly developed left psoas muscle abscess and spinal bony destruction were incidentally identified (Figure 3). Surprisingly, the patient did not have any back pain. Spinal MRI was conducted to confirm the diagnosis of TB spondylitis (Figure 4A). Ultrasound-guided aspiration for the paraspinal abscess was conducted, and TB PCR was positive. Abscess culture grew M. tuberculosis later. Bacterial and fungus culture grew no isolates. Follow-up chest CT revealed no aggravation of miliary TB. Thus, she was diagnosed with TB spondylitis. She discontinued all medications for CD treatment and maintained TB treatment for a total of 12 months because extrapulmonary TB had developed within 3 months after the end of her miliary TB treatment. TB treatment regimen included INH, ethambutol, rifampin, and pyrazinamide for a total of 12 months. Spinal magnetic resonance imaging (MRI) at 1-year follow-up after TB treatment revealed that her spinal lesions were cured (Figure 4B). MTX and mesalazine were restarted thereafter. However, symptoms of diarrhea and abdominal pain developed 2 months later. Her PCDAI score was 35 and the exacerbation of CD was confirmed by ileocolonoscopy. Again, acid-fast bacillus smear, culture, and PCR for TB were all negative. Due to the fear of another severe active TB with IFX treatment, vedolizumab (VDZ) was initiated instead. The patient is currently on VDZ for over a year and is maintaining clinical and biochemical remission. No serious adverse events, including TB reactivation, have occurred. Spinal MRI conducted 1 year after VDZ initiation showed no reactivation of her TB spondylitis (Figure 4C). This case report was approved by the Institutional Review Board of Kyungpook National University Chilgok Hospital (No. 2020-09-018). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.

crohn's disease, pott's disease, infliximab, tuberculosis, tumor necrosis factor, vedolizumab

PMC5165133_01

Female

A 78-year-old Japanese woman was found to have anaemia and reticular shadows on her chest X-ray during a health examination, for which she came to our hospital. She did not have any symptoms, including fever, cough, and purulent sputum, at that time. Her dietary habits were normal and she had not experienced any weight loss. Her haemogram and serum biochemistry revealed the following: haemoglobin: 7.8 (11.3-15.2) g/dL, MCV: 78.5 (79-100) fL, MCHC: 29.5 (30.7-36.6)%, serum iron: 62 (43-172) mug/dL, ferritin: 67.2 (4.6-204.0) ng/dL, unsaturated iron-binding capacity: 188 (137-327) mug/dL, vitamin B12: 470 (180-914) pg/mL, folic acid: 3.8 (3.1-9.7) ng/mL, blood urea nitrogen: 20.9 (8-22) mg/dL, creatinine: 1.13 (0.4-0.7) mg/dL, sodium: 145 (138-146) mEq/L, potassium: 3.5 (3.6-4.9) mEq/L, and chlorides: 109 (99-109) mEq/L. Her faecal occult blood test was negative. We diagnosed the cause of anaemia as defective iron utilization, and we followed up her laboratory data and chest X-ray findings to clarify the cause of defective iron utilization. Three months later, she was admitted to the hospital with renal failure, chest radiograph abnormality, and severe anaemia. She had a past medical history of hypertension but had never smoked and had no history of tuberculosis (TB). She had not been exposed to any fine particles. She did not have fever or any respiratory symptoms, such as breathlessness, cough, haemoptysis, dyspnoea, and chest pain. Physical examination showed a body temperature of 36.3 C and no crackles were audible on auscultation. Her chest X-ray showed persistence of the reticular shadows in the right middle and lower lung fields. In addition, a calcified lesion was observed in the left middle part (Figure 1(a)). Chest computed tomography (CT) showed a ground glass shadow and consolidation in the right upper and lower lobes with left sided pleural thickening and calcification (Figures 1(b)-1(e)). Her laboratory findings at this time were haemoglobin 6.9 g/dL, white blood cell count 6,600 (3,500-9,000)/muL, blood urea nitrogen 61.5 mg/dL, creatinine 2.56 mg/dL, C-reactive protein (CRP) 0.0 (<0.3) mg/dL, erythrocyte sedimentation rate (ESR) 90 (2-15) mm/h, myeloperoxidase (MPO)-ANCA 54 (<10) EU, proteinase 3 (PR3)-ANCA <10 (<10) EU, and anti-glomerular basement membrane (GBM) antibody <10 (<10) EU. More than 100 counts per high power field of red blood cell (RBC) casts were found on urinalysis. Renal biopsy was performed and pathological evaluation of the specimen revealed cellular crescent formations and lobulation in more than half the glomeruli (Figure 2). Evaluation of bronchoalveolar lavage fluid (BALF) revealed increased RBC counts, and cytology indicated that 90% of the detected macrophages were haemosiderin-laden. These findings indicated the presence of alveolar haemorrhage and, hence, she was diagnosed as MPA. She did not consent to undergo surgical lung biopsy at this time. We initially planned to treat her with corticosteroids and intravenous cyclophosphamide (IVCY), and, therefore, we first started treatment with corticosteroid therapy (prednisolone 50 mg/day) (Figure 3). After prednisolone therapy at this dose for 14 days, we started tapering it by 10 mg every 2 weeks, and once the dose of 20 mg was reached we tapered it by 5 mg every 4 weeks. This resulted in improvement in the renal failure, anaemia and lung abnormalities and, hence, IVCY was not required. Once the corticosteroid dose was reduced to 5 mg, it was combined with azathioprine. Currently, the patient is on maintenance therapy with corticosteroids (prednisolone 3 mg/day) and azathioprine (5 mg/day) without relapse of lung and renal lesions. She has been carefully followed up for development of TB by examination of chest X-rays once a month and sputum culture every three months, but with no TB prophylaxis.

PMC9246625_01

Male

The patient was a 24-year-old white male without pretransplant autoimmune conditions, diagnosed with precursor-B-cell acute lymphoblastic leukemia (ALL) in 2008. Cytogenetic analysis demonstrated near hypertriploid karyotype with trisomy 4, 10, and 17. After being treated with multiagent chemotherapy according to the AALL0232 protocol, he achieved complete remission. Six years later, he relapsed and was treated with the pediatric R3 protocol, achieving a second complete morphologic remission. He then received consolidation with cyclophosphamide 70 mg/m2 and total body irradiation (TBI, 1000 cGy) followed by an allogeneic HSCT from an HLA-matched unrelated female donor in February of 2015. Prophylaxis of GVHD consisted of a single dose of posttransplant cyclophosphamide (50 mg/Kg), tacrolimus, and mycophenolate mofetil. Donor and Recipient HLA type was A*03 : 01/24 : 02, B*07 : 02/50 : 01, C*07 : 02/06 : 02, Bw6, DRB1*04 : 01/07 : 01, and DQB1*03 : 01/02 : 02. The dose of infused total nucleated cells was 1.18 x 109 cells/kg with 92% viability, including 1.11 x 107 CD34+ cells/kg and 2.44 x 108 CD3+ cells/kg of body weight. Full donor CD3, CD20, and CD15 chimerism was attained by day +28. Of note, this was a minor ABO-incompatible HSCT as the patient's blood group was A+, whereas the donor was O+. On day +3 post-HSCT, the patient developed a nonpruritic, erythematous rash on his chest, abdomen, and extremities. A skin biopsy revealed interface dermatitis consistent with a drug reaction. He was transfused one unit of irradiated iRBCs on each of day +3, +5, +7, +8, and +10 (Figure 1(a)). The blood type of the iRBC units was A, O, O, O, and A, respectively. Additionally, two units of irradiated apheresis platelets (iPLTs) were transfused on days +3 and +10. Shortly after receiving the iRBC unit on day +10, the patient complained of worsening back pain and was noted to have decreased urine output, which prompted a transfusion reaction workup (Table 1). The blood samples collected before and after the transfusion were reported as A+ with mixed-field reaction, consistent with the presence of group O RBCs likely from his recent transfusions of O iRBCs. Although the plasma color posttransfusion was amber and did not show overt hemolysis, the serum haptoglobin was low and lactate dehydrogenase (LDH) and bilirubin levels were higher than pretransfusion values. A posttransfusion direct agglutination test (DAT) was also microscopically positive for IgG and C3 (1+) compared with a DAT on his pretransfusion blood sample, which was negative for IgG and microscopically positive for C3. His antibody screen was negative both pre- and posttransfusion, indicating that a non-ABO circulating alloantibody was unlikely present. At this point, it was evident that the blood bank had erroneously issued a group A iRBC unit using the electronic crossmatching method only. A serologic posttransfusion crossmatch could not be performed because the iRBC unit was not returned to the laboratory. However, clerical checks confirmed that the most recently given iRBC unit was A+. During the transfusion reaction workup, anti-A was newly identified in the patient's plasma at a titer 8, which was present in both samples collected immediately before and following the transfusion implicated in the reaction. A posttransfusion urinalysis showed moderate (3+) hemoglobinuria and 3-10 red blood cells/40x field, and both of which were absent in a urine sample collected before the transfusion of the triggering iRBC unit on day +10. Blood urea and creatinine both rose from normal values pretransfusion to abnormally high values postreaction (Table 1). The workup collectively indicated an acute hemolytic transfusion reaction with acute kidney injury, likely due to anti-A from the donor reacting with transfused and patient's own group A RBCs. In addition to receiving corticosteroids, an emergent red blood cell exchange was performed. During the procedure, approximately 70% of the patient's circulating red cells were replaced with seven units of group O iRBCs to achieve a final hematocrit of 24%. Following the exchange, the patient's clinical condition improved gradually, including his kidney function and hemoglobin level, which rose and remained above 7 g/dL. The haptoglobin returned to normal within 48 hours, and his blood type converted to group O by day +94. Around days +60 and +111, the patient developed acute gastrointestinal and cutaneous GVHD, respectively. He received systemic corticosteroids, immunosuppression with tacrolimus, and later, rituximab. As a steroid-sparing agent and for poor compliance with tacrolimus, he was also started on mycophenolate mofetil. In light of the history of HT in the donor, the patient was monitored with serum free-T4 (fT4) levels (Figure 1(b)), thyroid-stimulating hormone (TSH) (Figure 1(c)) and the presence of autoantibodies directed against the thyroid. His thyroid panel pretransplant was normal, including the absence of detectable antibodies. On transplant day +3, he also had normal TSH and fT4 of 0.744 microIU/mL (reference range: 0.45-5.5 microIU/mL) and 1.25 ng/dL (reference range: 0.62-1.57 ng/dL), respectively. On re-evaluation on day +46, TSH and T4 levels remained within the normal range while antithyroglobulin (anti-TG) and antithyroid peroxidase (anti-TPO) were undetectable. However, on day +358, TSH was 0.047 microIU/ml and fT4 was 1.62 ng/dL suggesting an initial hyperthyroid phase followed by a hypothyroid phase from day +372 with a high TSH (79.6 microIU/mL). Anti-TG was detected at a titer of 3 U (reference range: <0.5 U) at this time indicating the development of autoimmune hypothyroidism. Concurrent decrease thyroid function and the appearance of anti-TG antibodies in the serum suggest that complement-mediated injury may have also contributed the thyroid gland injury. Therefore, thyroid replacement therapy was initiated. An ultrasound on day +511 revealed a normal thyroid gland without evidence of nodules or parenchymal abnormalities and no increased blood flow. Grade 2 parenchymal echogenicity, high vascularity, and paratracheal lymph nodes enlargement typically seen on thyroid ultrasound during hypothyroidism were missing possibly because the patient has already been on replacement therapy for several months and was in an euthyroid state. Further follow-up on day +813 showed normal thyroid function and undetectable antithyroid antibodies. However, the patient was not compliant with his thyroid hormone replacement therapy for a long period during which fT4 level was low and TSH was high (Figures 1(b) and 1(c)). During this period, the patient complained of fatigue and had two admissions to the hospital for sepsis for which he recovered. Following several sessions of patient education on the importance of taking prescribed medications, the patient resumed thyroid hormone replacement therapy and both fT4 and TSH levels returned to normal values around day +2498 posttransplant. Seven years later, the patient remains on thyroid replacement therapy. The latest posttransplant course was complicated by oral and cutaneous chronic GVHD.

PMC10160796_01

Male

A 54-year-old previously healthy gentleman presented with 1-month history of persistent low back pain. The pain started suddenly, was dull in nature, non-radiating, and worse during the night. No alleviating or exacerbating factors. While he denied symptoms of urinary incontinence, saddle anesthesia, or peripheral numbness, he reported an occasional cough that was present since 1 year prior to presentation. Blood investigations were significant for ACE level of 102.2 U/L (reference: 12-68 U/L). Erythrocyte sedimentation rate (ESR) was elevated at 79 mm/h and C-reactive protein (CRP) was elevated at 52 mg/L. Complete blood count, electrolytes, calcium, hemoglobin A1c, fasting blood sugar, and lipid profile were within normal limits. A magnetic resonance imaging (MRI) of the lumbar spine showed diffuse metastatic osteolytic bone disease in the lumbar and dorsal spine with L5-S1 degenerative disk disease impinging on the S1 nerve root. A positron emission tomography (PET) scan showed radiotrace avid liver lesions with multiple bilateral fluorodeoxyglucose (FDG) avid pulmonary nodules. Enlarged mediastinal, bilateral hilar, bilateral axillary, abdominal, and pelvic lymph nodes were noted (Figure 1A to D). In addition, thickened left adrenal gland showing diffuse increased radiotracer uptake indicating likely disease involvement was noted. Furthermore, multiple lytic bone lesions, involving the axial and appendicular skeleton, the skull, ribs, and pelvic bones were evident. An ultrasound guided liver needle core biopsy was performed without evidence of malignancy. The liver was almost completely replaced by back to back non-caseating granulomas (Figure 2A). These granulomas were small and composed of tightly packed epithelioid histiocytes without associated necrosis, caseation, or acute inflammation (Figure 2B). Rare Langerhans-type multi nucleated giant cells were noted (Figure 2C). There were no Schaumann or Asteroid bodies noted in the giant cells. The granulomas were present in the hepatic parenchyma and also adjacent to bile ducts. Periodic acid-Schiff (PAS) and Grocott's methenamine silver (GMS) stains were negative for fungal organisms. Acid fast stain was negative for mycobacterium tuberculosis. The biopsy ruled out a malignant condition and was most consistent with sarcoidosis. However, other granulomatous conditions were entertained, such as tuberculosis, atypical mycobacteria, fungal infections, sarcoid-like lesions due to cancer, immunodeficiency or medications, heavy metal, and others. Subsequently, a computed tomography (CT) of the chest without contrast was positive for diffuse lung nodule pattern with dispersed lesions seen with mean 5 mm mostly compatible with sarcoidosis. Sub-axillaries and mediastinum small lymph nodes were noted. As the patient was not severely symptomatic, he was started on prednisone 20 mg daily for 1 week to be tapered by 5 mg weekly. In a 2-month post-treatment visit, the patient reported a significant improvement in the back pain, but slight improvement of the cough.

sarcoidosis, diagnostics, imaging, metastasis, pathology

PMC9282698_01

Female

We report a case of a 22-year-oldfemale patient, diagnosed to have HIV infection 8 years back. She was on antiretroviral therapy (ART) for the last 8 years. The patient had not been taking ART regularly for the last 2 years. Her CD4 count had gradually fallen to 238/mm3 from 520/mm3 over 2 years. She presented to us with complaints of headache and altered behavior for a week and focal fits for 2 days. She had holocranial, throbbing headache associated with episodes of vomiting. She was irritable and showed no interest in her surroundings. The mother found her muttering to herself for the last few days. She was scared and believed that someone wanted to kill her. Later, she had multiple fits in the form of right-sided facial twitching and clonic jerky movements of the right upper limb. There was no history of fever, neck pain, or loss of consciousness. Neurological examination was unremarkable. Her routine blood investigations were normal. CD4 count was 238/mm3. Cerebrospinal fluid (CSF) examination revealed total cell count of 30/mm3 with lymphocytic predominance. CSF protein was 68 mg/dl, while sugar was 72 mg/dl. On further testing, EBV was detected using polymerase chain reaction (PCR) test. While tuberculosis PCR, virology (including herpes simplex, varicella-zoster, cytomegalovirus, and JC virus), syphilis, toxoplasma serology, cryptococcal antigen, bacterial, and fungal cultures were negative in blood and CSF. The quantitative viral assay showed a high level of EBV in CSF (42,864 copies/ml). Magnetic resonance imaging of the brain revealed T2/fluid-attenuated inversion recovery hyperintensities involving the left frontal cortex left thalamus and right medial temporal cortex [Figures 1 and 2]. The patient was started on antiviral therapy with valganciclovir considering the diagnosis of EBV encephalitis. The patient completely recovered over the next few weeks. She was discharged on antiepileptic and ART.

encephalitis, epstein-barr virus, hiv

PMC3204652_02

Female

L. feeleii was first described in 1984 as the causative agent of a Pontiac fever outbreak. L. feeleii was responsible, according to a recent review, for only 10 reported cases of infections, all of which were pneumonia, only 1 complicated by endocarditis. Unlike lung abscesses, cutaneous lesions caused by Legionella spp. are uncommon. Recurrent soft tissue abscesses of the jaw, wrist, and arm caused by L. cincinnatiensis were described in a 73-year-old woman with nephrotic syndrome and idiopathic immunoglobulin gammopathy. L. micdadei has been found in a cutaneous abscess of the leg of a 62-year-old immunosuppressed woman, and it was responsible for necrotizing cellulitis that resulted in amputation of the left arm of a recipient of a cadaveric renal transplant. L. pneumophila with mixed flora was identified in a perirectal abscess and in skin samples from a patient with lymphoma and cellulitis associated with pneumonia. The infrequency of reporting Legionella spp. cutaneous infections may be explained in part by the fact that Legionella spp. agar is not routinely a part of media inoculated for cases of cutaneous abscess. Here we report the identification of L. feeleii in a cutaneous infection through the use of a shell vial culture protocol.

PMC8046476_01

Female

A 13-year-old right-handed girl fell on an out-stretched right arm after being tackled while playing basketball. The patient did not feel pain in the early stages. As the swelling of the elbow increased, the patient admitted to a state hospital's emergency service. A dorsal splint was applied as a first intervention and suggested for an orthopedic consultation. Two days later, an orthopedic surgeon examined the patient and made a closed reduction in the office. The surgeon ordered control radiography, but the patient left the hospital without control. The patient admitted 3 weeks later, and we removed the splint. The anteroposterior and lateral radiographs showed over 80 degrees of angulation at the radial neck and luxation of the radiocapitellar joint (Fig. 1). At this point, we decided on the surgical intervention. We attempted closed reduction maneuvers in the operation room, but we could not achieve an acceptable reduction. We corrected the radial head by a lateral approach with an osteotomy from the metaphyseal region while preserving medial periosteal continuity. We secured the reduction by two trans-epiphyseal percutaneous 1.7 mm Kirschner wires. We applied a dorsal splint to hold the elbow at 90 degrees of flexion (Fig. 2). The splint discontinued in the 3rd week post-operatively and started a gentle range of motion exercises for the elbow and wrist (Fig. 3). Kirschner wires were removed in the 1st month at the office, then started physiotherapy to stretch and strengthen (Fig. 4). Complete healing of the fracture with the alignment of the radial neck and radiocapitellar joint with no epiphyseal injury was provided by post-operative 6th-month follow-up. Painless full range of motion without any restriction on pronation and supination was achieved (Fig. 5, 6).

pediatric, late diagnosis, open reduction, radial neck fracture

PMC3065044_01

Male

A 14-year-old boy presented to us in July 2009 with low-grade, evening rise fever since March 2008. He also complained of reduction in appetite and weight loss of 8 kg during this period. He had a mild dry cough. However, there was no history of shortness of breath, chest pain, hemoptysis, hoarseness of voice, or dysphagia. There was no other significant history to localize the cause of fever. He received antituberculosis therapy (ATT) for these symptoms and abnormal chest radiograph. He was treated for the first time for 4 months from March to June 2008 and then for 6 months in a private hospital without any relief in his symptoms.

PMC3781908_01

Male

The subject was a 30-year old male with a body height of 1.80 m, a body mass of 93.8 kg, and a body mass index of 29.0 kg/m2. He was an experienced ultraendurance athlete (world champion in the Deca Iron ultratriathlon 2008, a world record holder in the 10-day triathlon, a finisher of the Trans Europe Footrace in 2009 and of the Race across Germany in 2010), and intending to run the first marathon in history under these conditions. One day before the experiment, a maximal treadmill test was performed to determine maximum oxygen uptake (VO2max). A running speed of 8.0 km/hour was set as the start speed. Every 3 minutes, the treadmill speed was increased by 2 km/hour until volitional fatigue. VO2 was determined using an expired air analysis by Meta Max 3B (Cortex Biophysik GmbH, Leipzig, Germany) and heart rate was measured using a portable heart rate monitor (RCX5, Polar Electro Oy, Kempele, Finland). Lactate threshold was determined using Ergonizer version 3.2.1 (K. Rocker, www.ergonizer.de) to enable data analysis. For the experiment, the athlete ran clockwise laps of 17.6 m in the climate chamber at the CEBra (Centrum fur Energietechnologie Brandenburg) of Brandenburg Technische Universitat in Cottbus, Germany (www.tu-cottbus.de/cebra). The investigating team was located outside the climate chamber. Each lap was counted using a laser-assisted photoelectric barrier. A computer counted the laps continuously and showed the distance covered at each moment. During the marathon, Tcore was measured in the rectum along with Tskin at three sites. Before the start, after 10.5 km, 21.1 km, 31.6 km, and at the end of the study, venous blood samples were drawn, urine and sweat were collected, and body mass was measured. Each measurement took on average 10 (8-12) minutes. The athlete changed clothes for comfort during the breaks. He started running with winter boots, winter gloves, a winter jacket, and a winter hat over his running clothes. After 10.5 km (at about -20 C), no changes in clothing were made. After 21.1 km (approximately +5 C), he took off his winter clothes and ran in his usual running clothes. After 31.6 km (around +30 C), he took off his shirt. Ratings of perceived exertion were not recorded. The hydration status of the athlete was not assessed before the marathon and he consumed food and drinks as he was used to doing during his races. Tambient was set at -45 C at the start and continuously increased to +55 C (Figure 1) at a rate of 1 C per 4.5-minute interval. At the start, humidity was set at 60%. After 210 minutes of running at an Tambient of 0 C, humidity was steadily reduced until it reached 20% by the end of the marathon. Temperature and humidity in the climate chamber were recorded every minute. Percent change was rounded to two decimal digits. The day before the climate chamber marathon, the athlete went with his crew to a supermarket to buy conventional food, such as bread, meat, cheese, fruit, and fluids, including mineral water and soft drinks. The athlete consumed food and drinks ad libitum during the marathon. All food and drinks were provided at ambient room temperature. At each point of measurement, his coached prepared the food and drinks as requested by the athlete. Intake of food and drinks was recorded to estimate the fluid and energy intake in a cumulative histogram (Figure 2). The composition of the fluids and solid food was estimated using the information on the products consumed by the athlete and a nutrition chart. While running, sweat was collected using a plastic bag attached to a 17 x 25 cm area on the back of the runner. To estimate total sweat production, the sweat produced on this area of the back was extrapolated to the whole body surface area. Body surface area (BSA) was estimated using the formula BSA = weight (kg)0.425 x height (m)0.725 x 0.007184 following Dubois and Dubois. Heart rate was recorded continuously during the marathon using a portable heart rate monitor (RCX5, Polar Electro Oy) to estimate energy expenditure, using the heart rate method. Tcore in the rectum and Tskin on the forehead, right wrist, and right ankle were measured using an EndoTherm Med device (EndoTherm GmbH, Arlesheim, Switzerland) every 10 seconds while running. The EndoTherm Med thermoelectric probes sensor has a guaranteed accuracy of 0.0625 C. The sensor for measurement of Tcore in the rectum was encased in a silicone capsule and packed into a fingerstall. The sensors used to measure Tskin were fixed using textile ribbons on defined spots. The sensors were evaluated by EndoTherm Control software (www.endotherm.ch) and showed a temperature variation of +-0.1 C (Figure 3). Before the start of the marathon and every 10.5 km, body mass was measured and samples of blood, urine, and sweat were collected. Body mass was measured using a commercial scale (Beurer BF 15, Beurer GmbH, Ulm, Germany) to the nearest 0.1 kg, after voiding the urinary bladder. Venous blood samples were drawn in a sitting position. Two serum tubes (Serum Sep Clot Activator, 5 mL, Greiner/Bio-One, Frickenhausen, Germany) and three ethylenediamine tetra-acetic acid (EDTA) tubes (BD Vacutainer , 3 mL, Becton Dickinson, Heidelberg, Germany) were drawn. One of the EDTA tubes, for the later performed blood count and measurement of lactate dehydrogenase, was stored at room temperature. The two tubes for serum and the remaining two tubes for EDTA plasma were centrifuged immediately at 3000 g for 10 minutes and the plasma was frozen on dry ice. Urine samples were collected after measuring total urinary volume at the defined times into a Vacuette system (10 mL, Greiner/Bio-One) and were also stored on dry ice. Sweat samples were collected from the defined skin area on the back. Foil was fixed using Tegaderm film (3M Medica, Neuss, Germany) to the 17 x 25 cm area on the back leading to a small reservoir at the caudal end. After documenting the quantity in mL, the sweat was transferred in empty sterile tubes (7 mL, Greiner/Bio-One) and also stored on dry ice. After collection, the EDTA blood samples were immediately transferred to the laboratory, and the blood counts were performed within 4 hours of blood sampling. The other serum, plasma, urine, and sweat samples remained stored on dry ice and were transported to the laboratory immediately after the experiment and stored there at -20 C until analysis. Blood counts were performed using the EDTA blood samples, and included a white blood count with differentiation, red blood count, hemoglobin, hematocrit, and platelets. Hematologic parameters were determined using the Cell-Dyn Sapphire (Abbott Diagnostics, Wiesbaden, Germany). Osmolality in serum, urine, and sweat was measured using an Osmomat 030 device (Gonotec, Berlin, Germany). Glucose in serum and lactate in plasma were measured using a Biosen 5140 system (Barleben, Magdeburg, Germany). Sodium, potassium, calcium, chloride, creatinine, urea, creatine kinase in serum and urine, C-reactive protein in serum, lactate dehydrogenase in plasma, and glucose in urine were measured using a DxC 800 system (Beckman Coulter, Krefeld Germany). Myoglobin, cardiac troponin I, free triiodothyronine, free thyroxine, thyroid-stimulating hormone (TSH), prolactin, cortisol in serum, and brain natriuretic peptide (BNP) in plasma were measured using an Advia Centaur XP (Siemens, Eschborn, Germany). Insulin in serum was measured using an AxSYM device (Abbott Diagnostics). Insulin-like growth factor 1 and interleukin-6 in serum were measured using the Immulite 2000 (Siemens). Somatotropic hormone in serum, and adrenocorticotropic hormone (ACTH) and renin in plasma were measured using a Liaison device (diaSorin, Dietzenbach, Germany). Procalcitonin was measured using a Mini-Vidas system (Bio-Merieux, Marcy l'Etoile, France). Aldosterone in plasma was measured using a radioimmunoassay kit (Beckman Coulter). Midregional proatrial natriuretic peptide, midregional proadrenomedullin, c-terminal proendothelin-1, and copeptin in plasma were measured using a Kryptor device (Brahms GmbH, Hennigsdorf, Germany). Sodium, potassium, and calcium in sweat were measured using the AAnalyst 100 (Perkin Elmer, Rodgau, Germany). Albumin in urine was measured using an Immage 800 device (Beckman Coulter). Metanephrines and normetanephrines in urine were measured using high-performance liquid chromatography (Recipe, Munich, Germany). We expressed urine concentration as fractional excretions. This applied to sodium, potassium, urea, and osmolality in urine. We used the general formula: fractional excretion of parameter = [(parameterurine x creatinineserum)/(parameterserumx creatinineurine)] x 100, following Espinel. Transtubular potassium gradient was calculated using the equation transtubular potassium gradient = (potassiumurine x osmolalityserum)/(potassiumserum x osmolalityurine) according to West et al. Glomerular filtration rate (GFR) was estimated using the four-variable MDRD4 formula (GFR [mL/min/1.73 m2] = 32841 x (creatinine [mumol/L][-1.154]) x age [years][-020]) following Levey et al. Creatinine clearance rate was estimated using the Cockcroft-Gault formula.

ambient temperature, endocrine regulation, skin temperature, sweat production, thermoregulation

PMC7490556_01

Male

A 50-year-old male, smoker (50 packs/year), was diagnosed in 2000 with chronic obstructive lung disease (COPD) and was admitted to a local hospital complaining of chest pain, cough with purulent sputum up to 150 ml/day, dyspnea on excretion and fever up to 39 S. He was treated with Amoxillin, Tiotropium bromide and Salmeterol. Due to the failure of conservative treatment, the patient was routed to the thoracic surgical clinic. A chest X-ray and CT scan revealed giant bullae in the upper parts of the lungs (2/3 of the left hemithorax and 1/2 of the right hemithorax). Some bullae in the right lung contained fluid. The lung tissue was emphysematous in the epiphrenic regions, but did not contain bullae (Fig. 1). During further examination, tuberculin tests were negative; acid fast bacilli (AFB) were not detected in the sputum neither microscopically nor by culturing. Spirometric parameters, the partial pressures of blood gases and 6-min walking test were decreased compared to normal (Table 1). Taking into account the spirometry indicators' discrepancy to COPD GOLD criteria, the absence of alfa1 antitrypsin level decreasing, we initially diagnosed bullous lung disease (vanishing lung syndrome) complicated by non-specific suppuration in the right lung with sputum culture revealed Streptococcus viridans at 3 x 107. Due to chronic infection persistence, not amenable to conservative therapy, and progressive respiratory failure, then a surgical intervention was the only option for this patient. At the first stage, the patient underwent a thoracoscopic lobectomy of the right upper lobe en-bloc with segment 6. At the second stage, the patient underwent a trisegmentectomy of the left upper lobe six weeks later. (Fig. 2). bullae of lung tissue with multiple cysts in the area of chronic inflammation with the presence of vascular malformation zones of organizing hemorrhagic infarcts next to lung cysts and vascular malformations, foci of non-specific inflammation fibrotic tuberculosis granuloma in the area of fibrocystic modified lung cystic change of the bronchi. Histological examination (Fig. 3) revealed: The histological report established the diagnosis: bullous disease type I (vanishing lung syndrome) complicated by suppuration (Streptococcus viridans). Polycystic lung with vascular malformation of the lung parenchyma. Small focal pulmonary tuberculosis. Antibiotic therapy was carried out for 3 weeks in accordance with bacterial sensitivity data. On discharge, 3 months post-surgery, the patient's condition was satisfactory with the signs of respiratory failure having significantly decreased. At a follow-up examination, 10 years later, the patient's status condition was good. He has continued to smoke. A chest X-ray did not demonstrate new bullae (Fig. 4). Spirometric parameters were satisfactory (Table 1). Positive dynamics of functional parameters and gas exchange was noted in comparison with previous data (Table 1).

bullae lung disease, cysts, lung vessels malformation, vanishing lung syndrome

PMC6877748_01

Female

The girl was the firstborn child of healthy nonconsanguineous Chinese parents from Anhui Province. She was cesarean born with a length of 47 cm (-2 SD), weight of 3180 g (-1 SD), and a head circumference of 31 cm (<-2 SD). From birth onward, she had feeding problems and febrile seizures, regularly. The electroencephalogram (EEG) was normal or slightly abnormal during the first year of life. She was able to sit unsupported around the age of 10 months and walk independently around the age of 23 months, and non-fluent motoric movements and hypoactivity were noted. She was described as having a broad-based clumsy tread, and exhibited a mild tremor. She started to pronounce syllables around 2 years old and used simple words around the age of 3 years. Nowadays, she could not speak with full sentences and presented with significantly lower IQ (67). At 4 years old, the girl had a slender posture with a length of 90 cm (-1.5 SD) and presented with significantly smaller head size of 38.5 cm (<-2 SD) compared to the same age children. Typical facial dysmorphisms included deep-set eyes, pointed nasal tip, large ears, a downturned mouth, and micrognathia (Figure 1A). A cerebral magnetic resonance imaging (MRI) showed mild widened lateral ventricles, enlarged pericerebral spaces, high palate, a thin corpus callosum, and delayed myelination but without structural congenital anomalies (Figure 1B). Chromosomal abnormalities and submicroscopic chromosomal imbalances at the whole genome level of the girl by CMA did not reveal any anomaly (data not shown). Using WES, a heterozygous nonsense variant (chr21:38865324C > A; c.930C > A; p.Tyr310*) in the coding region of exon 7 of the DYRK1A gene (NM_130436.2) was identified in the proband. Nevertheless, none of the mutation at this site was found in her parents (Figures 2A, B). Sanger sequencing confirmed this conclusion (Figure 2C). The nonsense variant in the amino acid residue tyrosine 310, a perfectly conserved amino acid in DYRK1A and DYRK1A vertebrate orthologues, was a heterozygous truncation mutation and interfered with the protein kinase activity. This variant was absent from the Genome Aggregation Database browsers (gnomAD, ) and the Exome Aggregation Consortium databases (ExAC, ) or dbSNP (), which excluded that it represents a polymorphism. Meanwhile, the loss-of-function intolerance (pLI) for DYRK1A is 1.00, which is based on the ExAC sequencing data, suggesting strong intolerance to functional mutations. Taken together, we hypothesize that the nonsense mutation causes the severe clinical phenotype by ACMG recommendations for standards and guidelines for the interpretation of sequence variants. A heterozygous variant in PKHD1L1 (NM_177531.6: c.9352G>T, Glu3118*); a heterozygous variant in PRODH2 (NM_021232.1: c.457C>T, Arg153*) and a heterozygous variant in SDK2 (NM_001144952.2: c.1865delT, Leu622Argfs*29) was also identified, which were ruled out because the genes were recessive inheritance and only one variant of each gene was identified in the patient. Moreover, the phenotype of the patient was not consistent with the genes ( Supplementary Table S1 ).

dyrk1a, intellectual disability, microcephaly, nonsense mutation, whole-exome sequencing

PMC3331879_01

Male

A 47-year-old local male presented with an 8-year history of severe disabling palmoplantar psoriasis. He was both hypertensive and diabetic (controlled adult onset). He had no previous history of systemic medications and showed low compliance with phototherapy. He was mainly treated with local applications of steroids, tar, salicylic acid and calcipotriol. The patient was started on acitretin 50 mg daily and 50% urea cream with only marginal response after 18 weeks. Due to the severity of the condition, the patient was screened before etanercept was added. All tests were within normal range, including negative TST and CXR. The patient completed 12 weeks with biweekly 50-mg subcutaneous injections, with minor improvement, followed by 12 weeks on once weekly 50 mg etanercept without significant change. Both drugs were discontinued and the patient was screened again before switching to another anti-TNF; this time IGRA was performed and the result was negative. He started adalimumab therapy and showed a good and stable response for 14 weeks until he developed fever, night sweating, chills, loss of appetite and persistent cough. The condition evolved rapidly, necessitating hospitalization. Bronchial lavage and pleural effusion tabbing of the right lung were both positive for TB by polymerase chain reaction. Anti-TB therapy was started and adalimumab was discontinued. Six weeks later, the chest condition showed marked improvement, while palmoplantar psoriasis worsened and the patient's ability to walk was limited. Based on the recommendation of the pulmonologist and the patient's consent, adalimumab was resumed on the condition of strict compliance with anti-TB therapy and close follow-up by the medical staff. The patient was followed up for 26 weeks, with complete clearance of both his chest condition and palmoplantar psoriasis. Follow-up of the patient will continue in order to rule out recurrence of TB.

biologics, psoriasis, reactivation, tuberculosis

PMC3331879_02

Male

A 38-year-old local male presented with a 23-year history of generalized plaque psoriasis. His BMI was 42, with a physician global assessment (PGA) of 4. He suffered from joint pain in both small and large joints, with no radiological findings. He had a positive family history but no history of systemic medications. The patient was screened before administration of infliximab therapy. All tests were within normal range, including IGRA and CXR. Infliximab was initiated with good response and a cessation of joint pain. No side effects were noted in the first year of therapy. During his annual checkup, an IGRA showed a positive conversion though CXR and microbiology for TB were negative; the patient was asymptomatic. LTBI was diagnosed by the pulmonologist and anti-TB treatment was started, with a 1-month cessation of infliximab therapy. The patient was followed up for another year; his condition is stable, with a continued response to infliximab and no side effects. Follow-up of the patient will continue in order to rule out recurrence of TB.

biologics, psoriasis, reactivation, tuberculosis

PMC3331879_03

Male

A 33-year-old local male presented with generalized psoriasis of PGA 3. He is the younger brother of case 2, however, with a less severe condition, lower BMI and no associated comorbidities. He was treated with short, irregular courses of narrow-band UVB due to poor compliance and no history of systemic therapy. The patient was screened before administration of etanercept injection. All tests were within normal limits, including IGRA and CXR. The patient showed good response to therapy; during his annual checkup he also showed a positive conversion of IGRA, while CXR and microbiology were negative for TB. He was referred to a pulmonologist who diagnosed the case similarly as LTBI. Anti-TB therapy was given, with a 1-month cessation of etanercept. The patient was followed up for 8 months, with continued efficacy of resumed etanercept injections and no report of side effects. Follow-up of the patient will continue in order to rule out recurrence of TB (table 1).

biologics, psoriasis, reactivation, tuberculosis

PMC5449726_01

Female

A 63-year-old female presented to her primary care physician with a 6-day history of fever, cough, and dyspnea. Her cough was productive of green sputum that was occasionally streaked with blood. She had mild chest discomfort but no chest pain or pleurisy at that time. Review of systems was otherwise unremarkable. Her medical history was significant for obstructive lung disease (COPD), hypothyroidism (well controlled), hypertension, and a long history of smoking (60 pack years). Two years ago, she had computed tomography (CT) scanning of the chest which showed emphysematous changes but no cavities. Despite having severe COPD, she continued to smoke daily and consume alcohol (80 units weekly). She used home nebulization for her COPD, generally utilizing sterile water, but occasionally tap water. There was no illicit drug use. She did not have any history of recent hospitalization within the preceding 90 days. On examination, the patient was not in any distress and auscultation revealed mild wheezing. She did not want to receive any further testing at that time and was prescribed a 5-day course of levofloxacin 750 mg daily. Two weeks later, the patient presented for follow-up with worsening cough, increasing hemoptysis, and respiratory distress. On examination, she was in moderate respiratory distress with an oxygen saturation by pulse oximetry of 92% on room air, but not febrile or tachycardic, with a blood pressure of 167/97 mmHg. Chest X-ray was done revealing right upper lobe opacification with a large air-fluid level suggestive of cavitating pneumonia (Figure 1). On admission then, leukocyte count was normal at 7.8 x 103/mL with no left shift; procalcitonin (PCT) was 0.12 ng/mL and C-reactive protein (CRP) was elevated at 143.8 mg/L. Testing for renal, thyroid, and hepatic function and cardiac enzymes was within normal. Autoimmune panel was unremarkable. Testing for human immunodeficiency virus (HIV), bacterial and fungal urine, and serum antigens was all negative. CT scanning confirmed extensive opacification nearly completely filling the right upper lobe (Figure 2). Also new were associated cavitary regions within the right upper lobe. The largest area of cavitation measured 5.1 x 4.2 cm. Two sputum cultures were collected separately and Gram stain revealed no squamous epithelial cells, few neutrophils, and Gram-negative rods. Within one day, both samples grew Pseudomonas aeruginosa, which was resistant to levofloxacin and ciprofloxacin. The patient was started on ceftazidime, as the isolate tested susceptible to cefepime, ceftazidime, gentamicin, piperacillin/tazobactam, and tobramycin. Two days into inpatient stay, the patient developed a leukocytosis of 13.1 x 103/mL with left shift. By that time, tuberculosis had been excluded with negative sputum for acid fast bacilli, along with a negative interferon-gamma release assay. Five days into admission, with no improvement, the patient underwent bronchoalveolar lavage and culture again grew P. aeruginosa with negative tuberculosis testing. Quantitative microbiologic analysis of the bronchoalveolar lavage was reported at 20,000 colonies/mL. The pattern of antibacterial susceptibility was exactly the same as that reported on the sputum cultures. One week into admission, the patient developed respiratory failure requiring intubation and was admitted to intensive care. Despite prolonged treatment, the patient died from progressive respiratory and multiorgan failure two weeks from admission.

