Although histoplasmosis is highly endemic in certain regions of the Americas, disease may be seen globally and should not be overlooked in patients with unexplained pulmonary or systemic illnesses. Most patients exhibit pulmonary signs and symptoms, accompanied by radiographic abnormalities, which often are mistaken for community-acquired pneumonia caused by bacterial or viral agents. Once a diagnosis is considered, a panel of mycologic and non-culture-based assays is adequate to establish a diagnosis in a few days to a week in most patients. Once diagnosed, the treatment is highly effective even in immunocompromised patients.

SummaryBackgroundWHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50–70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis.MethodsWe prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test.FindingsFrom Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47–87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23–66; 10/23) for Xpert and 43% (23–66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77–99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24–68]; 10/22; p=0·0010) or culture (45% [24–68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014).InterpretationXpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis.FundingNational Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation.

In the United States, histoplasmosis is generally thought to occur mainly in the Ohio and Mississippi River Valleys, and the classic map of histoplasmosis distribution reflecting this is second nature to many U.S. physicians. With the advent of the HIV pandemic reports of patients with progressive disseminated histoplasmosis and AIDS came from regions of known endemicity, as well as from regions not thought to be endemic for histoplasmosis throughout the world. In addition, our expanding armamentarium of immunosuppressive medications and biologics has increased the diagnosis of histoplasmosis worldwide. While our knowledge of areas in which histoplasmosis is endemic has improved, it is still incomplete. Our contention is that physicians should consider histoplasmosis with the right constellations of symptoms in any febrile patient with immune suppression, regardless of geographic location or travel history.

Background Cryptococcus is the most common cause of adult meningitis in Africa. We evaluated the activity of adjunctive sertraline, previously demonstrated to have in vitro and in vivo activity against Cryptococcus. Methods We enrolled 172 HIV-infected Ugandans with cryptococcal meningitis from August 2013 through August 2014 into an open-label dose-finding study to assess safety and microbiologic efficacy. Sertraline 100–400mg/day was added to standard therapy of amphotericin + fluconazole 800mg/day. We evaluated early fungicidal activity via Cryptococcus cerebrospinal fluid (CSF) clearance rate, sertraline pharmacokinetics, and in vitro susceptibility. Findings Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 (95%CI: −0·41, −0·33) colony forming units (CFU)/mL/day. Incidence of paradoxical immune reconstitution inflammatory syndrome (IRIS) was 5% (2/43) and relapse was 0% through 12-weeks. Sertraline reached steady state concentrations in plasma by day 7, with median steady-state concentrations of 201 ng/mL (IQR, 90–300; n=49) with 200mg/day and 399 ng/mL (IQR, 279–560; n=30) with 400mg/day. Plasma concentrations reached 83% of steady state levels by day 3. The median projected steady state brain tissue concentration at 200mg/day was 3·7 (IQR, 2·0–5·7) mcg/mL and 6·8 (IQR, 4·6–9·7) mcg/mL at 400mg/day. Minimum inhibitory concentrations were ≤2 mcg/mL for 27% (35/128), ≤4 mcg/mL for 84% (108/128), ≤6 mcg/mL for 91% (117/128), and ≤8 mcg/mL for 100% of 128 Cryptococcus isolates. Interpretation Sertraline had faster cryptococcal CSF clearance, decreased IRIS, and decreased relapse compared with historical experiences. Sertraline reaches therapeutic levels in a clinical setting. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. Funding National Institutes of Health, Grand Challenges Canada.

Endemic mycoses such as histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, and talaromycosis are well-known causes of focal and systemic disease within specific geographic areas of known endemicity. However, over the past few decades, there have been increasingly frequent reports of infections due to endemic fungi in areas previously thought to be “non-endemic.” There are numerous potential reasons for this shift such as increased use of immune suppressive medications, improved diagnostic tests, increased disease recognition, and global factors such as migration, increased travel, and climate change. Regardless of the causes, it has become evident that our previous understanding of endemic regions for these fungal diseases needs to evolve. The epidemiology of the newly described Emergomyces is incomplete; our understanding of it continues to evolve. This review will focus on the evidence underlying the established areas of endemicity for these mycoses as well as new data and reports from medical literature that support the re-thinking these geographic boundaries. Updating the endemic fungi maps would inform clinical practice and global surveillance of these diseases.