PMC9479327_01

Female

Silica is one of the most abundant minerals on earth, and exposure to silica dust has been identified as a risk factor for many SARDs, including SS, RA, SLE, and AAV. Individuals working in agriculture, mills, drilling, painting, and textiles have been identified to have a greater risk of developing AAV disease. Multiple case reports have shown that continuous exposure to silica increases the risk of positive ANCA. Several studies have described cases of silica exposure and AAV. A 74-year-old patient with AAV developed fever and malaise after prolonged exposure to silica. Main and Wroe described three cases of silica-exposed patients with AAV, two of whom still required dialysis after treatment. Analysis of the occupational histories of 16 patients with AAV revealed that patients with vasculitis were more likely to be exposed to silica than controls. Previous surveys on post-earthquake disease prevalence, such as the Kobe earthquake in Japan, the Great East Japan earthquake, and the Yunnan earthquake in China, showed that the incidence of AAV was higher than before. The change was attributed to the harmful effects of air pollution on the human body due to increased atmospheric levels of silica from the earthquake. Studies have confirmed the dose-related effects of silica exposure. A meta-analysis showed that silica exposure was positively associated with AAV. A case-control study suggested a 3.4-fold increased risk of ANCA serology positivity in individuals with occupational silica exposure. Only a few studies have proposed a relationship between sustained exposure to silica and AAV. However, research on the relationship between sustained exposure to silica and severity of AAV remains inadequate. The mechanism by which silica causes AAV is unclear. A previous study found that silica does not have a direct toxic effect on genetically susceptible individuals but rather enhances the immune response non-specifically, activates T cells and Treg cells, and leads to autoimmune dysfunction ( Figure 1 ). With continued exposure to crystalline silica, the body produces inflammatory cytokines, including interleukin-1(IL-1) and tumor necrosis factor-beta (TNF-beta), leading to inflammation and eventual fibrosis. Silica can induce apoptosis of neutrophils, macrophages, and monocytes, and damaged cells release many proteolytic enzymes, leading to chronic inflammation and tissue fibrosis. Another study suggested that silica can induce the expression of MPO in the cell membrane of neutrophils and monocytes, causing ANCA-related autoimmune responses. A previous study found that the incidence of AAV varies significantly with latitude, further supporting the influence of geographical region on AAV disease. Epidemiological studies have shown that the risk of GPA is high in the northern hemisphere of the earth, whereas the risk of MPA is high in the southern hemisphere. Quantitative changes showed marked changes, while the incidence of GPA and EGPA increased with increasing latitude and decreasing ambient UV radiation levels. Similarly, related studies have confirmed that the positive rate of PR3-ANCA decreases with increasing latitude and ultraviolet radiation intensity. UV radiation is a sensitive factor that varies with latitude, and related studies have found a close relationship between UV radiation and immune diseases. UV radiation, which changes with latitude, is considered to be the actual cause of AAV. UV radiation is necessary for the skin's synthesis of 1,25(OH)2 D3, which regulates immune system homeostasis. UV irradiation of the skin induces vitamin D synthesis, which in turn inhibits the proliferation of Th1 and Th17 cells and the production of cytokines. These changes cause the immune system to differentiate into Th2 cells, thereby enhancing the activity of CD24+, CD25+, and CD8+ cells. This is consistent with a mechanism mediated by Th1 and/or Th17 cells in the pathogenesis of GPA. This may explain why the association between MPA and UV light is not strong, since granulomas are not present in MPA. However, accurate estimation of the average amount of UV radiation in a region is challenging. The influence of immigration, clothing characteristics, skin color preferences, religious and cultural beliefs, and other factors need to be excluded, as well as the influence of dietary intake of vitamin D, related drugs, and other environmental factors on the final serum vitamin D level in each region. These challenges should be addressed in future studies. Microbial infection is considered to be an important risk factor for the development of AAV. Intranasal staphylococcus aureus (S. aureus) infection is most closely associated with AAV. The early symptoms of patients with GPA are mainly runny nose, nosebleeds, and other symptoms, because the most prominent feature of the disease is the granulomatous inflammation of the respiratory tract. S. aureus infection that colonizes the respiratory tract may trigger GPA disease activity. Previous studies have found that the detection rate of S. aureus in patients with GPA is significantly higher than that in healthy individuals, and patients with GPA with chronic S. aureus infection have a significantly increased risk of recurrence. A randomized controlled trial in the Netherlands showed that patients treated with trimethoprim/sulfamethoxazole (T/S, 960 mg three times a week) had a decreased recurrence rate by 66%. In contrast, prophylactic treatment of chronic S. aureus carriers with T/S did not reduce the risk of relapse. This may be related to factors, such as drug dosage and different bacterial detection methods. Further studies found that the imbalance in the proportion of various bacteria colonized in respiratory tract may contribute to the incidence of AAV. The proportion of S. aureus colonization in nasal samples of patients with GPA increased, but the diversity of the microbiome decreased. Current studies indicate that S. aureus is only related to the pathogenesis of GPA, but no obvious relationship seems to exist between S. aureus and the pathogenesis of MPA and EGPA. The role of S. aureus in the pathogenesis of AAV may be as follows: (1) Superantigens of S. aureus directly stimulate B cells and T cells. Among them is the polyclonal activation of B cells by S. aureus cell wall components. Additionally, S. aureus may directly initiate neutrophils, leading to surface expression of PR3. (2) S. aureus contains a highly homologous complementary form of the protein in humans. cPR-3 (105-201) acts as a protein complementary to the human autoantigen PR3 and elicits an autoimmune response. (3) The CpG motif of S. aureus may trigger B lymphocytes in the peripheral blood of patients in remission, leading to the production of ANCA and relapse of AAV. (4) The polypeptide 6-phosphogluconate dehydrogenase (6PGD) 391-410 encoded by the S. aureus plasmid is homologous to the previously determined immunodominant MPO-T cell epitope, and it is immunogenic in humans. Studies have shown that 6PGD induces MPO-related nephritis. (5) S. aureus-derived extracellular adhesion protein (EAP) and Staphylococcus peroxidase inhibitor (SPIN) can induce the body to produce ANCA. (6) S. aureus is an effective inducer of NETs, DNA extracellular complex, and antibacterial factors secreted by neutrophils. Exposure of ANCA antigens to the immune system can initiate an autoimmune response to AAV. Epstein-Barr virus (EBV) infection is most closely related to various SARDs. Multiple case reports found that patients with AAV may develop anti-MPO antibodies following EBV infection. Treatment with glucocorticoids combined with ganciclovir can significantly relieve clinical symptoms and reduce viral load. Lidar et al. found that anti-EBV capsid antigen antibodies and anti-EBV early antigen antibodies were significantly higher in the sera of patients with AAV than in healthy individuals. Treatment with glucocorticoids in combination with ganciclovir significantly relieved clinical symptoms and reduced viral load. Hepatitis B virus (HBV) and hepatitis C virus (HCV) may be triggers for SARDs. An Egyptian study found 62.7% hepatitis C virus infection in 42 patients with AAV, and C-ANCA levels were significantly correlated with hepatitis C virus antibody levels. Lee et al. found a significantly higher risk of relapse in anti-HBc-positive patients with EGPA. Resolved HBV infection may have an important impact on vasculitis activity at diagnosis and subsequent relapse after remission in patients with EGPA. Recently, ANCA has been identified in patients with coronavirus disease 2019 (COVID-19) infections, but relatively few cases have been reported. Studies have proposed the involvement of the parvovirus B19, human herpesvirus, and hantavirus in the occurrence of AAV. However, these studies are few and have not found a significant correlation between these viruses and the development of AAV. Few studies have been conducted on other microorganisms in AAV. A Japanese study reported that Aspergillus infections, including Candida, Candida, and Fusarium, were found in patients with both allergic bronchopulmonary mycosis (ABPM) and EGPA. Kuwabara et al. found that Mycobacterium tuberculosis infection and anti-tuberculosis drugs may be related to AAV. Fujita et al. found that the positive rate of Chlamydia pneumoniae in patients with MPO-AAV was 33%. A Japanese report described a woman who underwent total thyroidectomy, developed PR3-ANCA 3 months after surgery, and had a chronic infection with Tsukamurella pulmonis. GPA often occurs in gastrointestinal mucosal lesions, and the study detected 25 cases of Helicobacter pylori infection among 36 patients with GPA. Currently, the effect of these microorganisms on AAV is only speculative, and further large-scale studies are needed to verify. Drug-induced small vessel vasculitis is a small group of AAV disorders that still do not have a precise definition. Drugs that may be associated include hydralazine, allopurinol, propylthiouracil, phenothiazine, nitrofurantoin, methimazole, minocycline, phenytoin sodium, penicillamine, lorazepam, levamisole, cocaine, isoniazid, montelukast, erlotinib, and tofacitinib. Among them, the incidence of AAV caused by antithyroid drugs is higher, especially propylthiouracil. The clinical manifestations of propylthiouracil-induced AAV disease are similar to those of primary AAV, whereas the disease severity is less severe and prognosis is better. After cessation of antithyroid drug use, symptoms of patients with AAV gradually resolve and ANCA titers decrease significantly. Treatment strategies for drug-induced AAV differ from those for primary AAV. In patients with mild symptoms, immediate discontinuation of the relevant drug can lead to disease remission. Patients with severe diseases should be treated aggressively. However, immunosuppressive maintenance therapy is often unnecessary. The mechanism of drug-induced AAV disease may be related to NETs. However, further studies are needed to verify the exact mechanism. NETs are associated with inflammation in various ways. NETs can directly induce endothelial damage and activate alternative complement pathways. Additionally, they are a major component of thrombosis. The relationship between NETs and ANCAs seems to be bidirectional, a vicious circle. The efficacy of vaccines is based on the ability of the host immune response to the antigen to elicit a memory T-cell response over a period of time. The influenza vaccine is generally considered safe and effective. However, in recent years, the population after influenza vaccination has developed various autoimmune phenomena, such as Guillain-Barre syndrome, RA, pemphigus vulgaris, psoriasis, giant cell arteritis, and AAV. Several AAV cases associated with influenza vaccination have been reported, but influenza vaccination does not increase the recurrence rate of AAV disease. The exact etiology of AAV induced by influenza vaccination is unclear and may be related to molecular mimicry and autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). Recent studies have found that AAV may occur after receiving the COVID-19 mRNA vaccine, and patients with existing AAV may experience recurrence after receiving the COVID-19 mRNA vaccine. The mechanism of new or recurrent AAV after vaccination is still a mystery and may be similar to the mechanism of AAV caused by influenza vaccine. Additionally, the enhanced immune response and presence of monocytes after vaccination may cause MPO-ANCA and PR3-ANCA. However, this evidence originates from individual case reports, and no specific mechanism has been explored.

aav (anca-associated vasculitis), anca, air pollution, environmental risks, etiology, vasculitis

PMC7785387_01

Male

We present the case of a 76-year-old male with a history of benign prostatic hyperplasia and bladder cancer diagnosed in 2018. Following a transurethral resection of bladder tumor (TURBT) procedure, he received intravesical BCG. In May 2019, he presented with severe back pain and radiculopathy. A lumbar MRI study showed multilevel degeneration, severe canal stenosis, and morphological changes suggestive of infection for which he received L1-L5 laminectomies and foraminotomies. Three weeks later, he presented with recurrent back and hip pain. A repeat MRI study revealed progressive degeneration and a paraspinal mass. A biopsy showed granulomatous inflammation which stained negative for AFP, malignancy, and neoplasm. In addition, normal blood cell counts were not suggestive of infection. Two weeks later, he returned with night sweats, fever, and severe pain in his back and right lower extremity; imaging revealed nonenhancing psoas abscesses. Pathology from the spinal biopsy demonstrated chronic, necrotizing osteomyelitis/discitis. Biopsy of the psoas abscess showed fragments of the skeletal muscle with severe inflammation and necrotizing granuloma. Labs obtained at that time showed WBC: 8.6 K/uL (3.5-11.0 K/uL), hemoglobin: 11.1 g/dL (13.0-17.0 g/dL), platelet count: 231 K/uL (130-450 K/uL), BUN: 24 mg/dL (6-23 mg/dL), creatinine: 1.19 mg/dL (0.70-1.30 mg/dL), bicarbonate: 24 mmol/L (22-29 mmol/L), ESR: 72 mm/hr (<30 mm/hr), and CRP: 3.30 mg/L (1-3 mg/L). Cultures and urinalysis for multiple infectious agents were negative, but given his recent intravesical BCG treatment in August 2019, Mycobacterium infection was highly suspected, and the patient was started on empiric treatment with rifampin, isoniazid, and ethambutol. His back pain, fever, and night sweats improved initially, but after 3-4 weeks, the fever and back pain returned. Repeat labs showed WBC: 7.3 K/uL (3.5-11.0 K/uL), ALT: 81 U/L (8-66 U/L), AST: 75 U/L (13-44 U/L), ALP: 317 U/L (40-129 U/L), bilirubin: 0.4 mg/dL (0.2-1.3 mg/dL), ESR: 79 mm/hr (<30 mm/hr), and CRP: 2 mg/L (1-3 mg/L). He was started on vancomycin and cefepime in addition to the anti-mycobacterials for wider bacterial targeting. At this time, culture from the prior spinal biopsy returned positive for the Mycobacterium tuberculosis complex, and PCR was positive for M. bovis with pansensitivity. Broad-spectrum antibiotics were discontinued, and a steroid taper was started. In the following days, the patient's fever and back pain slowly improved. In December 2019, he underwent spinal stabilization surgery and completed ethambutol therapy. His symptoms have since resolved, and he continues to follow-up with Infectious Disease to complete his isoniazid and rifampin therapy.

PMC3785350_01

Male

A 17 year old Saudi male was diagnosed to have Pre-B ALL in March 2002 at King Fahad National Guard Hospital in Riyadh. He presented with fever, mucosal bleeding, generalized external lymphadenopathy, splenomegaly, thrombocytopenia, normal WBC count and Hb level, blasts on the blood film and a heavy infiltration of the bone marrow with blast cells in addition to complex cytogenetic abnormalities. He received an induction course of chemotherapy composed of cyclophosphomide, daunorubicin, vincristine, L-asparaginase, prednisone and intrathecal methotrexate, following which the first complete remission (CR) of his leukemia was achieved. Thereafter, the patient was given consolidation and maintenance courses of chemotherapy till March 2004. In February 2005, he had relapse of his ALL with almost the same clinical and laboratory abnormalities. However, he achieved a second CR following a salvage course of chemotherapy composed of high dose cytosine arabinoside and idarubicin. After identifying a healthy and an HLA-identical sibling donor, the patient was transferred to King Faisal Specialist Hospital and Research Centre (KFSH&RC) in Riyadh for an allogeneic HSCT. On admission to the HSCT unit on 18/4/05, he was asymptomatic and his physical examination revealed no abnormality. Complete blood count (CBC) showed WBC: 3.72 x 109/L, Hb: 136 g/L and PLT: 256 x 109/L. Blood film showed no blast cells and pre-HSCT bone marrow biopsy showed no evidence of leukemia. The patient received a conditioning protocol composed of cyclophosphamide and TBI. He was given acyclovir, trimethoprim-sulphamethoxa-zole (TMP/SMZ) and fluconazole as infection prophylaxis as well as cyclosporine and methotrexate as graft versus host disease (GVHD) prophylaxis. On 25/4/2005, the patient received his allograft without any complications. In the early post-HSCT period, he developed grade I mucositis treated with IV morphine infusion and two febrile neutropenic episodes treated empirically with tazobactampiperacillin, gentamicin and vancomycin. He engrafted his leucocytes on day +20 and his platelets on day +12 HSCT. On day +28 HSCT, the patient developed acute GVHD of the skin, which was treated with IV 6-methylpednisolone then oral prednisone. After controlling the skin GVHD, he was sent home on cyclosporine, zantac and prophylactic antimicrobials in addition to the tapered doses of prednisone. On day +135 HSCT, the patient was readmitted with an extensive chronic GVHD involving skin, mouth, colon and liver. He presented with fever, abdominal pain and diarrhea for one week and he gave history of taking food from a restaurant. Physical examination revealed an unwell young male with generalized pigmentation, jaundice and lichenoid oral eruptions but no leg edema or external lymphadenopathy. The chest was clear, the cardiovascular and the neurological examinations were normal but examination of the abdomen revealed diffuse tenderness, positive bowel sounds and no hepatosplenomegaly. The CBC showed: WBC: 6.3 x 109/L, Hb: 160 g/L and PLT: 271 x109/L. The renal function tests were normal. The hepatic profile revealed: serum bilirubin: 96 mumol/L, albumin: 35 g/L, ALT: 558 U/L, AST: 209 U/L and alkaline phosphate: 404 U/L. Colonoscopy was done and it showed grade I GVHD of the colon. The patient was kept on bowel rest and he was commenced on: intravenous (IV) fluids, IV methylprednisolone 1mg/kg twice daily, IV zantac 50 mg thrice daily and IV immunoglobulin 0.4 g/kg weekly in addition to prophylactic acyclovir and TMP/SMZ. The stool cultures grew Salmonella species so the patient received IV ceftriaxone 2 grams daily for 10 days. As diarrhea continued, the patient was commenced on: mycophenolate mofetil (MMF) 500 mg twice daily, ursodeoxycholic acid 300 mg orally twice daily, IV omeprazole and octreotide 50 mug IV thrice daily. On day +145 HSCT, he was started on IV ganciclovir: 5 mg/kg twice daily as cytomegalovirus (CMV) antigen test became positive. A repeat colonoscopy showed severe colitis with grade IV colonic GVHD (Fig. 1). Later on, the patient continued to have low grade pyrexia, abdominal pain and diarrhea so he was commenced on total parenteral nutrition and rabbit anti-thymocyte globulin 1.5 mg/kg on alternative days for a total of 3 doses and cyclosporine was replaced by tacrolimus. On day +152 HSCT, the patient was still having positive CMV antigenemia and the previously taken colonic biopsy became positive for CMV (Fig. 1) so IV ganciclovir was replaced by IV foscarnet 60 mg/kg thrice daily. Few days later, the bloody diarrhea and the abdominal pains decreased significantly, then the patient continued to improve clinically. On day +177 HSCT, the patient was having no more diarrhea or abdominal pain, so he was shifted to oral prednisone 1.5 mg/kg/day for 3 days and a maintenance dose of IV foscarnet 100 mg/kg/day. Four days later, the patient was asymptomatic and his physical examination showed hyperpigmentation but no jaundice or abdominal tenderness. The blood counts showed: WBC: 2.02 x 109/L, Hb: 10/g/L and PLT: 73 x 109/L. The renal function tests were all normal. The hepatic profile showed: bilirubin 82 mumol/L, ALT: 100 U/L and AST 31 U/L. The patient was sent home on: foscarnet 500 mg IV once daily for one more week, tacrolimus 5 mg orally twice daily, MMF 1 gram twice daily, prednisone 50 mg/day and ursodeoxycholic acid 150 mg daily. Thereafter, the patient had a regular follow up at the HSCT outpatient clinic and he sustained his clinical and laboratory improvement which allowed gradual tapering of his immunosuppressive therapy.

acute lymphoblatic leukemia, cytomegalovirus, graft versus host disease, hematopoietic stem cell transplant

PMC9367683_01

Female

A 23-year-old woman (gravida 1, para 0) weighing 60 kg was transferred to our hospital due to persistent fever up to 39 C for three days with bilateral edema of the lower limbs at 24 weeks of gestation. She had no history of autoimmune disease, and her family history was unremarkable. Upon examination, the following vitals were obtained: a temperature of 38.1 C (febrile), a resting heart rate of 105 beats/min (tachycardic), and a blood pressure of 97/58 mmHg (hypotensive). She received fluid resuscitation and empiric antibiotics. The dermatological and neurological examinations were unremarkable. A physical examination showed marked hepatosplenomegaly; however, no arthritis was noted. Pertinent laboratory findings indicated pancytopenia including the following: hemoglobin (HGB) of 9.3 g/dl; platelet (PLT) count of 80 x 109/L; and leukocyte (WBC) count of 3.45 x 109/L; slight liver dysfunction and elevated lactate dehydrogenase (LDH) level of 477 U/L (normal range [NR], 91-245); C-reactive protein (CRP) level of 17.26 mg/dl; and decreased albumin (ALB) level of 26 g/L (NR, 35-55). The following findings were also obtained: positive antinuclear antibody (1:1,000), anti-SSA >200 AU/ml (NR, 0-20), antidouble-stranded DNA antibody of 34.5 IU/ml (NR, 0-20), and negative anticardiolipin antibodies; complement C3 level of 0.32 g/L (NR, 0.9-1.8), C4 level of 0.1 g/L (NR, 0.1-0.4); EB virus capsid antigen IgA/IgM/IgG antibody, early antigen IgM, and nuclear antigen IgG negative. Serological investigations showed no evidence of active Epstein-Barr virus (EBV), cytomegalovirus disease (CMV), herpes simplex, leptospira, tuberculosis, hepatitis B, hepatitis C, VDRL, and human immunodeficiency virus (HIV); immunoglobulin IgE markedly elevated to 588 IU/ml (NR, 0-100); and urine occult blood and proteinuria. Other active infections were excluded. Abdominal ultrasound demonstrated a splenic swelling of 5.8 cm thick. Transthoracic echocardiography showed no obvious abnormalities. A diagnostic procedure for active SLE was purchased. The patient fulfilled the 2019 American College of Rheumatology (ACR) classification criteria: 24 points for SLE with a high activity index (SLEDAI of 15). As the patient was listless, we performed relative tests to rule out lupus encephalopathy. Neurological examinations, cerebrospinal fluid tests, magnetic resonance imaging, and electroencephalography were normal. The patient also showed no symptoms of lupus encephalopathy. Treatments including broad-spectrum antibiotics, intravenous immunoglobulin (15 g/day) with maintenance of high-dose prednisolone (40 mg/day), hydroxychloroquine 200 mg twice a day, and aspirin 50 mg once a day were started. However, the condition of the patient did not improve. Three days after admission, she developed butterfly erythema on her face and palm, and intermittent hyperpyrexia. Furthermore, the leukocyte count and hemoglobin decreased progressively; serum levels of alanine aminotransferase and aspartate aminotransferase were elevated to 59 U/L and 127 U/L, respectively; and serum ferritin, 1,859.80 ng/ml (NR, 11.0-306.8), NT-pro BNP, PCT, and D-Dimer were also elevated (Table 1). The 24-hour urine protein was 2.737 g/24 h (NR, 0-0.15). The SLEDAI score was estimated to be 17. The multidisciplinary consultation is recommended to replace prednisone with methylprednisolone pulse therapy (40 mg/day) in addition to 80 mg/day in the next 2 days. Moreover, the antibiotics were upgraded to meropenem. Although optimal management was provided, there was no relief of symptoms. On the sixth hospital day, the patient still suffered from daily fever (Figure 1) with further pancytopenia and elevated D-Dimer. The ALB decreased to 25.5 g/L. The dosage of methylprednisolone was adjusted to 80 mg and 40 mg in the morning and evening, respectively, according to the conditions for three consecutive days. Enoxaparin was administered to prevent thrombosis. She was transfused with red blood cells for anemia and was given albumin intravenously along with other symptomatic support treatments. A bone marrow biopsy revealed hemophagocytic cells (Figure 2). From these findings, a tentative diagnosis of SLE presenting as reactive HLH was made. Therefore, we organized the second multidisciplinary consultation. According to the laboratory findings, immunosuppressive therapy with dexamethasone at 15 mg/day (since methylprednisolone had been given 80 mg in the morning) and 30 mg/day on the first day and next 2 days, respectively, was found to be effective. The response to steroids was not immediately stimulated; hence, etoposide was considered. Since she was classified under US FDA pregnancy category D, the family of the patient refused its accompanied treatment options. Cyclosporine A is classified under class C, and informed consent was obtained to initiate 100 mg twice a day through oral administration. Afterwards, the fever, blood cell count, liver function, and coagulation dysfunction subsided gradually. Owing to the use of multiple drugs during pregnancy and the unpredictable prognosis of the fetus, the patient decided to terminate her pregnancy and gave up rescuing the newborn. A drug induced labor operation was successfully completed under close monitoring. On the day of labor induction, the patient developed high blood pressure, and oral labetalol and nifedipine failed to control it. Therefore, intravenous pumping of Urapidil hydrochloride injection was performed to control hypertension. Enoxaparin was administered to prevent thrombosis at 12 h postpartum. Unfortunately, chest discomfort and suffocation appeared in the first day after abortion. Transthoracic echocardiography showed tricuspid regurgitation (mild-moderate), pulmonary valve regurgitation (mild-moderate), pulmonary hypertension (mild), pericardial effusion (mild), and pleural effusion (mild). A third multidisciplinary consultation was established to develop a better plan. Since pulmonary embolism was considered, the experts suggested that corticosteroids, cyclosporine, hydroxychloroquine, and enoxaparin should be continued on the basis of the original therapeutic schedule. Furthermore, the following laboratory tests improved soluble CD25 by 4,027.91 pg/ml (NR, 458-1,997) and low natural killer (NK) cell activity by 1.00 (NR, 8.1%-25.6%). Genetic tests described the STX11 mutations. It was found to be positive for an exon 2, c.646C >A (p.R216s) heterozygous mutation. The placenta showed no microscopic abnormalities. Fortunately, the condition of the patient did not deteriorate further. The SLEDAI score was decreased to 10, including proteinuria, hematuria, and low complement protein3. Under our close supervision and careful treatment, the patient was discharged 2 weeks after the termination of the pregnancy. She chose to go to the local hospital for re-examination and continued to take prednisone 10 mg/day and cyclosporine 50 mg/day orally for 8 weeks, following the advice of the doctor. She has remained in remission for 7 months until now.

syntaxin 11, cyclosporine a, hemophagocytic lymphohistiocytosis, pregnant, systemic lupus erythematosus

PMC5491814_01

Female

A 74-year-old woman presented in September 2014 with a 2-week history of dry cough followed by progressive dyspnea and a fever. She was diagnosed with bacterial pneumonia 10 days later, for which she had received treatment with levofloxacin (500 mg/day orally) for 2 weeks, and was referred to our hospital with complaints of worsened dyspnea. She was a never-smoker and had not been exposed to known toxins. On an examination, she was alert and did not seem to be overtly sick. Her body temperature was 38.2C. Pulse oximetry showed an oxygen saturation of 94% on ambient air. Fine crackles were heard in the bilateral lung fields without wheezing. Physical examination findings were negative for signs of connective tissue disease such as heliotrope rash or Gottron's sign. Chest X-ray films showed right-sided predominant bilateral progressive pulmonary infiltrates (Fig. 1). High-resolution computed tomography (HRCT) of the chest revealed bilateral and progressive multiple areas of subpleural and peribronchial patchy consolidation with ground glass opacities (Fig. 2). An arterial blood gas analysis on room air revealed marked hypoxemia [partial pressure of oxygen (PaO2) 56.8 mmHg]. Blood and serologic examinations revealed leukocytosis (15.1x104 cells/muL) and mild eosinophilia (510 eosinophils/muL); markedly increased values of C-reactive protein (CRP) (23.34 mg/dL), erythrocyte sedimentation rate (ESR; 115 mm/60 minutes), and ferritin (1,725 ng/mL; normal female range: 3.6-11.4); and mildly-to-moderately increased values of surfactant protein-D (SP-D) (141.9 ng/mL; normal <110) and surfactant protein-A (SP-A) (92.3 ng/mL; normal <43.8). There was no notable increase in the value of Krebs von den Lungen-6 (KL-6) (Table and Fig. 3). On the fourth hospital day when the patient was transferred to the respiratory care unit, we managed to perform bronchoscopy under a clinical suspicion of organizing pneumonia. Bronchoalveolar lavage fluid (BALF) from the right B5a showed a cell count of 1.14x105 cells/mL, and a cellular analysis of the BALF revealed increased neutrophils (23.8%) and lymphocytes (5.2%), with a CD4+/CD8+ ratio of 3.2. No pathogens were cultured. A TBLB obtained two samples from the right upper lobe (rtB2b) and right lower lobe (rtB8b and rtB9b), and the TBLB specimens revealed histologic features of FOP (Fig. 4). One specimen from the right upper lobe showed hyalinisation and fibrosis of the central core of the Masson body, and another sample also from the right upper lobe showed granulation tissues in many terminal air spaces, mainly of the alveolar ducts, with adhesion of the alveolar duct walls due to intervening granulation tissues (obliterative alveolar duct fibrosis) and foamy cells in the alveolar spaces (Fig. 4e-h). The sample from the right lower lobe showed granulation tissues mainly in the alveolar ducts without adhesions of the alveolar duct walls. Another sample from the right lower lobe showed fibrination in the alveolar ducts and infiltration of a few neutrophils in the fibrin. The fibrination did not show organisation. We considered the possibility of an artificial effect from the transbronchial biopsy (not shown). None of the four lung specimens showed any malignant cells, granulomas, or significant infiltration of eosinophils or neutrophils (Fig. 4). Empirical broad-spectrum antibiotics were initially administered. However, during the subsequent four days, the patient's condition continued to deteriorate, with worsening of chest radiograph findings (Fig. 1, 2) and hypoxemia. She developed dyspnea on the seventh hospital day. On the eighth hospital day, mechanical ventilation and intravenous methylprednisolone treatment (1,000 mg per day for three consecutive days) was started (Fig. 3). On the seventh hospital day, a histopathologic diagnosis of FOP was rendered by the lung pathologist of this article (Fig. 4). The patient received 750 mg/day cyclophosphamide (CY) intravenously in addition to corticosteroid therapy. Initially, despite these regimens, her chest radiograph findings and hypoxemia did not stop deteriorating, Therefore, 100 mg (2.0 mg/kg) cyclosporin A (CsA) was added. The chest radiograph findings and hypoxemia gradually improved, and she was successfully extubated on hospital day 22. The peribronchovascular consolidation revealed by chest radiography resolved steadily. She was discharged on hospital day 73 when prednisolone was tapered to 20 mg/day (Fig. 3). Her symptoms and the HRCT findings of the lungs improved during the follow-up 150 days later. She was fine 500 days later and did not develop any symptoms or signs of connective tissue disease (Fig. 3).

bronchoscopy, cryptogenic organizing pneumonia (cop), fibrosing organizing pneumonia (fop), rapidly progressive bronchiolitis obliterans organizing pneumonia

PMC4745912_01

Female

An 18-year-old girl with history of chronic sinusitis and repeated childhood chest infections was referred to our hospital for work up of a nonresolving pneumonia. The patient was first seen and evaluated in Pulmonology Clinic. She had a chronic productive cough but no fever, weight loss, or hemoptysis. Chest X-ray revealed a residual right middle lobe infiltrate with no pleural effusion. Computed tomography (CT) scan of the chest revealed patchy airspace opacities in the right lower lobe associated with bilateral lower lobe bronchiectatic changes. Interestingly, there were multiple structural abnormalities incidentally found in the form of an abdominal situs ambiguous with the liver seen in the midline, a right-sided stomach, and multiple small splenules in the right upper abdomen (Figure 1). Bronchoscopy with bronchoalveolar lavage was positive for Haemophilus influenzae. All other differentials including Mycobacterium tuberculosis, fungal infections, and malignancy were ruled out. During that same period, the patient gave history of two new complaints: joint pain and swelling and amenorrhea. Regarding her joint complaints, the patient gave history typical of RA with symmetrical joint pain and swelling involving her small and large joints with early morning stiffness of more than an hour. On examination her tender joint count (TJC) was 10 and swollen joint count (SJC) was 7. She had a strongly positive Rheumatoid Factor of 350 and an anti-cyclic citrullinated peptide (Anti-CCP) of 133. Her erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were mildly elevated at 21 and 5.27 mg/L, respectively. The rest of her autoimmune panel including ANA and ENA profiles was negative. X-rays of the hands, elbows, shoulders, knees, and feet bilaterally revealed maintained joint spaces and no evidence of erosions. Based on these findings the patient was diagnosed to have RA. Her calculated DAS-28 score was 5.77, her Simple Disease Activity Index (SDAI) 32.5, and her Clinical Disease Activity Index (CDAI) 32, all reflecting high disease activity. She was started on Methotrexate at a dose of 12.5 mg orally once weekly with supplemental folate. She was also kept on Prednisolone 10 mg orally daily with calcium and vitamin D. As for her amenorrhea symptoms, the patient had irregular periods after menarche but became completely amenorrheic around 8 months prior to presentation. She had been married for one and a half years, had no children, and was not using any method of contraception. She was referred to Obstetrics and Gynecology Team for further evaluation and her work-up revealed the presence of a very high prolactin level of 4425 mug/L (normal range: 3-24 mug/L). another hormonal panel was within normal. She had no symptoms of galactorrhea, was not taking any new drugs, and had no history of renal, thyroid, or liver disease. She had no visual symptoms or headache or vomiting. Pelvic ultrasound showed a retroverted uterus with no abnormalities. She was given an appointment to do pituitary magnetic resonance imaging (MRI) in addition to Endocrinology followup. Due to the earlier CT findings of situs ambiguous and history of chronic bronchiectasis, the diagnosis of KS was entertained. CT scan of the paranasal sinuses was therefore requested and it confirmed the presence of pansinusitis with complete opacification of the maxillary, sphenoid, and ethmoid sinuses (Figure 2). Based on the presence of this triad, she was diagnosed with KS and was admitted for full work-up and treatment on the 20th of October 2014. Magnetic resonance imaging (MRI) of the pituitary gland was done and it revealed a 2.2 x 2.1 x 1.2 cm intrasellar pituitary macroadenoma (Figure 3). She was seen and evaluated by Endocrinology Team and started on Cabergoline 0.5 mg once weekly and discharged in a stable condition with outpatient followup. When the patient presented to Rheumatology Clinic the following month, she reported almost 80% improvement of her symptoms with significant reduction in her joint pain and complete resolution of morning stiffness and fatigue. Based on assessment that day, her DAS-28 score was 1.7 and her SDAI and CDAI scores were 4.9 and 3, respectively. Her prolactin level dropped to 293 mug/L. The patient achieved clinical remission and her Methotrexate dose was increased to 15 mg orally once weekly. She was instructed to taper down her steroids until tapering off. During the next visit three months later, she was still in remission with a DAS-28 score of 1.4, SDAI of 2.5, and CDAI of 2. Her Methotrexate dose was maximized to 20 mg once weekly. Repeated MRI of the pituitary gland revealed regression in the size of the macroadenoma to 1.4 x 1.4 cm with a further drop in her prolactin level to 28.9 mug/L. Cabergoline was increased to 1.5 mg orally twice a week on subsequent Endocrinology followup.

PMC6936928_01

Female

A 93-year-old Caucasian woman was referred to the Internal Medicine Consultation due to cervical adenopathies with 3 months duration. With respect to past medical history, 4 years earlier she had been diagnosed with cutaneous sarcomatoid carcinoma of the face and submitted to surgical excision. The patient denied having fever, asthenia, fatigue, weight loss or night sweats; furthermore, there were no respiratory symptoms. She denied having a previous history of tuberculosis (TB) and recent contact with people with known or suspected TB. There was no epidemiological context or contact with animals. On physical examination, an enlarged, mobile and painful right cervical lymph node was evident; the remainder of the examination was unremarkable. Cervico-thoraco-abdominal-pelvic computed tomography (CT) showed a right cervical mass (Fig. 1) with multiple adenopathies and some fibrotic lesions in the upper right lobe; there were no other adenopathies nor evidence of neoplastic disease. Fine needle aspiration (FNA) biopsy of the cervical node was performed and yielded a noncaseous granulomatous process. There was no evidence of Reed-Sternberg cells or neoplastic cells; Ziehl-Neelsen staining was negative, as well as polymerase chain reaction (PCR) assessment for Mycobacterium tuberculosis (MT) and culture. The patient was kept under close surveillance. In the meantime, an IgG lambda monoclonal gammopathy was diagnosed; renal function and calcium metabolism were normal, there was no anaemia or elevated urinary free light chains and beta-2 microglobulin was normal. Peripheral blood immunophenotyping demonstrated a polyclonal B cell population. In addition, serology tests for syphilis, human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus were negative, and QuantiFERON testing was positive. Two months later, the adenopathies had grown and there was cutaneous fistulization with suppurative lymphadenitis (Figs. 2A and 2B). Microbiologic examination of a suppuration swab was positive for Staphylococcus aureus and the patient was treated with cefuroxime, displaying only slight improvement. An excisional biopsy was programmed and histological examination revealed granulomas with caseous necrosis and suppuration. PCR assessment of the samples was negative for MT, Nocardia, Mycobacterium avium complex, Toxoplasma gondii, Aspergillus fumigatus, Bartonella spp., Treponema pallidum and Leishmania infantum. Considering the presence of persistent cervical lymphadenopathy with caseous granulomas, a positive QuantiFERON test, and the exclusion of other potential causes, the hypothesis of cervical tuberculous lymphadenitis was strongly suspected, even without a positive PCR test for MT. The patient started presumptive treatment with isoniazid, rifampicin, pyrazinamide and ethambutol. Afterwards, diagnostic confirmation was obtained by isolation of MT in one of the lymph node cultures. Antimicrobial susceptibility testing did not demonstrate resistances. The patient presented a favourable clinical outcome with gradual reduction in the size of the adenopathies and there were no side effects attributable to the antituberculous drugs.

cervical lymphadenopathy, cervical tuberculous lymphadenitis, differential diagnosis, excisional biopsy, fine needle aspiration biopsy

PMC10333992_01

Female

An 11-year-old girl was admitted in the pediatric infectious department of Imam Hossein Children's Hospital, Isfahan University of Medical Sciences, due to pain and swelling around the left eye (Figure 1). The patient developed redness and photophobia a week before admission, then gradually developed pain in the eye movements, swelling, and redness around the left eye. She had normal vital signs on examination. On physical examination, she had redness and swelling around the left eye. Globe movements were associated with pain and limitation. Visual acuity was 5/10 in the left and 10/10 in the right eye. Cranial nerve examination and other physical examinations were normal. The patient was diagnosed with preseptal cellulitis and treated with clindamycin intravenous infusion. The computed tomography (CT) scan orbit was normal, and no signs of orbital cellulitis were found. After 3 days of treatment, the patient's condition did not improve. Therefore, an ophthalmology consultation was done for the patient In ophthalmology consultation, posterior uveitis (diffuse choroiditis) was reported on the left eye with an ophthalmic examination. In the ultrasonography of the left eye, the thickness of the wall of the globe in the posterior pole was increased (2.4 mm), and the appearance of scleral edema with Classic view of T- sign Was seen, which confirmed episcleritis (Figure 2). Episcleritis and posterior uveitis were reported, and rheumatology consultation was recommended. Finally, the patient was transferred to the pediatric rheumatology department. A full history was taken there. The patient had a history of recurrent oral aphthous ulcers (5-6 times a year), genital ulcers, and chronic and vague abdominal pain. The results of laboratory tests including complete blood count, erythrocyte sedimentation rate, C-reactive protein, and serum electrolytes were normal. Serology tests for cytomegalovirus, toxoplasmosis, parvovirus B19, tuberculosis, and rheumatologic tests including angiotensin-converting enzyme, antinuclear antibody, and antiphospholipid antibodies were negative. The patient did not meet the laboratory and clinical criteria for lupus and granulomatosis with polyangiitis (GPA). Both human leukocyte antigen (HLA) B5 and HLA-B51 tests were positive. The result of the pathergy skin test was positive (Figure 3). According to the criteria of the International Study Group for Behcet Disease, the patient was recognized as a case of BD-related episcleritis and posterior uveitis, and the treatment started by prescribing pulse methylprednisolone and intravenous infliximab. Treatment was continued with oral prednisolone 2 mg/kg/d, azathioprine 2 mg/kg/d, and colchicine 1 mg/d. After a 1-month follow-up, the patient had no symptoms and ocular exam through slit lamp and funduscopy was normal. Infusion of infliximab 8 mg/kg was given, and oral prednisolone 1 mg/kg/d with azathioprine and colchicine was continued. Three months after discharge, the patient did not have any complaints about aphthous ulcers and GI system visual acuity of both eyes was 10/10, and ocular exam was normal.

behçet’s disease, case report, episcleritis, uveitis

PMC4239444_02

Female

A 77-year-old Tunisian woman was hospitalized because of massive painful ascites. Her family history did not include any autoimmune disease. She denied a history of hepatitis, jaundice or alcohol use. She had a history of diabetes, hypertension treated by glinide and calcium blocker. She was explored 4 years prior to admission for exudative pleuritis of the right lung without any established diagnosis after multiple explorations including thoracoscopy with biopsies. On admission, blood pressure was 150/70 mmHg, her rate was 80 /mn and body temperature was 37 C. The physical examination showed only abdominal distension related to the important ascites without collateral venous circulation. She had no skin lesions, lymphadenopathy, or hepatosplenomegaly and lower extremities showed no edema. Laboratory investigations showed: leucopenia with white blood cell count = 3100/mm3, lymphopenia = 840/mm3, hemoglobin = 10.5g/dL; low serum albumin level = 29g/L, 47;-globulin = 19g/L. blood glucose levels = 180 mg/dl and hemoglobin A1c = 8.6%. Urine analysis showed trace protein (0.03g/24h). Platelet count, activated partial thromboplastin time, liver function tests, blood urea nitrogen, serum creatinine, erythrocyte sediment rate and total cholesterol were within normal limits. Tests for HBsAg and HCV were negative. Abdominal ultrasonography showed ascitic fluid without any sign of bowel loop thickening or enteritis. Neither lymphadenopathy nor liver abnormality was present. A chest X-ray film disclosed bilateral pleural effusion. Ascitic obtained by aspiration contained 170 cells mm3 (67% lymphocytes), 46g/L protein, but no malignant cells. Cultures for bacteria and mycobacteria gave no growth. Tuberculosis investigation including initial tuberculin skin test and the research of Koch bacilli in sputum and urine were negative. Echocardiogram and electrocardiogram were normal. Computed tomographic scan showed massive ascites, no dysmorphic liver, and a mild bilateral pleural effusion. Pelvic examination was normal. Oesogastroduodenoscopy showed hiatal hernia without oesophageal varices. An exploratory laparoscopy was performed, revealing a large amount of ascite, a normal liver appearance, and no granulations suggesting tuberculosis or peritoneal carcinosis. Histological examination of the peritoneum showed non specific chronic inflammation. Systemic lupus erythematosus was suspected based on pleuritis, lymphopenia and leucopenia. An additional serologic survey revealed markedly elevated anti-nuclear antibody (ANA) titer of 1/1600 and a significantly elevated titer of antibody to double-stranded DNA (83 IU/mL; normal < 30 IU/mL). She had also positive serum antibody against the Smith antigen and low serum level of C3 complement component: 67 mg/dL (serum normal range: 84 - 151). Relying on these findings, the patient was diagnosed with SLE since 4 of the 11 diagnostic criteria of the American College of Rheumatology were met. The SLEDAI score according to Systemic Lupus Erythematosus Disease Activity Index was estimated to be 7 on admission. Hydroxychloroquine 200 mg daily in combination with diuretics was initiated. One month later, there was no detectable ascitic fluid and no pleural effusions. Five months later she remained free from symptoms while continuing to take Hydroxychloroquine

ascites, hydroxychloroquine, old-onset, systemic lupus erythematosus

PMC10219828_01

Female

Patient information: a 9-month-old female presented with a history of poor weight gain from birth, cough, and fever of 2 weeks, fast breathing of 1 week, and refusal to suck for one day. Weight loss was progressive despite adequate feeding. Cough was distressful, non-paroxysmal with no history of contact with an adult having a chronic cough. The fever was high-grade and continuous. Fast breathing was of insidious onset and had been progressive. She was unable to suckle from the breast for 24 hours prior to presentation despite her mothers concerted effort to breastfeed her. A review of systems revealed she had orthopnea, easy fatigability, excessive sweating, no cyanosis, no body swelling, and no seizures. She was referred to another hospital where she was admitted and had a blood transfusion without remarkable improvement. Prior to this, she had no previous hospital admission. Pregnancy, birth, and neonatal period were normal. Although her mother did not remember the birth weight. She was exclusively breastfed and commenced satisfactory complementary feeds. She was also adequately immunized and her development was within normal limits. She is the third of 3 children. Both parents were in their early thirties and from a low socio-economic class. Clinical findings: at presentation, she had dysmorphic features with upward slanting of the palpebral fissures, low-set ears, and flattened nasal bridge. She was also severely pale, in severe respiratory distress with subcoastal and intercoastal recessions, flaring alae nasi and she was saturating at 85% in room air. Her weight was 6kg (44% of expected and > -3 Z-score), height was 72cm (0.8 Z-score). She was tachypneic with a respiratory rate of 60 cycles per minute and had widespread crepitation. She also had an active precordium, apex beat was displaced to the fifth left intercostal space lateral to the mid-clavicular line, she had tachycardia with a heart rate of 160bpm and a grade 3/6 continuous systolic murmur, maximal at the left lower sternal border and radiating to the armpit. Abdominal examination showed a reducible umbilical hernia and tender hepatomegaly with liver 4cm below the right subcoastal margin. An initial working diagnosis was severe bronchopneumonia in heart failure in a child with acyanotic congenital heart disease and chromosomal abnormality probably Downs syndrome, failure to thrive with severe malnutrition. Diagnostic assessment: full blood count showed absolute leukocytosis with a white blood cell count of 22.7 x 109/L, and anemia with a packed cell volume of 28%, electrolytes urea, and creatinine showed hypokalemia of 2.4mmol/L, hypocalcemia with non-ionic calcium of 1.09mmol/L. The retroviral screening was seronegative. Chest X-ray (Figure 1), done showed: significant perihilar mottled and fluffy opacities involving all lung zones bilaterally, cardiomegaly with a cardiothoracic ratio of 61%, splaying of the carina suggestive of cardiogenic pulmonary edema. Electrocardiograph showed: sinus tachycardia, with a heart rate of 168bpm, right (rt) atrial enlargement, rt ventricle hypertrophy, and rt axis deviation. Echocardiography showed: 0.4cm PDA with continuous left to rt shunt at 74mmHg. The malaria parasite was positive. Therapeutic interventions: she was, commenced on parenteral antibiotics, diuretics, intranasal oxygen, nutritional rehabilitation, vitamin D supplementation, antimalarial medications, and hematinic. She was stabilized, discharged, and referred for PDA ligation which she had after 6 months. The operation was successful as there was good PDA ligation with no residual flow on the echocardiogram (Figure 2 A,B). Follow-up and outcome of interventions: a month post-surgery she started coughing and though she had started gaining weight which was now 94% of expected, she had localized rhonchi in the left upper lung zone posteriorly, she was managed for early pneumonia with a possible localized lung obstruction as a post-PDA ligation complication. A chest X-ray was ordered which was not done although she was placed on antibiotics, and chest physiotherapy. She was managed for uncomplicated pneumonia two more times on an outpatient basis. The cough however progressively worsened over 3 months and she also developed a fever and started losing the previously gained weight. On subsequent examination, she was tachypneic, and had coarse crepitations, bilaterally. She also had tachycardia with a gallop rhythm and tender hepatomegaly. She was admitted for severe bronchopneumonia in heart failure to rule out PTB. Chest X-ray (Figure 3) showed bilateral perihilar mottled opacity. GeneXpert test showed mycobacteria tuberculosis was not detected. A diagnosis of PTB was made and she was commenced on anti-tuberculosis drugs with a good response. She has had no recurrence of pneumonia and started gaining weight adequately six months into the treatment. Patient perspective: the mother was very satisfied and happy that her child has finally recovered. Informed consent: a written informed consent was given by the mother to have her child s case published.

patent ductus arteriosus, case report, children, comorbidity, tuberculosis

PMC7160728_01

Female

A 50-year-old woman was admitted to our outpatient clinic for medical workup of a severe form of postprandial hypoglycaemia. Seven years earlier, a Roux-Y gastric bypass was performed due to morbid obesity (preoperative BMI 44.7 kg/m2and weight 129 kg). Within two years, the patient lost 57 kg (BMI 25.5 kg/m2). A year later, the patient noticed, for the first time, hypoglycaemic episodes 1-2 hours after meal intake, which were mainly characterized by loss of concentration, severe fatigue, and auditory and visual impairment that quickly resolved after intake of carbohydrates. An oral glucose tolerance test, at that time, confirmed the presence of symptomatic postprandial hypoglycaemia (2.9 mmol/l). Symptoms persisted despite dietary modifications of up to twelve small meals, each containing a maximum of 20 g of carbohydrates. Off-label treatment with acarbose, saxagliptin, and metformin by her treating physician reduced the frequency and severity of hypoglycaemic episodes but did not significantly improve the situation. Eventually, the patient was referred to our hospital. Her remaining personal history included a mild form of orthostatic dysregulation, migraine, and a multilocular nodular hepatic hyperplasia that required a left-sided hemihepatectomy 17 years ago. The clinical examination was unremarkable apart from irritation-free scars after hemihepatectomy (height, 168 cm; weight, 72 kg; BMI, 25.5 kg/m2; blood pressure, 127/67 mmHg; regular heartbeat, 80 bpm). Laboratory analysis including blood smear; biochemistry comprising electrolytes and kidney and liver parameters; glycated haemoglobin; blood lipids; iron; vitamins B1, B6, B12, and D; and zinc were within reference ranges. A continuous glucose flash monitoring system confirmed a typical pattern of postbariatric hypoglycaemia without any signs of fasting or nocturnal hypoglycaemia. A mixed-meal test (300 ml Ensure plus ) containing 60 g of carbohydrates after a 10-hour fasting period confirmed symptomatic postprandial hypoglycaemia (sweating, drowsiness, odd behaviour, and incoordination) at a glucose level of 2.5 mmol/l, and intravenous glucose administration was required for immediate remission of symptoms (Figure 1(a)). Due to the severe symptomatic presentation of the patient, a 68Ga-DOTA-Exendin-4 PET/CT was performed to exclude an atypical presentation of an insulinoma or focal nesidioblastosis, which might be a surgical target. Therein, the pancreas showed a homogeneous signal distribution (SUV 5.7-8.3), but intensive uptake in the first and second part of the duodenum (SUVmax of 10.0) was observed (Figure 1(b)). To further differentiate this unexpectedly strong tracer accumulation, a double-balloon enteroscopy was performed, which revealed macroscopically unremarkable intraluminal structures in the duodenum. Histologically, there were no signs of malignancy or inflammation (Figure 1(c)). Representative biopsies of the pars 2 duodenii showed normal mucosa with hyperplastic Brunner's glands, which were strongly positive for the GLP-1 receptor on immunohistochemistry but negative for insulin (Figures 1(d) and 1(e)).

PMC5430503_01

Male

A 42-year-old male presented to the medical emergency department with complaints of weakness and significant weight loss over 1 year. He had episodes of low-grade fever in the past year, for which the patient was treated for pulmonary tuberculosis 2 years back. At present, he was again put on antitubercular therapy (ATT) for the past 1 month; however, no improvement was noted and hence the patient was referred to our hospital. There was no significant family history. On general physical examination, the patient was found to be thin built, pale, and afebrile with abdominal distension. Left submandibular and left axillary lymph nodes were enlarged and measured 1.5 cm in diameter. Mild hepatosplenomegaly was noted, however no fluid thrill could be discerned. Ultrasound abdomen revealed enlarged multiple conglomerate of mesenteric lymph nodes with the largest node measuring 22 mm x 18 mm. Clinical chemistry revealed A:G reversal with total protein of 9.5 g%, albumin of 2.0 g%, globulin of 7.5 g%, and A:G ratio of 1:3.75. Other parameters of liver function test and kidney function test were found to be within normal limits. Complete hemogram revealed pancytopenia with hemoglobin: 6 g%, total leukocyte count: 1800/muL, differential leukocyte count: polymorphs 47%, lymphocytes 51%, eosinophils 1%, monocytes 1%, platelets: 48,000/muL, and erythrocyte sedimentation rate (ESR) of 50 mm/h. Peripheral smear revealed the presence of rouleaux; however, no hemoparasite was noted. Fine needle aspiration cytology was performed on the left submandibular and axillary lymph nodes, which yielded thick aspirate. Smears prepared showed few epithelioid cell granulomas interspersed with discrete and aggregates of histiocytes in a background of reactive lymphoid cells and many plasma cells. Numerous intracellular as well as extracellular amastigote forms of Leishmania species were seen [Figure 1]. In view of strong clinical suspicion, Ziehl-Neelsen staining for acid-fast bacilli (AFB) was also done which came out to be negative. Both polymerase chain reaction for Mycobacterium tuberculosis and AFB culture yielded negative result. Later on, rK39 antigen was also found to be positive. Bone marrow examination (both aspirate and biopsy) revealed a prominence of plasma cells and histiocytes along with infiltration by numerous intracellular as well as extracellular amastigote forms of Leishmania spp. Average parasite density (APD) of 5+, i.e., 10-100 Leishman-Donovan (LD) bodies/field, was noted in the bone marrow aspirate (BMA) [Figure 2]. In view of high APD, the patient's human immunodeficiency virus (HIV) status was evaluated which showed positive serology. Immune status evaluation revealed a low CD4 count; 28/muL (reference range: 400-1600/muL). The patient was started on intravenous amphotericin B along with highly active antiretroviral therapy. Improvement was noted after 14 days of treatment (CD4 count: 36/muL). Subsequent bone marrow evaluations revealed a significant fall in APD and clinical improvement in patient's health; weight gain, improved appetite, and rise in CD4 counts.

co-infection, human immunodeficiency virus, lymph node, visceral leishmaniasis

PMC4247291_01

Female

A previously healthy 19-year-old female of Asian ethnic origin, visited our hospital for an evaluation of abnormal chest CT findings on routine physical examination. On admission the patient was asymptomatic, without fever, cough, lymphadenopathy, night sweats or weight loss. As shown in Table I, the patient had normal complete blood count. Additional tests revealed minimally elevated erythrocyte sedimentation rate. The antinuclear antibody test was negative. The levels of lactate dehydrogenase, beta2 microglobulin and liver function tests were normal. The tests for tuberculosis, human immunodeficiency virus and other viruses, including hepatitis A, B and C, were all negative. The spleen and liver were of normal size and echogenicity. Spiral lung CT revealed bilateral multiple pulmonary consolidations, with the largest lesion sized ~4.5x4.5 cm (Fig. 1). Bone marrow aspiration was negative for lymphoma involvement. The patient underwent CT image-guided biopsy and the diagnosis of pMALToma was confirmed. The microscopic examination revealed lymphoepithelial lesions characterized by diffuse infiltration of the lung parenchyma by small lymphocytes, monocytoid cells and plasma cells (Fig. 2). Immunohistochemical staining demonstrated that the cells were positive for CD20 and B-cell lymphoma 2 protein, with 10% nuclear staining for Ki-67. According to the pathological findings, the patient was treated with 6 courses of chemotherapy with 2 mg vincristine, 4 mg/day chlorambucil plus 30 mg/day prednisolone for 7 days. After 2 cycles of chemotherapy, all the pulmonary lesions were significantly reduced in size (Fig. 3). Complete remission of the lung consolidations was observed following 6 cycles of treatment, as visualized by CT scan (Fig. 4). Fifteen months after the last course of chemotherapy, the patient was in good condition without any evidence of relapse. The patient remains in follow-up.

lymphoma, mucosa-associated lymphoid tissue, pulmonary

PMC7431457_01

Female

A 27-year-old woman was admitted to our hospital (Nov 2, 2018), complaining of two weeks of cough, intermittent low fever and dyspnea during daily activity. Four months prior to the admission, she underwent a renal transplantation because of kidney failure caused by chronic glomerulonephritis. Following successful transplantation, she took immunosuppressive medication, including tacrolimus (2.5 mg twice a day), mycophenolate mofetil (750 mg twice a day) and methylprednisolone (12 mg daily) for four months. During this period, she did not receive influenza immunization or prophylaxis for opportunistic infections including Pneumocystis and cytomegalovirus (CMV) infections as per the Diagnosis and Treatment Guideline of Invasive Fungal Infections in Solid Organ Transplant Recipients in China (2016 edition). Two weeks prior to admission to our hospital, she presented to a local community hospital with complaints of fever, cough and dyspnea during daily activity. Chest X-ray showed bilateral patchy, cloudy opacities in the lower lungs with some adjacent pleural thickening and adhesion (Figure 1A). After empiric treatment with oral moxifloxacin for 7 days, there was no apparent improvement, with fever remaining high (38 C) and dyspnea aggravated. Upon admission to our hospital, physical examination found a normal body temperature of 36.7 C, blood pressure of 143/93 mm Hg, pulse of 116 beats per minute, and respiration rate of 24 per minute. Moist rales appeared bilaterally, with no lower-extremity edema. Due to hypoxemia (PO2: 63 mmHg, PCO2: 29 mmHg, SO2: 90%), she was given oxygen therapy with mask hydrogen inhalation shortly after admission. High-resolution computed tomography (HRCT) demonstrated diffused stripes and reticular and ground-glass opacity with honeycomb structures, primarily in the lower lungs (Figure 1B and C). Other laboratory tests revealed abnormal values for almost all parameters tested elevated levels of several biomarkers for inflammatory responses and decreased counts of lymphocyte and CD4 cells, as detailed in Table 1. Electrocardiogram was normal while echocardiogram showed left ventricular hypertrophy with decreased diastolic dysfunction. Serological assays showed positive results for IgM antibodies to Parainfluenza virus, but negative results for antibodies to respiratory syncytial virus, influenza virus (types A and B), cytomegalovirus (CMV), Adenovirus, Legionella pneumophila, Mycoplasma pneumonia, Chlamydia pneumoniae, Q-rickettsia, and Cryptococcus neoformans. Serum galactomannan and BDG levels were both normal (Table 1). Diff-Quick staining of sputum smear did not find Pneumocystis organisms. Blood culture was negative. Mycobacterium tuberculosis was negative based on blood test with T-SPOT.TB (Oxford Immunotec Ltd. UK) as well as acid-fast staining of sputum smear. Considering the patient was at the high-risk stage to develop opportunistic infections, she was firstly given intravenous antibacterial (meropenem 1g thrice a day) and antiviral (ganciclovir 125g twice a day) treatment on the first day of hospitalization. After 3 days of treatment, she still had fever (38 C) and dyspnea. The antimicrobial treatment was changed to intravenous caspofungin (50mg daily), oral trimethoprim-sulfamethoxazole (TMP-SMX, 320/1600mg quadruple a day), and intravenous methylprednisolone (40mg daily), which resulted in improvement of general conditions and abatement of fever and dyspnea in 3 days. However, chest HRCT showed worsening of the opacity in the lower lungs. On the 13th day of hospitalization, she underwent endobronchial ultrasound transbronchial lung biopsy combined with bronchoalveolar lavage fluid (BALF) collection under laryngeal mask airway instead of a regular bronchoscopy examination due to respiratory failure. Subsequent microbiological tests of BALF were negative for M. tuberculosis and P. jirovecii by the GeneXpert MTB/RIF assay (Cepheid, Sunnyvale, CA, US) and Diff-Quick staining, respectively. In addition, BALF culture revealed no growth of bacteria or fungi; galactomannan level was in the normal range (OD index <0.5). The consistently negative results in all etiological tests prompted us to submit 3 mL of BALF for mNGS by the Beijing Genomics Institute (Wuhan, Hubei Province, China) using the MGISeq 2000 platform (MGI Tec, Shenzhen, China). The results of mNGS were received <72h after shipping out the BALF sample. Based on the mNGS report (Table S2), there were 10 bacterial species (5 to 1406 reads per species), 1 fungal species (1,665,693 reads) and 1 viral species (12 reads). None of these species are well-established pathogenic organisms causing respiratory infections in humans except for the fungus P. jirovecii, which is the most dominant species, accounting for 99% of all microbial reads (6.8% of the total filtered reads including human DNA reads). The reads for P. jirovecii allowed assembly of the complete mitogenome of P. jirovecii (35,285 bp, GenBank accession number MT319762), which is 98-99% identical to 13 known P. jirovecii mitogenomes. In addition, these reads allowed assembly of the partial nuclear genome of P. jirovecii, which is ~90% complete compared to the P. jirovecii RU7 reference genome and which is included in a separate manuscript to be published elsewhere. Examination of the mitochondrial and nuclear genome assemblies showed no known nonsynonymous mutations in the dihydropteroate synthase (dhps), dihydrofolate reductase (dhfr) and cytochrome b (cob) genes. One week after transbronchial lung biopsy (5 days after receiving mNGS report), pathological examination of lung biopsy with hematoxylin-eosin (HE) stain (Figure S1a) reported that alveolar spaces were filled with abundant foamy or granular eosinophilic exudate as well as a few lymphocytes infiltrate; the alveolar septa became thickened due to edema and dilated capillaries. Gomori methenamine-sliver staining of the lung biopsy displayed a plenty of dark brown oval or cup-shaped organisms in alveolar spaces, consistent with the morphology of P. jirovecii (Figure S1b). After completion of the treatment regimen with caspofungin for 14 days and TMP-SMX for 16 days, her symptoms disappeared, general conditions returned to normal and laboratory findings improved (Table 1). The patient was discharged after 16 days of hospitalization. She continued to take oral TMP-SMX for another two weeks. At her 2-week follow-up visit, she had no symptoms and chest HRCT scan exhibited no abnormal finding except for a faint patchy opacity in the lateral segment (Figure 1D and E). At her 9-month follow up, she appeared healthy with no symptoms and chest HRCT was normal.

pneumocystis jirovecii pneumonia, diagnosis, metagenomic next-generation sequencing, renal transplant

PMC5892343_01

Male

An otherwise healthy 14-year-old boy was admitted to the emergency unit of the Department of Ophthalmology, Aghia Sophia Children's Hospital, Athens, Greece, complaining of swelling of his right eye. A few hours earlier, he had sustained a blunt trauma to his right orbit as the result of an elbow strike during a basketball game. Physical examination revealed periorbital eyelid swelling with moderate subconjunctival emphysema. No crepitation was present upon palpation. A moderate limitation of upgaze without diplopia was noted (Fig. 1). Visual acuity was 10/10 on the Snellen chart. His pupils were equal in size and normally responsive to light. No paraesthesia of the cheek or teeth was noted. Anterior segment examination and dilated fundoscopy were unremarkable. CT with 2.5 mm slice thickness showed a minimally displaced fracture of the ethmoid bone without haemorrhage, enophthalmos, and a gross accumulation of air in the right eyelid followed by pressure exertion over the right globe (Fig. 2, 3). The patient was advised not to blow his nose forcefully. He was treated prophylactically with oral antibiotics and steroids with progressive tapering. The boy was followed up once weekly for a period of 1 month and then every month until 3 months after the accident without any clinical signs or complications (Fig. 1). CT at 1 month showed completely resolved enophthalmos and periorbital emphysema (Fig. 4).

enophthalmos, isolated medial orbital wall fracture, periorbital emphysema

PMC9289754_01

Female

A 29-year-old Algerian woman with a history of schizophrenia was referred to our Mental Health Center (MHC) by her primary care physician because of severe behavioral alterations and positive psychotic symptoms consisting of delusions and verbal hallucinations. She was diagnosed with schizophrenia at age 19 in her home country due to auditory hallucinations, incoherent speech, and bizarre behavior. Haloperidol was prescribed and self-discontinued after several months of poor compliance due to non-specific adverse effects reported by the patient. No further treatments were attempted at that time. Notably, she was never admitted to a psychiatric inpatient unit. Family psychiatric history includes schizophrenia in her father. No personal or family history of substance or alcohol use was reported. Shortly after arriving in Spain, the patient developed referential and persecutory delusions, secluding herself at home and partly destroying the furniture for fear of being watched or controlled. Subsequently, she required forced inpatient psychiatric hospitalization, and pharmacological therapy with risperidone was introduced. Due to the early appearance of EPS (muscle stiffness and distal tremor) associated with risperidone, she was switched to olanzapine up to 30mg daily with persistent symptoms of hallucinations, disorganized speech and behavior, apathy, and anhedonia, although no EPS were reported. Owing to the lack of response to olanzapine after a 14-day trial, clozapine was initiated, and the dose was uptitrated to 400 milligrams daily, achieving adequate control of her psychiatric symptoms, although she complained of drowsiness and sialorrhea. Given the improvement, the patient was discharged to the community to stay with her sister. Approximately eight months after discharge, the patient developed intermittent episodes of mutism, isolated herself in her room, and refused to leave her apartment to attend follow-up appointments with her psychiatrist. Eventually, a year after being discharged, her sister persuaded her to go to the Mental Health Center. Psychopathological exploration revealed she was exhibiting soliloquies, incoherent speech, auditory hallucinations, and mannerisms. Additionally, during the interview, the patient appeared drowsy and slowed down, which she and her sister attributed to clozapine. On collateral information obtained from her sister, she presented bizarre behaviors at home, accompanied by social withdrawal, distrust, hostility, and aggressive outbursts. After a year of treatment with clozapine, only partial remission of psychotic symptoms was accomplished. Additionally, the patient complained that clozapine caused her to be sedated, cognitively blunted, and apathetic. Adequate adherence was confirmed by plasma clozapine levels, ranging 375-415 ng/mL throughout the year of treatment. In light of the recent worsening of the symptoms and limiting side effects, alternative treatment approaches were considered, and treatment with cariprazine was proposed. Switching from clozapine to cariprazine was conducted through a five-week cross-titration process. In the first week, cariprazine was started at a dose of 1.5 mg per day without any dose reduction of clozapine. Subsequently, weekly increases of 1.5 mg of cariprazine were made until reaching a dose of 6 mg daily. Simultaneously, starting on week 2, clozapine was reduced at a weekly rate of 100mg until discontinued. During the five weeks of the titration process, the patient did not exhibit worsening psychotic symptoms and experienced improvement in sedation and cognitive blunting. The only side effect reported was a mild self-limited headache during the first week after introducing cariprazine. She denied any EPS. Four months after having completed the titration process, the patient showed a significant decrease in verbal hallucinations and mannerisms and a reduction in language and thought disorganization. Additionally, her sister described a marked improvement in functionality that could be seen in a greater tendency to relate to her relatives, frequent outdoor activities, and a better ability to collaborate with household chores. The patient also reported feeling less apathetic, and more motivated, and that she had recovered some capacity to enjoy daily activities. In the follow-up after one year of the introduction of cariprazine, the patient reported adequate adherence to treatment as she continued to be in remission and displayed a stable functional status, which her sister corroborated.

atypical antipsychotics, cariprazine, clozapine, resistant schizophrenia, schizophrenia

PMC5577081_01

Female

A 58-year-old woman visited her primary physician with a chief complaint of exertional dyspnea that began 2 months before hospitalization. Chest radiography showed a reticulated pattern in both lower lung fields and bilateral hilar lymphadenopathy. The patient was referred to our hospital and admitted for further evaluation. She was a current smoker with 60-pack-year smoking history. The findings on admission were as follows: New York Heart Association (NYHA) Class III, body temperature, 36C; blood pressure, 118/72 mmHg; pulse rate, 78/min; respiratory rate, 28/min; and SpO2, 88% (room air). The laboratory tests on admission (Table 1) showed mild elevations in the patient's lactate dehydrogenase (LDH), surfactant protein-D (SP-D), carcinoembryonic antigen (CEA), and rheumatoid factor (RF) levels. The patient was negative for all connective tissue disease (CTD) markers. An arterial blood gas analysis showed hypoxemia and respiratory alkalemia. Pulmonary function tests showed a mild restrictive disorder (vital capacity, 76.9%), whereas the diffusing capacity of the lung for carbon monoxide (DLCO), as determined by the steady state method, was reduced to 33.5% of the predicted value. An electrocardiogram showed peaked p waves in leads II, aVF, and V1. Echocardiography showed that the left ventricular systolic function was maintained, while the right ventricular systolic pressure (RVSP) and tricuspid regurgitation pressure gradient (TRPG) were mildly elevated at 52.0 mmHg, 42.0 mmHg, respectively and the right ventricle was enlarged. We did not perform a 6-minute walk test. Chest radiography on admission (Fig. 1) showed a reticular pattern in both lower lung fields, bilateral hilar adenopathy, and right atrial enlargement. Chest computed tomography (CT) on admission (Fig. 2) showed bilateral hilar and mediastinal lymphadenopathy, ground glass opacities with lobular septal thickening, predominantly in both lower lung fields, and pulmonary artery enlargement. Bronchoscopy was performed on hospital Day 5. TBLB of the right lower, middle, and upper lobes was performed. The histopathology was nonspecific, showing only alveolar septal fibrosis and small round cell infiltration, leading to a pathological diagnosis of chronic interstitial pneumonitis. The TBLB findings were again reviewed after the diagnosis was made. Although alveolar septal fibrosis and the fibrous obliteration of the small veins and venules were present (Fig. 3), these changes were slight and could not lead to the correct diagnosis. A thoracoscopic lung biopsy was contraindicated because of the high risk of morbidity and mortality. She was discharged from hospital on Day 17 with home oxygen therapy (1.5 L/min at rest and 3 L/min during exertion) to maintain SpO2 level of >90%. We continued the prescription of furosemide (20 mg/day) and enalapril (2.5 mg/day), which had been prescribed by her primary care doctor before admission. However, the patient's symptoms did not improve. At approximately 6 months after her discharge from hospital, her dyspnea worsened due to a cold and she revisited our hospital. Since her SpO2 was 80-85% with 2 L/min of oxygen by cannula, the patient was readmitted to our hospital. Laboratory tests showed an elevated LDH level, severe hypoxemia and the deterioration of her respiratory alkalemia (Table 2). An electrocardiogram showed peaked p waves in leads II, aVF, and V1, a deep S wave in lead I, and a negative T wave in lead III, all of which were consistent with right heart overload. Echocardiography showed a decreased left ventricular systolic function with an ejection fraction (EF) of 50%. Her RVSP and TRPG values were further elevated to 72.0 mmHg and 60.0 mmHg, respectively, and right ventricular enlargement and ventricular septal flattening were observed. In addition to a reticular pattern in both lower lung fields and bilateral hilar lymphadenopathy, chest radiography also showed right atrial enlargement and a right pleural effusion (Fig. 4). Chest CT revealed an increase in bilateral hilar and mediastinal lymphadenopathy, a small amount of right pleural effusion, a severely enlarged pulmonary artery, increased pulmonary vascular markings, and a reticular granular pattern, predominantly in the lower lung fields (Fig. 5). We could not perform pulmonary function tests or a 6-minute walk test. Based on the marked hypoxemia, the imaging findings of a reticular pattern with lobular septal thickening, and the TBLB findings during her previous hospitalization, an acute exacerbation of interstitial pneumonitis was initially considered. Steroid pulse therapy (methylprednisolone [1 g for 3 days]) was started on admission. Her SpO2 was maintained at about 95% with an oxygen cannula (2 L/min), and there was a slight temporary improvement in her exertional dyspnea. However, on hospital Day 14, the patient's dyspnea and oxygenation worsened, and 12 L/min of 50% oxygen by venturi mask was required to achieve an SpO2 of 95%. Thus, a second course of steroid pulse therapy was administered. In addition, her brain natriuretic peptide (BNP) was elevated to 827 pg/mL, pleural effusion developed, and echocardiography showed an increase in TRPG to 62.1 mmHg (Fig. 6a). Diuretics were added to treat the patient's worsening right heart failure. Her respiratory status improved with an SpO2 level of >=90% on 6 L/min of oxygen by cannula. However, the patient developed severe lower leg edema, and echocardiography on hospital Day 42 showed a further increase in TRPG to 72.9 mmHg (Fig. 6b). For the PH with right heart failure, beraprost sodium (120 mug/day) was started on hospital Day 43. On hospital Day 48, however, her respiratory status worsened again and required 8 L/min of oxygen by reservoir mask. Chest radiography showed an increased reticular pattern in both lungs, again suggesting an acute exacerbation of interstitial pneumonitis. A third course of steroid pulse therapy was given, and then prednisolone (30 mg) was initiated as an after-treatment. Nevertheless, the respiratory insufficiency progressed, and the patient died suddenly on hospital Day 59 (Diagram: Fig. 7). Consent was obtained from the patient's family for an autopsy. The left lung weighed 485 g, and the right lung weighed 445 g. A histopathological examination showed hyaline fibrosis of the alveolar septa and fibrous obliteration and concentric intimal thickening of the venules (Fig. 8a and b). Heath-Edwards grade II medial hypertrophy of the pulmonary artery was present, but plexiform lesions were not observed (Fig. 8c). There were also dilated, multi-layered capillaries, hemorrhages in the alveolar spaces and alveolar septum, and areas of hemosiderosis (Fig. 8d). The mediastinal lymph nodes were enlarged to 40 mm x 35 mm x 15 mm, with enlarged lymph sinuses and histiocytic hemophagocytosis (Fig. 8e). A diagnosis of PVOD was made based on the clinical course and autopsy findings. We concluded that her cause of death was respiratory failure by progressive right heart failure.

exertional dyspnea, pulmonary hypertension, pulmonary veno-occlusive disease, sudden death

a: Chest CT on initial admission (lung fields). Ground glass opacities with lobular septal thickening were predominant in both lower lobes.

PMC5577081_01

Female

A 58-year-old woman visited her primary physician with a chief complaint of exertional dyspnea that began 2 months before hospitalization. Chest radiography showed a reticulated pattern in both lower lung fields and bilateral hilar lymphadenopathy. The patient was referred to our hospital and admitted for further evaluation. She was a current smoker with 60-pack-year smoking history. The findings on admission were as follows: New York Heart Association (NYHA) Class III, body temperature, 36C; blood pressure, 118/72 mmHg; pulse rate, 78/min; respiratory rate, 28/min; and SpO2, 88% (room air). The laboratory tests on admission (Table 1) showed mild elevations in the patient's lactate dehydrogenase (LDH), surfactant protein-D (SP-D), carcinoembryonic antigen (CEA), and rheumatoid factor (RF) levels. The patient was negative for all connective tissue disease (CTD) markers. An arterial blood gas analysis showed hypoxemia and respiratory alkalemia. Pulmonary function tests showed a mild restrictive disorder (vital capacity, 76.9%), whereas the diffusing capacity of the lung for carbon monoxide (DLCO), as determined by the steady state method, was reduced to 33.5% of the predicted value. An electrocardiogram showed peaked p waves in leads II, aVF, and V1. Echocardiography showed that the left ventricular systolic function was maintained, while the right ventricular systolic pressure (RVSP) and tricuspid regurgitation pressure gradient (TRPG) were mildly elevated at 52.0 mmHg, 42.0 mmHg, respectively and the right ventricle was enlarged. We did not perform a 6-minute walk test. Chest radiography on admission (Fig. 1) showed a reticular pattern in both lower lung fields, bilateral hilar adenopathy, and right atrial enlargement. Chest computed tomography (CT) on admission (Fig. 2) showed bilateral hilar and mediastinal lymphadenopathy, ground glass opacities with lobular septal thickening, predominantly in both lower lung fields, and pulmonary artery enlargement. Bronchoscopy was performed on hospital Day 5. TBLB of the right lower, middle, and upper lobes was performed. The histopathology was nonspecific, showing only alveolar septal fibrosis and small round cell infiltration, leading to a pathological diagnosis of chronic interstitial pneumonitis. The TBLB findings were again reviewed after the diagnosis was made. Although alveolar septal fibrosis and the fibrous obliteration of the small veins and venules were present (Fig. 3), these changes were slight and could not lead to the correct diagnosis. A thoracoscopic lung biopsy was contraindicated because of the high risk of morbidity and mortality. She was discharged from hospital on Day 17 with home oxygen therapy (1.5 L/min at rest and 3 L/min during exertion) to maintain SpO2 level of >90%. We continued the prescription of furosemide (20 mg/day) and enalapril (2.5 mg/day), which had been prescribed by her primary care doctor before admission. However, the patient's symptoms did not improve. At approximately 6 months after her discharge from hospital, her dyspnea worsened due to a cold and she revisited our hospital. Since her SpO2 was 80-85% with 2 L/min of oxygen by cannula, the patient was readmitted to our hospital. Laboratory tests showed an elevated LDH level, severe hypoxemia and the deterioration of her respiratory alkalemia (Table 2). An electrocardiogram showed peaked p waves in leads II, aVF, and V1, a deep S wave in lead I, and a negative T wave in lead III, all of which were consistent with right heart overload. Echocardiography showed a decreased left ventricular systolic function with an ejection fraction (EF) of 50%. Her RVSP and TRPG values were further elevated to 72.0 mmHg and 60.0 mmHg, respectively, and right ventricular enlargement and ventricular septal flattening were observed. In addition to a reticular pattern in both lower lung fields and bilateral hilar lymphadenopathy, chest radiography also showed right atrial enlargement and a right pleural effusion (Fig. 4). Chest CT revealed an increase in bilateral hilar and mediastinal lymphadenopathy, a small amount of right pleural effusion, a severely enlarged pulmonary artery, increased pulmonary vascular markings, and a reticular granular pattern, predominantly in the lower lung fields (Fig. 5). We could not perform pulmonary function tests or a 6-minute walk test. Based on the marked hypoxemia, the imaging findings of a reticular pattern with lobular septal thickening, and the TBLB findings during her previous hospitalization, an acute exacerbation of interstitial pneumonitis was initially considered. Steroid pulse therapy (methylprednisolone [1 g for 3 days]) was started on admission. Her SpO2 was maintained at about 95% with an oxygen cannula (2 L/min), and there was a slight temporary improvement in her exertional dyspnea. However, on hospital Day 14, the patient's dyspnea and oxygenation worsened, and 12 L/min of 50% oxygen by venturi mask was required to achieve an SpO2 of 95%. Thus, a second course of steroid pulse therapy was administered. In addition, her brain natriuretic peptide (BNP) was elevated to 827 pg/mL, pleural effusion developed, and echocardiography showed an increase in TRPG to 62.1 mmHg (Fig. 6a). Diuretics were added to treat the patient's worsening right heart failure. Her respiratory status improved with an SpO2 level of >=90% on 6 L/min of oxygen by cannula. However, the patient developed severe lower leg edema, and echocardiography on hospital Day 42 showed a further increase in TRPG to 72.9 mmHg (Fig. 6b). For the PH with right heart failure, beraprost sodium (120 mug/day) was started on hospital Day 43. On hospital Day 48, however, her respiratory status worsened again and required 8 L/min of oxygen by reservoir mask. Chest radiography showed an increased reticular pattern in both lungs, again suggesting an acute exacerbation of interstitial pneumonitis. A third course of steroid pulse therapy was given, and then prednisolone (30 mg) was initiated as an after-treatment. Nevertheless, the respiratory insufficiency progressed, and the patient died suddenly on hospital Day 59 (Diagram: Fig. 7). Consent was obtained from the patient's family for an autopsy. The left lung weighed 485 g, and the right lung weighed 445 g. A histopathological examination showed hyaline fibrosis of the alveolar septa and fibrous obliteration and concentric intimal thickening of the venules (Fig. 8a and b). Heath-Edwards grade II medial hypertrophy of the pulmonary artery was present, but plexiform lesions were not observed (Fig. 8c). There were also dilated, multi-layered capillaries, hemorrhages in the alveolar spaces and alveolar septum, and areas of hemosiderosis (Fig. 8d). The mediastinal lymph nodes were enlarged to 40 mm x 35 mm x 15 mm, with enlarged lymph sinuses and histiocytic hemophagocytosis (Fig. 8e). A diagnosis of PVOD was made based on the clinical course and autopsy findings. We concluded that her cause of death was respiratory failure by progressive right heart failure.

exertional dyspnea, pulmonary hypertension, pulmonary veno-occlusive disease, sudden death

c: Chest CT on initial admission (mediastinum). Pulmonary artery enlargement was observed.

PMC5577081_01

Female

A 58-year-old woman visited her primary physician with a chief complaint of exertional dyspnea that began 2 months before hospitalization. Chest radiography showed a reticulated pattern in both lower lung fields and bilateral hilar lymphadenopathy. The patient was referred to our hospital and admitted for further evaluation. She was a current smoker with 60-pack-year smoking history. The findings on admission were as follows: New York Heart Association (NYHA) Class III, body temperature, 36C; blood pressure, 118/72 mmHg; pulse rate, 78/min; respiratory rate, 28/min; and SpO2, 88% (room air). The laboratory tests on admission (Table 1) showed mild elevations in the patient's lactate dehydrogenase (LDH), surfactant protein-D (SP-D), carcinoembryonic antigen (CEA), and rheumatoid factor (RF) levels. The patient was negative for all connective tissue disease (CTD) markers. An arterial blood gas analysis showed hypoxemia and respiratory alkalemia. Pulmonary function tests showed a mild restrictive disorder (vital capacity, 76.9%), whereas the diffusing capacity of the lung for carbon monoxide (DLCO), as determined by the steady state method, was reduced to 33.5% of the predicted value. An electrocardiogram showed peaked p waves in leads II, aVF, and V1. Echocardiography showed that the left ventricular systolic function was maintained, while the right ventricular systolic pressure (RVSP) and tricuspid regurgitation pressure gradient (TRPG) were mildly elevated at 52.0 mmHg, 42.0 mmHg, respectively and the right ventricle was enlarged. We did not perform a 6-minute walk test. Chest radiography on admission (Fig. 1) showed a reticular pattern in both lower lung fields, bilateral hilar adenopathy, and right atrial enlargement. Chest computed tomography (CT) on admission (Fig. 2) showed bilateral hilar and mediastinal lymphadenopathy, ground glass opacities with lobular septal thickening, predominantly in both lower lung fields, and pulmonary artery enlargement. Bronchoscopy was performed on hospital Day 5. TBLB of the right lower, middle, and upper lobes was performed. The histopathology was nonspecific, showing only alveolar septal fibrosis and small round cell infiltration, leading to a pathological diagnosis of chronic interstitial pneumonitis. The TBLB findings were again reviewed after the diagnosis was made. Although alveolar septal fibrosis and the fibrous obliteration of the small veins and venules were present (Fig. 3), these changes were slight and could not lead to the correct diagnosis. A thoracoscopic lung biopsy was contraindicated because of the high risk of morbidity and mortality. She was discharged from hospital on Day 17 with home oxygen therapy (1.5 L/min at rest and 3 L/min during exertion) to maintain SpO2 level of >90%. We continued the prescription of furosemide (20 mg/day) and enalapril (2.5 mg/day), which had been prescribed by her primary care doctor before admission. However, the patient's symptoms did not improve. At approximately 6 months after her discharge from hospital, her dyspnea worsened due to a cold and she revisited our hospital. Since her SpO2 was 80-85% with 2 L/min of oxygen by cannula, the patient was readmitted to our hospital. Laboratory tests showed an elevated LDH level, severe hypoxemia and the deterioration of her respiratory alkalemia (Table 2). An electrocardiogram showed peaked p waves in leads II, aVF, and V1, a deep S wave in lead I, and a negative T wave in lead III, all of which were consistent with right heart overload. Echocardiography showed a decreased left ventricular systolic function with an ejection fraction (EF) of 50%. Her RVSP and TRPG values were further elevated to 72.0 mmHg and 60.0 mmHg, respectively, and right ventricular enlargement and ventricular septal flattening were observed. In addition to a reticular pattern in both lower lung fields and bilateral hilar lymphadenopathy, chest radiography also showed right atrial enlargement and a right pleural effusion (Fig. 4). Chest CT revealed an increase in bilateral hilar and mediastinal lymphadenopathy, a small amount of right pleural effusion, a severely enlarged pulmonary artery, increased pulmonary vascular markings, and a reticular granular pattern, predominantly in the lower lung fields (Fig. 5). We could not perform pulmonary function tests or a 6-minute walk test. Based on the marked hypoxemia, the imaging findings of a reticular pattern with lobular septal thickening, and the TBLB findings during her previous hospitalization, an acute exacerbation of interstitial pneumonitis was initially considered. Steroid pulse therapy (methylprednisolone [1 g for 3 days]) was started on admission. Her SpO2 was maintained at about 95% with an oxygen cannula (2 L/min), and there was a slight temporary improvement in her exertional dyspnea. However, on hospital Day 14, the patient's dyspnea and oxygenation worsened, and 12 L/min of 50% oxygen by venturi mask was required to achieve an SpO2 of 95%. Thus, a second course of steroid pulse therapy was administered. In addition, her brain natriuretic peptide (BNP) was elevated to 827 pg/mL, pleural effusion developed, and echocardiography showed an increase in TRPG to 62.1 mmHg (Fig. 6a). Diuretics were added to treat the patient's worsening right heart failure. Her respiratory status improved with an SpO2 level of >=90% on 6 L/min of oxygen by cannula. However, the patient developed severe lower leg edema, and echocardiography on hospital Day 42 showed a further increase in TRPG to 72.9 mmHg (Fig. 6b). For the PH with right heart failure, beraprost sodium (120 mug/day) was started on hospital Day 43. On hospital Day 48, however, her respiratory status worsened again and required 8 L/min of oxygen by reservoir mask. Chest radiography showed an increased reticular pattern in both lungs, again suggesting an acute exacerbation of interstitial pneumonitis. A third course of steroid pulse therapy was given, and then prednisolone (30 mg) was initiated as an after-treatment. Nevertheless, the respiratory insufficiency progressed, and the patient died suddenly on hospital Day 59 (Diagram: Fig. 7). Consent was obtained from the patient's family for an autopsy. The left lung weighed 485 g, and the right lung weighed 445 g. A histopathological examination showed hyaline fibrosis of the alveolar septa and fibrous obliteration and concentric intimal thickening of the venules (Fig. 8a and b). Heath-Edwards grade II medial hypertrophy of the pulmonary artery was present, but plexiform lesions were not observed (Fig. 8c). There were also dilated, multi-layered capillaries, hemorrhages in the alveolar spaces and alveolar septum, and areas of hemosiderosis (Fig. 8d). The mediastinal lymph nodes were enlarged to 40 mm x 35 mm x 15 mm, with enlarged lymph sinuses and histiocytic hemophagocytosis (Fig. 8e). A diagnosis of PVOD was made based on the clinical course and autopsy findings. We concluded that her cause of death was respiratory failure by progressive right heart failure.

exertional dyspnea, pulmonary hypertension, pulmonary veno-occlusive disease, sudden death

a: Chest CT on readmission (lung fields). An increase in the reticular granular pattern was observed, predominantly in both lower lobes, along with increased pulmonary vascular markings.

PMC9852885_01

Female

A two-year-old girl was hospitalized for "hepatic dysfunction and recurring oral candidiasis for more than ten months." She was hospitalized at a local hospital with "bronchitis" at the age of one year and one month, where she was found to have liver dysfunction with ALT and AST levels of 624 U/l and 644 U/l, respectively. Her condition improved after one week of treatment with glutathione and bicyclol. After continuing glutathione and bicyclol for more than one week, the liver enzyme levels returned to normal. At the age of one year and five months, she was treated at a local clinic for approximately three days due to oral candidiasis and poor appetite, and her ALT and AST levels were 1,019 U/L and 898 U/L respectively. She was admitted to the hospital. A liver, gallbladder, pancreas, and spleen ultrasound indicated gallbladder wall edema and splenomegaly. The child was then given anti-infective ceftezole and ganciclovir antiviral therapy. The treatment, however, proved ineffective, and the patient was moved to our hospital. Laboratory tests were performed during hospitalization with the following results: LDH 638 U/L (120-300 U/L), AST 1539 U/L (<=40 U/L), ALT 607 U/L (<=41 U/L), gamma-GT 109 U/L (10-71 U/L), total cholesterol 2.52 mmol/L (<5.18), and total bile acid 58.3 micromol/L. There was no obvious coagulation abnormality. Screening for antibodies against hepatitis C virus (HCV), HAV, HEV, HIV, PVB, Treponema pallidum (TP), and hepatitis B virus (HBV) were negative; The concentration of Immunoglobulin A was 0.15 g/L (0.11-1.45 g/L), Immunoglobulin G was 8.8 g/L (3.3-12.3 g/L), Immunoglobulin M was 0.79 g/L (0.33-1.75 g/L), Complement C3 was 0.81 g/L (0.65-1.39 g/L), and Complement C4 was 0.23 g/L (0.16-0.38 g/L). The levels of blood ammonia (57 micromol/L) and ceruloplasmin (0.498 g/L), and the results of the lymphocyte subset analysis [T cells, B cells, and natural killer (NK) cells] indicated no significant abnormalities (Supplementary material Table S1). The level of anti-CMV-IgM and anti-CMV-IgG was 2.85 AU/ml and 89.74 AU/ml, respectively. IgG antibody against Epstein-Barr virus early antigen and nuclear antigen was <5.0 U/ml and 140.0 U/ml, respectively. The levels of IgG and IgM antibodies against Epstein-Barr virus capsid antigen were 39.2 U/ml and <10.0 U/ml, respectively. The Epstein-Barr virus DNA assay showed 9.08E + 002 copy/ml (0-500 copy/mL). Mycobacterium tuberculosis was not cultured either in a solid or liquid medium. The analysis of autoantibodies revealed cytoplasmic antinuclear antibodies as granule 1:100 and anti-liver cytosol-1 antibody (ALC-1) as suspicious, whereas screening for anti-GP210 antibody was weakly positive (Supplementary material Table S2). Retest The child was diagnosed with liver dysfunction, oral candidiasis, acute bronchial pneumonia, and cytomegalovirus infection. Liver protection was provided by administering enzyme-lowering (glutathione, bicyclol, magnesium isoglycyrrhizinate) and anti-infective (cefoperazone and sulbactam sodium, voriconazole) substances. Then the child was discharged and was orally administered bicyclol and glutathione tablets to reinforce treatment. For the next four months, liver function was measured in conventional outpatient clinics and was high (ALT: 50 U U/L, AST: 137 U/L). Since the cause for this elevated liver function remained unclear, the child was readmitted to the hospital. Liver biopsy and high-precision clinical display PLUS detection were conducted with the consent of the guardians. Liver perfusion analysis revealed incomplete lobular structure, partial hydrolysis of some hepatocytes, infiltration of a few lymphocytes into the portal area, and mild hyperplasia of the fibers. These observations were consistent with the pathological changes observed in G1S1 chronic hepatitis (Figure 1). A liver biopsy under an electron microscope showed that the liver tissue was slightly swollen with a reduced endoplasmic reticulum, slight hyperplasia, expansion of the smooth endoplasmic reticulum, and blurred mitochondrial structures. Most of the hepatocytes showed a slight increase in the number of small lipid droplets in their cytoplasm, with few showing depositions of not many cholestatic pigment particles. The gaps between hepatocyte surfaces were slightly wider, and a few capillary bile ducts were somewhat dilated and cholestatic. Hepatic stellate cells were prominent in the Disse cavity, and focal bundles of collagen fibers were deposited. Kupffer cells were observed in the hepatic sinusoids with no portal area (Figure 2). High-precision clinical display PLUS detection revealed a heterozygous GOF mutation (p.R274W) in the coiled-coil (CC) domain of the transcription factor STAT1 (Figure 3). The legal guardian provided written informed consent to participate in this study. We monitored the clinical progress of this child for more than three years. After multiple treatments (antifungal voriconazole, nystatin treatment for oral Candida, antibiotics against bacterial infection, and liver protection with bicyclol and glutathione), the child still exhibited splenomegaly. Serial radiological investigations of the chest were conducted (Figure 4). We intermittently gave the child glutathione, bicyclol treatment, and oral antifungal therapy during this period. The child's family members were very cooperative with the doctor's treatment and brought her to the hospital regularly for re-examination to evaluate her liver function. Fortunately, the child's condition is stable, with no further clinical progress.

gof-stat1 mutation, chronic mucocutaneous candidiasis, fungal infections, liver dysfunction, pediatric

PMC3295742_01

Male

A 23-year-old male presented in the emergency department of a district general hospital with an acute onset of left upper quadrant abdominal pain and a syncopal episode one hour prior to his admittance. Abdominal pain had a sudden outburst while the patient was resting at home, and there was no indication of trauma history. The patient reported one-week history of fever up to 40 C, sore throat, and malaise, as well as oral consumption of 5 to 8 tablets of 500 mg of acetylsalicylic acid within the two previous days. On initial examination he was in shock, pale, tachycardic with a heart rate of 110 beats per minute, tachypnoeic and hypotensive with a blood pressure of 90/60 mm Hg, and a fever of 38.5 C. Physical examination revealed bilateral nontender cervical lymphadenopathy and diffuse abdominal guarding with rebound tenderness. Kehr's sign was also positive. Admission laboratory tests revealed a WBC count of 17.000 cells/muL with 53% atypical lymphocytes while the value of Hb was 9 g/dL. The patient's platelet count was normal (170.000/muL), prothrombin time (PT) was 13.8 sec (reference time: 13 sec), international normalized ratio (INR) was 1.06, and activated partial thromboplastin (aPTT) time was 30.6 sec (normal: 28-40 sec). Serum transaminases were slightly elevated with an ALT 152 U/L and AST 138 U/L. The patient's history of fever, lymphadenopathy, sore throat, atypical lymphocytosis combined with his clinical presentation of peritonitis, and hypotension in the absence of a trauma incidence was suggestive of a possible diagnosis of spontaneous splenic rupture on the basis of the underlying IM. After initial resuscitation with 3 liters of intravenous crystalloids, an emergency abdominal CT was carried out to confirm the diagnosis. CT showed a large splenic hematoma and large amounts of fluid in all four abdominal quadrants and in the pelvis (Figure 1). An exploratory laparotomy was undertaken. During laparotomy, there was a notable amount of fresh and clotted blood in the abdomen while the spleen was large and congested. It had a 5 cm capsular tear near the hilum and a large subcapsular hematoma. The enlarged, friable spleen was almost completely devoid of capsule. We performed an uncomplicated splenectomy, and after a thorough lavage of the peritoneal cavity, no other abnormal findings were revealed. The patient returned to the surgical ward hemodynamically stable, and no blood transfusion was necessary. Pathologic examination revealed an enlarged spleen 15 x 7 x 5 cm, weighing 430 gr. Microscopic examination accented an expanded red pulp and moderate follicular hyperplasia. The diagnosis of IM was later confirmed by the presence of IgM antibodies to Epstein-Bar virus capsid antigen (VCA). The patient recovered uneventfully and was discharged on the 7th postoperative day.