Introduction TB meningitis (TBM) diagnosis is difficult and novel diagnostic methods are needed. The World Health Organization recommends Xpert MTB/RIF (Xpert) as the initial TBM diagnostic test, based on two studies reporting suboptimal sensitivity (~50–60%). Objective To study the effect of cerebrospinal fluid (CSF) centrifugation on Xpert performance for TBM detection. Design 107 predominantly HIV-infected adults with suspected meningitis were screened prospectively in Kampala, Uganda. CSF was tested by 1) microscopy for acid-fast bacilli; 2) Mycobacteria growth indicator tube culture; 3) Xpert of 2mL of unprocessed CSF; 4) Xpert of centrifuged CSF. Diagnostic performance was measured against an a priori composite reference standard of any positive CSF tuberculosis test. Results 17% (18/107) of participants had definite TBM. When CSF was centrifuged, Xpert had better sensitivity (72%, 13/18) than when using 2mL of unprocessed CSF (28%, 5/18; P=0.008). The median centrifuged CSF volume was 6mL (IQR 4–10mL). Mycobacterial culture yielded 71% (12/17) sensitivity at a median delay of 27 days. Only 39% were positive both by culture and centrifuged Xpert, with additional cases detected by Xpert and culture. Conclusions Centrifuging of CSF optimizes Xpert diagnostic performance for detection of TBM. A combination of culture and Xpert detected the largest number of cases.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) develops in 9 %–47 % of persons with HIV infection and a CNS opportunistic infection who start antiretroviral therapy and is associated with a mortality rate of 13 %–75 %. These rates vary according to the causative pathogen. Common CNS-IRIS events occur in relation to Cryptococcus, tuberculosis (TB), and JC virus, but several other mycobacteria, fungi, and viruses have been associated with IRIS. IRIS symptoms often mimic the original infection, and diagnosis necessitates consideration of treatment failure, microbial resistance, and an additional neurological infection. These diagnostic challenges often delay IRIS diagnosis and treatment. Corticosteroids have been used to treat CNS-IRIS, with variable responses; the best supportive evidence exists for the treatment of TB-IRIS. Pathogenic mechanisms vary: Cryptococcal IRIS is characterized by a paucity of cerebrospinal inflammation prior to antiretroviral therapy, whereas higher levels of inflammatory markers at baseline predispose to TB meningitis IRIS. This review focuses on advances in the understanding of CNS-IRIS over the past 2 years.

Introduction In the current time where we face a COVID-19 pandemic, there is no vaccine or effective treatment at this time. Therefore, the prevention of COVID-19 and the rapid diagnosis of infected patients is crucial. Method We searched all relevant literature published up to February 28, 2020. We used Random-effect models to analyze the appropriateness of the pooled results. Result Eighty studies were included in the meta-analysis, including 61,742 patients with confirmed COVID-19 infection. 62.5% (95% CI 54.5–79, p < 0.001) of patients had a history of recent travel endemic area or contact with them. The most common symptoms among COVID-19 infected patients were fever 87% (95% CI 73–93, p < 0.001), and cough 68% (95% CI 55.5–74, p < 0.001)), respectively. The laboratory analysis showed that thrombocytosis was present in 61% (95% CI 41–78, p < 0.001) CRP was elevated in 79% (95% CI 65–91, p < 0.001), and lymphopenia in 57.5% (95% CI 42–79, p < 0.001). The most common radiographic signs were bilateral involvement in 81% (95% CI 62.5–87, p < 0.001), consolidation in 73.5% (95% CI 50.5–91, p < 0.001), and ground-glass opacity 73.5% (95% CI 40–90, p < 0.001) of patients. Case fatality rate (CFR) in <15 years old was 0.6%, in >50 years old was 39.5%, and in all range group was 6%. Conclusions Fever and cough are the most common symptoms of COVID-19 infection in the literature published to date. Thombocytosis, lymphopenia, and increased CRP were common lab findings although most patients included in the overall analysis did not have laboratory values reported. Among Chinese patients with COVID-19, rates of hospitalization, critical condition, and hospitalization were high in this study, but these findings may be biased by reporting only confirmed cases.