PMC3064863_01

Male

In mid-January 2010, a 49-year-old male with pulmonary asthma and a prior history of nasal polyps woke up at 00.30 at night with a feeling of tongue swollenness. Upon standing up, he noticed paraesthesia of the left hand and a left facial droop. When the emergency medical staff arrived, he was sitting, his speech was blurred, and the muscle strength of his extremities was unaffected. Due to the wake-up nature of the mild hemiparesis, he was not considered a candidate for thrombolysis treatment when he was pre-notified to the neurological emergency by the emergency medical staff. The patient had never smoked, and his previous medical history was free of cardiac symptoms, hypertension, hyperlipidaemia, diabetes, or migraine. He was in excellent physical condition and had done a 10-km cross-country skiing trip 2 days before. In addition, he had previously run several marathons. Physical examination at the emergency department revealed a slight pronation of the left arm and a mild slowness of the diadochokinesia of the left hand together with a residual paresis and paraesthesia of the lower facial area. The head CT scan showed no findings, and neither did the plain chest X-ray. The patient was admitted to a neurological ward with a working hypothesis of brain stem infarction, and acetylsalicylic acid was administered at a loading dose of 250 mg orally, which was continued at a dose of 100 mg daily. The next day, a head MRI and MR angiography (MRA) revealed a fresh minor infarction at the corona radiata on a FLAIR sequence (fig. 1a), with a diffusion-weighted image showing restricted diffusion of the lesion, consistent with an infarct (fig. 1b), as well as a 3-mm hemosiderin ring at the right putamen (fig. 1c). The MRA of the intracranial and neck vessels was unremarkable. The left hemiparesis progressed to sensory-motor hemiplegia on the 4th day. The head CT scan showed an expansive right-sided intracerebral haemorrhage in the basal ganglia extending to the corona radiata (fig. 1d). The ancillary aetiological studies of the haemorrhagic infarction included transcranial Doppler sonography, which showed right-sided microemboli that were increased after a Valsalva manoeuvre. Correspondingly, a minor atrial septal defect (ASD) with shunting was suspected at transthoracic echocardiography. The patient had a heterozygotic clotting factor V R506Q mutation, i.e. activated protein C (APC) resistance. On admission, the blood chemistry showed mild leucocytosis of 9.2 E9/l and the C-reactive protein (CRP) level was 7 mg/l. Head CT scan revealed asymptomatic pansinusitis of the frontal, ethmoidal, and left sphenoidal cavities, and the patient was given oral amoxycillin. However, during the first 10 days, the CRP level rose up to 185 mg/l, and the leucocyte count up to 20.7 E9/l. Chest X-ray remained normal. Maxillary puncture was performed, and the bacterial cultures of the pus grew coliforms and local normal flora, susceptible to the antimicrobials being used. The empiric antimicrobial therapy was changed to cefuroxime and metronidazole and then piperacillin plus tazobactam, without any response in the inflammatory parameters. The patient had high fever (up to 38.8 C) and intense muscle pain, but blood cultures were negative. Consequently, contrast-enhanced body CT was performed and showed wide-spread bilateral nodular chest infiltrates in all pulmonary lobes and reactive lymph nodes in the upper mediastinal area. Bronchoalveolar lavage was not possible due to the haemorrhagic brain infarction. An infectious diseases specialist was consulted, and further diagnostic work-up showed a remarkable blood eosinophilia of 4.89-9.8 E9/l (30-42%) (fig. 2), positive anti-neutrophilic cytoplasmic antibodies (P-ANCA) antibody titer (200; reference value <20), a high serum myeloperoxidase antibody level (63.4 IU/ml; reference value <6) and slightly positive serum proteinase 3 antibodies (9.9 IU/ml; reference value <4), slightly decreased levels of serum IgA (0.74 g/l; reference value 0.88-4.84), normal IgG, but elevated IgG4 (4.45 g/l; reference value 0.08-1.4) (table 1). The patient had never visited the tropics. Also, stool examinations were negative for parasites including amoeba staining and Strongyloides culture, and the patient did not show serum antibodies against Trypanosoma, Toxocara, Echinococcus, Fasciola, schistosoma, Filaria, Strongyloides or Toxoplasma. Additionally, serologic tests for HIV, cytomegalovirus, Epstein-Barr virus, human herpes virus 1 and 2, and for hepatitis A, B and C were all negative. The patient did not have anti-phospholipid antibodies. HLA typing showed HLA-B*35 allele (heterozygous mutation). The bone marrow aspirate revealed normal morphology and relatively strong eosinophilia, and the chromosomal investigation was unremarkable. Interferon gamma release assay for M. tuberculosis was negative. The combination of asthma, sinusitis, history of nasal polyps, and eosinophilia, together with the detection of antinuclear and anti-neutrophilic antibodies evoked the suspicion of Churg-Strauss syndrome, leading to the treatment decision of a 3-day therapy with intravenous pulse methylprednisolone (1 g/day). The blood eosinophils and ANCA antibodies were undetectable 3 days and 1 month after treatment onset, respectively (fig. 2). Beta-lactam antimicrobials were changed to clindamycin together with ciprofloxacin. There were no skin or joint manifestations, cardiac dysfunction or signs of peripheral neuropathy at the time of the diagnosis, nor did the head MRA demonstrate findings that would have confirmed the CNS vasculitis as aetiology of the haemorrhagic brain infarction. The cerebrospinal fluid was not investigated, nor was a brain biopsy taken to confirm the CNS vasculitis, because of the urgent need to start immunomodulatory therapy due to the suspicion of Churg-Strauss syndrome with a cytotoxically high eosinophil level. Nasal mucous membrane biopsy did not confirm vasculitis either. No renal biopsy was performed; however, the CT scan showed wedge-like lesions, suggesting renal infarcts. In addition, urine examination showed slight microscopic haematuria and proteinuria (834 mg/l). Alanine aminotransferase temporarily increased to 509 U/l. After treatment with high-dose corticosteroids i.v. for 3 days, the patient was first given cyclophosphamide for 2 weeks together with oral prednisolone, until he developed prolonged neutropenia and fever. During that time, he also developed ileus, which was managed conservatively. Later, a colonoscopy was performed which showed a rectal tubular polyp but no ischaemia or inflammatory lesions. At that time, he was started on immunoglobulins (0.4 g/kg i.v.) given every 3 weeks as an additive immunomodulatory treatment together with oral corticosteroids (fig. 2). Three months after the start of the immunosuppressive treatment, while on oral corticosteroids (prednisolone 20 + 10 mg) and azathioprine (100 mg), the patient suddenly and unfortunately developed peritonitis. A laparoscopy showed an ileal perforation, but there were no histological changes suggesting vasculitis. Though taken during immunosuppressive treatment, electroneuromyography (ENMG) suggested vasculitis-like neuropathic changes, but an undiagnostic muscle biopsy from the right vastus lateralis muscle contained only subcutaneous tissue with no signs of necrotizing vasculitis or eosinophils. The left-sided sensory-motor hemiplegia and the neuropsychological symptoms indicated physio- and ergotherapeutic as well as neuropsychological rehabilitation, which was actively continued after the initial complications. The patient was still in a neurological rehabilitation institution almost 7 months after the ictus.

atrial septal defect, churg-strauss syndrome, eosinophilia, factor v leiden, haemorrhagic stroke, patent foramen ovale, small vessel vasculitis, mutation

PMC5702861_01

Female

A 28 years old female presented to ENT outdoor with complaint of growth over hard palate and pain in the lesion for 2 months. Patient had episodes of bleeding from the growth off and on. The growth was polypoidal, exophytic, firm and bled on touch. The general physical examination did not reveal any abnormality. However, she also had pain in left lower limb and was lethargic most of the times. Her laboratory reports revealed the following: Hb- 9.6 gm/dl, TLC- 13000/cmm, DLC- P78 L18 M2 E2, platelets were normal. ESR 110 mm/hr, blood urea 35 mg%, S. Creatinine- 0.7 mg%. fungal stains and Xpert TB were negative. Computed tomography (CT Scan) showed an evidence of heterogenously enhancing nodular oral cavity mass lesion causing destruction of hard palate and alveolar process of maxilla and it was bulging into the nasal cavity (Fig. 1). Further, CT head showed multiple lytic lesions in calvaria (Fig. 2). Positron Emission Tomography (PET) revealed hypermetabolic lytic lesions involving axial and appendicular skeleton. Keeping in view her symptomatology, Magnetic Resonance Imaging (MRI) of left knee was also performed which revealed diffuse marrow infiltrative disorder possibly leukemia or lymphoma. Biopsy from hard palate growth was done. It showed a diffuse infiltration by medium sized tumor cells, of plasmablastic morphology with fine reticular nuclear chromatin, large nucleus, with very little perinuclear hof (Fig. 3). Immunohistochemistry (IHC) Panel applied revealed strong positivity of tumor cells for kappa light chains, while these cells were lambda chains negative. CD 38 and CD 138 were also positive. CD20, CD5, CD 10, CD 3, BCL 6 and Cyclin D1 were negative. Ki67 index was high (60%). EBER (ebstein barr virus encoded RNA) was also negative, ruling out the differential of plasmablastic lymphoma (Fig. 4). So, a final diagnosis of plasmablastic myeloma was made. Serum protein electrophoresis yielded hypoalbuminemia and M spike in gamma region (2.4 g/dl), further corroborating the diagnosis of plasma cell disorder. Thus, the diagnosis of plasmablastic myeloma was confirmed. The case was discussed in multidisciplinary tumor board. She was taken up for surgery followed by chemo-radiation. But unfortunately, she did not respond well to treatment and finally succumbed to her illness after 6 months.

ceber, case report, extramedullary myeloma, multiple myeloma in young, plasmablastic lymphoma, plasmablastic myeloma

CT scan showing heterogenously enhancing nodular lesion causing destruction of hard palate and alveolar process of maxilla.

PMC8255476_02

Female

She was placed in foster care at the age of 6 years old due to severe neglected behaviors from her parents. She has experienced a very insecure environment leading to an early attachment disorder and anxiety disorder. During primary school, major global learning disabilities were reported. In this context, she was evaluated by a standard metric test (EXALANG 5-8 years). The initial evaluation found severe attentional and behavioral difficulties leading to poor reading and writing skills. Writing rehabilitation was prescribed but stopped due to behavioral disorders. At the age of 9 years old, the Wechsler Intelligence Scale for Children (WISC:IV) was homogeneous with intellectual disability (verbal comprehension index = 69; perceptual reasoning index = 82; processing speed index = 71; full scale IQ = 69). Rapidly, she presented severe outbursts and tantrums leading to hetero-aggressiveness and self-injuries. In the meantime, she started to exhibit many simple motor tics associated with simple verbal tics characterized by facial grimacing, arm jerk, obscene gesture, and scream compatible with Tourette syndrome. The worsening of the Tourette syndrome associated with intellectual deficiency led to many changes in her living environment and many long-term hospitalizations. She was unsuccessfully challenged by risperidone, aripiprazole, fluoxetine, propericiazine, haloperidol, zuclopenthixol, and naltrexone. During her last admission in our specialized unit, our clinical assessment underlined the severity of her attachment disorder with severe ambitendency toward her relationship with peers and caregivers, many simple and complex motor/verbal tics, aggressiveness, strong impulsivity, and numerous self-harm behaviors. A clinical examination did not find any abnormality, and the result of a standard blood workup (CBC and liver and kidney function) was normal. Given the overall resistance to atypical and typical antipsychotics, the severity and burden of the automutilations, and the impulsivity, the off-label use of clozapine was considered legitimate by the medical team. We quickly reported low clozapine plasma levels (275 ng/mL), regardless of the progressive increase of clozapine dosage (500 mg/day). After excluding all known food or drug interactions, a pharmacogenetic testing on cytochromes was performed and identified the CYP1A2*1F/*1F genotype (see Table 1). This genotype is associated with ultra-rapid drug metabolism, therefore explaining the low clozapine plasma levels. We decided to add fluvoxamine to clozapine to inhibit the CYP1A2 subunit and to enhance the clozapine plasma level. Within the next days after fluvoxamine introduction (50 mg/day), we observed a major increase of clozapine plasma level (503 ng/mL) (see Figure 1). Clinically, we reported a drastic improvement regarding automutilations and impulsivity, with a 32% reduction in the ABC:irritability subscale and 33.3% in the ABC:hyperactivity subscale. Regarding tolerance, we did not report any side effect, and no hematological adverse event was reported (see Supplementary Figure 1).

child and adolescent psychiatry, clozapine, cytochrome polymorphism, fluvoxamine, resistant psychiatric disorder

PMC8255476_03

Male

B is a 9-year-old African boy who was born at term after a normal pregnancy. He was placed in foster care at the age of 3 years old due to severe physical and psychological violence within the family and severe neglected care. He barely had contact with his mother and his father. His family background is marked with a psychotic disorder in one first-degree relative. He quickly presented a delay in language and motor skills. An ear, nose, and throat (ENT) exploration and audiometry were performed at the age of 4 years old without any abnormalities. He did not receive speech therapy or psychomotor therapy. His academic performances were severely impaired due to his global and severe neurodevelopmental delay. School was quickly impossible and interrupted due to repetitive admission in psychiatry for tantrums and severe outbursts. Around the age of 8 years old, B presented an increase of behavioral disorders occurring at school and at home, leading to several hospitalizations for severe outbursts, self-harm, and aggressive behaviors. At the same time, he reported a progressive onset of visual and auditory hallucinations. Risperidone was initiated at 2 mg/day but without any efficacy. At the admission in our unit, B presented delusional ideas, hallucinations, and mental automatism. He exhibited a disorganized and dissociative motor behavior, disorganized processes of thinking with speech disorder, and cognitive impairment. A clinical examination did not find any abnormality, and the result of a standard blood workup (CBC and liver and kidney function) was normal. After an extensive screening panel (see Supplementary Figure 2 for details of the screening panel), no organic cause was retrieved, and the diagnosis of EOS was retained. Aripiprazole was introduced at 15 mg/day and associated with levomepromazine at 15 mg/day. However, the patient's tolerance was questioned with a severe sedation and a worsening of delusions and hallucinations. The aripiprazole plasma level showed an overdose at 835 ng/mL (therapeutic reference range: 150-500 ng/mL) regardless of the proper dosage-weight ratio. Aripiprazole was then switched to haloperidol gradually at up to 1.5 mg/day. There was no improvement regarding positive symptoms. The haloperidol and levomepromazine plasma levels showed an underdose, respectively, at 1.1 and 5 ng/mL. After excluding all known food or drug interactions, a heterogenous genotype CYP metabolism was suspected. Pharmacogenetic testing for cytochromes was performed, and it identified CYP2D6*1/*10 and CYP2D6*1/*41 heterozygous genotypes and a CYP3A5*1/*1 homozygous genotype (see Table 1). These genotypes are associated with a partial deficiency in CYP2D6 activity and an ultra-rapid metabolizer phenotype CYP3A5, respectively. Therefore, these genotypes are genetic explanations of the high aripiprazole plasma level and low haloperidol plasma level. Given the resistance to two atypical antipsychotics and one typical antipsychotic and the severity and the burden of the psychotic features, the off-label use of clozapine was legitimate. However, during a progressive increase of clozapine dosage (300 mg/day), we reported a low clozapine plasma level (124 ng/mL). After a multidisciplinary staff consensus, we decided to add on fluvoxamine to clozapine. A few days after fluvoxamine's introduction (50 mg/day), the patient presented an extreme sedation and QTc prolongation, requiring a transfer to the pediatric cardiology department for continuous monitoring and discontinuation of the drugs. Indeed a relatively high levomepromazine plasma level (140 ng/mL; therapeutic reference range in adults: 5-25 ng/mL) was retrieved due to CYP2D6 inhibition by fluvoxamine. The clozapine plasma level was low (139 ng/mL). Therefore, the extreme sedation was secondary to an overdose of levomepromazine, leading to the discontinuation of the drug. Clozapine was introduced once again in association with a low dose of fluvoxamine (25 mg/day). Within the next days after fluvoxamine's introduction, the plasma clozapine level dramatically increased (see Figure 1), which was associated with an important improvement of the clinical state regarding positive symptoms (66% reduction in the SAPS) and a reduction of aggressive behavior. Regarding tolerance, besides the drug interactions described above, we did not report any other side effect, and no hematological adverse event was reported (see Supplementary Figure 1).

child and adolescent psychiatry, clozapine, cytochrome polymorphism, fluvoxamine, resistant psychiatric disorder

PMC9677258_01

Female

This study included 374 patients who underwent surgery for TBPI. Of these, 322 (86.10%) were males and 52 (13.90%) females. The median age of these patients was 26 years (7-77). Dividing these patients into age groups, 45.45% of patients were between 20 and 29 years of age with 86.47% of them were males (Figure 1). The male patients' ages ranged from 7 to 77 years, while the female patients were 11-68 years old. The TBPI patients mostly came from the same province (45.20%), followed by the patients who came from the same region (32.33%), and the rest came from all over Indonesia (22.47%.) Among the mechanism of injury, the majority of cases were caused by traffic accidents (91.98%) which was dominated by motorcycle accidents (94.48%). Other mechanisms were domestic (5.61%) and industrial accidents (2.41%) (Table 1). The interval between the trauma and first surgery for the brachial plexus varied as shown in Figure 2. Based on the side of the lesion, 58.02% of the patients had right-sided injuries, 41.71% had left-sided injuries, and 1 patient (0.27%) had bilateral injuries. Traction injuries occurred in most of the patients. According to the anatomical classification, the complete pre-ganglionic type accounts for 48.93%, followed by the upper (33.15%) and complete (17.64%) post-ganglionic type. Only 1 patient (0.27%) was the lower type lesion (Table 2). As many as 52.67% of the patients had concomitant injuries. Fractures were the most common concomitant injuries (90.73%). Among them, most (99.07%) were closed fractures. Closed anterior dislocation of the glenohumeral joint was the second most common concomitant injury (3.38%), followed by the head/intracranial injury (3.09%), and the rest were acromioclavicular joint disruption, nerve lesion (peroneal nerve), lacerated wound, vascular rupture, crush injury, and hyphema (Table 3). Interestingly, these patients mostly visited the hospital within 24 hours after injury and were treated accordingly due to the concomitant injury. Upper limb fractures were commonly associated with TBPI (84.52%) with humerus fracture being the most common (29.10%), followed by radius (21.98%), and clavicle (16.10%) (Table 4). In preoperative clinical examination, Horner's syndrome (ptosis and miosis ipsilateral) was found in 177 patients, hemidiaphragm palsy in 4 patients, and winging scapula in 17 patients. Diagnostic studies were performed to support the diagnosis. MRI examination was done in 85 patients, CT scan in 22 patients, and electrophysiological studies in 89 patients. In the preoperative predictive value analysis of root injury, at least one root abnormality of MRI was 71.28% and 70.10% of CT scans. The electrophysiological studies diagnosed 60.15% of preganglionically injured roots. The total procedures done in this study were 474 procedures, consisting of nerve procedures, tendon transfers, arthrodesis, and free functional muscle transfer (FFMT). Nerve procedures were performed in 272 patients (57.38%) for patients who came less than 12 months. External neurolysis was performed in 42 patients (15.44%) of all nerve procedures. Among them, external neurolysis alone was performed in 4 TBPI patients that intraoperatively had a visibly intact plexus (surrounded by fibrosis) which transmitted nerve action potential (NAP) from the nerve stimulator. Nerve transfers (neurotization) were performed in 230 patients (84.56%) divided into supraclavicular neurotization for 139 patients (60.43%) and infraclavicular neurotization for 91 patients (39.57%). In supraclavicular neurotization, intraplexal donor nerves (2 patients/1.44%) used were mainly from C5 and C6 roots. Extraplexal donor nerves were the phrenic nerve (74 patients), spinal accessories nerve/SAN (51 patients), the platysma motor branch (2 patients), and the great auricular nerve (1 patient). The nerve graft source used in this study were the sural nerve (83 patients) and the lateral antebrachial cutaneous (LABC) nerve (2 patients). The average length of used graft was 18.55 cm. The recipient nerves for these procedures were SSN (suprascapular nerve), MCN, and median nerve. In infraclavicular neurotization, Oberlin I and Oberlin II procedures were performed in 10 patients and 67 patients respectively. The Somsak Procedure was done on 14 patients. The secondary procedures done were tendon transfer (36.92%), modified Steindler flexorplasty (32.57%), trapezius transfer procedures (59.43%), and tendon transfer for wrist, thumb, and finger extension (6.85%) Another secondary procedure was arthrodesis procedures that were performed on 12 patients (2.53%). Three joints that had already undergone surgery for arthrodesis were the glenohumeral joint (9 patients/75.0%), the wrist joint (2 patients/16.67%), and the carpometacarpal joint (1 patient/8.33%). Lastly, free functioning muscle transfer (FFMT) using gracilis muscle was performed in 13 patients (2.74%). The summary of procedures done for TBPI is presented on Table 5.

epidemiologic study, surgical treatment, tertiary hospital, traumatic brachial plexus injury

PMC6761247_01

Female

A 10-week-old extremely preterm girl was admitted to our hospital for severe paroxysmal cyanosis and tachypnea. The infant was the product of a 25-week-and-4-day gestation and was a test-tube baby, from a gestational diabetes mother. The pregnancy was otherwise uneventful. A vaginal delivery was performed. The infant was 890 g with Apgar scores of 5, 9, and 9 at 1, 5, and 10 min, respectively. The infant was independent on the oxygen when she was discharged after 58 days of hospitalization with 2,020 g. At day of life 70, the infant presented with symptoms of poor response and appetite, but her parents did not notice these symptoms. At day of life 72, the infant has symptoms of paroxysmal cyanosis and tachypnea, then was subsequently admitted to our hospital. Upon arrival to our hospital, vital signs were notable for respiratory rate of 70 per minute and heart rate of 170 beats per minute. Physical exam revealed coarse breath sounds and pulmonary moist rales. The infant was diagnosed with severe pneumonia and we immediately gave CPAP assisted ventilation (FiO2 50% PEEP 5 cmH2O). Meanwhile, we actively carried out blood culture, sputum culture, throat swab, respiratory virus (respiratory syncytial virus, influenza viruses, parainfluenza viruses, adenovirus, rhinovirus) and mycoplasma detection from blood and galactomannan detection. Then intravenous fluids and meropenem were administered (Figure 1). Chest X-ray showed high-density shadow in the left middle lobe lung on Day 1. But her general condition progressively worsened after 3 days. Her white blood cell count increased from 5.71 x 109/L (with 52% neutrophils and 27.5% lymphocytes) to 16.37 x 109/L (with 74.9% neutrophils and 16.7% lymphocytes), whereas her C-reactive protein and procalcitonin levels were normal. Pulmonary atelectasis in the right upper lobe and bilateral alveolar consolidation by chest computed tomography on Day 6 after the onset of symptoms (Figure 2A). Meanwhile repeated blood and sputum secretions were negative for bacteria, respiratory virus, tuberculosis, and fungi in cultures, and G-test (1,3 -beta-D-glucan test) and GM-test (galactomannan test), respectively. Her oxygenation index was 125 at admission, indicating a bad oxygenation status. And her echocardiography and blood pro-brain natriuretic peptide readings were normal. During this period, the infant showed polypnea, paroxysmal dysphoria, cough, and abundant yellow sticky respiratory secretions. Given the concern for a severe infection, empiric broad-spectrum antibiotics consisting of meropenem, vancomycin, and voriconazole to cover typical bacterial pathogens and fungal infection after a second infectious workup was performed including repeated blood culture, sputum culture (Figure 1). At day 10, the microbial species were then assessed by metagenomic analysis. Deoxyribonucleic acid libraries for Next-generation sequencing (NGS) were prepared as previously described. Sequencing was performed on an Illumina MiSeq instrument. Total numbers of raw reads were 13849671, and non-human reads accounted for 5.92%. Stenotrophomonas maltophilia reads (428) were the only bacterial pathogen in blood (Figure 3A). In addition, we also detected several fungi pathogens in blood, including Penicillium chrysogenum reads (404), Pichia anomala reads (134), and Candida parapsilosis reads (Figures 3B-D). The infant was then treated with Tazobactam and Piperacillin (TZP) and trimethoprim/sulfamethoxazole (TMP-SMX) successively, subjected to non-invasive positive pressure ventilation. Her oxygenation status and chest computed tomography showed significant improvement after treatments (Figure 2B), and the infant was discharged on Day 30 after admission. Two weeks after discharge, the infant appeared good responses and appetite, and her chest computed tomography showed distribution of the two slightly thickened lung markings, clear lung fields and no substantive changes (Figure 2C).

stenotrophomonas maltophilia, infant, metagenomics, next-generation sequencing, severe pneumonia

PMC9218804_01

Female

Case 1. Diffuse large B cell lymphoma. A 58-year-old female presented after 2 months with right chest and back pain with no fever ( Figure 4A ). A CT scan revealed destruction of the 9th thoracic vertebra and the right appendix with paravertebral soft tissue shadow ( Figure 4B ). Magnetic resonance imaging (MRI) revealed abnormal signals of the 9th thoracic vertebra and right arch with swelling of the surrounding soft tissue. Pathologic results of the bone biopsy indicated infection. The patient was treated empirically with vancomycin and fosfomycin (switched to linezolid due to nausea and vomiting) administered i.v. for 3 weeks. The patient developed paralysis of the lower extremities and difficulty urinating. Repeated MRI showed that the lesion had become significantly larger with spinal compression. Onco-mNGS analysis failed to detect microorganisms in her peripheral blood, but revealed deletions and duplications of large segments in several chromosomes that generated a strong abnormal CNV-based tumor signal ( Figure 4C ). This finding encouraged treating physicians to obtain a second bone biopsy; the result revealed diffuse large B cell lymphoma of the non-germinal center B cell type ( Figure 4D ). The patient received R-CHOP chemotherapy afterwards and the symptoms were mildly relieved. The fluctuation in chromosomal variation was much smoother in the fourth, compared to previous, Onco-mNGS tests suggesting that the proportion of tumor cells had decreased. Case 2. NK/T cell lymphoma. A 23-year-old male presented after 2 weeks of fever and vomiting. Upon admission, the patient exhibited a low platelet count (45x109/L) and elevated levels of inflammatory markers (C-protein: >199 mg/L; procalcitonin: 13.92 ng/mL). Tests for pathogens that included Epstein-Barr virus (EBV), cytomegalovirus (CMV), cryptococcus, tuberculosis, and parasites were negative; blood cultures for bacteria, acid-fast bacilli, and fungi were also negative. A PET-CT scan showed an enlarged spleen with increased uptake of FDG indicator. The patient underwent two diagnostic bone marrow punctures and a splenectomy; the results, however, did not support a definitive diagnosis. The patient was treated empirically with meropenem, vancomycin, doxycycline, gentamycin, and trimethoprim-sulfamethoxazole administered sequentially, but became worse with progressive hepatic deterioration (total bilirubin: 356.4 micromol/L). The results of a third bone marrow biopsy revealed NK/T cell lymphoma. Onco-mNGS results showed disruptions in several chromosomes indicative of a tumor. This was confirmed by the results of a third bone marrow smear. Unfortunately, this information was not considered a priori by the attending physicians and the patient soon died of tumor progression. Case 3. Lung adenocarcinoma. A 71-year-old female presented after 2 months of cough and sputum, but no fever. Her chest CT scan showed pneumonia; Mycoplasma pneumoniae-specific IgM antibody was positive. She was treated with cefuroxime and azithromycin administer i.v. for 6 days, then switched to oral moxifloxacin for 10 days. The patient did not improve in clinical or radiological presentation. Repeated, M. pneumoniae serum antibody was negative. Bronchoscopy was conducted, but tests for pathogens including bacteria, acid-fast bacteria, and fungi in BALF were negative. Tumor markers in this patient, i.e., CA199, CEA, CA125, CY211 and SCC, were in the normal range. The patient received a pulmonary lobectomy and the pathological result indicated lung adenocarcinoma.

copy number variation, infection, next-generation sequencing, pathogen, tumor

PMC9234253_01

Male

A 77-year-old man with a history of abnormal chest radiography finding was referred to our hospital. The patient had hypertension, dyslipidemia, and an operative history (total resection for prostate cancer). He had a 20-pack-year smoking history but no family history of connective tissue and pulmonary diseases. Laboratory examination showed the following: Krebs von den Lungen-6 level, 10726 U/mL; surfactant protein-D, 302 ng/mL; positivity for anti-nuclear antibody (1:320, nucleolar pattern); and negativity for anti-scl-70 antibody, anti-RNA polymerase 3 antibody, and anti-centromere antibody. Chest radiography revealed ground-glass opacity in the bilateral lower lung fields, and a chest computed tomography scan revealed ground-glass opacity in the basal area of both lungs and a nodule in the left lower lobe (Fig. 1). The pulmonary function test result was normal. Flexible bronchoscopy revealed normal intraluminal findings. Following this, a 51% recovery rate was achieved using bronchoalveolar lavage from the superior lingular segment; it indicated 59% lymphocytes and no malignant cells. The finding of hyperlymphocytosis in bronchoalveolar lavage fluid was considered primarily due to the etiology of ILD. Culture samples collected using bronchoscopy tested negative for common bacteria, mycobacteria, and fungus. Prior to TBLC, we introduced a 1.4-mm 20-MHz radial probe (PB2020-M; Fujifilm) with a guide sheath into the target bronchus and checked whether any blood vessel ran parallel to the bronchus. We obtained the endobronchial ultrasonographic view of "adjacent to the lesion" from B9a. We performed TBLC with a 1.9 x 1150-mm flexible cryoprobe (ERBECRYO 2 system; Erbe Elektromedizin GmbH, Tubingen, Germany) introduced through the guide sheath using an endobronchial balloon as an endobronchial blocker. Freezing time was set as 6 s. There was minor bleeding, which was easily controlled with an endobronchial blocker and an intrabronchial injection of an epinephrine-saline mixture (1-mL epinephrine with 19-mL saline). On high-resolution computed tomography (HRCT), the nodule was located in the left lateral basal segment (S9), and the TBLC sites were left B8b, B9a, and B9b. The pathological findings of the TBLC-collected specimen from left B9a showed the deposition of Congo red-stained AL with birefringence under polarized light (Fig. 2A-C). Except for the lesion of pulmonary amyloidosis, ground-glass opacities in both lungs were diagnosed as interstitial pneumonia, most likely due to chronic hypersensitivity pneumonia or interstitial pneumonia with autoimmune features. An additional biopsy was performed using bone marrow and subcutaneous adipose tissue samples, and the result was negative. Hence, the patient was diagnosed with localized nodular pulmonary amyloidosis. Since the condition was asymptomatic, he refused medical intervention. During follow-ups, he was found to have a good clinical condition.

pulmonary amyloidosis, surgical lung biopsy, transbronchial cryobiopsy

Chest computed tomography scan revealed ground-glass opacity in the basal area of both lungs and nodule in the left lower lobe.

PMC9234253_02

Male

A 62-year-old man with systemic AL amyloidosis was admitted to our hospital because of fever. The patient had noticed bilateral leg edema one year ago, and an annual medical check-up revealed an abundance of protein in the urine. He was referred to a different hospital for further investigation and a renal biopsy, followed by the diagnosis of AL amyloidosis. Amyloidosis was found in the heart, intestines, and tongue, among other organs. The Department of Hematology in our hospital was referred to the patient. In the hematology department, he received autologous peripheral blood stem cell transplantation after receiving combined melphalan and dexamethasone therapy. Following this, he was treated with six courses of combined melphalan and dexamethasone therapy. Laboratory tests showed elevated C-reactive protein levels at 5.29 mg/dL and normal cell count. He presented with mild renal impairment (serum creatinine level of 1.08 mg/dL). Moreover, his immunoglobulin G level decreased to 753 mg/dL. Additionally, we tested him for beta-D-glucan, Aspergillus galactomannan antigen, cytomegalovirus antigen, and anti-glycopeptidolipid-core IgA for Mycobacterium avium and performed interferon-gamma release assay; however, these tests were negative. Chest radiography showed pleural effusion in the right thoracic cavity and bilateral ground-glass opacity. Chest computed tomography scan revealed right pleural effusion and multiple micronodules with a random distribution in both lung fields (Fig. 3). Transthoracic echocardiography revealed a low ejection fraction with moderate left ventricular hypertrophy and granular myocardial appearance. Hence, miliary tuberculosis was suspected. Next, sputum, urine, and blood smear assessments were performed to detect mycobacterium. However, Ziehl-Neelsen staining showed no acid-fast bacillus. Exudates were discovered during a thoracocentesis, although the culture of pleural effusion samples did not show common bacteria or acid-fast bacteria. Although there was a risk of TBLC in patients with lung volume loss and a low ejection fraction, we considered that the risk of cancer was significantly higher than that of TBLC. The patient then underwent flexible bronchoscopy to examine the cause of multiple pulmonary micronodules. The bronchus surface was normal on flexible bronchoscopy. We collected lung specimens from the right B2b, B3a, and B4a via both forceps biopsy and cryobiopsy. We used a guide sheath under radiographic guidance and performed TBLB and TBLC through the same guide sheath left behind in the target bronchus. This approach allowed us to take both TBLB and TBLC specimens theoretically from the same place in the lung, minimizing the difference in the sampling error between TBLB and TBLC. The forceps biopsy specimen showed no microbiological findings based on gram staining, Ziehl-Neelsen staining, and Grocott staining. Further, the specimen cultures had negative results. The pathological findings of the specimen collected via forceps biopsy showed no evidence of amyloidosis. However, those taken via TBLC revealed mild thickening of the alveolar wall and pulmonary arterioles, both of which had amyloid deposition with a positive finding on Congo-red staining (Fig. 4A-D) accompanied by birefringence using polarized light (Fig. 4E). The lung lesion was associated with systemic amyloidosis. The patient then received continuous chemotherapy for systemic amyloidosis with melphalan and dexamethasone, and his disease behavior has been stabilized for one year to date.

pulmonary amyloidosis, surgical lung biopsy, transbronchial cryobiopsy

Chest computed tomography scan revealed right pleural effusion and multiple micronodules with a random distribution in both lung fields.

PMC6477468_01

Male

A 72-year-old male was admitted to the hospital due to chronic rhinosinusitis and recurrent nasal polyps. Additionally, numerous hemorrhagic bullae, palpable purpura, and necrotic maculae on the face and upper and lower limbs were found, as well as oral ulcers (Fig. 1). Red skin lesions on his face had appeared during the last two outbreaks of nasal polyps too. These lesions had disappeared spontaneously after treatment of the nasal polyps by surgery and steroid nasal spray treatment. Furthermore, late-onset treatment-refractory asthma had recently been diagnosed. Moreover, he complained of numbness in his left leg and weight loss of 5 kg in the previous 2 weeks. He denied fever, headache, abdominal pain, diarrhea, hematuria, and arthralgia. A biopsy of the nasal mucosa revealed eosinophilic infiltration. Further, a skin biopsy demonstrated perivascular eosinophilic infiltrate and necrotizing vasculitis, as well as a granulomatous reaction (Fig. 2). Direct immunofluorescence showed slight deposition of complement component C3 in blood vessels. Laboratory studies demonstrated leukocytosis (20.6 x 109/L) with distinct eosinophilia (4,280 eosinophils/muL, 59% of the total leukocyte count), a high erythrocyte sedimentation rate (52 mm in the first hour), elevated immunoglobulin E (568 kU/L), and a slightly elevated antinuclear antibody level (1: 320 titer). The other blood tests, p-ANCA, c-ANCA, ENA titer, rheumatoid factor, and hepatitis serology, were negative. Subsequently, EGPA pursuant to the American College of Rheumatology (ACR) 1990 criteria was diagnosed. A chest X-ray and lung function tests, electrocardiography, transthoracic echocardiography (echo), and a stool culture were normal. After ruling out the involvement of other organs, 100 mg per day of oral methylprednisolone (1.5 mg/kg/day) was administered, which was gradually tapered afterwards. Upon observing clinical improvements under methylprednisolone, oral azathioprine at 50 mg daily was administered as an immunosuppressive agent. The dosage was later increased to 150 mg daily. Seven weeks later, the patient showed up in our clinic with complete clinical and laboratory remission (Fig. 3). By then, he was taking methylprednisolone 20 mg daily and azathioprine 150 mg daily (2 mg/kg).

antineutrophil cytoplasmic antibody-associated vasculitis, azathioprine, eosinophilic granulomatosis with polyangiitis

PMC3634206_01

Female

A 25-year-old female presented with a painless lump in her right breast for 1 month duration. She gave history of low grade fever off and on for the last 2 weeks. There were no other complaints like weight loss, loss of appetite, and any cough. She was unmarried and there was no positive family history of breast tuberculosis. On local examination, a non-tender lump of size 3 x 4 cm was felt in lower quadrant of the breast [marked with a line as a - Figure 1]. It was freely mobile and no axillary nodes were present. Another 1 x 1.5 cm swelling was present in infra-mammary area just below and medial to the above mentioned lump [marked by line b; Figure 1]. Her systemic examination was non-contributory. On routine blood investigations, total leucocyte count was 12,000 mm3 and erythrocyte sedimentation rate (ESR) was 60 mm at the end of 1 h, and HIV test was negative. Her fasting blood sugar and blood urea levels were normal. Chest X-ray was normal. Fine needle aspiration cytology (FNAC) of the breast and infra-mammary lump showed granulomas, epitheloid cells, and mixed inflammatory cells [Figure 2]. Background consisted of necrotic material and ZN stain for acid fast bacilli (AFB) was positive in the FNAC of both lumps. Mountex test was not done as on FNAC diagnosis already was made. Final diagnosis made as breast TB. She was put on a 6-month course of anti-tubercular therapy with a 2 month intensive phase of rifampicin, isoniazid, ethambutol, and pyrazinamide followed by a consolidation phase of rifampicin and isoniazid for another 4 months. The lump size was decreased within 3 weeks of initiation of ATT and at 3 month follow-up the patient remains asymptomatic and both lumps disappeared. She was advised to continue treatment.

abscess, breast, extra–pulmonary, infra-mammary, lump, tuberculosis

PMC4835740_01

Male

A 24-year-old man presented to the emergency department with dyspnea and persistent cough. In physical exam, no abnormality was found. His past medical history was normal. Such an episode occasionally presented in the past year. There was no recent weight loss, cough, sputum production, exposure to tuberculosis, joint pain, or rash. The electrocardiogram (ECG) was normal. Chest X-ray showed a large opacity obscuring the right heart border (Figure 1). His trans-thoracic echocardiogram showed an echo-lucent space next to the right atrium at the right cardiophrenic angle. His echocardiogram was normal, and no pericardial effusion was found. The apical four-chamber view of the transthoracic echocardiogram showed an echolucent space next to the right atrium at the right cardiophrenic angle, consistent with a pericardial cyst. The right and left ventricular chamber size and function were normal, and there was no valvular heart disease Then computed tomography (CT) was recommended. CT revealed no pleural effusions, and a large fluid collection at the right pericardial border (Figure 2). Extensive work-up for infectious and inflammatory causes, including blood cultures, viral antibodies, sputum acid fast bacilli's (AFB), PPD testing, and collagen vascular disease markers was negative. The patient was referred to a cardiac surgeon. After midsternotomy, the pericardium was opened. No fluid or pathologic finding was seen in the pericardium. On the right side and outside the pericardium, a huge pericardial cyst measuring approximately 13 x 8 x 5 cm in diameter was found and totally excised (Figures 3 and 4). After 5 days, the patient was discharged uneventfully. Pathologic report confirmed the diagnosis. The patient remains symptom-free in the 12 month follow-up visit.

cardiac surgery, mediastinal cyst, pericardial cyst

PMC2813617_01

Female

An 18-year-old female with recurrent esophageal variceal bleeding due to extrahepatic portal venous obstruction was referred to us for surgical management. On general physical examination she was pale. There was no jaundice or lymphadenopathy. Abdominal examination disclosed a massive splenomegaly (12 cm below the costal margin). Laboratory tests revealed a hemoglobin of 85 g/L, a total leucocyte count of 4.2x109/L and the platelets were 30x109/L. Liver function tests and other biochemical investigations were within normal limits. Color Doppler sonography revealed multiple collateral channels replacing the portal vein (portal cavernoma) and massive splenomegaly. Furthermore, it demonstrated multiple, small foci of echogenic nodules with no acoustic shadowing in the spleen. Non-enhanced CT divulged massive splenomagaly with a pressure effect on the ipsilateral kidney and multiple, discrete, millimetric hyperdense spots in the spleen (Figure 1). A contrast-enhanced splenoportovenogram confirmed the presence of portal cavernoma, esophageal varices, multiple perisplenic collaterals and extensive thrombosis of the splenoportal venous axis. A diagnosis of extrahepatic portal vein obstruction leading to portal hypertension was made. Pneumococcal and Haemophilus influenzae vaccines were given and the patient underwent a modified Suguira procedure consisting of extensive esophagogastric devascularization combined with esophageal transaction, reanastomosis and splenectomy. The postoperative hospital period was uneventful and the patient was discharged on the tenth postoperative day. Histopathological examination of the spleen disclosed an abnormality. What is the preoperative diagnosis of the splenic lesions? What is the differential diagnosis of small, discrete, hyperdense splenic lesions? This patient had ultrasound evidence of splenomegaly with discrete, multiple, small echogenic foci in the splenic parenchyma. Both color Doppler and CT splenoportovenography revealed evidence of extrahepatic portal hypertension. In addition, CT confirmed the presence of multiple hyperdense foci in the splenic parenchyma (Figure 1). In this clinical setting, the splenic lesions represent Gamna-Gandy bodies (GGB). The differential diagnosis of small, discrete, hyperdense splenic lesions apart from GGB would also include sarcoidosis, miliary tuberculosis, histoplasmosis and Pneumocystitis carinii infection. Microscopic examination of the splenic lesions revealed typical spheroid, bamboo-shaped fibers resembling mycelial structures (Figure 2, 3). There was also evidence of infiltration of the macrophages and foreign body giant cells. Hence, a histopathological diagnosis of GGB in the spleen was made.

PMC7403915_01

Female

A 37-year-old female with no past medical or ocular history presented with 2 weeks of redness, pain, and photophobia of her right eye (OD). She was diagnosed with acute anterior uveitis by an outside provider and started on topical difluprednate four times daily (QID) and cyclopentolate once daily (QD) OD. Upon presentation to our facility, she reported slight improvement in her symptoms 2 weeks into treatment. On initial examination, visual acuity was 20/20 in her right and 20/20 in her left eye (OS) with unremarkable pupillary exam and normal intraocular pressure. Anterior segment examination of the right eye (OD) revealed 2 areas of anterior corneal stromal scarring and 0.5+ anterior chamber cell without flare. One area of anterior stromal scarring and trace cell without flare was seen OS. Fundoscopy revealed 0.5+ vitreous cell without haze in both eyes (OU); healthy appearing optic nerves OU; and extensive, serpentine peripapillary chorioretinal scarring OU with extension into the macula (Figures 1(a) and 1(b)). There were no hemorrhages or vascular sheathing, and the peripheral retina was unremarkable. Fluorescein angiography (FA) was performed, which demonstrated hyperfluorescence at the lesion margins visible on gross funduscopy. Fundus autofluorescence (FAF) demonstrated hyperautofluoresence at lesion margins and hypoautofluorescence in areas of atrophic retina. Pertinent laboratory workup included negative QuantiFERON-TB Gold, fluorescent treponemal antibody (FTA), and Lyme IgM and IgG. A diagnosis of serpiginous choroidopathy was made, and the patient started on oral prednisone 60 mg daily, with a taper of the difluprednate OD by one drop per week. The patient rapidly improved, and immunomodulatory therapy was initiated with a standard steroid taper. At one-month follow-up, en face OCT reflectance and OCTA imaging were obtained, which demonstrated severe atrophy with outer retinal tubules and patchy dropout of choriocapillaris in areas of otherwise normal-appearing retina, respectively (Figure 2). Over the next 2 months, the prednisone was slowly tapered and she continued mycophenolate mofetil 1 gram twice daily without recurrence of intraocular inflammation or activation of disease at the lesion margins. Repeat SD-OCT and OCTA imaging remained stable.

PMC6029598_01

Female

Hypertension is highly prevalent in Malawi with nearly a third of 25- to 64-year-olds having raised blood pressure or taking antihypertensive medication. This is consistent with data that suggest an increasing prevalence throughout the African region with a marked rural-urban gradient implicating changes in lifestyle as a key contributor. Figure 1 demonstrates how age-standardized prevalence rates of hypertension in Malawi and SSA have increased over the past 40 years and now exceed the falling rates in high-income Western countries. The global risk factor analysis carried out by the INTERSTROKE study estimated the population attributable risk resulting from hypertension for all types of stroke to be 90.3%. This may help to explain the WHO statistics that attribute the majority of Malawi's CVD mortality to stroke; 5.7% of all deaths, compared to 3.3% for ischemic heart disease. One study from a large tertiary hospital in the northern region of Malawi reported that patients with hypertensive heart disease accounted for almost a quarter (24%) of those attending outpatient cardiology clinics. Many studies have shown preponderance for people of Afro-Caribbean ethnicity to develop hypertension and hypertension-related complications earlier and more frequently than Caucasian people, which are attributed to several proposed physiological differences. These include a reduced suppression of the renin-angiotensin-aldosterone system in the setting of high sodium intake and a lower threshold for pressure-mediated vascular dysfunction. Studies demonstrating these ethnic differences have reported a higher stroke rate in African participants but a lower risk of coronary artery disease. However, these studies are often confounded by marked socioeconomic differences between the 2 groups. Smoking-related mortality from CVD in Malawi has increased by 20% over the 23-year period from 1990 to 2013, though this in fact constituted a 31% increase in males and a 3% decrease in females. Despite these figures - and despite a commensurate increase in CVD mortality - CVD mortality rate in men is less than in women. This indicates that cardiovascular risk in Malawi is truly multifactorial, whereby certain factors such as obesity and raised cholesterol that are significantly more prevalent in women may outweigh the increased risk in men caused by a higher smoking rate. The poor affordability of cigarettes and the typically high nicotine content of Malawian tobacco mean that fewer cigarettes are smoked per day by the average "smoker" than in a developed country (rarely more than 5). This may make smoking tobacco a weaker risk factor for CVD in this population. Dietary factors like low seed, nut, and vegetable intake and high sodium intake are regarded as risk behaviors contributing to the increase of CVDs across SSA. Sodium intake is increasing, with every published sodium consumption study in Tanzania (with which Malawi shares a border to the north-east) reporting consumption greater than the WHO set guidance limits of 2 g/day. Data from Malawi are scarce, with only 1 study published in 1986, which although it demonstrated intake below the 2 g limit, also demonstrated that intake in urban areas was almost double that of rural areas (0.86 g vs 1.65 g). Globally, 1.7 million CVD deaths each year are estimated to be due to excess sodium intake. Multiple meta-analyses have demonstrated the correlation between low fruit and vegetable intake and an increase in both all-cause and cardiovascular mortality, often attributed to the deficiency in protective compounds contained in them including vitamin C and flavonoids, which may help to reduce oxidant vascular damage. The paucity of data on this subject in Africa is evident and no meta-analyses on this subject include studies from the region. Obesity can be regarded as a disorder of chronic inflammation and is likely to contribute to CVD by additional mechanisms independent of its contribution to a state of insulin resistance (explained in the following text). CRD include chronic obstructive pulmonary disease (COPD), asthma, and occupational lung diseases. Although endemic in Malawi, these diseases are often overlooked, and data are scarce due to much of the focus being on the much larger burden of communicable lung diseases such as TB, childhood pneumonia, and HIV-related lung diseases such as pneumocystis pneumonia. Malawi has a low prevalence of asthma of approximately 5%, especially when compared to the UK, which has one of the world's highest prevalence rates of >12%. Despite this, it is likely that asthma remains underdiagnosed and under-treated in Malawi, evidenced by an asthma age-standardized mortality rate higher than that of the UK. As well as this, the ISAAC study series has shown a trend of increasing incidence across the African region indicating that the epidemiological transition may be accompanied by a commensurate rise in asthma rates consistent with the "hygiene hypothesis" of asthma pathogenesis. Smoking epidemiology is described previously; more men and fewer women smoke in Malawi than the average number in low-income countries. The major obstacles that Malawi faces in combating smoking rates and related mortality are related to being one of the most tobacco-dependent economies in the world, with little regulation on the sale and advertisement of tobacco products. An economy so dependent on an industry with a combined revenue far in excess of Malawi's GDP weakens the ability to legislate to enforce effective public health policies against tobacco consumption. The financial and political pressure exerted by the tobacco industry has been highlighted in recent years by high-profile cases like the 2010 legal case "Phillip Morris vs Uruguay" where a large tobacco multinational company attempted to sue a country for brand devaluation due to the introduction of anti-smoking legislation. Recent reports have revealed court cases against African countries by multinational companies including Uganda, Kenya, and the Democratic Republic of Congo. Asthma allergens and risk factors implicated in asthma differ from those established in North-America and Europe, though mostly due to differences in occupational exposures and local fauna rather than differing pathogenesis. Some studies have suggested that infections with helminths such as Schistosoma, which is found in abundance in Lake Malawi, may attenuate the atopic response to allergens. A study in Gabonese children found that those with urinary schistosomiasis reacted to dust-mite allergen skin prick less frequently than those without. Occupational lung disease in Malawi is not well researched but certain workers are recognized to be at risk, namely those in the textiles, wood-cutting, tea and coffee processing, and tobacco industries. Malawi is one of the top 10 exporters of tobacco worldwide and there is likely to be an underappreciated burden of occupational disease associated with its production. "Tobacco Worker's Lung" is an extrinsic allergic alveolitis in response to the Aspergillus fungus that is often found in fields and factories; there are no data on the incidence in Malawi. Ambient air pollution is recognized as a global risk factor for respiratory disease and is emerging as a previously under-appreciated risk factor for CVD. Two industrializing African urban centers, Kaduna (Nigeria) and Kampala (Uganda), were highlighted in a recent study where harm from inhaled particulate matter was estimated to negate the health benefits of cycling after 105 and 90 minutes, respectively. The high levels of particulate matter in these cases are usually attributable to unregulated industrial emissions, low-quality fuel combustion, and the burning of waste material for disposal. Levels of such particulate matter are low in Malawi with its small industrial sector, reliance on renewable energy (95% of national grid electricity coming from a hydroelectric source), and 85% of the population living in rural areas. However, the population may instead be at increased risk from high levels of "indoor" air pollution. Only 9% of the Malawian population is connected to the power grid, with this minority also experiencing regular power cuts. This means 95% of people rely on burning wood or other plant materials as their main source of domestic energy. In a 2008 study of 62 Malawian homes, 100% had fine particulate matter levels that exceeded WHO limits for outdoor air. Although no studies exist in Malawi, biomass fuel use is an established risk factor for the development of COPD and may in fact be the most important risk factor worldwide. Indoor pollution in Malawi may be a more significant problem in females, especially due to the cultural practice of spending more time cooking with biomass in poorly ventilated homes. This may explain a Ugandan study that described similar COPD prevalence in both sexes despite more than double the proportion of women with COPD being never smokers (74% vs 31%). It has been suggested that biomass-related COPD represents a separate disease phenotype with a younger age of onset (earlier exposure), more frequent symptomatic wheeze, and less parenchymal damage. The large burden of infectious disease has a significant effect on the epidemiology of cancer in Malawi. Worldwide, cancer is predominantly a disease of later life; with life expectancy in Malawi averaging 59 years for males and 60 years for females, a low incidence of cancer could be expected. However, for some types of cancer Malawi has some of the highest incidence rates in the world. Infectious agents have a role in the pathogenesis of many cancers in Malawi, and the endemic nature of these infections, in addition to a high number of immunocompromised individuals due to coexisting HIV infection (1 in 10 people), is likely to contribute to these high rates. Cancer surgery with curative intent is very limited in Malawi, and management of most solid tumors is palliative. Overall, the age-standardized incidence rates for all cancers in Malawi is 156 cases per 100,000, which although higher than the average for SSA of 121 is still much lower than the rates in high-income Western countries, the EU average standing at 278 and the USA at 318. Esophageal cancer incidence rates in Malawi are the highest in the world at 24.2 cases per 100,000 with no single identifiable causative risk factor. The current consensus is that the excess risk is multifactorial and may be a combination of high levels of aflatoxin in the diet (a mycotoxin found in improperly stored maize, the staple crop in Malawi), high strength alcohol consumption and tobacco consumption. There has been specific interest in the homebrewed maize spirit known as Kachasu due to its high alcohol percentage (up to 70%) and high levels of nitrosamines and contaminants such as zinc. There is an indication that HIV infection may have a role in esophageal carcinogenesis, with 1 study noting that esophageal cancer rates have paralleled those of Kaposi's sarcoma. Kaposi's sarcoma is the most common cancer in Malawi, constituting over 50% of all cancer diagnoses. The pathogenesis of Kaposi's sarcoma is related to infection with human herpesvirus-8 in HIV-positive patients with low CD4 counts. Bladder cancer mortality rates in Malawi are the 3rd highest in Africa. As previously mentioned, infection with the helminths Schistosoma haematobium and Schistosoma mansoni is common in Malawi, with a systematic review finding reports of prevalence in some areas as high as 94.9% and 67.0%, respectively. Schistosomal infection of the bladder is a recognized risk factor for the development of squamous cell carcinoma of the bladder (SCC) with egg deposition in the bladder wall causing local inflammation and enabling some schistosomal antigens to inhibit host cell apoptosis. Unlike the predominantly transitional cell tumors seen in developed countries, schistosomal-associated SCC is usually well differentiated and only locally invasive. Despite this, late presentation and few facilities for resection mean that mortality in Malawi remains high. Cervical cancer incidence and mortality in Malawi are the highest in the world and it is the most commonly diagnosed cancer in Malawian females at 75.9 cases per 100,000. This is attributed to the high prevalence of human papillomavirus (HPV) infection, which is known to lead to dyskaryosis and malignant change of the cervical epithelium. HPV and HIV are both thought to predispose to infection with each other, and HIV co-infection is believed to accelerate the rate of malignant transformation in those with HPV-related dyskaryosis; the high levels of both viruses in the population act synergistically to produce the high incidence rates of cervical cancer. In Malawi, non-Hodgkin's lymphoma (NHL) is the third most commonly diagnosed cancer. These are predominantly cases of Burkitt lymphoma (BL), a B-cell lymphoma that is characterized by a range of chromosomal translocations and genetic mutations; particularly of the c-myc oncogene. Epstein-Barr virus (EBV) is believed to have a role in the deregulation of this oncogene as well as promoting the survival of malignant cells. Epidemiological clustering of both diseases suggests an association between BL and Plasmodium falciparum infection, though a definitive role and interaction with EBV has not been established. Certain plant toxins such as those from the Euphorbiaceae family have been suggested as co-factors in BL development and have been shown to induce EBV-associated chromosomal abnormalities in vitro. A 1993 case-control study from Malawi reported that people with BL were significantly more likely to have Euphorbiaceae plants at their homes. The occurrence rate of BL is also increased in people with concurrent HIV infection, which increases the occurrence of all types of NHL by a factor of 60-200. Diabetes prevalence is increasing throughout SSA, with the age-standardized prevalence rates for men in Malawi and SSA approaching those rates in high-income Western countries and rates in women surpassing them (Figure 2). Much of this increase is due to the rise in type 2 diabetes, although epidemiological studies do not differentiate between type 1 and 2. The paucity of data from throughout the African region means that prevalence and trends are based on estimation calculations using low-quality epidemiological studies; in a Lancet worldwide diabetes study "21 (39%) of the 54 countries without data were in sub-Saharan Africa". Estimates of prevalence in Malawi range from 2.3% (updated figures seen when URL was updated) (IDF) to 5.7% (2009 STEPS Survey), the latter approaching the prevalence in the UK (6%) despite having less than half of the percentage of people classed as overweight or obese (21.9% vs 62.9%). The dominant theory of diabetes risk is one of "lifestyle factors" whereby an increasingly sedentary lifestyle with concurrent calorie excess predisposes to the development of the "metabolic syndrome". Diabetes epidemiology in SSA shows a 2-5 times increased risk for diabetes or impaired fasting glucose in urban areas, which are more associated with these lifestyle risk factors. With rural to urban migration forming part of the wider epidemiological transition across the region (SSA has the fastest urbanization rate in the world), this trend is likely to continue. In keeping with worldwide trends, studies across Africa show a significant positive correlation between increased body mass index (BMI) and diabetes risk. More than 1 in 5 Malawians are overweight or obese, with the rate in females significantly greater than in males (28.1% vs 16.1%). Debate remains over the best measure of adiposity in African populations due to a lack of data. Some studies have suggested that African populations may have a lower percentage body fat than Europid populations at the same BMI, although epidemiological data for the SSA regions indicated that they may develop diabetes at lower BMIs on average. Roles for other measurements like waist circumference (WC) and waist hip ratio (WHR) have not been established but in a small study in northern Malawi, WHR was found to have a greater sensitivity to detect diabetes patients than BMI and WC when using WHO-recommended cutoffs. It appears that the central distribution of this more hormonally active fat is important, with 1 study including Afro-Caribbean participants finding that WC was associated with metabolic syndrome clustering, independent of BMI. Growing service sector industries and changing leisure activities across SSA mean people are engaging in less physical activity. Job transition from agricultural to service sectors typically is associated with a decrease in physical activity, and recreational exercise is a culturally uncommon pastime, perhaps due to the historically strenuous nature of subsistence farming. One Cameroonian study reported significantly decreased energy expenditure in urban dwellers compared to rural dwellers as well as a significantly increased rate of diabetes. Urban dwellers recorded shorter walking and cycling times per week and "lighter intensity" occupations. The trend of decreasing physical activity as SSA undergoes further economic development will likely worsen the "energy imbalance" associated with the obesity epidemic whilst also increasing diabetes risk by mechanisms independent of weight gain. A number of prospective and cross-sectional studies have shown even moderate exercise to reduce the risk of developing diabetes across numerous ethnic groups, believed to be due to exercise-induced augmentation of insulin action. Aside from calorie excess, additional dietary factors have been associated with diabetes risk and are prevalent in Malawi. Data from the Nurses' Health Study showed that participants with a diet of high glycemic load or glycemic index in addition to low cereal fiber intake had an approximately 50% increased risk of developing diabetes. In Malawi, the staple carbohydrate dish Nsima is made from ground maize (cornmeal) and water; it has both a high glycemic index (94.06 in 1 study) and low cereal fiber content. Nsima can be made from flour of various particle sizes according to grinding. Smaller particle flour increases the glycemic index of the meal and the ability to adjust the level of grinding, and therefore adjustment of the glycemic profile of the meal presents an opportunity to reduce dietary risk with simple changes to food preparation. Fiber and antioxidant (especially vitamin C) intake from fruit and vegetables has shown associations with decreased diabetes risk in observational studies but the exact significance is unclear. In the Malawi STEPS survey, fruit and vegetable intake was low with 97.5% of people eating fewer than 5 servings of fruit and vegetables per day, the average being 2.1 servings a day. Sugar sweetened beverages (SSBs) or "soft drinks" are widely consumed in Malawi and are available for lower prices than bottled water at many retailers. Consumption is increasing - especially in young people, with 1 study of Malawian schoolchildren reporting that 50 out of 60 (83.3%) were consuming SSBs at least once a day. A meta-analysis of 11 studies showed that people consuming this level of SSB had a 26% greater risk of developing metabolic syndrome or diabetes than those consuming <1 a month, proposed to be the effect of the added dietary glycemic load. Hypertension in Malawi is most often managed using thiazide diuretics due to their low cost and widespread availability. Insulin resistance and hyperglycemia are recognized side effects of thiazide medications and widespread use may be contributing to diabetes risk. As is clear in the case of cancer, often a distinction between communicable diseases and NCDs is not possible - especially in a population where HIV is endemic. HIV is increasingly recognized as a risk factor for CVD, with a meta-analysis of 20 studies reporting the relative risk of CVD, in HIV-infected patients compared to uninfected patients, to be 1.61. Antiretroviral drugs used to treat HIV can cause hypertriglyceridemia, hypercholesterolemia, and hyperglycemia; in the same study, the relative risk for HIV patients taking ART treatment was higher at 2.00. The hyperglycemia side effect - especially from protease inhibitors - may also contribute to diabetes risk. Reciprocally, NCDs may increase the burden of communicable disease, for example diabetes patients are over 3 times more likely to become infected with TB. These findings are the basis of the bidirectional screening programs that are being established in some low-middle income countries. Early intervention in Malawi's NCD epidemic may be more effective in reducing risk behaviors and adjusting how health care infrastructure is developed. For example, taxation to deter the purchase of calorie dense convenience foods and SSBs is likely to be more politically acceptable and effective if introduced before consumption becomes more widespread. Two important primary steps to address NCD rates in Malawi would be to gather more epidemiological data, especially regarding prevalence, and establish a health promotion strategy to raise awareness about the most common NCDs, to health care providers and the public. Electronic registries to collect data on NCDs would be relatively simple to set up with the ability to attach additional modules to existing systems already used to manage and monitor HIV patients. A campaign of health promotion is essential to help control rates of all NCDs in Malawi, from CVD where almost all dietary sodium is added during the cooking process, to respiratory disease and cancer where the health implications of tobacco are poorly publicized, especially on packaging. Promoting better ventilation whilst using wood burning stoves inside the home, such as using the stove in doorways or next to windows, is a simple way to help reduce the exposure to indoor air pollution. Health promotion strategies for the public can be modeled on those currently used for HIV where print materials, television broadcasts, and public billboards have all been utilized to good effect. SMS-based health promotion is also emerging as an effective way to deliver health education in an inexpensive and widespread manner as mobile phone ownership continues to increase rapidly across SSA. In the case of diabetes and CVD, cultural beliefs regarding what constitutes a health body weight may be contributing toward rising obesity rates. In a small outpatient survey of 40 patients in northern Malawi, 57.4% of respondents selected a BMI of 40 kg/m2 as the "healthiest body weight" when presented with 5 images corresponding to BMIs ranging from 18 to 40 kg/m2. The reasons for this are complex; it is a combination of the cultural perceptions of body image in addition to obesity reflecting wealth and status and weight loss being associated with the wasting from AIDS and malnutrition. In this instance, educational initiatives targeted at schoolchildren and already effectively employed in HIV education can begin to challenge these beliefs about body weight. National standards could be set for school curricula to focus on dietary education, for example teaching portion control by using tangible measurements like a fist. There could also be a greater emphasis on structured recreational sports to help make exercise a more normal part of daily life from an early age. Governmental funding for such schemes is low, and these public health campaigns are usually provided by non-governmental organizations and charities. Although taking on an additional educational initiative could be an overwhelming workload, the current HIV campaign is becoming increasingly self-sufficient within the involved schools and it is important to utilize the existing infrastructure to promote awareness of other diseases.

malawi, cancer, cardiovascular disease, chronic respiratory disease, diabetes, non-communicable diseases

PMC9048082_01

Male

A 64-year-old male with a history of moderate persistent asthma and long-standing interstitial lung disease (ILD) classified several years ago as bronchiolitis obliterans with organizing pneumonia (BOOP) presented to general pulmonary clinic with a progressively worsening cough and sputum production. Recently he had been increasing use of his albuterol rescue inhaler to multiple times daily. He previously carried the diagnosis of BOOP from an outside hospital in 1992 incidentally noted on CXR imaging. He was additionally found to be purified protein derivative (PPD) positive at that time and treated with isoniazid for 6 months for latent tuberculosis. He was followed with serial pulmonary function testing and imaging noting stable disease for years prior to establishing care at our clinic. He had an extensive travel history to several African countries. An HRCT of his chest showed diffuse peribronchovascular consolidations with basilar and peripheral predominance, and diffuse perivascular calcifications (Fig. 1, Fig. 2, Fig. 3, Fig. 4). His right lower lobe showed subpleural scarring, and his left lower lobe showed bronchial obstruction with distal reconstitution. Serologic work-up was negative for autoimmune conditions, immunodeficiencies, chronic infections, and cystic fibrosis. Absolute eosinophils were noted to be 1168 cells/uL on complete blood count with differential (CBC). Serum IgE was elevated at 1133 kU/L, with positive IgE for Aspergillus fumigatus at 6.12 kU/L. He was diagnosed with allergic bronchopulmonary aspergillosis (ABPA) and started on treatment with two weeks of prednisone 30mg oral daily followed by a six month prolonged taper. Following this taper, the patient reported significant symptomatic improvement and continued his maintenance treatment for asthma and airway clearance. Later surveillance imaging after treatment did not show any significant change in his imaging findings. Serum IgE downtrended to 167 kU/L and peripheral eosinophils decreased to 377 cell/uL with steroid treatment.

abpa, allergy, aspergillosis, asthma, radiology

Transverse slice of a high resolution computed tomographic scan of the chest on inspiration with thin slices using lung windowing demonstrating both the bilateral pulmonary opacities, calcifications, and mild bronchiectasis throughout the bilateral lower lobes of the lungs.

PMC7322736_01

Male

A 58 year-old gentleman presented to the hospital with worsening bloating and a gradual increase in his abdominal girth. He had also noted a loss of weight of more than 10 kg over the last 2 years. The patient otherwise denied any abdominal pain or change in his bowel habit. He was known to have a history of well-controlled diabetes mellitus, hypertension, hyperlipidaemia and atrial fibrillation. There was no previous history of pancreatitis or abdominal surgery. The patient had recently undergone a gastroscopy and colonoscopy the previous year for iron deficiency anaemia. This had shown gastritis as well as the presence of pandiverticular disease and a sub-centimeter colonic polyp. Histology showed the polyp to be a tubular adenoma with low-grade dysplasia (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6). Clinical examination showed an adequately nourished gentleman but with a large abdominal mass occupying most of his abdomen. It was possible to feel over the superior edge but the inferior edge extended into the pelvis. The mass was non-tender on palpation. Digital rectal examination was unremarkable. In view of the above findings, the patient underwent a computed tomography (CT) of the abdomen and pelvis. This showed a large 25 x 17 x 22 cm cystic lesion extending from the mid-abdomen to the pelvis. The lesion was thin walled and contained homogenous low density fluid (14 Hounsfield unit). There was no septations, irregularity or abnormal thickening of the cyst wall. The cyst was noted to have a mass effect but not invading the surrounding bowel loops and the urinary bladder. It was found to be separate from the liver and the kidneys. The pancreas was normal in appearance. The CT scan was otherwise unable to identify the origin of the giant cyst. As this was a thin walled cyst with no irregular or solid component, a fine needle aspiration (FNA) was not suitable as there was no specific area to target. Aspiration of the fluid was also unlikely to yield any meaningful finding for diagnosis. Further imaging such as a MRI would also not help in identifying the origin or the diagnosis of the cyst. The possibility of a mesenteric or omental cyst was therefore discussed and surgical excision was offered to the patient. Tumour markers were not performed as it would not have affected the management. An elective exploratory laparotomy was performed via a midline incision. A giant cyst was immediately identified but was found to have multiple adhesions to the peritoneum, omentum, mesentery, urinary bladder as well as the small and large intestines. However, the cyst was not found to be originating from any of the above organs or the vas deferens. The cyst was entirely within the abdominal cavity and did not originate from within the mesentery. A controlled decompression of the cyst was made through a purse-string encircled incision in the anterior wall. This was performed to aid with retraction and visualization of the posterior surface. Thick purulent fluid was aspirated until dry. The cyst was subsequently excised in whole. The patient underwent an uneventful recovery with a brief period of expected post-operative ileus. He was discharged on post-operative day 6. Follow-up visits showed complete resolution of his initial symptoms and a vast improvement in his appetite. Culture of the fluid was positive for Streptococcus agalactiae. Fungal culture and tuberculosis polymerase chain reaction (TB PCR) tests were negative. Cytology of the fluid showed mainly neutrophils. Histological examination of the cyst showed thick fibrous walls covered with coarse fibrillary strands admixed with fibrin. There were also large numbers of mature IgG plasma cells with aggregates of neutrophils and scattered lymphocytes. No viable epithelial lining was identified. The walls stained positive for AE1/3 suggesting myofibroblasts. They were negative for CD117 and DOG-1 and therefore not suggestive of a gastrointestinal stromal tumour. This was therefore treated as a benign cyst of an undetermined origin. The patient was last seen in clinic two months after his surgery with a significant improvement in his appetite and oral intake. He was thereafter discharged from follow-up as the likelihood of recurrence was low considering that the cyst had been excised entirely with no remnant wall left behind.

giant cyst, intra-abdominal cyst

PMC7737464_02

Male

This male infant was born at term and had uneventful perinatal and postnatal periods until about 4 months of age. His birth weight was 2.8 kg. Unfortunately, he was not screened for the presence of TREC at birth, as current national neonatal screening programs in the UAE does not include testing for primary immunodeficiencies. At birth, he received the routine BCG and hepatitis B vaccines. At 2 and 4 months of age, he received the routine DTaP (diphtheria, tetanus, acellular pertussis), HiB (haemophilus influenzae type b conjugate), and 13-valent pneumococcal conjugate, rotavirus (RV1,Rotarix ), and oral IP (inactivated polio) vaccines. At 41/2 months, he developed severe respiratory infection and refractory diarrhea, which required hospitalization and intravenous antibiotics. His blood and stool cultures were negative. The stool was positive for rotavirus. His chest radiographs showed bilateral infiltrations, and the thymus was not visible (Figure 1(a)). On admission, his neutrophil count was 10.5 x 109/L and lymphocyte count was 10.4 x 109/L, with a normal hemoglobin concentration and platelet count. His serum IgE and IgA were unmeasurable, IgG <0.5 g/L (normal, 3.5 to 12.2), and IgM = 0.14 (normal, 0.18 to 1.08). He was started on a regular intravenous gammaglobulin infusion. The results of his lymphocyte immunophenotyping were as follows: total lymphocyte count, 3,715/microL; CD3+, 96 cells/microL (normal: 2,530 to 4,510); CD4+, 82 cells/microL (normal: 1,640 to 2,980); CD8+, 1 cell/microL (normal: 780 to 1,500); CD19+, 3,000 cells/microL (normal: 1,160 to 2,420); and NK, 514 cells/microL. Diagnostic (whole) exome sequencing revealed two pathogenic variants: homozygous NM_000732.4(CD3D):c.128G > A, p.Trp43* (VCV000643120.1; pathogenic; https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQUEST=CCDS&DATA=CCDS8394) and hemizygous NM_001287344.1 (BTK):c.80G > A, p.Gly27Asp (novel). Pathologic variants of CD3D (CD3 antigen, delta subunit, autosomal recessive; MIM#186790) cause "immunodeficiency type 19" (MIM#615617). His CD3D variant creates a premature stop-gain, resulting in a loss-of-function due to absent protein product. Pathologic variants of BTK (Bruton agammaglobulinemia tyrosine kinase; MIM#300300), on the other hand, cause "agammaglobulinemia, X-linked 1 (MIM#300755) and "isolated growth hormone deficiency, type III, with agammaglobulinemia" (MIM#307200). His novel BTK variant had conflicting predictions of interpretation: MutationTaster: 0.810 (pathogenic), LoFtool: 0.953 (pathogenic), and CADD: 7.6 (benign). The parents, second cousins, had four healthy boys and one healthy daughter. They also had a daughter who passed away at the age of 4 months of an undetermined disease. The mother had four miscarriages in the first trimester. In addition, she and six of her sisters had hypothyroidism; one sister also had autoimmune hepatitis. Over the following six weeks, he continued to suffer from high-fever, dyspnea (requiring oxygen), maculopapular rash, severe oral thrush, poor feeding, severe diarrhea, failure-to-thrive, and E. coli urosepsis. On physical examination, he had moderate hepatomegaly, mild splenomegaly, and palpable left axillary lymph nodes; the largest measured about 2 cm in diameter. Neck, chest, and abdominal CT scans confirmed generalized lymphadenopathy, including his left axillary lymph nodes (Figure 1(b)). Excisional left axillary lymph node biopsy showed numerous acid-fast bacilli (AFB), consistent with tuberculous (TB) lymphadenitis (Figure 2). As expected, IGRA (Interferon Gamma Release Assay) was negative. His BCG-related lymphadenitis and systemic TB infection were treated with rifampicin, isoniazid, ethambutol, and pyridoxine. He was maintained on regular immunoglobulin infusion, trimethoprim-sulfamethoxazole for Pneumocystis jiroveci prophylaxis, fluconazole for fungal prophylaxis, and broad-spectrum antibiotics. His brother was a 10/10 HLA match. Bone marrow transplantation was performed before 8 months of age.

PMC2939501_01

Male

A fifteen-year-old male presented at 0100 to the local emergency department complaining of increasing dyspnea, chest pain and a sore throat. He denied any nasal discharge, cough, nausea or vomiting. His symptoms had started the previous afternoon on the first day of football practice. He had been running 24 100-yard sprints as a conditioning exercise, and about 2/3-way through, he started becoming symptomatic. There had been no contact drills. He had been able to complete the exercise, but his symptoms continued to worsen throughout the evening. He never had a similar episode. He did not recall any Valsalva-like maneuvers, nor did he lift any weights. He denied being a smoker and had no past history of asthma, respiratory problems, or other significant health issues. He denied any illicit or recreational drug use. On exam, the patient was a 6'3'', 270 lbs, large teenager who appeared slightly dyspneic, but not distressed. Blood pressure was 128/70, heart rate 80, respiratory rate 28, and temperature 97.8 F; SaO2 was 97% on room air. HEENT exam was unremarkable, and the oral cavity showed normal appearing tonsils and a midline uvula. Speech was normal sounding, with no nasal quality. There was no erythema and no exudates. There was no subcutaneous emphysema or crepitus in the neck or the chest area. Lungs were clear to auscultation bilaterally with no adventitial lung sounds. CV showed a regular rate and rhythm with no murmurs, clicks, gallops, or extra heart sounds, specifically no systolic crepitations. Abdomen was benign, and the rest of the exam was unremarkable. Chest X-ray (Figure 1) showed subcutaneous emphysema, with air tracking into the neck area bilaterally, and a para-aortic air stripe of the left. There was also evidence of a minimal left apical pneumothorax (PNX). The trachea was midline, and the remainder of the lung fields and cardiac silhouette were normal. The patient was diagnosed with pneumomediastinum and transferred to a tertiary care facility where he was admitted, placed on high flow oxygen, and observed. Later that morning, he was still noted to be dyspneic and complaining of chest pain. The following morning, the patient was asymptomatic, and was discharged. At a followup visit to his pediatrician 2 weeks later, the chest X-ray (Figure 2, expiration view) showed complete resolution of his previous lung findings, and he was given clearance to return to physical activity.

PMC10410139_01

Male

Legend has it that Blues guitarist extraordinaire Robert Johnson sold his soul to the devil in return for being taught how to play the guitar. The deal was consummated at the crossroads of Highway 49 (known as the Blues Highway) and Route 61 in Clarksdale, Mississippi in 1927. Robert Johnson went on to become the father of American blues music, The King of the Delta Blues, spawning a generation and genre of African-American Blues musicians. It remains to be determined whether the podocyte in being positioned also at the crossroads of innate and adaptive immunity, was by divine intervention, or perhaps a deal made with the devil, similar to that of Robert Johnson. This is of more than passing interest, since it may well relate to podocyte longevity and lifetime/survival. You see, Robert Johnson died at the age of 27, starting a sad legacy of rock musicians who did not make it past their 27th birthday (see Supplemental Appendix). In a similar fashion, the podocyte may live out its functional existence in a normal fashion, or if it is involved in a disease process, for example focal segmental glomerulosclerosis (FSGS), may die young, the equivalent of an unfortunate 27 year-old rock musician. Please indulge this metaphysical conceit (with appreciation to John Donne), placing glomerular podocytes involved in FSGS in a position similar to doomed rock musicians. It is particularly fitting that it was Robert Johnson who wrote the song "Crossroads" (originally "Cross Road Blues"), emphasizing for us the intersection of two key immune pathways. Our mission is to determine how best to protect, preserve, and/or restore the life of our kidney rock star, the podocyte. Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with nephrotic syndrome and > 80% foot process effacement on electron microscopy. FSGS accounts for about 20% of cases of nephrotic syndrome in children and 40% in adults, and is the most common glomerular disorder leading to end stage kidney disease (ESKD) in the United States with a prevalence of 4%. Progression to ESKD occurs in 40-60% of patients within 10-20 years from diagnosis, making this the most common primary glomerular disease leading to dialysis in the United States. Despite many clinical trials, no effective treatment has been identified. Following transplantation, recurrence of FSGS occurs in 20-50% of adults and up to 80% in high-risk pediatric patients. Risk factors for recurrent FSGS include younger age (children less than 6 at onset), non-black race, rapid progression to ESKD (less than 3 years from diagnosis), severe proteinuria immediately prior to transplantation, and the loss of a previous allograft(s) to recurrence. Recurrence of FSGS increases the risk of renal dysfunction and early graft loss. Recurrence of FSGS can develop rapidly after transplantation, sometimes within minutes to hours, suggesting the presence of a circulating factor(s) that could mediate an early injury to the glomerulus. Further evidence includes the following: 1) plasmapheresis can induce remission of proteinuria, and 2) serum from patients with FSGS induces proteinuria in rats, and alters albumin permeability in isolated glomeruli. Moreover, in two clinical reports, living donor kidney transplant recipients who experienced severe recurrent FSGS, underwent transplant nephrectomy with re-transplantation of the affected kidney into a non-FSGS recipient resulting in rescue of the donor kidney function with resolution of proteinuria, providing further evidence for a circulating factor(s). Several review articles provide details supporting the existence of circulating factors that are beyond the scope of this article. Despite the lack of evidence of immune infiltrates in human FSGS biopsy samples, an immune component has been thought to contribute to FSGS. For example, the identification of IgM and C3 in glomerular deposits which was associated with both unfavorable response to therapy and worse renal outcomes supports this concept. T-cell involvement has been described in the Buffalo/Mna rat model of FSGS recurrence after renal transplantation, and in human recurrent FSGS needle aspirate samples. However, neither B cell nor T cell infiltrates are consistently found in FSGS. Nonetheless, immunosuppression, which was associated with reduced proteinuria in the Buffalo/Mna rat model, has been the main therapy in humans after plasmapheresis or plasma absorption. The most studied immune-directed therapies have included corticosteroids, inhibitors of T lymphocyte calcineurin (cyclosporine A and tacrolimus), alkylating agents (cyclophosphamide and chlorambucil), and mycophenolate mofetil. A number of case reports and non-controlled series have reported benefit from rituximab but this has not been universally successful. Similarly, it remains unclear if the benefit of these immunosuppressive agents is linked to immunomodulatory functions or to direct podocyte effects. The glomerular capillary wall consists of three layers: 1) the fenestrated endothelial cell, 2) the glomerular basement membrane (GBM), and 3) the podocyte, the last barrier to prevent loss of protein into Bowman's space. Thus, the podocyte is anatomically located in a position to be a sentinel for the kidney's innate immune system. The mammalian innate immune system was originally intended to protect its host from outside pathogens, for example viruses, bacteria and fungi - pathogen associated molecular patterns (PAMP's) and in the process distinguish self from non-self. The theory of immunity has since evolved to the recognition of danger signals proposed by Polly Matzinger and more recently to the discontinuity theory: that immune activation can be induced by changes (any) in the environment or the cell rather than by detection of specific, defined molecules. Ultimately, the innate immune response requires a balance between the appropriate degree of aggression in the face of a serious pathogenic threat, but also the ability to limit local tissue damage with a controlled response. Podocytes have been shown to express Toll-like receptors (TLRs), which recognize PAMPs, and certain endogenous signals, for example cellular breakdown products (Damage-Associated Molecular Patterns- DAMPs), e.g. reactive oxygen species, mitochondrial or, endoplasmic reticulum stress, DNA, RNA, nucleic acid fragments, etc.. TLRs which bind to DAMP's/PAMP's are part of the cellular (host) innate immune defense system, which, once activated, induce secretion of specific cytokines and chemokines that prompt the recruitment of other components of the innate immune response. TLR stimulation activates nuclear factor Kappa B (NF Kappa B) in podocytes, and key components of TLR signaling including MyD88, IRAK, TRAF 6, etc. ( Figure 1 ). It has been proposed that the podocyte's role in innate immunity may predispose it to injury, depending on chronicity. This is supported by the demonstration that TLR stimulation leads to podocyte apoptosis, and that blocking this pathway may prevent the progression of fibrosis and disease. In addition to TLRs there are a number of other important Pattern Recognition Receptors (PRRs) that are expressed by podocytes. These include the major components of the inflammasome, Nod-like receptors (NLRP3), ASC and caspase 1. The inflammasome is an intracellular protein complex involved in innate immune function including autophagy, apoptosis, fibrosis and secretion of pro-inflammatory cytokines including IL1-Beta and IL18. Podocytes also express retinoic acid-inducible gene 1 (RIG-1) that belongs to the family of RIG-I-like helicases that recognize viral RNA. Other family members include MDA5 and upon activation by recognition of viral RNA by cytoplasmic sensors, signal to the mitochondrial adaptor MAVS inducing an Interferon-regulatory factor (IRF)3, and IRF7-mediated type 1 IFN response ( Figure 1 ). Recently, the cGAS-STING axis has been identified as playing an important role in podocyte innate. Immunity. cGAS, a PRR, is considered to be a key sensor of cytosolic DNA leading to catalyzation of second messenger 2'3'-cGAMP, which binds to the endoplasmic reticulum membrane adaptor STING (encoded by TMEM173) leading to activation of TANK-binding kinase 1 (TBK1), which in turn activates nuclear interferon regulatory factor 3 (IRF3) and leads to the production of type I interferons ( Figure 1 ). The development of the cGAS-STING cytoplasmic defense system provides recognition of foreign nucleic acids, including pathogens/PAMPs, and DAMPs, as well as self-mitochondrial DNA leakage, cellular stress, and senescent break down products. This remarkably complex and efficient system based on the spatial coordination of DNA induced-cGAS-STING activity allows for antiviral immunity and balanced innate immune responses toward self-DNA. While the crucial roles of the cGAS-STING pathway in immune cells and the immune defense have been extensively investigated, its function in non-immune cells, such as podocytes, remains largely unknown. It is not known if STING contributes to the development and/or progression of glomerular diseases, however, our group has been investigating this, and our work is summarized in this article. Beyond its role in innate immunity, the podocyte is capable of contributing to the adaptive immune response. The podocyte has been shown to possess properties of non-hematopoietic professional antigen-presenting cells (APCs). Expression of both class I MHC antigens and, under certain inflammatory conditions, MHC class II antigens, contributing to the activation of CD8 and CD4 positive T cells, respectively, has been demonstrated on the podocyte. Moreover, podocytes express B7-1 (also known as CD80), a co-stimulatory molecule for T cells which is inducible under conditions of stress and was first reported in the context of the nephrotic syndrome. B7-1/CD80 is part of the B cell and APC repertoire and provides the second signal to T cells that allows amplification of the response to peptide antigens presented in the context of the appropriate MHC class I/II background (signal 1). B7-1 binds to CD28 on the T cell membrane, resulting in a positive co-stimulatory signal (signal 2). Interestingly, B7-2 (CD86), a co-stimulatory molecule presents on B cells and APCs that is also capable of binding to CD28 on T cells, is not present on podocytes. The podocyte is in a position to integrate and act upon the range of immune signals, from T/B cell secreted cytokines to DAMPs/PAMPs. When podocytes are activated, through TLR's, cGAS-STING, or B7-1, etc., the change, mediated through the actin cytoskeleton, can affect the slit diaphragm proteins, allowing the passage of protein (proteinuria) or potentially danger signals, e.g. pathogens, into Bowman's space, and hence into the urine and excreted. This potential for the excretion of danger/pathogen imbues the kidney, by virtue of the podocyte, with the capacity for immune defense mediated through a combination of innate and adaptive immune mechanisms. Importantly, clearance of danger into the urine avoids the activation of inflammatory mediators/cytokines that could result in unnecessary local tissue damage.

adaptive immunity, immune pathway, innate immunity, kidney, podocyte

PMC10061095_01

Female

A 6-year-old girl presented with facial erythematous plaques that had gradually spread into her limbs over the course of a year (Figure 1A). The center of some erythematous plaques was ulcerated and scabbed spontaneously. She appeared to be predisposed to respiratory infections since birth. Multiple biopsies of the plaques revealed necrotizing granulomatous inflammation (Figure 1D). No microorganisms were identified on PAS and acid-fast stains, tissue cultures, and PCR assays for fungi and mycobacteria. Dense lymphocyte infiltrate with lymphoid follicle formation in the dermis with adnexal involvement was also found in a biopsy from the left upper arm (Figure 1C). Most lymphocytes were T-cells (CD3+) with mixed CD4+ and CD8+ cells. Some lymphocytes showed mild cytological atypia. Clonal expansion of the T-cell population was detected through T-cell receptor gene rearrangement studies. The patient had neutropenia and lymphopenia of T cells, B cells, and NK cells. Specifically, cell counts of CD3+ T cells, CD4+ T cells, and CD8+ T cells were all lower than normal. Subpopulations of the CD3+/CD8-/IL-4+ lymphocytes and CD3+/CD8-/IFN-gamma+ lymphocytes were higher than normal, and CD3+/CD4+/CD25+/FOXP3+ lymphocytes and CD3+/CD8-/IL-17A + lymphocytes were lower than normal. Serum IgA and IgM levels were significantly lower, and the patient's C3 level was slightly lower than normal (Table 1). No clinically significant nodular metabolic enhancement was observed on PET-CT. The timeline of the patient's care is summarized in Figure 2. Because mycobacterial infections were not ruled out, a diagnostic therapeutic 8-week course of quadruple antituberculosis therapy was performed but without effect. Repeated metagenomic DNA and RNA mNGS analyses were performed, and rubella virus (RuV, read 7280) was detected. A serology test showed RuV IgM was 1.41 S/CO (positive range:>=1), and the RuV IgG titer was 243.7 IU/mL (positive range:>=10). Therefore, a diagnosis of rubella virus-induced cutaneous granulomatous dermatitis was reached. Considering RuV-associated granulomas are rare and almost exclusively occur in the context of immune deficiency, and the patient had signs of immunodeficiency, a whole- exome sequencing was performed, and heterozygous mutations in DCLRE1C gene as c.352G>T (p.G118X) and c.328C>G (p.L110V) were detected (Figure 3). It was concluded that hypomorphic heterozygous mutations of DCLRE1C genes led to an atypical SCID in this girl, who developed RuV-induced cutaneous granulomatous dermatitis, likely after inoculation with the rubella virus through vaccination. The patient had been waiting for hematopoietic stem-cell transplantation (HSCT) for the previous 10 months, and no other treatments had been initiated. An increase in the number and size of plaques on her face and limbs had been noted (Figure 1B), and the plaques had remained asymptomatic. The patient was hospitalized for pre-transplant examination and preparation.

dclre1c gene, granulomatous, next-generation sequencing, rubella virus, severe combined immunodeficiency syndrome, whole-exome sequencing

PMC5398518_01

Unknown

Almost all infants studied showed a minimal septal defect and only one infant had dyspnea and showed a large membranous VSD. All atrial septal defects had < 4 mm in diameter which are very likely to decrease in size or completely close on follow-up. However a small or moderate ventricular septal defect may still be significant if it causes aortic insufficiency or outflow tract obstruction as in the case of double chamber right ventricle. The size alone does not necessarily mean it is not hemodynamically significant. Furthermore it is not known if Zika exposed infants have the same spontaneous regression or closure rate of minor CHD as described in a normal population. Infants with small muscular VSDs might be easily missed without colour Doppler echocardiography. Muscular VSD closed earlier than perimembranous VSD and a recently review observed that all muscular VSD < 3.0 mm closed before the age of 3 years old. This corroborates our finding that only one of the 103 infants studied had signs and symptomns of CHD. This is the first time that CHD was assessed in infants with presumed congenital Zika syndrome. Currently there are no reports or autopsy evidence of any cardiac defects associated with presumed congenital Zika syndrome. Many others malformations have been described in the presumed congenital Zika syndrome, especially the central nervous system manifestations. As congenital Zika syndrome has many similarities with congenital Rubella syndrome it would be important to rule out cardiac involvement. This study seems to add a new contribution by showing apparently an increased rate of CHD in infants with congenital Zika infection. As we are reporting preliminary findings in a few infants, our results need to be confirmed by others studies. Currently studies on the relationship between Zika virus infection and heart involvment are lacking. Other Flavivirus such as dengue virus have been associated with myocarditis and pericarditis -. We did not find in our studied infants evidence of pericardium or myocardium involvement in echocardiography, besides these infants did not have any clinical manifestation. Recently Krittanawong et al highlight the potential cardiovascular complications of Zika virus infection and suggested a prompt cardiovascular screening in suspect cases of Zika virus infection. Our observational study has some limitations. At first we could not make serological diagnosis in all studied infants; 80 infants did not perform this test because this exam was not available at that time. However Zika virus IgM antibody was detected in cerebrospinal fluid samples of 23 infants and all infants had microcephaly and neuroimages alterations compatible with congenital Zika infection. Besides the current outbreak of microcephaly associated with Zika infection during pregnancy in Brazil especially in the Northeast region where IMIP is located makes the diagnosis of congenital Zika infection quite plausible. Second, stillbirths were not studied and this exclusion may underestimate the CHD prevalence in congenital Zika syndrome.

PMC9096266_01

Female

A 33-year-old Han Chinese woman was admitted to a local hospital due to irregular vaginal bleeding. The patient had no sexual history, so a transrectal ultrasound was performed instead of a gynecological examination, but no apparent abnormalities were found. So, the patient received hemostasis treatment but still experienced abnormal vaginal bleeding. Then, reexamination ultrasonography revealed a mass with rich blood supplies in the vagina, which had no clear boundary with the cervix, and subsequent magnetic resonance imaging (MRI) also found a 4.5 cm lesion filling the vagina, which was considered endometriosis or tumor. Then, the patient underwent hysteroscopy, and an elliptic mass was found at the cervical-vaginal junction. The mass was partially lobulated, with a smooth surface and a wide pedicle, and no noticeable abnormal vessels were observed. Later, the transvaginal cervical tumor resection was performed for the patient. Intraoperative investigation revealed that the tumor was in the anterior cervix lip and extended to the vaginal dome. It was pink, brittle, and had a rich blood supply. The histopathology of the excised specimen showed that the tumor tissue was composed of diffused spindle cells, and mitosis was active [>30/10 high power fields (HPFs)]. Collagen fiber degeneration around the vessels and lymphocyte infiltration were also observed, but necrosis was not detected. Immunohistochemical (IHC) staining was performed at the local hospital to differentiate it from other malignancies, such as high-grade endometrial stromal sarcoma or uterine leiomyosarcoma, and to determine its molecular subtype. It was found that the tumor was positive for S-100, CD34, vimentin, and cyclinD1 and negative for EMA, CK7, P53, P16, desmin, caldesmon, myoD1, myogenin, ALK, ER, PR, CD10, catenin-B, CD99, SATB2, BCL-2, CD117, BCOR, SOX10, HMB45, and melan-A. The tumor was suspected to be a special type of sarcoma, and then, the pathological sections were consulted by our hospital. We found that Pan-TRK, S-100, and CD34 were positive by IHC analysis, while SOX10 and desmin were negative in the tumor. Combined with its morphological characteristics and immunophenotype, it was suspected an NTRK fusion sarcoma. Since NTRK1 is the most common fusion type, it was investigated by fluorescence in situ hybridization (FISH) assay. The results showed that approximately 11% of cells were 0r-1Gr-1Fu, which did not support the existence of NTRK1 rearrangement (NTRK1 gene signal was mostly 1-3FU) in the tumor (Supplementary Figure 1). The patient was transferred to our hospital for further treatment. The MRI in our hospital showed a neoplastic lesion on the anterior wall of the cervical-vaginal junction (Figure 1A). The serum levels of tumor markers were as follows: HE4 25.2 pmol/L, CA125 62.9 U/ml , SCC 0.8 ng/ml, beta-HCG <0.1 mIU/ml, AFP 1.92 ng/ml, CEA 0.71 ng/ml, CA199 7.27 U/ml, and NSE 12.17 mug/L. Meanwhile, a hysteroscopy examination was performed to distinguish it from endometrial stromal sarcoma. During the operation, a 0.5 x 1.5 cm neoplasm was found on the posterior wall of the uterus, and the pathological examination revealed an endometrial polyp (Supplementary Figure 2). Then, the patient underwent an extensive laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, and partial vaginal resection. The histopathology revealed the macroscopic feature of the tumor: the tumor tissue was composed of diffused spindle cells with fascicular, nested, or uniform patterns, and vascularization and nuclear atypia (low to moderate) were observable (Figure 1B). Meanwhile, there was no lymph node metastasis, lymph vascular space invasion (LVSI), and parauterine/interstitial infiltration. Furthermore, IHC analysis revealed that the Ki-67 labeling index (LI) was 30-40%, indicating highly proliferative tumor cells, and a large portion of tumor cells strongly expressed Pan-TRK, S-100, and CD34, while negative for vimentin, SOX10, and desmin (Figures 1C,D). Consequently, based on the morphological and IHC results, we diagnosed the patient as NTRK fusion cervical sarcoma. According to the 2018 Federation International of Gynecology and Obstetrics (FIGO) staging system for cervical cancer, the stage of the patient was IIA2. Postoperatively, the patient received 6 courses of adjuvant chemotherapy with doxorubicin hydrochloride liposomes and nedaplatin. On the completion of chemotherapy, the patient received pelvic MRI and abdominal computed tomography (CT) examinations, and the results showed no abnormalities. Meanwhile, she visited our hospital to monitor the CA125 level in the next 3 months, which were 46.3 U/ml , 25.7 U/ml, and 20.5 U/ml, respectively. Two months after her last follow-up, the patient visited our hospital for diplopia in the right eye and right facial numbness, and the MRI examination revealed a mass in the right trigeminal nerve area, which was considered trigeminal schwannoma (Figure 2A). Consequently, she underwent cerebellopontine angle lesion resection in the Neurosurgery Department. During the operation, it was found that the tumor was, in fact, undemarcated with the trigeminal nerve. Grossly, the tumor was gray and fragmentary. Microscopic examination revealed that the tumor was spindle cell sarcoma (Figure 2B), which was diffusely expressed of CD34, vimentin, S-100, and Pan-TRK (Figures 2C,D), but negative for SOX10, EMA, SSTR2, PR, and STAT6. More importantly, the next-generation sequencing (NGS) identified an EML4 (NM_019063.5: exon 2)-NTRK3 (NM_001012338.2: exon 14) gene fusion variation in the tumor tissue. Together, the IHC and NGS results confirmed that the patient had a spindle cell sarcoma with EML4-NTRK3 fusion in the middle cranial fossa. To assess the condition of the lungs, the patient received the chest CT scan, which showed multiple metastatic lesions in both lungs, and the largest lesion was approximately 1.9 x 2.4 cm (Supplementary Figure 3). One month later, the patient presented vaginal bleeding, a gynecological examination found a mass protruding from the vaginal external orifice, and MRI revealed a 1.5 x 1.6 cm mass from the posterior of the vagina to the vulva, which was considered tumor recurrence (Figure 3A). The patient suffered from bleeding due to the mass and underwent lesion resection. Microscopically, the resected specimen was also composed of spindle cells (Figure 3B) and showed strongly positive for Pan-TRK, S-100, CD34, and vimentin but negative for SOX10 and desmin (Figures 3C,D). The results pointed to the recurrence and invasion of the NTRK rearrangement tumor. Also, the diagnosis indicated that the patient might benefit from TRK inhibitors, which, unfortunately, were not widely available in China currently. We sought a clinical trial of TRK inhibitor for this patient, but her condition progressively worsened and presented drowsiness, salivation, and left leg weakness. Unfortunately, the patient passed away one month later without being enrolled in the clinical trial.

ntrk gene fusion, case report, cervical sarcoma, literature review, survival analysis

PMC4681999_01

Male

A 65-year-old man was referred to our hospital due to dyspnea upon exertion. He was an occasional smoker and had been exposed to asbestos from 18 to 20 years old while employed in the construction industry, cutting asbestos-containing building material. Chest X-ray showed left pleural effusion (Fig. 1A), and computed tomographic (CT) images revealed left pleural effusion and calcified pleural plaques without pleural tumor (Fig. 1B). Thoracoscopic exploration revealed red-brown pleural effusion and plaques, but no tumor was detected on the pleura. Culture of the pleural effusion was negative, and cytological examination revealed a cellular distribution of 1.0% macrophages, 1.5% neutrophils, and 97.5% lymphocytes. Other examinations of the fluid showed nonspecific findings. Pleural biopsy showed no evidence of malignancy. During follow-up, the patient repeatedly exhibited accumulation of left pleural effusion, which was treated each time with thoracentesis. Four years after the first admission, analysis of pleural effusion from the fourth thoracentesis revealed large atypical lymphocytes with distinct nuclear bodies and a high nucleus-to-cytoplasm ratio (Fig. 2). Malignant lymphoma was suspected and thoracoscopic pleural biopsy was performed again, and the biopsy specimen from the fibrin tissues attached to the parietal pleura showed several groups of small round atypical lymphocytes. All of acid-fast bacteria stain, PCR analysis of tuberculosis, and culture for acid fast bacillus were negative. A culture test for standard plate count bacteria was also negative. Immunohistochemical analyses revealed that these cells were CD20+ (Fig. 3), CD3-, CD5-, and CD10-. Based on these findings, the diagnosis was confirmed as diffuse large B-cell lymphoma (DLBCL). Contrast-enhanced CT imaging of whole body (neck to pelvis) revealed no lymphadenopathy or tumor. Serological tests for hepatitis-C virus, human T-cell lymphoma virus-1, and Epstein-Barr virus were negative, as was the immunohistochemical analysis for HHV8. The patient has been followed-up, and has shown no disease progression for 3 years.

asbestos, ct, computed tomography, dlbcl, diffuse large b-cell lymphoma, hhv, human herpesvirus, lymphoma, mesothelioma, pel, primary effusion lymphoma, pleural effusion, thoracoscopy

PMC5508482_01

Female

23-year-old female, who was having history suggestive of chronic rhino bronchial allergy for the past five years, attended pulmonology outpatient with the complaint of cough, dyspnea and fever since more than four weeks. Vital signs were within normal range with SpO2 of 96%; her physical examination revealed bibasal lung crackles. Her past medical history revealed treatment with inhaled corticosteroids and fluticasone nasal spray on an irregular basis during exacerbations. She complains of recurrent headaches and underwent septoplasty with submucosal diathermy three years ago. Her routine blood work was within normal range with no peripheral eosinophilia and no sputum eosinophilia; her total serum IgE level was 731 ng/ml; her spirometry revealed mild restrictive ventilatory defect. Serum 25 hydroxy vitamin D3 was 9.12 ng/ml; chest radiograph showing bilateral infiltrates prompted for a computed tomography scan of chest (HRCT- Chest). The latter revealed multiple small well defined and ill-defined centrilobular nodules in both lungs, significantly in the left inferior lingula and in the basal segments of left lower lobe. The lesions show areas of tree-in-bud appearance and areas of confluence. Few small scattered centrilobular nodules were seen in the right lung in all the lobes (Fig. 1, Fig. 2). Clinicoradiological opinion was either atypical pneumonia or to rule out tuberculosis. She underwent fiberoptic bronchoscopy for bronchial wash and transbronchial lung biopsy; bronchial washings sent for smear for acid fast bacilli and fungal elements were negative, with gram stain showing occasional polymorphs; geneXpert MTB/RIF was not detected; 20 ml of bronchial washings which was hemorrhagic revealed an occasional alveolar macrophage with many neutrophils with a background of blood elements. Trans bronchial lung biopsy (TBLB) revealed histological features suggestive of Lipoid Pneumonia (Fig. 3). Meticulous history, retrospectively, revealed patient habituated to applying a petrolatum ointment to the nose, externally, daily at night since more than a year. She was treated with oral prednisolone, tapered over a period of six months, apart from her regular inhaled corticosteroid and Fluticasone nasal spray. Her follow up HRCT-Chest at the end of one year showed partial resolution of the previous lesions, and patient is clinically stable without any relevant symptoms. (Fig. 4).

exogenous lipoid pneumonia, petrolatum ointment, prednisolone, transbronchial lung biopsy, treatment

Axial HRCT section at the level of the lower chest reveals multiple tiny centrilobular nodules in the posterior basal segment of the left lower lobe and few nodules in the left lingula, right middle lobe and lateral basal segment of the right lower lobe.

PMC5508482_01

Female

23-year-old female, who was having history suggestive of chronic rhino bronchial allergy for the past five years, attended pulmonology outpatient with the complaint of cough, dyspnea and fever since more than four weeks. Vital signs were within normal range with SpO2 of 96%; her physical examination revealed bibasal lung crackles. Her past medical history revealed treatment with inhaled corticosteroids and fluticasone nasal spray on an irregular basis during exacerbations. She complains of recurrent headaches and underwent septoplasty with submucosal diathermy three years ago. Her routine blood work was within normal range with no peripheral eosinophilia and no sputum eosinophilia; her total serum IgE level was 731 ng/ml; her spirometry revealed mild restrictive ventilatory defect. Serum 25 hydroxy vitamin D3 was 9.12 ng/ml; chest radiograph showing bilateral infiltrates prompted for a computed tomography scan of chest (HRCT- Chest). The latter revealed multiple small well defined and ill-defined centrilobular nodules in both lungs, significantly in the left inferior lingula and in the basal segments of left lower lobe. The lesions show areas of tree-in-bud appearance and areas of confluence. Few small scattered centrilobular nodules were seen in the right lung in all the lobes (Fig. 1, Fig. 2). Clinicoradiological opinion was either atypical pneumonia or to rule out tuberculosis. She underwent fiberoptic bronchoscopy for bronchial wash and transbronchial lung biopsy; bronchial washings sent for smear for acid fast bacilli and fungal elements were negative, with gram stain showing occasional polymorphs; geneXpert MTB/RIF was not detected; 20 ml of bronchial washings which was hemorrhagic revealed an occasional alveolar macrophage with many neutrophils with a background of blood elements. Trans bronchial lung biopsy (TBLB) revealed histological features suggestive of Lipoid Pneumonia (Fig. 3). Meticulous history, retrospectively, revealed patient habituated to applying a petrolatum ointment to the nose, externally, daily at night since more than a year. She was treated with oral prednisolone, tapered over a period of six months, apart from her regular inhaled corticosteroid and Fluticasone nasal spray. Her follow up HRCT-Chest at the end of one year showed partial resolution of the previous lesions, and patient is clinically stable without any relevant symptoms. (Fig. 4).

exogenous lipoid pneumonia, petrolatum ointment, prednisolone, transbronchial lung biopsy, treatment

HRCT section at the level of the lower lobes reveals mild cylindrical bronchiectasis in the left lower lobe, faint tiny centrilobular nodules in the left lower lobe, right lower lobe and fibrotic lesions in the left lingula.

PMC3932400_01

Male

A 60-year-old male was admitted to the gastrointestinal medical clinic of Severance Hospital to undergo an operation for duodenal cancer. The patient had developed renal tuberculosis 30 years previously, received medical treatment for several months, and was completely cured. In June 2009, he visited a local clinic after experiencing general weakness and melena over a period of 1 month, was diagnosed with duodenal cancer with multiple liver metastases (Fig. 1A and 1B), and was transferred to our hospital. Esophagogastroduodenoscopy (EGD) (Fig. 1C) confirmed an ulcerofungating mass with poorly differentiated neuroendocrine carcinoma at the superior duodenal angle of the duodenum (Fig. 2A and 2B). Initial computed tomography (CT) showed multiple liver metastases. From November 2009 to January 2010, six cycles of palliative chemotherapy comprising 5-fluorouracil (5-FU) at 1,000 mg/m2 (days 1 to 3), etoposide at 100 mg/m2 (days 1 to 3), and cisplatin at 70 mg/m2 (day 1) were performed. After these treatments, fludeoxyglucose uptake was no longer seen on positron emission tomography (PET)-CT. There was no remnant malignant lesion on EGD, and the patient had only pathologically confirmed chronic gastritis. Two more cycles of chemotherapy were performed. He was subsequently confirmed to have no evidence of disease in February 2010. In June 2010, a polyp was detected in the former lesion site and was confirmed to be chronic inflammation by EGD biopsy. There were no abnormal findings on CT. In February 2011, a polyp was detected by EGD at the same site as that of the former polyp (Fig. 3A). This was pathologically confirmed to be adenocarcinoma by immunohistochemical staining. Chromogranin A and synaptophysin, which are neuroendocrine markers, were negative. Carcinoembryonic antigen (CEA), which is usually detected in cases of adenocarcinoma, was positive (Fig. 3B). The patient was admitted for an operation. Upon examination, his vital signs were normal. He reported no symptoms, and there was no palpable mass, organs, or tenderness in the abdomen. The results of a complete blood count were normal, as were the plasma levels of routine chemistry and tumor markers (CEA and CA 19-9). Magnetic resonance imaging (MRI) and PET-CT showed no abnormal findings at the site of the duodenal lesion, which was detected by EGD. However, there were suspicious metastatic lesions at segments 6/7 and segment 7 of the liver, so intraoperative radiofrequency ablation was planned and performed on 28 February 2011. The duodenal adenocarcinoma was not invading the mesentery. Pylorus-preserving pancreaticoduodenectomy was performed. A definite lesion was not found by intraoperative sonography, but a lesion was found attached to the right margin of the right hepatic vein on preoperative MRI. Thus, right posterior segmental curative resection of the liver was performed. The surgical pathology results showed moderately differentiated duodenal adenocarcinoma at the site of the primary lesion, and mild nonspecific reactive hepatitis was confirmed in the liver via immunohistochemical staining (Fig. 4). At the site of the primary lesion, there were no neuroendocrine cells; only pure adenocarcinoma cells were present. Therefore, the final stage was T1N0M0, and the patient underwent no further adjuvant chemotherapy. The patient is undergoing follow-up in the outpatient department without recurrence.

drug therapy, duodenal neoplasms, neuroendocrine tumors

PMC5569393_01

Male

A 48-year-old male was admitted to our neurosurgical unit because of a frontal swelling with purulent discharge from a cutaneous fistula. In his clinical history, he reported a previous frontal TBI when he was 9-year-old. For this reason, he had undergone a frontal craniectomy with subsequent unspecified CP. Since that, his clinical history has been unremarkable for 39 years, without any surgical or infective complications related to the cranial surgical procedure. A week before his admission he had been stung by a hornet while he was working in the countryside, with a progressive swelling of frontal soft tissues, temperature raising, and local pain with inflammatory state. During that week, a progressive purulent discharge has onset from the site of the sting, so he referred to the emergency department. At the admission, he was awake and aware [Glasgow Coma Scale 15 (GSC 15)], his temperature was 37.8 C and his neurological examination was negative. Initial laboratory studies revealed a pathological increased value of white blood cell (WBC) count (22 x 109/L with 82% neutrophils, 14% lymphocytes, and 7% monocytes) and of serum C-reactive protein level (57 mg/dL with a normal range 0.08-1.5 mg/dL). A head CT scan revealed an irregular subcutaneous fluid collection, adherent to the graft's anterior face, a peripheral soft tissues edema, and a frontal hypodensity in brain parenchyma contiguous to the graft. The administration of contrast medium revealed a moderate peripheral enhancement of the collection. Because of the radiological evidence of the graft infection with subcutaneous abscess, the patient was then transferred to our neurosurgical unit. A swab test of the purulent discharge from the cutaneous fistula was performed, and, after a multidisciplinary consult, a polychemotherapy was started (1 g of vancomycin and 2 g of cefepime every 12 h). Thirty-six hours after his admission, the patient underwent surgical toilet and removal of the graft. This appeared as a porous acrylic graft, with several fibrotic bands firmly tied with the skin and the underlying synthetic dural substitute. All the samples were harvested for microbiological exam, while the surgical site was washed with iodine solution, peroxide, isotonic saline, and rifampicine. At the end, a spongy layer of dural substitute with two overlaying patch of fibrin sealant (Tachosil ) and some fibrin glue (Vivostat ) was then used to ensure dural seal and to contribute in protecting the brain parenchyma under the bone defect [Figure 1a-d]. Nor titanium mesh or other allograft was applied on the former craniotomy in order to prevent the rejection, waiting for the resolution of the infection in analogy with other surgical procedures. Further bacteriological tests revealed Staphylococcus aureus as causal agent of that graft infection. Due to this, the patient was discharged 7 days after surgical procedure under an antibiotic therapy with linezolid and ceftazidime and he is still in follow-up for further CP after the infection resolution and inflammatory markers normalization.

cranioplasty, late infection management, risk factors, surgical complications

PMC8374937_01

Male

Three months after birth, the patient had recurrent mycotic stomatitis, tinea capitis and onychomycosis. He had a poor physique throughout childhood and often went to the hospital because of Candida dermatitis (Figure 1D). Because of long-term malnutrition, he was thin with a body mass index of 16.52. Knowing the medical history, it was found that he had no other obvious infection except Candida dermatitis. At the age of 20, he was admitted to the hospital with severe pneumonia. His body temperature reached a peak of 39.3 C. He had chills, cough and white sticky sputum but no night sweats, no chest tightness, no headache, and no abdominal pain or diarrhea. Pulmonary CT revealed bilateral pulmonary infection with bilateral pleural effusion, a patchy high-density shadow near the right lung hilum, a paraspinal mass in the right lower mediastinum, and pericardial effusion (Figures 1A, B). Fiberoptic bronchoscopy showed that the mucosal surface of each segment of the right bronchus was covered with a large amount of white caseous necrotic tissue. Acid-fast bacilli staining and testing for Mycobacterium tuberculosis DNA in bronchoalveolar lavage fluid were both negative. Sputum acid-fast staining was performed repeatedly during hospitalization, and all of the results were negative. During this hospitalization, routine bone marrow smears showed poor megakaryocyte function and macrophage phagocytosis of red blood cells, white blood cells and platelets. He was positive with IgG antibodies of Rubella virus, Herpes virus, and Epstein-Barr virus (Table 1). Upon physical examination, the patient was awake, thin, and had normal secondary sexual characteristics, chapped and brittle nails on his hands and feet, a thick white membrane on his tongue, no ulcers, and no obvious swelling of bilateral tonsils. No bleeding was observed on the skin or mucosa, and no rashes, no enlargement of the liver or spleen, no tenderness of the abdomen, no rebound pain in the abdomen, no palpation of superficial lymph nodes and normal auscultation of the heart and lungs were observed. After admission, empirical anti-infective treatment was performed with meropenem and voriconazole due to his unidentified pathogenic infection.

stat1, talaromyces marneffei, chronic mucocutaneous candidiasis, gain-of-function mutation, primary immune deficiency

PMC6319523_01

Male

Patient A was a 73-year-old male who presented to the emergency department (ED) with abdominal pain and low-grade fevers. He presented 6 months after the last of his five intravesical BCG instillations for his known non-muscle invasive urinary bladder papillary TCC. His medical profile included COPD, Type II diabetes, hypertension, dyslipidemia, and macular degeneration. There was history of remote TB exposure in childhood with no treatment or related hospital admissions. In ED, his complete blood cell count was within normal limits. Serum C-reactive protein was elevated at 58.6 mg/L (normal: 0-8.0 mg/L). Initial cross sectional imaging at the time of presentation demonstrated a new, multi-septated peripherally enhancing 6.3 cm x 1.9 cm x 5.6 cm, low-density collection within the retrocrural/posterior mediastinal region abutting the descending thoracic aorta along 180 degrees of circumference of the vessel (Fig. 1). Along the right posterolateral wall, an enhancing focal outpouching arising from the descending thoracic aorta was also identified. On positron emission tomography/computed tomography (PET/CT), this lesion demonstrated peripheral intense hypermetabolism with central photopenia. PET/CT did not demonstrate any additional hypermetabolic lesions and was negative for tumor recurrence or metastatic disease elsewhere. A follow-up MRI of the thoracic spine was negative for discitis or osteomyelitis. CT-guided aspiration of the retrocrural abscess yielded mycobacterium bovis consistent with BCG on pathology. Given the constellation of findings and pathology results, the patient was treated with Isoniazid, rifampin, pyrazinamide, ethambutol, and Vitamin B6. Given the patient's medical comorbidities, the mycotic aneurysm identified on CT was treated with endovascular stent graft placement as opposed to open surgical repair. No post-procedural complications were identified on CT. Adjunctive percutaneous drainage of the periaortic collection was also performed. Subsequently, over a course of 6 months the patient has remained asymptomatic, although the lesion has shown no signs of regression.

bcg, mycotic aortic aneurysms

PMC6319523_02

Male

Patient B was a 67-year-old male who presented to ED with weight loss and night sweats. His complete blood cell count was within normal limits. Serum C-reactive protein was elevated at 41.1 mg/L. He had received fifteen intravesical BCG instillations for his low-grade papillary urothelial carcinoma and his last BCG instillation was 4 months prior to his ED presentation. His medical profile was otherwise negative apart from a remote uncomplicated appendectomy. Outpatient abdominal ultrasound was suspicious for periaortic lymphadenopathy. Follow-up CT scan of the abdomen and pelvis showed a centrally low density and peripherally enhancing periaortic collection measuring up to 5 cm x 1 cm x 4.6 cm in the infrarenal region. At this level, a focal outpouching arising from the aorta posteriorly measuring up to 0.8 cm x 2.2 cm x 0.9 cm (APxTRVxCC) was suspicious for a mycotic aneurysm (Fig. 2). A percutaneous CT-guided biopsy of the periaortic collection demonstrated necrotizing granulomatous inflammation, highly suspicious for BCGosis. This patient's mycotic aneurysm was treated with a surgical resection of the infected infrarenal aortic segment and repaired using an autologous graft harvested from the patient's left femoral vein. He had an uneventful postoperative course in the hospital and was discharged on a standard antituberculosis medication regime including isoniazid, rifampin, pyrazinamide, ethambutol, and Vitamin B6. Patient has remained asymptomatic awaiting six-month follow-up imaging studies.

bcg, mycotic aortic aneurysms

PMC5702933_01

Female

A 37-year-old foreign domestic worker with no history of major infection and 3 previous vaginal births presented with a one-week history of suprapubic pain associated with fever. The patient also experienced loss of appetite and loss of weight. On examination, she was tachycardic with high-grade fever of 38.9 C. Abdomen examination revealed tenderness over her suprapubic area; however, pelvic examination showed no abnormality. Her total white cell count was 5.9 x 109/L, with predominantly lymphocytes (16.5 x 109/L) and monocytes (2.6 x 109/L). Her C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were elevated at 29.9 mg/dl and 100 mm/Hr. Chest radiograph showed bilateral perihilar opacities which could represent enlarged hilar nodes. There was no evidence of fibrosis, pleural effusion, or infective changes (Figure 1). Ultrasound scan showed presence of right complex mass measured 12 x 6 x 6 cm with minimal free fluid at the pouch of Douglas. Cancer antigen 125 (CA 125) was elevated at 97 u/ml. Working diagnosis of tuboovarian abscess was made, and she was treated with a broad-spectrum intravenous antibiotic. Despite 48 hours of parenteral antibiotic, she did not improve clinically. After discussion, she opted for exploratory laparotomy. There were moderate amount of ascitic fluid with the presence of slough and cheesy materials covering the entire abdominal and pelvic cavities. However, there was no tubercle noted over the peritoneal surface. There was a right ovarian cyst measuring 12 x 6 cm and features suggestive of a mature cystic teratoma. Right salpingo-oophorectomy was performed (Figure 2). Peritoneal fluid cytology showed no malignant cells, and there was no acid-fast bacilli (AFB) seen on AFB staining. Mycobacterium culture did not yield any positive AFB even after 6 weeks. In view of high index of suspicion for TB, peritoneal fluid was also sent for polymerase chain reaction (semiauto TB PCR machine, Rotor-Gene Q , Qiagen) testing, which was positive for NTM but negative for the Mycobacterium tuberculosis complex. Bronchoalveolar lavage was done as the patient was unable to produce sputum, which was negative for TB as well. Infective screening such as HIV, venereal disease research laboratory (VDRL), and hepatitis was nonreactive. Histopathological examination confirmed a right mature cystic teratoma. She remained well postoperatively and completed intravenous ceftriaxone and metronidazole for 10 days. She was initially planned for anti-TB (isoniazid, rifampicin, pyrazinamide, and streptomycin) following positive PCR testing for NTB. However, upon discharge, she was sent back to home town immediately by her employer. Hence, we have no further information about her progress.

PMC5196242_01

Female

The first case involves a six year old girl who was apparently well until the age of six months. Thereafter, she had started developing repeated episodes of cough and cold, respiratory distress with wheezing and was hospitalised on many occasions where she was treated with antibiotics, inhaled bronchodilators and inhaled corticosteroids. Her symptoms responded only to recur again in a few weeks interval. There was no history of exposure to pets or home exposure to smokes. She was then referred to our institution for further evaluation and management for ongoing symptoms. There is no history of contact with tuberculosis. On admission, the patient was noted to be pale, clubbed but not cyanosed with faltering weight gain (height and weight both below the 5th percentile). Examination of the chest revealed a pectus carinatum deformity (Fig. 1) and increased work of breathing (tachypneic at 32/min, bilateral wheeze and recessions). A Chest x-ray performed on admission revealed bilateral patchy opacities (Fig. 2). Her total leukocyte counts were elevated at 10,650/mm3 with 9% eosinophil in peripheral smear (absolute eosinophil count of 850/mm3). Serum IgE level was elevated at 1020 ng/mL. Sputum for acid fast tubercular bacilli and TB NAAT was negative. Flexible bronchoscopy revealed intra-bronchial mucus plugs. A high resolution chest CT scan (HRCT) showed 'tram track' bronchial dilatation and, 'tree in bud appearance' confirming bronchiectasis (Fig. 3). Her sweat chloride estimation and CFTR gene mutation (for DeltaF508) for cystic fibrosis was reported as negative. Her skin prick test to aspergillus (what reagent and what was the reading) serum IgE specific to aspergillus fumigatus were positive e. A diagnosis of ABPA was made and she was treated with oral prednisolone started at the dose of 0.75mg/kg/day over 2 week then gradually tapered over next 2 months and oral itraconazole 200 mg twice daily for 4 months. She responded favourably with progressive resolution of radiological opacities in serial chest x-rays.

allergic bronchopulmonary aspergillosis (abpa), asthma, bronchiectasis, cystic fibrosis (cf)

Chest CT scan (HRCT) showed 'tram track' bronchial dilatation and, 'tree in bud appearance' confirming bronchiectasis.

PMC5196242_02

Male

A seven year old boy presented with history of recurrent respiratory distress with wheezing since five years of age. There is a history of an allergic rash since two year of age that has often accompanied these episodes. Moreover, there was family history of atopy and asthma. In this case also there was no socio-environmental cause of asthma exacerbation. On clinical examination there was clubbing and evidence of increased work of breathing (subcostal suction, bilateral wheeze and crepitations). A chest x-ray revealed bilateral patchy pulmonary opacities (Fig. 4). A transient improvement was recorded post bronchodilator therapy. Investigations revealed a total leukocyte count of 13,500/mm3 with 6% eosinophil (absolute eosinophil count of 800/mm3). Serum IgE level was elevated at 2500ng/ml. Tests were negative for tuberculosis. Sweat chloride estimation and CFTR gene mutation was negative thereby ruling out cystic fibrosis. HRCT chest showed changes suggestive of bronchiectasis, 'signet ring sign' (Fig. 5). Skin prick tests were positive for Aspergillus fumigatus and Aspergillus versicolor. Serum IgE antibodies specific against Aspergillus fumigatus was found to be positive. As like the other patient, the patients responded favourably to treatment (oral corticosteroids alone of total 2 months duration).

allergic bronchopulmonary aspergillosis (abpa), asthma, bronchiectasis, cystic fibrosis (cf)

PMC7433307_01

Female

A 38-year-old woman started antiretroviral therapy (ART) in 2007 with zidovudine (AZT), lamivudine (3TC) and efavirenz. Her baseline human immunodeficiency virus (HIV) viral load and cluster of differentiation 4 (CD4) cell count results were not available. In September 2009, she experienced virological failure (this HIV viral load result is not available), and a genotypic antiretroviral resistance test showed a thymidine analogue mutation (TAM, K219KE [i.e. mixed population of mutant and wild type at that codon]), M184M/V and three non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations (A98G, E138A and K238T) (see Table 1). Based on this genotype, her regimen was changed to tenofovir (TDF), emtricitabine (FTC) and ritonavir-boosted atazanavir. She then transitioned from HIV care in the private sector to the public sector where she was changed to abacavir (ABC), 3TC and ritonavir-boosted lopinavir. When she returned to private sector care in May 2017, she reported severe diarrhoea, resulting in poor adherence to ART. Her medication was switched to ABC, 3TC and ritonavir-boosted atazanavir and the diarrhoea settled. In June 2017, she was diagnosed with tuberculosis (TB) and was started on a rifampicin-based TB treatment. Her HIV viral load at this time was 345 406 copies/mL. As she already had significant diarrhoea on standard dose ritonavir-boosted lopinavir, it was felt that double-dose ritonavir-boosted lopinavir during TB treatment would not be tolerated. Given that AZT was still fully susceptible at the time of first-line failure, it was thought that AZT would still be susceptible and therefore providing one active nucleoside reverse transcriptase inhibitor (NRTI) to accompany dolutegravir (DTG). The patient was therefore switched to AZT, 3TC and DTG 50 mg 12-hourly. The patient informed her doctor in July 2017 that she was experiencing insomnia on this regimen. She was reassured and advised to continue until she had completed TB treatment. There were regular pharmacy claims for treatment from June 2017 until November 2017 when her viral load was 2800 copies/mL. A resistance test was performed in February 2018, and the following mutations were observed: three integrase mutations (T66TI, G118R and E138EK) resulting in high-level resistance to raltegravir and elvitegravir and intermediate resistance to DTG (based on the Stanford score), M184V and two NNRTI mutations (A98G and E138A). A sample was also collected for phenotypic testing at monogram and the results showed that there was a 21-fold reduction in DTG susceptibility. Furthermore, all the other available integrase inhibitors had reduced susceptibility (3.92; 32- and 24-fold reduction to bictegravir, elvitegravir and raltegravir, respectively). She then admitted to only taking DTG 50 mg in the morning because she had experienced insomnia with twice daily dosing, which resolved if she skipped the evening dose. Based on the resistance test result, her ART regimen was changed to TDF, FTC and ritonavir-boosted atazanavir in February 2018 with rifabutin replacing rifampicin for the remaining months of TB treatment. An HIV viral load performed 3 months after the change was 230 copies/mL, and subsequent viral loads have been below 20 copies/mL for about 12 months.

hiv drug resistance, antiretroviral therapy, dolutegravir, regimens, rifampicin

PMC8083891_01

Female

A 70-year-old woman was admitted to the hospital because of shortness of breath. The symptoms started one month before admission and worsened over the following weeks. On the day before admission, the patient's condition worsened, and she experienced substernal chest pain and palpitations. She had a history of hypertension and type 2 diabetes mellitus. On physical examination, mild distress, tachypnea, and tachycardia were observed. There was a pulsus paradoxus of 10 mmHg (110 mmHg decreasing to 100 mmHg). She was normoxemic while breathing ambient air. Mild jugular venous distention was also observed. Heart auscultation revealed mildly diminished heart sounds. A 12-lead electrocardiogram revealed sinus tachycardia. Bedside echocardiogram showed circumferential pericardial effusion and respiratory variation in the intracardiac flows; all findings were consistent with increased intrapericardial pressure (Figure 1A). Chest computed tomography (CT) showed mild left pleural effusion and signs of circumferential pericardial effusion (Figure 1B). The patient underwent an urgent surgical pericardial window with a pericardial biopsy. Approximately 550 mL of bloodstained fluid with exudative properties was removed from the pericardium. Fluid analysis revealed three leukocytes. The adenosine deaminase level was 37 IU/mL. Polymerase chain reaction for Mycobacterium tuberculosis complex showed negative results. Histological analysis of the pericardium did not reveal any granulomas; however, acid-fast bacilli were identified (Figure 2). Therefore, the diagnosis of tuberculous pericarditis was confirmed, and quadruple therapy was started according to the guidelines. The patient had a favorable evolution and was discharged after one week. Posterior culture from the pericardial tissue was negative.

PMC3878030_01

Male

The patient was a 38 year-old healthy male without a history of cardiovascular or psychiatric disease who experienced a sudden collapse while bicycling to work. On primary assessment by paramedics he was found to be pulseless. Cardiopulmonary resuscitation was initiated. He was electrically cardioverted, resuscitated, and rushed to the nearest hospital. To preserve cerebral function, the patient was placed in an induced hypothermic and comatose state. During his recovery he experienced an episode of ICU delirium with agitation resulting in administration of sedative medication. After recovering from this delirium, he reported discrete retrograde memory loss from 1 day prior to the event through the first week after his SCA. He underwent ICD implantation (dual lead, atrial and ventricular, Medtronic Inc. St Paul, MN) at 2 weeks for secondary prevention of sudden death, and was discharged from the hospital shortly afterwards. He returned to work 3 weeks after the event. Immediately after ICD implantation the patient described being very fearful of being alone in the house with his young children. In response, he and his wife developed procedures to ensure that their children knew how to call emergency medical services if he were to become unresponsive or be shocked. The patient experienced his first ICD shock 11 months later, while riding the exercise bike at a local gym. He received a total of 6 shocks over approximately 2-3 min. After realizing he was being shocked, he did not recall experiencing anxiety. Rather, he described responding calmly and without terror, in a way that did not distract or alert others to his experience (i.e., no social disruption). In the patient's words: "they had told me it would feel like getting kicked in the chest by a horse. It didn't really feel like that. It was just a very loud, like a 'thunk!' sound. I maintained consciousness. At first I wasn't sure what it was. By the time the second one came, I realized this must be the defibrillator going off. And I was conscious the whole time, and walking. I don't know what the interval was, probably I guess 15-20 seconds in between [each shock]." Patient's wife: "you weren't very fazed by it though, and nobody else knew what was happening." Patient: "Right. And that goes to some of my anxiety, and why some of the subsequent shockings impacted me more than that one. This one I was able to keep private. Nobody knew what was happening. I knew I got shocked. I went home, called my doctor. It wasn't a very big public scene." The patient experienced his second episode of repeated ICD shocks while at the gym, after 15 min of jogging on the treadmill. He received a total of 7 shocks approximately 20 s apart. He again denied experiencing any social disruption, but this time felt terror over the lack of control over his symptoms. He also described experiencing physical pain with the shock. In the patient's words: "It's not so much the pain of the shock as much as, is there another one coming? Is this the last one, or am I bracing for another one? I'm trying to calm down, to get my heart rate down, but it's almost impossible because I'm under this utter terror that another one is coming, and another one, and is it ever going to stop?" During this second set of shocks, despite the reported fear and aversive anticipation of subsequent shock, he denied experiencing thoughts of death. When asked how he considered the meaning of the shocks, he stated "I'm not afraid I'm going to die, I don't feel like this event is going to kill me. At that time I'm more concerned with 'will it stop? How can I make it stop, and who is going to help me make it stop?' I feel somewhat powerless in this whole sequence of being subjected to these shocks, with really no ability to make it stop at some point. That's what impacts me most when it's happening." He further noted: "When I got my defibrillator originally, I remember this distinctly, my doctor told me 'You're gonna die some day. But it's not going to be from this. You've got the defibrillator now, you're not going to die from this.' And I certainly took some comfort from that." After uploading data from the ICD to his cardiologist, which demonstrated a ventricular tachycardia progressing to ventricular fibrillation, he was referred for further treatment via cardiac catheter ablation procedure to target a focus of premature ventricular contractions (PVCs) that had been previously identified. He also underwent an atrial lead revision and generator change during a separate procedure. After the second set of shocks, the patient became preoccupied with the potential impact the shocks might have on his social milieu, a fear that "I'm gonna get shocked in front of other people and they will think I'm defective." He developed several avoidance behaviors. He stopped exercising or engaging in all activities that could potentially increase his heart rate (including sex), under the belief that this would cause him to experience another shock. Hypervigilance emerged: he began scanning his body for signals that could predict a shock, such as feeling a fast heartbeat, or a "not good" feeling. He began to seek further reassurance that he was unlikely to receive another shock, by frequently contacting his cardiologist and frequently monitoring his ICD's electronic output. During each of these visits, no abnormalities were found. Two and a half years after receiving his first shock, the patient reported being shocked "in a different way." While out of town and walking with some co-workers, he received a shock and fell to the ground, grunting and groaning. There was no loss of consciousness. He continued to receive a total of 8 shocks in a row. Paramedics arrived at the scene and administered anxiolytic benzodiazepines, which the patient believes aborted the shocks. He was hospitalized for 4 days. Interrogation of his ICD revealed he had received appropriate ICD discharges in response to the spontaneous development of ventricular tachycardia. There were no further abnormal findings on electrophysiological exam, and he was discharged without application of any specific procedures or medications. This experience affected the patient differently, because "I could no longer hide it. There's shame involved, [that] there's something wrong with me." The lack of specific treatments rendered further anxiety. Riding home alone on the airplane he was extremely anxious about being shocked again, without access to emergency medical services. He experienced his first panic attack in midair, with prominent dyspnea, palpitations, dizziness, and fear of losing control over his mind and body. He also worried that being shocked in front of other people would cause them to think he was defective. After arriving home safely, he began to experienced recurrent panic attacks, approximately 10-15 times per month. These were often provoked when in open or crowded spaces, and so he began avoiding them. He began to avoid conversations while walking, "because that's what I was doing when I got shocked." He also experienced several spontaneous attacks without a clear trigger. Due to continued distress from these symptoms, the patient established his first contact with a mental health provider 3 years and 9 months after receiving his first shock. He began counseling treatment with a licensed clinical social worker, every 2 weeks, for a total of 6 visits. He learned basic relaxation techniques including deep abdominal breathing. Other elements of the treatment, in the patient's words included: "He told me how to deal with the shame of the event, by telling people around me what could happen, what they should do. He told me that if I told more people about it, I wouldn't be as concerned about the public spectacle." The patient did not receive any psychiatric evaluation or other forms of treatment. A week and half prior to psychiatric evaluation at UCLA, and nearly 4 years after his initial SCA, the patient received his fifth set of ICD shocks while at work. During a meeting he had a "premonition" and began to feel anxious about being shocked. He began to feel "not good," felt his heart beating faster and "I knew that a shock was coming." After receiving his third shock, he told a coworker to call emergency medical services. He received a series of 13 shocks over a period of minutes. He recalls that when the paramedics arrived and administered IV lorazepam, the shocks seemed to stop. He was again hospitalized for medical evaluation. According to his wife, he would often receive intravenous lorazepam for anxiety, particularly prior to his physicians' arrival for morning rounds, and was discharged with a prescription to take this on an as needed basis. Based on the pattern of recurrent ICD shocks, the patient was referred by his cardiologist for consideration for BCSD at UCLA. He underwent this procedure the day after his psychiatric evaluation. In addition to experiencing SCA, the patient had been diagnosed with a polymorphic ventricular tachycardia, undergone a dual lead ICD implantation. Surgical procedures included cardiac catheter ablation for PVCs, atrial lead and generator replacement, right shoulder dislocation with subsequent shoulder surgery, and appendectomy. The patient received a bachelor's degree in computer engineering and was currently employed as an engineer in a hardware design firm. There was no history of developmental disabilities. He was married, with two children. He denied any history of abuse or arrests. In reference to his early social life, he described himself as an "awkward teenager," whose friendships were mainly with "outcast kids." The patient reported a brief period of marijuana use in college, but otherwise denied any regular alcohol, tobacco or illicit substance use. Family history was notable for a myocardial infarction (paternal grandfather), and alcohol dependence (uncle). There was no other family history of psychiatric illness, and no family history of suicide. At the initial evaluation, the patient was prescribed the following medications: lorazepam 1mg BID prn (patient reported using 2 mg BID for the prior 10 days), metoprolol 10 mg BID, verapamil 120 mg BID, and aspirin 81 mg daily. After undergoing a structured clinical interview utilizing MINI International Neuropsychiatric Interview (Sheehan et al.,), the patient met DSM IV-TR diagnostic criteria for Post-Traumatic Stress Disorder, Panic Disorder with Agoraphobia, and Social Anxiety Disorder. There was no evidence of axis II pathology. Symptom severity was assessed using several quantitative clinical measures. These indicated "severe" levels of general anxiety (via Beck Anxiety Inventory, BAI (Beck and Steer,), "markedly ill" levels of panic (via Panic Disorder Severity Scale, PDSS) (Furukawa et al.,), and borderline clinical depression (via Beck Depression Inventory, BDI) (Beck and Steer,) (Table 1). In an attempt to reduce susceptibility to recurrent ventricular tachycardia, partial sympathectomy via BCSD has been applied in selected treatment refractory patients at UCLA (Ajijola and Shivkumar,; Ajijola et al.,; Vaseghi et al.,). Bilateral cardiac sympathetic lesioning decreases sympathetic efferent noradrenergic innervation to the heart, and putatively mitigates the pro-arrhythmic effects of sympathetic innervation (Ajijola et al.,). The patient underwent this procedure, consisting of a resection covering the lower half of the stellate ganglion and the bodies of sympathetic chain from T2 through T4. He has been followed for approximately 1 year. Immediately after recovering from the surgery, the patient reported continued episodes of anxiety, including one nocturnal panic attack. He continued utilizing lorazepam 2 mg daily as needed for anxiety, but during these episodes noted "I couldn't feel my heart racing." After 2 weeks, he continued experiencing anxiety that "comes and goes." He was still using lorazepam as needed, approximately every 2-3 days. He had not experienced any further panic attacks. After 1 month, the patient had returned to work and reported "I'm starting to feel better." However, he avoided his first work meeting by calling in from home, and still endorsed "a lot of anxiety" related to being in situations where he had been shocked previously, including work. When he did eventually attend a work meeting with a colleague, he denied experiencing anticipatory sensations as before, including the absence of a rapid pulse, causing the patient to spontaneously note "I have noticed differences in how my body reacts." When referring back to his home vital sign monitoring records, he reported that his average heart rate had decreased from the 80's to 65. Quantitative examination of his psychiatric symptoms at this time compared to prior to BCSD revealed an unchanged level of general anxiety (via BAI) and slightly decreased intensity of panic (via PDSS) (Figure 1). Based on these continued symptoms, he was referred for cognitive behavioral therapy (CBT) with a PhD psychologist specializing in treatment of PTSD. At 1 month he reported experiencing a single atypical shock. In the patient's words: "when leaving work today I was fixing something on the floor. When I stood back up I did not feel right. Not dizzy just felt that something was not right. I took a sip of water to try and calm myself but the feeling did not go away. I walked downstairs and the sensation got stronger. Then I got a single shock. Seemed more mild than others. After the shock I had a real difficult time calming my body down as with prior incidents. Despite this I did not receive a cascade of shocks. Perhaps the benefit of the procedure:stopping my body reaction from impacting the ability of the heart to return to normal rhythm. Despite my panic, I only received a single shock. In the past my inability to calm myself down would result in multiple shocks usually until EMS arrived and administered a calming medication." Analysis of his ICD data showed a fast ventricular tachycardia that was different from previously observed ventricular fibrillation. It was felt that this could be due to post-lesion cardiac remodeling. He was started on amiodarone 200 mg BID. Three months after undergoing BCSD, the patient reported he was "doing better." He was receiving weekly psychotherapy via CBT and had completed 8 sessions. He was learning "more awareness of what anxiety is and what a panic attack is." He was also learning different strategies to cope with and manage his anxiety, including advanced deep breathing techniques and guided pre-recorded audio meditations. He had not started exposure and response prevention, a common and effective behavioral component of CBT, but had begun discussing this approach with his therapist. He reported experiencing continued panic attacks 1-2 per week, but felt these were less severe, and of shorter duration (1-2 min in duration vs. 10 min). In addition, he continued to note "I don't feel my heart rate like I did during anticipation of shock. I also don't feel PVCs as much as I used to." Although he reported walking more, he was still avoiding most meetings by calling in sick, and avoiding going to the gym. Due to his continued symptoms he had been referred to a psychiatrist, had been prescribed a low dose of an SSRI, sertraline, initially 12.5 mg daily and up to 25 mg daily at the time of contact. He continued taking lorazepam on an as-needed basis, but at a lower dose of 1 mg daily three to four times per week. Quantitative review of his symptoms now demonstrated a nearly 50% drop in general anxiety down to a 'mild' level (via BAI), a continued decrease in panic severity (via PDSS), and a small but clinically insignificant decrease in depression (via BDI; Figure 1). He had not experienced any further shocks, and no further ICD events were detected. Six months after undergoing BCSD, the patient continued receiving weekly psychotherapy. He had begun conducting prolonged exposures, a common treatment for psychotherapeutic treatment of PTSD, tailored toward the experience of being shocked. These pertained to "the memories of the two most significant shock events that have been very difficult for me to think or talk about. I discuss the memory in detail and record it on my phone and then listen to the recording multiple times. It has helped a lot and I no longer have a significant reaction to thinking about those memories." He stated he was no longer avoiding going to the gym, and was no longer avoiding individual meetings at work. He continued to express concern about attending group meetings. Sertraline had been increased to 150 mg daily. He noted difficulty "to differentiate the benefits of the sertraline and [psychotherapy]." He had not experienced any further shocks, and no further ICD events were detected. In reviewing his progress, he spontaneously noted, "all in all, I have improved significantly from last fall and I can see a day when I will return to my prior self." Quantitative review of his symptoms now demonstrated a nearly 50% drop in general anxiety (via BAI) and a continued decrease in panic severity (via PDSS), with a small but clinically insignificant increase in depression (via BDI; Figure 1). Nine months after undergoing BCSD, the patient reported "I have been feeling a lot better lately." He continued seeing his therapist but on a slightly decreased basis, weekly to bimonthly. His sertraline had been increased to 200 mg daily. He continued to refrain from utilizing lorazepam. He had not experienced any further shocks, and no further ICD events were detected. Quantitative symptom review revealed that most of the patient's symptoms had continued declining. His general anxiety level was in the "very low" range, and symptoms of panic were now in the "borderline ill" range (Furukawa et al.,). His depression was now in the non-clinical range of "normal ups and downs." The patient summarized his progress at 9 months as follows: "At times not even thinking about my condition. Previously, it was a constant thought - constant polling of my body to make sure I felt ok. There have been days where I have felt completely normal. I'm now getting active again. Starting on the treadmill. A remaining fear is associated with activity and getting my heart rate up. Breathing hard is especially a trigger that I have avoided. The difference now is that I no longer view getting on the treadmill as impossible. I feel like I can do it:gradually. Feeling better in social situations also. Had an impromptu lunch with two colleagues last week. Felt good for the entire lunch and participated in conversation and started some conversations. Previously, I had avoided this type of situation. I did have one episode yesterday that caught me off guard. At the end of a meeting we were talking about general things. We were talking about injuries and one person mentioned my SCA [Sudden Cardiac Arrest]. Everyone there knew about my history but one. I have talked about it recently without issue. However, after I started telling the story of my original SCA I had a very strong sensation:rushing feeling like someone is cranking up the volume inside my body. I tensed up expecting a shock. No shock occurred but I got up and returned to my desk and relaxed to decrease my pulse rate." 1 year after undergoing BCSD the patient's anxiety, panic and depression symptoms remained markedly attenuated, and in non-clinical ranges (Figure 1). He continued psychotherapy at a further decreased frequency, once per month, and anticipated discontinuing this soon afterwards. He continued on an unchanged dose of sertraline, 200 mg daily. He no was no longer utilizing lorazapam. Other medications included verapamil 120 mg BID, metoprolol 50 mg daily, and aspirin 81 mg daily. His cardiologist had tapered and discontinued amiodarone 1 week before. He had not experienced any further shocks. Review of his ICD data showed no events over the past 6 months, which was the "first time that has ever happened since my initial arrest." This information was particularly "surprising," as this objective record failed to corroborate the subjective diary records of the exact dates and times when he had perceived the body sensations of an abnormal event during that time period. In subjectively reviewing his symptoms 1 year after BCSD, the patient noted "I'm starting to have days were I do not constantly think about whether a shock is imminent. I no longer struggle and avoid social situations." He noted the lingering presence of cognitive threat appraisals: "I do still encounter thoughts of playing out scenarios of what would happen if my defibrillator went off:who would see, what would happen. This happens when I'm in social situations especially when walking. I do very occasionally have episodes of what I call an 'attack.' Basically, having a physical sensation that mimics the feeling that I get right before a shock. It is like a rushing feeling:tensing up in my body:bracing for the shock. When that happens I usually quickly excuse myself from the situation and calm down and the 'attack' passes." He reported further decreased avoidance of exercise: "I have started walking on the treadmill on a regular basis. Fast walking. Enough to sweat:about 40 min. However, I make a conscious effort to control my breathing and not let my pulse rate get elevated." Despite his increased exercise capacity, at 1 year the patient reported he had sustained a 50 pound weight gain. He also endorsed continued preoccupation with receiving a shock during physical exertion: "The one remaining aspect of my treatment is dealing with my fear of activity. I'm terrified that elevating my heart rate will result in a shock. Frankly, I don't think I will ever move past this fear. The times I have been shocked my pulse has been high. The procedure effectively lowered my pulse rate. So logic leads me to thinking that if the procedure lowers my heart rate then why would I increase it purposefully." Exactly 1 year after his worst shock episode, these preoccupations were reflected by moderately elevated scores on the SCS and FSAS, and clinically significant scoring on the PCL (Figure 1). The patient did not experience Horner's Syndrome, an occasional occurrence with stellate ganglion nerve blocks (Schurmann et al.,; Lipov,). This was due to the selectivity of the patient's lesion, which spared the caudal head of the stellate ganglion, a region carrying sympathetic nerve fibers to the eye and face. The patient did report the subsequent absence of sweating of the palms and head, and development of hyperhidrosis of the trunk and legs, which have been described as compensatory responses to the severing of sympathetic nerve fibers to the trunk (Hashmonai et al.,; Drott et al.,). Subscale examination of the patient's anxiety revealed several notable patterns (Figure 2, Table 2). During the 2 weeks after undergoing BCSD, the patient reported an overall increase in feeling bothered by several cognitive and interoceptive components of anxiety. The former may have been related to uncertainty about receiving future shocks, and concern about the successfulness of the surgery. The latter may have been related to post-lesion remodeling within the autonomic nervous system that can result in the symptoms of heat sensations, flushing and difficulty breathing reported by the patient. Despite these increases, the patient reported decreases in feeling bothered by dizziness and lightheadedness, and a reduction in feeling bothered by the experience of his heart pounding and racing (Figure 3). Both of these decreases appeared clinically significant, i.e., the symptoms decreased from the maximum score ("severely:it bothered me a lot") to a mild score ("mildly but it didn't bother me much"). Furthermore, these reductions were sustained throughout the year. In the case of heartbeat sensations, at 1 year the patient reported a complete cessation of symptoms (Figure 3). The only other symptom that declined with a similar magnitude was the feeling of being scared, which decreased entirely between 2 weeks and 3 months after the procedure. Of note, this timeframe corresponded to the initiation of CBT, and formation of a therapeutic bond with his psychologist. It seems unlikely this drop was due to pharmacotherapy, as the patient was no longer utilizing benzodiazepines at that time and had only recently initiated a subtherapeutic dose of sertraline (25 mg daily). The patient also demonstrated a decline in shock related catastrophic thinking (via SCS) between 6 and 9 months post-lesion. This timeframe corresponded to completion of the majority of his CBT visits, and also to the titration of sertraline to a therapeutic dose. Given the concomitant nature of both interventions, is therefore difficult to distinguish which was more likely responsible for the decrease in catastrophizing symptoms during that timeframe. With regard to symptoms of PTSD assessed via PCL, the patient demonstrated low-moderate scores between 3 and 9 months, which were in the non-symptomatic range via scoring criterion 2 (Blanchard et al.,). Exactly 1 year after the patient's last episode of ICD shock storm, the patient's PCL score increased into the symptomatic range. Similarly, at 1 year the patient's score on the FSAS was in the moderate range. Subsequent inquiry revealed that the patient was quite aware of this epoch, and had been thinking about his last shock episode during the days and weeks leading up to this anniversary event. He also explained that he had recently began pushing the limits of his exercise comfort level as a part of his exposure and response prevention psychotherapy, which is known to temporarily increase anxiety levels (Craske and Barlow,). It is possible that his FSAS score could have been decreased (or elevated) prior to this time period, but this remains speculative as this data was unavailable for earlier time points.

ptsd, anxiety disorders, autonomic nervous system, cognitive behavioral therapy, electrical storm, implantable cardioverter defibrillator, interoceptive awareness, stellate ganglion

PMC3878030_03

Female

The patient was employed as an assistant restaurant manager. She was married with a 1 year-old daughter. She had received an associates degree in culinary arts. There was no family history of psychiatric illness or cardiovascular disease or syncope or sudden death. No history of substance abuse. At the initial evaluation, the patient was prescribed the following medications: Metoprolol 25 mg BID, Phenytoin 300 mg qHS and KCL 10mEq daily. After undergoing a structured clinical interview utilizing MINI International Neuropsychiatric Interview, the patient met DSM IV-TR diagnostic criteria for an adjustment disorder with mixed anxiety and depressed mood. We assessed the degree of severity of the patient's symptoms using several quantitative clinical measures. These indicated "severe" levels of general anxiety (via BAI) and borderline clinical depression (via Beck Depression Inventory, BDI) (Beck and Steer,) (Table 3). The patient underwent a neurology consultation including EEG, to evaluate the possibility of a seizure disorder. The EEG was conducted with the patient in the awake and asleep states. Hyperventilation and photic stimulation were not performed as activating maneuvers, and no sedation was given. While maximally awake, the posterior dominant rhythm was 9-10 Hz, which was symmetric, synchronous and reactive to eye opening and eye closure. Three brief periods of high amplitude theta activity (4-7 Hz) were captured and reported as paroxysmal in nature. They appeared generalized, without a focal cortical distribution, lasting approximately 1-2 s. These slowings occurred in the wakeful and/or drowsy state, with no evidence of epileptiform behaviors at the time. They were interpreted as potentially consistent with physiological drowsiness. In one instance the slowing appeared notched, which could indicate possible epileptiform activity. However, as a fast alpha variant was present at the same time, it was considered suggestive against an epileptic etiology. Vertex waves signifying drowsiness were noted later in the recording, but not at the time of the paroxysmal slowing. This was also considered suggestive against an ictal semiology. Overall, the EEG was judged to be normal in wakefulness and stage II sleep, without any clear electrographic features of seizure. No epileptiform behaviors were identified during clinical observation. Despite the lack of clear electrographic evidence of a seizure disorder the periods of high amplitude generalized slowing and the reported phenomenology of her episodes were felt to be possibly consistent with a seizure disorder. Seizure prophylaxis was continued, but switched from Phenytoin to Levetiracetam 1000 mg BID. After further consultation, the patient elected to undergo BCSD. The resection covered the lower half of the stellate ganglion and the bodies of sympathetic chain from T2 through T4. Discharge medications included Levetiracetam 1000 mg BID and Propranolol 40 mg TID. Evaluation of the patient's symptom scores at 1 month post-BCSD revealed clinically significant decreases in depression (via BDI), anxiety (via BAI) and shock catastrophizing (via SCS) (Figure 4). Clinical evaluation at 1 month post-BCSD, revealed that she had not experienced any further shocks, and no further ICD events had been detected. The patient the patient reported her mood and anxiety symptoms were much improved. She declined the recommendation to seek further psychiatric follow up, and as she was subsequently lost to follow-up no further psychometric data are available. Continuous measures of skin conductance level (SCL), systolic blood pressure (SBP), and diastolic blood presssure (DBP) were recorded during psychophysiological assessment using Biopac MP150 hardware and Acqknowledge 4.3 software (Biopac, Santa Barbara, CA). Two isotonic 1-cm diameter gel electrodes were attached to the thenar and hypothenar eminence of the subject's nondominant hand to assess SCL. This tonic measure of galvanic skin resistance was selected as a measure of sympathetic arousal due the prolonged time intervals examined (Naqvi and Bechara,). Blood pressure was continuously assessed using the CNAP 500 Monitor (CN Systems, Graz, Austria) with finger cuffs, which were placed between the proximal and distal interphalangeal joints of the third and fourth digits of the subject's nondominant hand. Heart rate was not examined due to the presence of atrial pacing in both patients, which kept the heart rate constant. The psychophysiological assessment began with a 5-min resting baseline during which the subject was seated in a chair and instructed to remain at rest and minimize movement. Psychophysiological measures (SCL, SBP, and DBP) were assessed during the 5-min baseline. As the pre-BCSD testing occurred in an inpatient setting, the first 2 min of the 5-min baseline period were discarded in order to account for possible environment-related influences on autonomic tone. Data for each measure for the final 3 min was averaged to provide a baseline value for that session. Additional interventions to reduce outside distraction included closing the door of the patient's single occupancy room, and silencing the alarms of monitoring equipment. The resting baseline period was followed by 3 tasks in the following order: a valsalva task, a handgrip task, and a mental arithmetic task. The valsalva task involved performing two sustained valsalva maneuvers while in a seated position. The subject was given the following instructions, "During this task, I will place my hand on your abdomen. The goal is to push my hand away as far as you can by protruding your abdomen. Hold this position for as long as you can. Remember to keep breathing while bearing down." The procedure was demonstrated by the assessor, practiced once by the subject, and then performed twice by the subject. Each trial period lasted approximately 15-25 s. Psychophysiological measures were assessed during the two valsalva trials, and scores on SCL, SBP, and DBP were averaged across the two trials. The isometric handgrip task involved a hand dynamometer held by the subject's dominant hand. The following instructions were provided before performing the task, "During this task you will squeeze a hand dynamometer for 2 min at a specific grip strength level with your dominant hand. I will first determine your maximum grip strength level by asking you to squeeze the dynamometer with as much force as possible." Following determination of subject's maximum grip strength, the dial on the dynamometer was placed at 30% of the maximum grip strength, and the subject was instructed to squeeze the grip at that level for 2 minutes. Values on SCL, SBP, and DBP were averaged across this 2-min period. The mental arithmetic task was selected as a cognitive stressor and adapted from the Trier Social Stress Task (Kirschbaum et al.,). This modified protocol consisted of a 5-min period during which the subject was instructed to consecutively subtract by 13's starting at 1022, in front of two experimenters. The subject was told to perform this task aloud as quickly and accurately as possible, was corrected each time an error was committed, and then told to start over at 1022. Mean SCL, SBP, and DBP were assessed across the 5-min period. Acqknowledge software, version 4.3, was used to process all data collected during the psychophysiological assessment sessions. Using Acqknowledge, SCL was averaged across the pre-specified 2 min resting baseline and specified periods during each task described above. The Acqknowledge blood pressure classifier analysis feature was used to identify SBP and DBP at each heartbeat. Means for SBP and DBP were determined for resting baseline and for specified periods during each task. This study was approved by the Unversity of California Los Angeles Institutional Review Board, and all participants provided informed consent prior to participation. Mean values of the autonomic testing in Case 2 are displayed in Table 4. Figures 5-7 show changes in each measure from the resting baseline value pre- and post-BCSD. Compared with before BCSD, the patient demonstrated clear declines in baseline adjusted systolic and diastolic blood pressure response for the valsalva and handgrip tasks, but less so with the mental arithmetic stressor, which did not show robust changes at either time point. Comparing pre- vs. post-BCSD, the patient demonstrated prominent declines in baseline adjusted SCL for all tasks (Figure 7).

ptsd, anxiety disorders, autonomic nervous system, cognitive behavioral therapy, electrical storm, implantable cardioverter defibrillator, interoceptive awareness, stellate ganglion

PMC4546785_01

Female

An eight years old girl has presented to pediatric emergency with a recent history of febrile odynophagie subsequently complicated by a torticollis that has settled 5days after. Clinical examination has found a febrile child at 39 C and a bulging anterior pillar of the right tonsil without rash or conjunctival hyperemia. CT scan was performed and has revealed right peritonsillar and parapharyngeal abscess (Figure 1). At laboratory tests we found a white blood cell count (WBC) of 14000/mm3 and C - reactive protein (CRP) of 102mg / l. The child underwent a trans-oral drainage of the abscess under general anesthesia and airway protection. The bacteriological sampling objectified mixed unspecific flora sensitive to amoxicillin-clavulanic acid with no evidence of mycobacterium tuberculosis. Antibiotherapy was prescribed based on amoxicilline- clavulanic acid (80mg/kg a day) and aminoglycoside (3mg/kg a day for 5 days). The child was apyretic 48 hours after, and C- reactive protein 72 hours later was at 45 mg/l. Cervical spine traction was not necessary since the torticollis has been resolved after 5 days.

fever, children, parapharyngeal abscess, torticollis

PMC2989694_01

Male

The institutional IRB was consulted and waved the need for approval of the publication of this case. The patient is a 12-year-old, right-handed, 52 kg African-American male without any significant medical history other than nocturnal enuresis. His father woke him up at 04:00 on the morning of admission as was customary in their home to prevent bedwetting. While initially he responded appropriately, the child collapsed to the ground after standing and became unresponsive. He was transported to an outlying emergency department where he was noted to have aphasia and left dense hemiplegia. Computed tomography demonstrated signal attenuation and edema in the vascular distribution of the right middle cerebral artery. Right lateral ventricle compression and midline shift were noted. The patient was transferred to our institution by helicopter and was briefly examined in the emergency room prior to transfer to the magnetic resonance (MR) imaging suite. He was awake, with stable airway, anxious and frustrated by inability to speak, but was cooperative and able to follow some commands. Heart rate was 50-60 beats per minute and blood pressure was 130-140/80-90 mm Hg. He demonstrated lack of language expression, flaccid paralysis of the left face, upper extremity, and lower extremity. His NIH stroke score was 16. MRI and MRA studies revealed occlusion of the right middle cerebral artery with restricted diffusion in the right basal ganglia and the posterior lateral aspect of the caudate head (Figure 1). There was mass effect on the right lateral ventricle and midline shift. Our information was that 6 h had elapsed since the onset of neurologic symptoms. Taking into account the possibility of a devastating clinical outcome and in conjunction with adult stroke and interventional radiologist specialist, the decision was made to attempt to restore arterial patency. The patient was anesthetized, intubated, and cooled to 33-35 C (mild therapeutic hypothermia). A thrombus was located (Figures 2 and 3); endovascular mechanical embolectomy with a Merci retrieval device was attempted without success. Recombinant tissue plasminogen activator (rt-PA) was infused into the MCA in doses of 0.7, 2, and 4 mg with minimal improvement in blood flow. Abciximab and nitroglycerin (25 mug) were then infused with considerable improvement in blood flow (Figures 4 and 5). The patient was transferred to the pediatric ICU and remained sedated and mechanically ventilated. Neurosurgical consultation was obtained for an intracranial pressure (ICP) monitoring, but this was not placed due to recent thrombolytic administration and the initiation of systemic anticoagulation. Heparin was administered for 7 days, Abciximab (10 mug/min for the first 12 h), aspirin (325 mg/day), magnesium sulfate (2000 mg/24 hrs), 25% albumin (1 g/kg IV every 6 h for the first 5 days), and memantine HCL (10 mg nasogastric each day for 3 days). Mild therapeutic hypothermia was maintained for 4 days to decrease acute postischemic cerebral edema followed by passive rewarming over a 24-hour period. A CT scan obtained at 24 hrs showed a decrease in the midline shift. The central venous pressure (CVP) was maintained at 8-10 cm H2O and mean arterial pressure (MAP) at 75-80 mm Hg. A dual channel near infrared spectroscopy (NIRS) probe was applied to the scalp overlying both frontal lobes. Initially, there was a discrepancy between the two sides with the ischemic right side 10%-15% lower than the left side (40%-50% versus 65%-70%). Increasing CVP or MAP served only to augment the discrepancy. Subsequently, the partial pressure of arterial carbon dioxide was allowed to increase from 35-40 to 46-55 mm Hg with resolution of the discrepancy (both sides equal to 60%-65%). MR studies on the 7th day revealed appropriate MCA blood flow and partial resolution of the ischemic changes in the basal ganglia. Mass effect and right lateral ventricle compression by the basal ganglia were improved. He was extubated on day 10 and was able to communicate verbally, written, and receptive but had a small degree of residual left hemiparesis. He was transferred to a rehabilitation facility on day 15 where he exhibited an almost complete recovery within the following two weeks and was discharged home. Subsequent followup by our pediatric neurology service over the next year has demonstrated complete recovery to baseline without deficits. One year later he is taking advanced placement classes in school, playing junior high school basketball and baseball, and having no demonstrable neurological deficits. Cerebral angiography and serologic studies did not find the presence of dissection, vasculitis, or autoimmune disease; transthoracic echocardiography ruled out structural heart disease, intracardiac thrombus, and right to left intracardiac shunt, and hemoglobin electrophoresis, hypercoagulability studies, and lipid panels were all unremarkable. Doppler studies of the veins of the lower extremities and pelvis were all negative for deep venous thrombosis. An etiology for this patient AIS has not been found. An MRI performed 3 months after the events showed resolution of the edema and restricted diffusion with a residual hyperdense signal abnormally in the periventricular region (Figure 6).

PMC4387618_01

Male

In this study, we report a case of a healthy, 25-year-old male patient with presyncope during a football match divergent blood pressure, and a grade 3/6 aortic diastolic murmur. The echocardiogram showed a rounded structure in the basal area of the interventricular septum adjacent to the aortic valve, which causes inadequate commissural support, communicating with the left ventricle (LV). There was moderate secondary aortic insufficiency and dilated LV with preserved contractility. MRI revealed myocardial density in the structure without delayed enhancement. After follow-up, the LV increased further in size and syncope on exertion. The patient underwent surgery and the anatomic pathologist diagnosed left ventricular diverticulum. The diverticulum, a congenital protrusion in the myocardial wall of the LV, differs from an aneurysm by its close connection to the chamber and presence of myocardial fibers in the composition of the wall. It most often affects the LV or right ventricular apex and is rare in the septum.

PMC7582089_01

Female

A 36-year-old woman from Cameroon (immigrated 10 years ago) with no past medical history presented to the Emergency Department with increasing abdominal swelling over months. She had no respiratory symptoms, no abdominal pain, no constitutional symptoms such as fever or weight loss, and reported prior negative tuberculin skin testing. Physical exam was notable for normal vitals. She appeared healthy. Heart exam was normal without murmurs, rubs or gallops. She had absent breath sounds on auscultation of the right lung, clear breath sounds on the left, and a distended non-tender abdomen with a fluid wave. She had no edema of her lower extremities. Complete blood count and basic metabolic profile were remarkable only for a mild anemia (hemoglobin of 11.9 g/dL). A Computed Tomography (CT) scan of the chest (Fig. 1) revealed complete opacification of the right hemithorax with right lung collapse and mediastinal shift to the left consistent with large pleural effusion. CT of the abdomen and pelvis demonstrated extensive abdominal ascites with nodularity of the peritoneum and a left adnexal cystic lesion (Fig. 2). A follow-up ultrasound of the abdomen revealed a complex cystic lesion within the left ovary concerning for a possible ovarian malignancy. Chest tube placement drained dark brown pleural fluid (Fig. 3) that was exudative and negative for bacterial and fungal cultures as well as Mycobacterium tuberculosis. Cell count revealed 490 nucleated cells/high-power field and 59% histiocytes and 273,000 RBCs/HPF (Fig. 4). Cytology was sent and was negative. Notably, there was a markedly elevated ADA of 102.4 IU/L. A paracentesis revealed similar dark brown fluid with comparable cellular characteristics (Fig. 4). Further work-up including tumor markers (cancer antigen-125, carcinogenic embryonic antigen, and cancer antigen 19-9) were all within normal limits. Interferon gamma release assay assessing for prior exposure to tuberculosis was negative. Patient was subsequently taken for exploratory laparotomy by gynecology-oncology which revealed a large amount of hemorrhagic ascites, multiple endometriotic implants, and a right ovarian endometrioma. Pathology of biopsy specimens from the right ovary, peritoneal implants and left ovarian fossa were consistent with a diagnosis of endometriosis from all samples. The patient was sent for video-assisted thoracoscopy. Decortication was performed on the thin fibrous peel surrounding the left lung. A 2 mm defect in the R medial diaphragm was identified and closed. Pathology of the pleural peel revealed reparative and reactive changes including chronic inflammation and granulation tissue. There was no evidence of malignancy or granulomas. Smears and cultures were negative on all specimens for Mycobacterium tuberculosis.

adenosine deaminase, thoracic endometriosis syndrome

CT of chest revealing large right pleural effusion with right lung collapse and mediastinal shift to the left.

PMC8634645_01

Female

A 7-year old previously healthy girl of non-consanguineous Caucasian parents was admitted due to the first occurrence of a brief self-limiting afebrile focal onset seizure (twitching of the right arm). Retrospectively, the patient reported intermittent abdominal pain and a brief period of intermittent double vision preceding the seizure by ~4-5 h on the day of admission. Initial blood tests showed a normal hemogram, blood glucose levels (5.8-6.3 mmol/L), coagulation parameters, and renal retention parameters. CRP was mildly elevated to 22 mg/l [n.v. <8] and D-dimers were increased to 3.8 mg/l [n.v. <0.5]. Electroencephalogram (EEG) demonstrated severe bi-hemispheric slowing, especially in the right parieto-occipital region. Shortly after admission, the patient reported a sudden episode of abdominal pain, headache, loss of vision and suffered from another seizure with focal onset with evolution to generalized seizure activity. The seizure, together with the other symptoms, resolved after ~3 min without medical intervention. The cranial MRI (cMRI) performed on the first day of admission was consistent with PRES showing multiple spot-like, partly confluent cortical/subcortical hyperintensities predominantly in the bilateral parietal region on FLAIR/T2-weighed images with slight focal swelling (Figures 2A,B). On diffusion weighted images, the involved cortical ribbon and the adjacent subcortical white matter were hyperintense to a large extent without hypointensity on the ADC map indicating vasogenic edema. Only small cortical sections showed hypointensities on the ADC map in terms of diffusion restrictions. Typical watershed infarcts or microbleedings could not be detected. The patient's blood pressure was relatively low on the first night, with systolic pressures ranging from 98 to 100 mmHg and diastolic pressures ranging from 44 to 47 mmHg with a normal heartbeat rate of 86-125/min. Vasculitis workup was negative as demonstrated by normal von-Willebrand-Antigen, ANAs and p- und c-ANCAs, anti-ds ABs, ENAs, C3, C4. Cerebrospinal fluid showed no cells and normal levels of lactate, glucose, and protein. Microbiological workup and PCR investigations for neurotropic viruses were negative. Shortly after the admission, several petechiae developed on the forearms and lower limbs. Within the first 5 days of admission, the patient showed progressive petechial bleeding signs, which progressed to the classical and diagnostically groundbreaking palpable purpura (Figure 3), and suffered from another short episode of confusion and blurred vision. Concerning other organ manifestations, urine diagnostics and duplex-sonography of kidneys and gut demonstrated repeatedly normal findings. Arthralgia was not noted. After the second seizure on the day of admission, the girl suffered from headaches and mild behavioral changes but was overall in a stable condition. The patient was treated with acyclovir and ceftriaxone until a microbial etiology for the symptoms was excluded by blood- and spinal fluid analyses. In the course of the disease, blood pressure became elevated, reaching 150 mmHg systolic on the second day. Therefore, antihypertensive medication was initiated with dihydralazine and gradually extended with ramipril, amlodipine, and repeated doses of nifedipine, resulting in levels around 130/75 mmHg. Repeated abdominal ultrasound showed kidneys and gut normally perfused. Urine workup showed no hematuria, and an albumin/creatinine ratio of 33 mg/g ruled out renal impairment. Extended secondary hypertension diagnostics showed normal findings for ocular fundus, electrocardiogram, echocardiography, and endocrine disorders. Four days after the seizure, a non-tender purpuric rash appeared on the lower extremity and buttocks/forearms/and on the trunk in loco typico for IgAV (Figure 2). Abdominal pain and nausea returned 2 days later, so intravenous methylprednisone 2 mg/kg/d was administered for 3 days. Daily abdominal ultrasound excluded intussusception. Under combined antihypertensive medication, the patient fully recovered neurologically without any further seizures. Blood pressure decreased to levels of 100 mmHg systolic under continued treatment with ramipril and amlodipine after 1 week. The benefit of steroids in IgAV has only been shown for abdominal involvement, whereas no studies compare the neurologic outcome with steroids to no or other treatment. As our patient did not show neurological symptoms after the remission of the initial seizure during her entire stay and for the potential additional effects on the blood pressure, we did not administer steroids until the return of abdominal symptoms. Following three courses of i.v. methylprednisone (2 mg/kg), which were well-tolerated, medication was switched to an oral equivalent and tapered. At 1-month follow-up, no neurologic residues were notable, EEG showed slow wave-complexes in the occipital areas and was otherwise normal, renal ultra-sound and urine workup remained without abnormalities. Hypertension diminished, and the antihypertensive medication could be discontinued after a total of 4 weeks. At 6-month follow-up, clinical and neurological examination and urine workup and blood pressure remained normal. EEG findings had significantly improved, showing only mildly slow waves in the occipital region. An externally acquired brain MRI follow-up was normal without residual lesions. Today, with a follow-up of 3 years, the patient remained symptom-free. Literature search with the aforementioned MeSH terms yielded 325 studies, of which 22 included patients with seizures or PRES associated with IgAV and two studies with IgAV associated with cerebral vasculitis. From these studies, clinical data of a total of 28 patients could be collected. Reports in English and German were evaluated independently by two authors. In addition, citations from reviews were checked, but no further reports could be identified by this (Table 1). In total, we identified 28 cases with IgAV and reversible encephalopathy. Twenty six cases were associated with seizures, and thereof 14 cases fulfilled all clinico-radiological criteria of PRES. Lava et al. indicated the existence of seven other cases, which, however, were not available in English or did not fulfill the radiologic diagnostic criteria of PRES and were therefore not considered a confirmed PRES diagnosis in this summary. In contrast to the general prevalence of IgAV (male 2:1 female), neurological involvement in pediatric patients was nearly equally contributed, with 13 girls and 13 boys affected, respectively. Two cases of adult males (22 and 42 years of age) and one female patient were found. Berube et al., however, reported a 1.5:1 preponderance of male patients. The mean age of patients was 11.2 years (median 8.0, range 5-42 years), and no ethnic prevalence was found. The clinical spectrum of the given IgAV cohort is summarized in Figure 4.

cns involvement, henoch-schönlein purpura (hsp), iga vasculitis, cerebral vasculitis, encephalopathy syndrome, review, small-vessel vasculitis, treatment

PMC5437444_01

Male

A 63-year-old male with a past medical history of remote facial trauma presented to our hospital with a 1-month long history of fever, headache, and gait instability. The headaches were left sided, constant, and throbbing with associated nausea and vomiting that was worse in the morning. During that month, he also developed progressive difficulty with balance and a fine tremor in his bilateral upper extremities which worsened with activity. He complained of daily chills and was found to be febrile on presentation. On physical exam, he was noted to have mild ataxia with finger-to-nose testing in both arms and inability to perform tandem walking. Neurologic exam was otherwise without focality or meningeal signs. Laboratory studies were only significant for nonspecific markers of inflammation such as C-reactive protein (CRP) (92 mg/L) and erythrocyte sedimentation rate (37 mm/h). Magnetic resonance imaging (MRI) of the brain with and without gadolinium demonstrated scattered nonspecific T2 hyperintensities in bilateral cerebral white matter, without abnormal enhancement, as well as maxillary sinus disease. His headache was treated with steroids, ketorolac, and anti-emetics with mild improvement. His fever was not noted again in his hospital course. Two months later, he presented again with continuing intermittent episodes of headache, fever, unsteady gait, and vomiting. He underwent a LP at this time which showed elevated protein, pleocytosis with neutrophilic predominance, and normal glucose. He was started on empiric antibiotics for meningitis. Extensive workup for bacterial, fungal, viral, and autoimmune etiologies was negative during this hospitalization, as well as subsequent hospitalizations. CSF studies included basic studies (Table 1) as well as testing for acid-fast bacilli stain, anaerobic culture, Aspergillus galactomannan, cryptococcal antigen, cytomegalovirus, enterovirus, fungal culture, group B Escherichia coli, Haemophilus influenza type B, herpes simplex virus 1 and 2, JC virus, Listeria antibody, multiple sclerosis IgG synthetic rate, Streptococcus pneumonia antigen, Tropheryma whippelii, varicella zoster, venereal disease research lab test (VDRL), and 14-3-3 protein. Hematologic infectious workup included blood cultures, complete blood count, antistreptolysin O titer, blastomycoses antibody, Brucella IgG, Coccidioides immitis, diphtheria, Epstein-Barr virus, Ehrlichia antibody, fluorescent treponemal antibody absorbed test (FTA-ABS), hepatitis C, human herpes virus 6 (HHV-6), Histoplasma galactomannan antibody, HIV 1 and 2, Listeria antibody, Lyme antibody, mumps IgG antibody, Mycobacterium tuberculosis, pneumococcal antibody, procalcitonin, rapid plasma regain (RPR), and toxoplasma IgG, which were all negative. Hematologic autoimmune and neoplastic workup included anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibody (P-ANCA, C-ANCA), cyclic citrullinated peptide (CCP) antibody, complement C3 and C4, cryoglobulin screen, IgA, IgG, IgM, N-methyl-D-aspartate (NMDA) receptor antibody, rheumatoid factor (RF), serum protein electrophoresis (SPEP), SSA/SSB antibody, and voltage-gated potassium channel antibody, which were similarly unremarkable. This workup included paraneoplastic testing for antineuronal nuclear antibody types 1-3, antiglial nuclear antibody type 1, Purkinje cell cytoplasmic antibody type 1-2 and TR, amphiphysin antibody, CRMP-5 IgG, striational antibody, P-Q type calcium channel antibody, N-type calcium channel antibody, and acetylcholinesterase receptor-binding antibody. MRI with and without gadolinium was repeated showing previously noted T2 hyperintensities as well as new areas of hyperintensities in the right cerebral hemisphere, right caudate, and the brainstem without abnormal enhancement. His symptoms improved with antibiotic therapy and he was discharged with a peripherally inserted central catheter (PICC line) to complete a treatment course of meropenem for presumed atypical bacterial meningitis. Over the subsequent year, he returned to the hospital on a monthly basis with worsening fever, headache, tremor, gait instability, as well as an intermittent diffuse macular rash. As time progressed behavioral changes, including abulia and apathy, were becoming problematic. Repeat MRI with and without gadolinium at this point demonstrated diffuse T2 hyperintensities in both cerebral hemispheres, basal ganglia, and brainstem, as well as new bilateral leptomeningeal enhancement (Fig. 1). Repeat LPs consistently showed substantial pleocytosis and elevated protein (Table 1). Other extensive workup was pursued including vascular imaging of his head and neck, CT chest, abdomen, and pelvis, temporal artery biopsy, and brain biopsy, which were nondiagnostic. Dilated ophthalmologic exam did not show any evidence of uveitis. Repeated treatments with broad-spectrum antibiotics did not improve his course and the patient's condition continued to deteriorate over the course of 1 year, leading to progressive decline in functional status. He was continually readmitted with a cyclical presentation of fever, each time at a worse baseline. On his final admission, he was significantly altered and found to be in generalized nonconvulsive status epilepticus. At this juncture, without a known infectious or neoplastic etiology confirmed, the team suspected that an autoimmune etiology may be causative. Steroid and antiepileptic treatment was initiated which caused nearly immediate improvement in the patient's mental status. Unfortunately, despite improvement in mental status and behavior, he continued to have periodic flares of fever and rash nearly every 2 weeks. Over the next several months, intravenous immunoglobulin and mycophenolate were trialed; however, the patient continued to be readmitted on a monthly basis. After failing these typical treatments for autoimmune meningoencephalitis, an interleukin-1 (IL-1) receptor antagonist called anakinra was trialed in this patient. The choice for this medication was mainly due to his cyclical fever/rash presentation, despite genetic testing being negative for periodic fever syndromes, including ELANE, LPIN2, MEFV, MVK, NLRP3, PSTPIP1, and TNFRSF1A. Remarkably, after being started on anakinra our patient experienced resolution of his meningoencephalitis, fevers, and rash. Over time, his other neurologic symptoms such as tremor, gait, abulia, and apathy also improved. His CRP and erythrocyte sedimentation rate, both of which remained elevated throughout his many hospitalizations, had normalized. His follow-up MRI of the brain with and without gadolinium following 1 year of treatment demonstrated resolution of the basal ganglia and midbrain hyperintensities and resolution of all leptomeningeal enhancement. Given the clinical and radiographical improvement, repeat LP was not done.

anakinra, autoimmune meningoencephalitis, encephalitis, meningitis, periodic fever syndrome

PMC7305368_01

Male

An 11-year-old male presented with worsening respiratory symptoms for two weeks, weight loss, and cervical lymphadenopathy. His past medical history included asthma and severe atopic dermatitis, which at presentation were inadequately controlled. Clinical examination revealed hypoxaemia (oxygen saturation <92% in room air), respiratory distress and enlarged non-tender cervical lymphadenopathy. The chest roentgenogram showed bilateral diffuse micronodular opacities (Fig. 1). The leading diagnostic consideration at this point was miliary tuberculosis given the high prevalence of tuberculosis in our region. However, thorough microbiological investigation, including mycobacterial culture and polymerase chain reaction (PCR) failed to demonstrate Mycobacterium tuberculosis. Tissue was obtained from one of the enlarged cervical lymph nodes to investigate the possibility of lymphoma. Histopathology of the core biopsy showed focal involvement by metastatic carcinoma demonstrating papillary-cystic growth with scattered solid islands and psammoma bodies (Fig. 2). The neoplastic cells displayed nuclear enlargement with irregular nuclear membranes, nuclear overlap and "Orphan Annie eye" nuclear inclusions. Immunohistochemical interrogation revealed positivity with cytokeratin (CK) 7, thyroid transcription factor 1 (Fig. 3), and thyroglobulin. These findings supported the pathological diagnosis of metastatic PTC. Retrospectively, further clinical examination revealed an ill-defined 2,5 x 1,5 cm left thyroid nodule. Ultrasonography confirmed a heterogeneous left thyroid nodule with internal calcifications. Considering the histological diagnosis, the chest roentgenogram findings were reviewed to now include carcinomatosis of the lung. Uncontrasted magnetic resonance imaging (MRI) of the mediastinum and neck revealed a lobulated, predominantly solid thyroid mass that returned heterogeneous T2 high signal and T1 low signal, with associated extensive bilateral cervical lymphadenopathy. Preoperative thyroid scintigraphy was not performed due to local unavailability of radioactive iodine during the Covid19 pandemic. Total thyroidectomy with central and modified left cervical lymph node dissection was performed, preserving the sternocleidomastoid muscle, accessory nerve and internal jugular vein, and removing nodes from zones 2-6. Surgical findings revealed a firm, ill-defined mass involving the left lobe of the thyroid, invading the strap muscles. Multiple pathological lymph nodes were noted in both the central and the left lateral compartments of the neck. Pathological evaluation of the resection specimen revealed extensive multifocal involvement by PTC, with extrathyroidal extension and widespread involvement of cervical lymph nodes. Seven out of 9 nodes in the central compartment were positive, and 15 out of 59 nodes were positive in the lateral compartment. Immunohistochemistry for BRAFV600E was negative. Postoperative calcium-phosphate metabolism was normal, and the patient did not experience any further adverse events. The postoperative thyroid hormone status was as follows: thyroid stimulating hormone (TSH) 16.47 mU/L (normal range 0.57-4.03), thyroxine (T4) 9.0 pmol/L (8.5-13.6), thyroglobulin 4081.0 ug/L (normal range 3.5-77.0) and antithyroglobulin 15 (normal <115 U/mL). Postoperative levothyroxine was initiated because of the hiatus in receiving radioactive iodine therapy for the metastatic lung disease. Prior to initiation of thyroid hormone replacement, a whole-body diagnostic I-131 scan revealed extensive uptake of iodine in the lungs bilaterally. This finding confirmed the preoperative impression of widespread pulmonary metastases. The patient was discharged from hospital pending the first course of therapeutic radioactive iodine (RAI) to treat the metastatic lung disease.

endocrine pathology, lymphangitic carcinomatosis, papillary thyroid carcinoma

PMC4475710_01

Female

A 64-year-old female with a history of ventilator dependent respiratory failure secondary to end-stage chronic obstructive pulmonary disease (COPD) and bioprosthetic mitral valve replacement 8 years ago was admitted to the medical intensive care unit (MICU) for worsening respiratory failure from pulmonary edema and multifocal pneumonia secondary to Escherichia coli. She was diuresed and completed a course of antibiotics with ceftriaxone. A transesophageal echocardiogram (TEE) was performed during this admission revealing severe prosthetic mitral valve stenosis, mildly elevated pulmonary artery pressures, a normal tricuspid valve, and no vegetation on any valve. She was ultimately transferred to a long term postacute care hospital. Over the following month, the patient continued to decline in clinical status, and further investigation was undertaken. Rapid-growing mycobacterium was isolated from three cultures for mycobacteria from a tracheal aspirate. Interferon Gamma Release Assay (IGRA) and M. tuberculosis complex polymerase chain reaction (PCR) of a tracheal aspirate were negative. Rapid-growing mycobacterium was isolated from multiple blood cultures from a peripherally inserted central catheter (PICC) and from peripheral venipuncture. M. fortuitum was the organism identified in all cultures. Empiric antibiotic therapy was initiated with amikacin, imipenem, and clarithromycin; and the PICC line was removed. The resistance-pattern confirmed that the isolate was sensitive to amikacin and imipenem, but resistant to clarithromycin. The patient was ultimately readmitted to the MICU for hypotension and concerns for overdiuresis and volume depletion. A transthoracic echocardiogram (TTE) was performed (40 days after the previous TTE and 12 days after initiation of antibiotics) revealing a new 10 mm x 11 mm vegetation on the ventricular aspect of the pulmonic valve, severe tricuspid regurgitation, and severe prosthetic valve mitral stenosis (Figure 1). The patient was not a candidate for pulmonic valve replacement and medical management was continued. Given the grim prognosis, the patient ultimately decided to stop antibiotic therapy and entered hospice where she ultimately passed away. The patient completed 16 days of antibiotics at the time she was discharged to hospice.

PMC7365854_01

Female

Compared with Wuhan, the 29 cases of COVID-19 in Jinan exhibited mild or moderate symptoms, which are mainly imported cases from Wuhan's contact history (Tables 1, 2). Of the 29 cases, 44.8% had a history of contact with Wuhan person, while others were clustering disease. The average age of the patients was 38.2 years old (SD = 13), including male (11[37.9%]) and (18[62.1%]) female. SARS-CoV-2 nucleic acid was detected in all patients by real-time RT-PCR. But two of them were asymptomatic, and they were compulsively detected nucleic acid because of close contact with confirmed cases. Asymptomatic patients were also treated in hospital's isolation wards until their detection turned negative, with one patient of them showing stool positive before being discharged. All patients were tested for the nucleic acid of Influenza A and B viruses (FluA, B) and respiratory syncytial virus (RSV). We did not find the co-infection of SARS-CoV-2 and Flu A, B, or RSV viruses in the patients because of the low sample size. Patients had clinical manifestations of fever (18 [62.1%] patients), cough and pharyngalgia (9 [31%] patients), pneumonia (25 [86.2%] patients), muscle aches (4 [13.8%] patients), fecal nucleic acid positive (4 [13.8%] patients). According to imaging examination, 25 [86.2%] patients showed pneumonia (Tables 1, 2). We sorted out 10 representative cases and combed the timeline of the positive throat and stool samples (Figure 1). Four cases are enrolled in Jinan, and the rest of the cases are reported by other agencies. In addition to patients whose initial symptoms of infection are diarrhea, there are some particular cases. After the throat swab turned to negative, their stool samples became positive again, and most of the clinical manifestations appeared 5-7 days after the pulmonary symptoms. Some patients with gastrointestinal infections were secondary to pulmonary infections, and during the patients' recovery period, the virus may still be released from the patient's gastrointestinal tract for 7 days, or even longer. We inferred virus being excreted through the intestine may be more beneficial to the recovery of patients. The replication and duration of SARS-CoV-2 detoxification is directly related to the prognosis of patients. Patients with different clinical symptoms may be closely related to the route of the virus during transmission. The infection sites of virus causing different clinical symptoms and directly affects the course of disease. We speculated several different clinical symptoms may reflect various transmission pathways of SARS-CoV-2 shown in Figure 2. The symptomless SARS-CoV-2 carriers were divided into two groups, i.e., the throat swab positive or the stool sample positive, which reflected the different target sites of a susceptible patient. Study on the first clinical symptoms and the progression of the disease, lungs-intestine transmission route showed that there are three kinds of routes: from the lungs to intestine, the self-infection from the intestine to lungs, co-infection of lungs, and intestine. Combing the time points of patients' hospitalization may be helpful to provide a guideline for COVID-19 diagnosis and treatment. Whether the excretion of feces in vitro during the recovery period is infectious remains to be further studied. The criteria of patients discharged should be reassessed, and the nucleic acid testing of anal swabs or stool samples should be added. Environmental samples detection of four patients with early diagnosis, including eye and conjunctival secretions, telephone surfaces, hands surface, masks, the surface of door handles and bed at home, and other samples in the isolation ward, were all negative except their masks. The virus nucleic acid testing of the blood and stool samples were all negative on admission. But the nucleic acid test of their stool samples became positive after the patients were hospitalized for 8-10 days, while nucleic acid test of throat swab turned to negative. SARS-CoV-2 is mainly transmitted through the respiratory tract in the early stage and can be survival longer on the mask. The epidemiological survey showed the four patients had no recurrence of human transmission before isolated by the hospital. Cases in Jinan are mainly mild symptoms, which indicated that timely diagnosis, early detection, early isolation are very effective approaches before the virus becomes highly contagious. There are no new cases reported for the 26 successive days in Jinan. The fundamental measure for controlling infectious diseases is to cut the source of infection. It is suggested that study on the transmission routes of the virus is a feasible pathway in controlling the disease effectively and we summarize the transmission routes of SARS-CoV-2 systematically. Just like SARS-CoV, SARS-CoV-2 is a typical respiratory virus causing highly contagious potentially lethal disease. The mucous membranes infection is still the main transmission. Many clinical cases developed influenza-like symptoms, with a 2-4 days history of cough and subjective fever (Wang D. et al.,; Wu F. et al.,; Zhu et al.,). Coronavirus gains entry into host cells through recognizing and binding to the host receptor ACE2 distributed from the conjunctiva (Wan et al.,). Once exposed directly or indirectly to the virus (infectious droplets, body fluids, virus-carrying hands), the mucosal cells in the conjunctiva, mouth, nasal cavity, or throat were susceptibility infected by the virus for replicating (Gao et al.,; Zhou P. et al.,). A larger amount of virus was assembled and released into the human lungs through the respiratory tract, resulting in various types of fever, cough, or ground-glass opacity of lung on CT examination results and even respiratory failure. The SARS-CoV-2 mainly spread from person to another through small respiratory droplets from the nose or mouth when a person confirmed COVID-19 coughs or exhales (Figures 3, 4). These droplets land on objects and surfaces around the person. Other people may catch the virus by breathing in droplets or touching these objects or surfaces, then touching their eyes, nose, or mouth. The risk of catching SARS-CoV-2 from someone with no symptoms is very low. However, many people with SARS-CoV-2 experience only mild symptoms, particularly true in the early stages of the disease. Some cases reported that conjunctivitis was the first symptom and they were infected while had a history of close contact with a patient with COVID-19 (Chen L. et al.,; Lu C. W. et al.,). It speculates that there may be a risk of tears and conjunctival transmission. Growing evidence shows that the virus attacks multiple organs in the body. During the outbreak of SARS-CoV-2, some patients developed symptoms of conjunctivitis. Some patients even suffered the ocular diseases in clinical diagnosis before fever and cough (Chen L. et al.,). There have been case reports in which many ophthalmologists were found to be infected through routine diagnosis and treatment with only his eyes unprotected (Chan et al.,; Xia et al.,). Therefore, if conjunctivitis as the initial symptom of confirmed COVID-19 patients was neglected and contacted without comprehensive measures, the infectious tears and body fluids containing the virus could infect other persons (Belser et al.,; Lu C. W. et al.,). Those results suggested that the eyes route of transmission existed (Chan et al.,; Huang et al.,). Deng et al. demonstrated that macaques can be infected with SARS-CoV-2 via the conjunctival route. We proposed that the SARS-CoV-2 transmitted and infected through eyes including two routes (Figure 3). One is direct contact and the other is indirect contact transmission. The direct route is that droplets with virus enter through the eyes. For example, in a fever clinic, a relatively closed environment, there is a high risk of eye infections. When medical personnel performs close-up operations, virus droplets (aerosols pollution) will spray out which may splash into the eyes and cause infections, so medical staff are strongly recommended wearing goggles or a mask. A virus presented in these body fluids may affect our precautionary practices and sites of sampling for diagnostic tests. Recently, Jiang et al. found that the virus was present both on surfaces and in the air (Jiang et al.,). The two positive areas were the surfaces of the nurse station in the isolation area with suspected patients and the air of the isolation ward with an intensive care patient. So high contraction of nucleic acid may exist in the aerosol and influence operator, even the test result. Another route is through indirect contact infection, that is, accidentally touching the virus droplets with your hands and rubbing your eyes or noses may cause conjunctival infection. Therefore, once SARS-CoV-2 infected and replicated in eyes, it will be transmitted through two ways (Figure 3), one is outward transmission, eye secretions, or tears with virus contaminating the hands, and then there is a risk of viral transmission through hands. Another route is an inward transmission. If the virus infects person through eyes, conjunctival secretions, and tears can flow into the mouth through the nasopharyngeal tube which will ultimately reach the lungs or gastrointestinal tract and more infections may occur. Routes of transmission of SARS-CoV-2 other than respiratory droplets and stool are still enigmatic. The proportion of patients confirmed SARS-CoV-2 with conjunctivitis is much smaller than respiratory symptoms, which reflect that the eyes are not the most important organ for propagating the virus. For instance, the eyes cannot generate infectious aerosol unless an eye ezamination has performed. But we still insist that the eyes are important portals of entry for virus. Moreover, increasing reports each day suggesting that SARS-CoV-2 cases began with eye redness and tingling as the leading symptoms, and the literature suggests that viruses can infect the human body through conjunctiva (Lu C. W. et al.,; Wang W. et al.,). These results showed that a few new cases of COVID-19 began with conjunctivitis as the first symptom, and the SARS-CoV-2 containing in the eye surface may enter into the nasal cavity and throat through drain tears. SARS-CoV-2 can be transmitted through the nose-eye, possibly through the way of increased oral pressure caused by coughing or sneezing, and reverse transmission of the virus through the nasolacrimal duct to the dacryocyst and then infect the conjunctival cornea (Sun et al.,; Zhou Y. et al.,). Thus, this route is a two-way transmission route (Figure 4). The lacrimal route, via drainage of tear fluid including virus from punctum in the upper and lower eyelid through canaliculi to the lacrimal sac, and further through the nasolacrimal duct to the nasal cavity, would be another pathway available for SARS-CoV-2 infection. During replication in the ocular tract there will be a continuous influx of virions to the nasal cavity, and respiratory infection may be established. The possibility of subclinical and/or prolonged virus replication in the eye, followed by continuous transfer to the respiratory tract cannot be excluded. Generally, many respiratory pathogens, such as influenza, SARS-CoV and MERS-CoV, cause enteric symptoms, so is SARS-CoV-2 (Holshue et al.,). Diarrhea was observed in a considerable number of patients. In early reports from Wuhan, 2-10% of patients with COVID-19 had gastrointestinal symptoms such as diarrhea or vomiting (Chen N. et al.,; Wang D. et al.,). Abdominal pain was reported more frequently in patients admitted to the intensive care unit than in individuals who did not require intensive care unit care, and 10% of patients presented with diarrhea and nausea 1-2 days before the development of fever and respiratory symptoms (Yeo et al.,). The study found that the detection of SARS-CoV-2 nucleic acid positive in a few feces of patients with confirmed COVID-19 cases indicated the presence of a live virus. Nanshan Zhong and Lanjuan Li teams have isolated SARS-CoV-2 from the fecal swab specimens of the pneumonia patient with COVID-19 separately. These findings demonstrated the presence of live viruses in the feces of patients. The recent occurrence of two COVID-19 patients in the same building in HongKong also provide the evidence of fecal transmission. Indeed, the SARS-CoV-2 receptor ACE2 is highly expressed on differentiated enterocytes. SARS-CoV-2 can infect enterocyte lineage cells in a human intestinal organoid model (Lamers et al.,). Fecal transmission mode accounts for a small proportion of respiratory virus transmission. Most of the virus transmitted through the feces are enteroviruses, and respiratory viruses are mainly transmitted through droplets and contact. However, more than 15% of cases showed that the anal test of several patients had become positive at the later stage, while the chest radiographic evidence and viral clearance in respiratory samples from the upper respiratory tract showed significant improvement, so fecal formation route cannot be ignored. Pan et al. reported that the viral loads of stool samples were less than those of respiratory samples, so whether the excretion of feces in vitro during the recovery period is infectious remains to be further studied. Considering the evidence of fecal excretion for SARS-CoV-2, the virus can also be transmitted via the fecal-oral transmission route or re-transmitted through the formation of aerosols in virus-containing feces. The transmission route of the tract may not be a single transmission. It may be a medium channel for other routes (Figure 4). Therefore, the standard procedure of stool sample collection and examination in patients with SARS-CoV-2 is important to protect medical staff and reduce the risk of infection. Cytokines (CK) are key factors regulating the immune response caused by many infectious pathogens that can significantly damage host organs and tissues. In the early stages of SARS-CoV infection, cytokine levels in the blood, such as Il-6, Il-8, and TNF-alpha, are rapidly elevated, the elevation of which is associated with the progression of lung invasion and injury (Wong et al.,). MERS-CoV infection was also reported inducing increased concentrations of proinflammatory cytokines (IFNgamma, TNFalpha, IL15, and IL17) (Mahallawi et al.,). Huang et al. reported 41 patients with laboratory confirmed SARS-CoV-2 infection and those high concentrations of cytokines recorded in plasma of critically ill patients (Huang et al.,). The concentrations of various cytokines (Il-6) in the blood of severe patients with SARS-CoV-2 infection were significantly higher than those of non-serious patients. The concentration of cytokines can indicate the severity of the disease. Liu et al. analyzed the blood immunological indexes of 33 patients with new coronary pneumonia and found that after SARS-CoV-2 infection, the pathogenic T cells were quickly activated to produce granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-6 (Liu J. et al.,). GM-CSF further activates CD14, CD16 inflammatory monocytes, producing more IL-6 and other cytokines, resulting in a cytokine storm that leads to severe immune damage to the lungs and other organs. More and more cases reported that the brain, kidney, and heart impairment induced by the virus infection, may contribute to multi-organ failure and death eventually (Li et al.,; Wu C. et al.,). Those cases with SARS-CoV-2 indicate that there is a dissemination way (lymphatic, hematogenous, direct invasion of adjacent tissues, and pathogenic implantation) in blood vessels of viral infection, which usually occurs in critical patients. This potential way for the viral spread is that SARS-CoV-2 enters into the lung from mouth and throat and then infects cells. The virus replicates in the cell and releases more new viruses. Massive accumulation of SARS-CoV-2 leads to a surge of immune cells and more and more pro-inflammatory cytokines, resulting in a rapid increase in CK levels in the blood, or releasing more virus particles into the blood circulation. The virus and cytokines positively induce high expression of ACE2 in the intestinal epithelium and other organs which accelerated over-expression of ACE2 and viral binding, causing systemic infections with the virus (Figure 5). The model might explain why the SARS-CoV-2 nucleic acid testing in the stool of some patients turns to positive occurs in the later days of treatment.

covid-19, sars-cov-2, asymptomatic patients, eyes-oral transmission, transmission routes

PMC4599705_01

Male

A 19-year-old man was referred to the OCD Research Clinic at Butler Hospital/Brown Medical School for evaluation for neurosurgical treatment. He had separation anxiety as a young child, followed by development of OCD at age 13 years. Premorbid personality and functioning were relatively intact. Primary OCD symptoms included contamination obsessions, and extensive handwashing and showering compulsions. Co-occurring depressive symptoms included anhedonia, amotivation, sleep disturbance, and irritability, with long periods of isolation and considerable time spent in bed. School attendance was inconsistent, with frequent late arrivals due to compulsions eventually resulting in homeschooling. Internet gambling also developed in his teens, resulting in significant financial loss. His treating psychologist and psychiatrist referred the patient for surgical evaluation at age 18 years after aggressive, sustained but unsuccessful attempts with multiple medication combinations and therapy. Thorough record review and interviews with prior treatment providers confirmed lack of response to adequate trials of serotonin reuptake inhibitor (SRI) monotherapies including fluoxetine, fluvoxamine, clomipramine, paroxetine, sertraline, and escitalopram. Medication augmentation (combination) strategies were also used, including the addition of atypical neuroleptics and medications from other chemical classes to augment SRI therapies. These were quetiapine, lamotrigine, olanzepine, ziprasidone, aripiprazole, valproic acid, lithium, and clonazepam. In addition to numerous medication trials, he participated in individual cognitive-behavioral therapy (CBT) involving weekly ERP exercises for approximately 2 years. The patient experienced difficulty committing fully to treatment with poor treatment adherence. He exhibited a low tolerance for discomfort and avoided situations that caused him distress including planned ERP exercises. Consequently, he made minimal treatment gains during this time. At the age of 17 he attended two specialized OCD treatment programs which required participation in intensive behavioral therapy involving daily ERP sessions. Difficulties with anger, rigidity, and frustration often led to conflict with program staff members. He experienced modest gains during and directly following these intensive treatments; however, his symptoms rapidly remitted after returning to his home environment. Given his intractable illness, he and his family explored surgical interventions, namely GVC, prompted by meeting another OCD sufferer whose similarly highly refractory illness had improved after that procedure. Alternative surgeries, including anterior cingulotomy and deep brain stimulation (DBS), were also discussed and considered. They opted to pursue GVC given the relatively large experience with this intervention compared, for example, to DBS where studies were just beginning. Clinical and structured interviews with the patient and his parents confirmed disabling, chronic OCD, and recurrent major depressive disorder. Medical and neurological histories were unremarkable aside from occasional tic-like blinking. On the Y-BOCS, a structured interview assessing OCD symptom severity, he scored in the severe to extreme range (Y-BOCS = 34). At pre-surgical assessment, he had been housebound for 8 months. He was reluctant even to enter his backyard due to fear of bugs, dogs, and other potential "contamination sources." Most waking hours were consumed by intrusive obsessions and compulsions. Handwashing alone consumed 4+ hours/day. He avoided showering since bathing rituals often lasted up to 8 hours driven by a feeling of incompleteness. TV-watching was severely compromised by obsessions that he had missed something important, leading to reviewing rituals, lasting up to 4 hours for a 1-hour show. His intractable illness, which included aggressive outbursts when he felt contaminated or frustrated by symptoms, profoundly disrupted family life. Lorazepam and local anesthesia (Lidocaine 1%) were administered preoperatively prior to the attachment of a Leksell stereotactic frame to the skull. A preoperative stereotactic MRI was obtained. Dose planning and target selection used a dedicated software platform (Leksell GammaPlan). Bilateral "double shots" were targeted at the ventral half of the anterior limb of the internal capsule in a coronal plane 8 mm anterior to the posterior border of the anterior commissure. Converging gamma beams from [60]Co sources using 4-mm collimators were targeted to place two shots on each side covering the ventral half of the internal capsule within the 50% isodose line, which included the adjacent dorsal part of the ventral striatum. A dose of 180 Gy was prescribed per shot at 100% for a total exposure time of 543.92 minutes. He tolerated the treatment without complications. Psychotropic medications fluoxetine 80 mg/day and lamotrigine 300 mg total/day were continued, as before surgery. Three months following GVC he returned to active CBT with his previous therapist (FP). Notably, he described his post-surgery experience of behavioral therapy as qualitatively different than prior to the GVC procedure. He was clearly more motivated to confront OCD-symptom-triggering situations that he had previously avoided in ERP. For example, he allowed his therapist to conduct a large-scale home-based exposure session to address fears of contamination. He described changes in both his ability to do therapeutic exposures and in his memory of successfully completing them: Before, I felt like I could not handle the exposures. I had a lot more trouble forcing myself to do it. I had times where I could do the ERP, but I could not keep what I had learned in my head. After, I felt more determined. I felt like I could handle the exposures. I felt like I could keep them in my head and remember them. The surgery helped in that it made ERP easier to do, easier to hold onto, and easier to keep doing. It seemed like it sunk in more. It was easier to process and understand. OCD symptoms gradually decreased over 36 months. The pre-surgical Y-BOCS score of 34 (consistent with his prior course), decreased successively to scores of 26, 20, and 11, at 6, 12, and 36 months, respectively. During this period, a typical shower routine that would have lasted 7 hours at baseline (due to washing compulsions) gradually decreased to 15 minutes 3 years after surgery. Although residual handwashing and checking symptoms remained, these were relatively minor and not impairing, as reflected by a YBOCS of 11, below the typical severity threshold of 16 for patients meeting OCD diagnostic criteria. Co-morbid depressive symptoms also decreased markedly. His Beck Depression Inventory (BDI) score at pre-surgical baseline was 32, indicating severe depression, decreased to 4 (below diagnostic threshold) 3 years after the GVC procedure. Daily functioning also improved substantially. He enrolled in college, began to socialize with classmates, and re-engaged in sports and other activities he had enjoyed before his OCD had worsened dramatically in his mid-teens.

PMC9112304_01

Male

A 53-year-old male patient was referred to the ICU of Bach Mai hospital with a 2-week history of persistent high fever and acute hepatomegaly. There was no medical history. He lived in a rural area in Hai Phong city and had a cow. The patient had a high fever of about 39 C at the time of onset and took some antipyretics without symptoms alleviation. He was admitted to a local hospital after 3 days. The physical examination revealed hepatomegaly whilst laboratory investigation showed pancytopenia (WBC 2.7 G/L, PLT 129 G/L, RBC 3.52 T/L), elevated liver enzymes (GOT 110 U/L, GPT 70.7 U/L). After 10 days of treatment with Ceftazidim, the patient had no response, maintained fatigue, and high fever; he was referred to our hospital. On admission, the patient was conscious with a body temperature of 39 C, pulse rate of 86 bpm, blood pressure of 110/70 mmHg, respiration rate of 26 bpm, hepatomegaly of 2 cm below the costal margin. Blood tests revealed pancytopenia (RBC 3.54 T/L, HGB 111 g/L, MCV 86.4 fL, MCH 31.4 pg, MCHC 360 g/L, PLT 63 G/L, WBC 0.57 G/L, NEU 17.5%, LYM 63.2%), elevated liver enzymes with normal bilirubin (GOT 208 U/L, GPT 369 U/L, total/ direct bilirubin 11.8/5.5 micromol/L), slightly increased Procalcitonin of 0.108 ng/mL. Other biochemical markers were in normal range, such as: Urea, creatinine, glucose, protein, albumin, electrolytes (Na, K, Cl), and urinalysis (10 parameters). Viral serologies including HIV, hepatitis A, B, C; EBV, CMV, dengue, and leptospira were negative. Blood and urine cultures were negative. Chest X-ray was normal, thoracic CT scan excluded lymphadenopathies. Both abdominal ultrasound and abdominal CT scan showed hepatomegaly. The transthoracic echocardiogram was normal. Other tests for tuberculosis, lupus, and autoimmune hepatitis were negative. Bone marrow aspiration and biopsy were performed on day 2 after admission. The bone marrow aspiration smear was hypocellular but there was an increase in macrophages (Figure 1). On the bone marrow biopsy slide, many fibrin ring granulomas were seen (Figure 2), suggesting Q fever. Two daily 100 mg doses of Doxycycline were started after these bone marrow analysis results. 2 weeks later, the diagnosis of Coxiella burnetii was confirmed by PCR which was positive in the 16S primer sequence with primers 400 (Table 1). Doxycycline was continued for 14 days with clinical improvement with no fever. About laboratory test, CBC revealed HGB 121 g/L, PLT 154 G/L, WBC 3.2 G/L; and liver enzymes returned to normal range (GOT 36 U/L, GPT 43 U/L). The patient was discharged from the hospital after 20 days of treatment.

coxiella burnetti, q fever, bone marrow biopsy, fibrin ring granuloma, zoonotic infectious disease

PMC4894734_01

Female

A 18-year-old women presented with chronic productive cough, and intermittent bilateral nasal obstruction. She had a history of recurrent episodes of respiratory tract infection and facial pain since childhood, and did not suffer from hearing loss or recurring otitis media. She could independently perform activities of daily living. On examination, the patient was pleasant, no chest pain, no distress, she spoke abnormally, and she had difficult to pronounce some letters. Blood pressure, pulse, oxygen saturation were normal. On chest auscultation, there were coarse crackles audible over both lung fields, and her heart sounds were heard best on the right side of the chest. Her chest X-ray PA view revealed the cardiac shadow and apex on the right side. She presents a dextrocardia (Figure 1). Electrocardiogram (ECG) showed inverted "P" waves in L1 and AVL on left-sided chest leads (Figure 2). High resolution computed tomography (HRCT) chest revealed bronchiectasis changes, CT abdomen confirmed situs inversus, and the sinus CT scan reveals maxillary sinusitis and filling of nasal pits mainly on the left side (Figure 3, Figure 4, Figure 5). in laboratory work-up, hemogram was normal, no anomaly in the protein electrophoresis, reactive protein C was normal, antinuclear antibody, antineutrophil cytoplasmic antibody,anti CCP antibody,rheumatoid factor, HIV serology were negative. Sputum for acid fast bacilli didn't reveal the tuberculosis bacilli. The speech therapy examination report revealed the presence rhinolalia clausa associated with a single articulation disorder. Nasal fiberoptic endoscopy was performed and showed bilateral grade 1 nasal polyposis and oral examination showed posterior rhinorrhea. Ear microscopic examination and the audiogram were normal (Figure 6). On spirometry, expiratory value in the first second (FEV1),84% of the reference value (2.31 l); forced vital capacity( FVC), 73% of the reference value (2.36 l); FEV1 /FVC, 97. She was diagnosed with kartagener syndrome based on her clinical and radiological presentation, and currently she is reviewed in speech therapy for reeducation and under local nasal corticosteroid. The evolution was favorable with a subsided of swelling on 6 months after the end of treatment. The child shows no signs of local recurrence or other tuberculous location.

kartagener′s syndrome, nasal polyposis, rhinolalia, sinusitis, situs inversus

HRCT of the chest in parenchymal window and in axial section reveals bronchiectasis and dextrocardia.

PMC7553885_01

Male

A male patient, meloderma, a construction worker, 24 years old. He presented himself at the Oral and Maxillofacial Surgery Service complaining about mouth injury, causing dysphagia due to burning and pain. In the anamnesis, there was a clinical course with an evolution of approximately 3 years, with hospitalizations occurring under suspicion of severe tonsillitis with no positive response for treatment. Physical examination revealed an individual with a symmetrical, normocorate and a febrile face; Absence of regional infracted and painfully lymph nodes. Intraorally, total denture with satisfactory hygiene; presence of a non-bleeding erythro-leucoplastic lesion with irregular surface and diffuse contours that affected the soft palate and oropharynx (Fig. 1). On the Computerized Tomography (CT) of the face examination, it was possible to observe muco-periosteal thickening of apparently inflammatory origin in the soft palate region with absence of bone involvement in the involved region, with free airways (Fig. 2). Negative results for HIV, Syphilis (VDRL / FTABS) and Tuberculosis (Escarro T.); without radiographic signs of paracoccidioidomycosis (Paracoccidiodesbrasiliensis) in the thorax. Material was collected for incisional biopsy demonstrating non-specific chronic inflammatory tissue sections with immunohistochemical markings for Paracoccidiodesbrasiliensis (Fig. 3). The patient was asked to go to the Center for Tropical Diseases of the Evandro Chagas Institute/PA where he was diagnosed with Leishmaniasis by Montenegro intradermoreaction (MIDR). The treatment was started with Fluconazole 400 mg twice a day for one month in combination with Nystatin-based mouth wash three times a day. In 10 days', return there was a slight improvement in the condition.

leishmaniasis, oral manifestations, paracoccidioidomycosis, parasitological association

PMC4356039_01

Female

The patient was an 81-year-old woman. Around June 2012 she noticed difficult breathing while walking; then as the symptom worsened she visited our hospital in October 2012. In December of the same year, bronchoscopy together with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) were performed. The dominant cells in BAL fluid were monocytes, and TBLB demonstrated mild lymphocyte infiltration and fibroblast hyperplasia. Respiratory function tests showed restrictive lung disorder with a percentage vital capacity (%VC) of 63.0%, forced vital capacity (FVC) of 1.05 L, percentage forced vital capacity (%FVC) of 55.5%, forced expiratory volume in one second (FEV1) of 1.05 L, percentage of predicted forced expiratory volume in one second (FEV1%) of 107.1%, and percentage of forced expiratory volume in one second (Gaensler's FEV1%) of 100.0%. Computed tomography (CT) showed honeycombing along with traction bronchiectasis in the subpleural and basal areas of both lungs (Fig. 1a). Findings of physical examination and blood tests showed no evidence of collagen-vascular disease or any other condition apart from idiopathic pulmonary fibrosis. Thus, based on clinical findings, the patient was diagnosed idiopathic pulmonary fibrosis (IPF). In addition, the transthoracic echocardiography showed a tricuspid regurgitation (TR) pressure gradient of 31.7 mmHg and a pulmonic regurgitation (PR) pressure gradient of 6.2 mmHg. The patient was started on oral pirfenidone in February 2013, but this was discontinued in October 2013 because of difficulty taking oral medication. As for imaging examinations, in August 2013 these ruled out progression of IPF, but the patient showed aggravation of dyspnea and decreased oxygen saturation, as well as onset of orthopnea and rapidly progressing edema. Transthoracic echocardiography demonstrated findings consistent with congestive heart failure secondary to pulmonary hypertension (PH), and thus the patient was started on diuretic therapy. However, her condition showed little improvement and the patient was thus hospitalized for detailed examination and treatment in October 2013. Findings of physical examination upon admission included body temperature 36.9 C, blood pressure 94/52 mmHg, regular heart rate at 95 beats per minute, respiratory rate 25 breaths per minute, oxygen saturation 80% (on oxygen 3 L/min by nasal cannula), engorged jugular veins on inspection, and bilateral crepitations on auscultation. Exacerbation of IPF was unlikely because the only significant finding from imaging examination and blood tests was elevated KL-6 that was attributed to influence of diuretic therapy given since before her admission and influence of congestion (Table 1 and Fig. 1b). In addition, after admission, transthoracic echocardiography and right heart catheterization were performed. The transthoracic echocardiographic finding suggested severe PH and a congestive condition (TR pressure gradient was 86.6 mmHg and PR pressure gradient was 16.1 mmHg total ejection isovolumetric (Tei) index was 0.44 and tricuspid annular plane systolic excursion (TAPSE) was 1.13 cm). (Fig. 2a). Right heart catheterization showed systolic and diastolic pulmonary artery pressure (PAP) of 54 and 24 mmHg, respectively (mean PAP was 39 mmHg) and a systolic and diastolic pulmonary capillary wedge pressure (PCWP) of 16 and 0 mmHg, respectively (mean PCWP was 9 mmHg) (Table 2). After various examinations including lung perfusion scintigraphy that ruled out other diseases causative of PH, the diagnosis of PH due to IPF was established. Since treatments such as diuretic therapy and oxygen therapy do not improve circulatory failure associated with PH, on Day 12 of hospitalization the patient was started on oral bosentan at a dose of 125 mg/day, leading to rapid improvement of circulatory failure associated with PH. The dose of bosentan was increased to 250 mg/day from hospital Day 25 onward. After improvement of symptoms and findings, the patient was discharged from the hospital on long-term oxygen therapy (using Oxymizer ; dose of oxygen was 3 L/min at rest and 6 L/min on exertion) (Table 2). At the follow-up assessment one year later her pulmonary function showed no significant changes and no apparent worsening of arterial blood gases, with evident improvement of PH, WHO functional class, maximum exercise tolerance on treadmill exercise testing, right heart catheterization, and transthoracic echocardiography (Table 2 and Fig. 2b).

bosentan, endothelin antagonist, ipf, idiopathic pulmonary fibrosis, idiopathic pulmonary fibrosis, pap, pulmonary artery pressure, ph, pulmonary hypertension, pulmonary hypertension, respiratory failure

Chest roentgenogram and computed tomography (a). Chest roentgenogram and computed tomography at the initial visit Honeycombing along with traction bronchiectasis in the subpleural and basal areas of both lungs were detected.

PMC4356039_01

Female

The patient was an 81-year-old woman. Around June 2012 she noticed difficult breathing while walking; then as the symptom worsened she visited our hospital in October 2012. In December of the same year, bronchoscopy together with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) were performed. The dominant cells in BAL fluid were monocytes, and TBLB demonstrated mild lymphocyte infiltration and fibroblast hyperplasia. Respiratory function tests showed restrictive lung disorder with a percentage vital capacity (%VC) of 63.0%, forced vital capacity (FVC) of 1.05 L, percentage forced vital capacity (%FVC) of 55.5%, forced expiratory volume in one second (FEV1) of 1.05 L, percentage of predicted forced expiratory volume in one second (FEV1%) of 107.1%, and percentage of forced expiratory volume in one second (Gaensler's FEV1%) of 100.0%. Computed tomography (CT) showed honeycombing along with traction bronchiectasis in the subpleural and basal areas of both lungs (Fig. 1a). Findings of physical examination and blood tests showed no evidence of collagen-vascular disease or any other condition apart from idiopathic pulmonary fibrosis. Thus, based on clinical findings, the patient was diagnosed idiopathic pulmonary fibrosis (IPF). In addition, the transthoracic echocardiography showed a tricuspid regurgitation (TR) pressure gradient of 31.7 mmHg and a pulmonic regurgitation (PR) pressure gradient of 6.2 mmHg. The patient was started on oral pirfenidone in February 2013, but this was discontinued in October 2013 because of difficulty taking oral medication. As for imaging examinations, in August 2013 these ruled out progression of IPF, but the patient showed aggravation of dyspnea and decreased oxygen saturation, as well as onset of orthopnea and rapidly progressing edema. Transthoracic echocardiography demonstrated findings consistent with congestive heart failure secondary to pulmonary hypertension (PH), and thus the patient was started on diuretic therapy. However, her condition showed little improvement and the patient was thus hospitalized for detailed examination and treatment in October 2013. Findings of physical examination upon admission included body temperature 36.9 C, blood pressure 94/52 mmHg, regular heart rate at 95 beats per minute, respiratory rate 25 breaths per minute, oxygen saturation 80% (on oxygen 3 L/min by nasal cannula), engorged jugular veins on inspection, and bilateral crepitations on auscultation. Exacerbation of IPF was unlikely because the only significant finding from imaging examination and blood tests was elevated KL-6 that was attributed to influence of diuretic therapy given since before her admission and influence of congestion (Table 1 and Fig. 1b). In addition, after admission, transthoracic echocardiography and right heart catheterization were performed. The transthoracic echocardiographic finding suggested severe PH and a congestive condition (TR pressure gradient was 86.6 mmHg and PR pressure gradient was 16.1 mmHg total ejection isovolumetric (Tei) index was 0.44 and tricuspid annular plane systolic excursion (TAPSE) was 1.13 cm). (Fig. 2a). Right heart catheterization showed systolic and diastolic pulmonary artery pressure (PAP) of 54 and 24 mmHg, respectively (mean PAP was 39 mmHg) and a systolic and diastolic pulmonary capillary wedge pressure (PCWP) of 16 and 0 mmHg, respectively (mean PCWP was 9 mmHg) (Table 2). After various examinations including lung perfusion scintigraphy that ruled out other diseases causative of PH, the diagnosis of PH due to IPF was established. Since treatments such as diuretic therapy and oxygen therapy do not improve circulatory failure associated with PH, on Day 12 of hospitalization the patient was started on oral bosentan at a dose of 125 mg/day, leading to rapid improvement of circulatory failure associated with PH. The dose of bosentan was increased to 250 mg/day from hospital Day 25 onward. After improvement of symptoms and findings, the patient was discharged from the hospital on long-term oxygen therapy (using Oxymizer ; dose of oxygen was 3 L/min at rest and 6 L/min on exertion) (Table 2). At the follow-up assessment one year later her pulmonary function showed no significant changes and no apparent worsening of arterial blood gases, with evident improvement of PH, WHO functional class, maximum exercise tolerance on treadmill exercise testing, right heart catheterization, and transthoracic echocardiography (Table 2 and Fig. 2b).

bosentan, endothelin antagonist, ipf, idiopathic pulmonary fibrosis, idiopathic pulmonary fibrosis, pap, pulmonary artery pressure, ph, pulmonary hypertension, pulmonary hypertension, respiratory failure

(b). Chest roentgenogram and computed tomography at exacerbation of pulmonary hypertension Compared with Fig. 1a, the findings did not show marked progression of IPF, while congestion was prominent with an increased cardiothoracic ratio.

PMC3598197_01

Female

A five year old female presented, shortly after migration from Africa, with chronic scalp infection and otitis media. She was noted to have symptomatic hyperglycaemia, with a history dating back possibly to two years of age. She was observed to have several cutaneous and facial features typical of the RMS phenotype (Figure 1). Biochemical insulin resistance was documented, with elevated fasting plasma insulin level of 1836 pmol/L (normal laboratory value: 9-80 pmol/L). At age six, diabetes mellitus was diagnosed with the classical pattern of daytime postprandial hyperglycaemia, but paradoxical nocturnal fasting hypoglycaemia. Genetic testing demonstrated a homozygote mutation at position 119 of the mature alpha subunit of the insulin receptor, but a normal beta subunit. She is of African ethnicity, and was born of a consanguineous union between first cousins. There is no other family history of insulin resistance. Her diabetes was initially managed with Metformin (currently 3 grams/day) followed by a brief trial of added pioglitazone. She rapidly progressed to insulin, with a current insulin requirement of 2100 units per day (>50 units/kg/day). Despite this, her glycaemic control remains suboptimal, with an HbA1c of 75 mmol/mol (9%). She has a current weight of 36 kg, height of 148 cm (Z score -1.1) and BMI of 16.6 kg/m2. Enlarged kidneys were noted from six years of age. Ultrasonography revealed persistent renal sizes greater than two standard deviations for her age (11 cm diameter left, 10 cm diameter right), with poorly defined medullary renal pyramids, loss of normal cortico-medullary differentiation, and a mildly dilated right collecting system. There were no renal cysts or duplex system. Nephrocalcinosis was identified, and appropriate biochemical studies were done, revealing hypercalciuria (Table 1). At age of eight years a mercaptoacetyl triglycine MAG 3 renogram demonstrated normal function bilaterally with an effective renal plasma flow (ERPF) from right kidney of 379 mL/min and left kidney of 404 mL/min (normal ERPF>300 ml/min). At the age of eleven years she presented with recurrent left flank pain, associated microscopic haematuria, and albuminuria on dipstick examination. There were no features to suggest an infective or traumatic aetiology to her symptoms. She was pre-pubertal. Ultrasonography showed a right kidney of 12.3 cm, left kidney of 13.2 cm, with multiple bilateral renal calculi, the largest 10mm in diameter. The right renal pelvis was dilated (1.2 cm), and a simple 10 mm cyst seen in the left kidney. The bladder was normal. A CT urogram revealed a 2 mm calcification seen to the left of the true renal pelvis, suggestive of an intraluminal ureteric calculus. Intravenous pyelogram further demonstrated paintbrush-like appearances of the renal pyramids, consistent with MSK (Figure 2). The patient had the most severe form of MSK, grade 4, with involvement of all the calyces in both kidneys. Her nephrocalcinosis was actively managed by optimising fluid intake and a trial of thiazide diuretic. Treatment was ceased at 3 months, at the request of the family as she remained asymptomatic from her nephrocalcinosis. No further acute episodes of nephrocalcinosis or pain have recurred.

PMC4706388_01

Female

A 39-year-old, white, female healthcare worker, with a past medical history significant for diverticulosis, was presented to the emergency department with acute abdominal pain. She also complained of increased stress, severe night sweats, and progressive weight loss beginning more than 10 weeks prior to admission. On physical examination, she was febrile and cachectic with no appreciable clinical lymphadenopathy. Erect chest radiograph was done to rule out cardiopulmonary causes, and the results were normal. Due to a history of diverticulosis, CT of the pelvis and abdomen was done to rule out diverticulitis. The result showed abnormally dilated loops of the small bowel throughout the abdomen and pelvis, with the gas/fluid levels as shown in Figure 1. Multiple loops of distal small bowel demonstrated abnormal circumferential wall thickening with extensive mesenteric fat edema and inflammation. There was a large amount of free fluid in the pelvis and a 5.0 x 3.6 cm low-density lesion in the right adnexa with a thick ring of soft tissue. Laboratory tests revealed WBC 16,500 with a differential of 40 polymorphonuclear leukocytes with 58 bands, one metamyelocyte, and one mononuclear cell; hemoglobin 12.3, CA-125 39 U/mL, Na 132, K 3.4, Cl 93, CO2 26, and creatinine 0.93. Due to the patient's reproductive age combined with the CT and laboratory results, pelvic inflammatory disease leading to tubo-ovarian abscess was suspected, and the gynecology service was consulted. Diagnostic laparoscopy followed by laparotomy was performed. The laparoscopy on the right adnexa revealed an enlarged ovary with multiple small cystic lesions. The cyst was characterized as a mucinous-like yellow cyst measuring approximately 5 x 5 mm and was sent for culture. The left ovary was normal. Further dissection revealed extensive peritonitis with granuloma located at the left upper abdominal wall near the splenic flexture (Fig. 2), which was biopsied. Pathology reported signs of chronic inflammation but no malignancy. The culture obtained from draining the pyosalpinx was negative for aerobes and anaerobes; however, the cytology was not ordered. Special bacteriological stain used to identify acid-fast organisms, such as Ziehl-Neelson stain, was also not sent despite the clinical suspicion of tuberculosis. The postoperative diagnoses were right pyosalpinx and clinical tuberculous peritonitis. The patient was then discharged because the pathology report did not support the clinical diagnosis of tuberculosis. Ten days later, she presented back to the hospital Emergency Room complaining of pleuritic chest pain. CT scan of the chest showed calcified granuloma in the right lower lobe with no hilar adenopathy and nonspecific pleural thickening, which corresponded to the location of the pain. Electrocardiogram and cardiac enzymes were negative. Quantiferon gold was obtained and was equivocal. The pain was believed to be secondary to pleurisy. After re-evaluating the patient's symptoms and CT results, disseminated tuberculosis was suspected. A biopsy was planned to rule out histopathology diagnosis with diagnostic laparoscopy. Thoracoscopy was declined by chest surgeons due to insufficient evidence of pulmonary TB to justify a lung biopsy. A second laparoscopy was performed to obtain biopsies of the clinically suspected tuberculous lesions, which showed similar - but more extensive - findings as the first laparoscopy. Disseminated lesions were observed throughout the abdomen and pelvic/parietal/visceral peritoneum (Fig. 3). Biopsies and documentary digital photographs were obtained. Cultures were sent for tuberculosis, actinomyces, and fungus, and they all came back negative. Due to continued symptoms of severe night sweats and fever, other possible etiologies were considered, including histoplasmosis. This was tested for using a histoplasmosis urine antigen test that returned positive at 6.47 (negative results are 0.00-3.50, positive results are >4.50). The patient was placed on itraconazole for disseminated histoplasmosis. After several weeks of treatment, the patient was symptom free.

diverticulitis, histoplasmosis, peritonitis, tubal abscess, tuberculosis