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Background: Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis that have rapidly innovated international guidelines. The 2010 Infectious Diseases Society of America (IDSA) cryptococcal meningitis guideline has not been updated with recent trials. The 2022 AMBITION-cm trial found that a single 10-mg/kg dose of liposomal amphotericin B plus daily flucytosine and fluconazole for 2 weeks was noninferior to 1 week of amphotericin B deoxycholate with flucytosine. It is unknown whether physicians in high-resource settings are using this regimen or more traditional regimens., Methods: We developed an electronic survey in June 2023 to better understand whether physician members of the IDSA Emerging Infections Network (EIN) and Mycoses Study Group Education and Research Consortium (MSG-ERC) had used the AMBITION-cm induction regimen, would use the regimen in hypothetical clinical scenarios, and what perceived barriers to use existed., Results: A total of 242 of 561 (43%) physicians responded to the survey, of whom 205 provided care for persons with cryptococcal meningitis in the last year. Overall, 29 (14%) had used the AMBITION-cm regimen, and 176 (86%) had not. In various hypothetical clinical scenarios, only ∼10% of 209 respondents selected the AMBITION-cm regimen as preferred. Perceived barriers to uptake included the applicability of trials performed in low-resource settings to high-resource settings, that the regimen is not recommended in the 2010 IDSA guidelines, and the applicability to persons without HIV., Conclusions: Most respondents had not used the single-dose liposomal amphotericin B regimen, but the regimen is being used. Further study of this regimen in other patient populations and settings is necessary., Competing Interests: Potential conflicts of interest. N.C.B., A.S., and D.R.B. are co-authors on clinical trials testing single-dose liposomal amphotericin B for histoplasmosis and/or cryptococcal meningitis, for which Gilead Sciences has donated liposomal amphotericin. A.S. reports grants and personal fees from Astellas Global Development Pharma and Mayne Pharma; grants from Scynexis, Cidara and IMMY; and personal fees from Viamet. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nonadherence to antiviral therapy can lead to poor clinical outcomes among patients with chronic hepatitis B (CHB). We used a claims database to evaluate risk factors for nonadherence to antiviral therapy among commercially insured patients with CHB in the United States., Methods: We obtained data for commercially insured adult patients with CHB prescribed entecavir or tenofovir disoproxil fumarate (TDF) in 2019. Primary outcomes were adherence to entecavir and adherence to TDF. Enrollees with a proportion of days covered (PDC) ≥80% were considered adherent. We presented adjusted odds ratios (AORs) from multivariate logistic regressions., Results: Eighty-three percent (n = 640) of entecavir patients were adherent, and 81% (n = 687) of TDF patients were adherent. Ninety-day supply (vs 30-day supply; AOR, 2.21; P < .01), mixed supply (vs 30-day supply; AOR, 2.19; P = .04), and ever using a mail order pharmacy (AOR, 1.92, P = .03) were associated with adherence to entecavir. Ninety-day supply (vs 30-day supply; AOR, 2.51; P < .01), mixed supply (vs 30-day supply; AOR, 1.82; P = .04), and use of a high-deductible health plan (vs no high-deductible health plan; AOR, 2.29; P = .01) were associated with adherence to TDF. Out-of-pocket spending of >$25 per 30-day supply of TDF was associated with reduced odds of adherence to TDF (vs <$5 per 30-day supply of TDF; AOR, 0.34; P < .01)., Conclusions: Ninety-day and mixed-duration supplies of entecavir and TDF were associated with higher fill rates as compared with 30-day supplies among commercially insured patients with CHB., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Pneumocystis jirovecii pneumonia (PCP) is a serious, emerging complication of coronavirus disease 2019 (COVID-19)., Methods: We performed a systematic review of published cases. We describe 6 new cases of PCP/COVID-19 coinfection. Among our cases (n = 6) and those in the literature (n = 69) with available data, the median age (interquartile range [IQR]) was 59 (44-77) years (n = 38), 72% (47/65) were male, and the mortality rate was 30.9% (21/68)., Results: Long-term corticosteroid use was noted in 45.1% (23/51), advanced HIV infection (defined as a CD4 count <200 cells/μL) in 17.6% (9/51), and antineoplastic chemotherapy in 13.7% (7/51), consistent with known PCP risk factors. Notably, 56.7% (38/47) had verifiable risk factors for PCP (high-dose corticosteroids, immunosuppressive therapy, and HIV infection) before COVID-19 infection. A median absolute lymphocyte count (IQR) of 0.61 (0.28-0.92) ×10 3  cells/mm 3 (n = 23) and CD4 count (IQR) of 66 (33-291.5) cells/mm 3 (n = 20) were also discovered among the study population., Conclusions: These findings suggest a need for greater attention to PCP risk factors among COVID-19 patients and consideration of PCP prophylaxis in these high-risk populations., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Pulmonary infections due to Aspergillus , Mucorales, and Nocardia have high morbidity and mortality, in part due to diagnostic challenges. Commercially available molecular assays on bronchoalveolar lavage fluid (BALF) may have increased sensitivity over currently available diagnostic options. Our aim was to characterize the diagnostic performance of assays for each of these pathogens in our patient population., Methods: The medical records of patients whose BALF was tested by polymerase chain reaction (PCR) for Aspergillus , Mucorales, and Nocardia between 2019 and 2021 were reviewed in a cross-sectional manner. European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) definitions of "proven," "probable," and "possible" infection were used, including histopathology, serology, and culture. We used (1) "proven" or "probable" infection by EORTC criteria, (2) improvement or stabilization on targeted antimicrobial therapy, and (3) absence of a more likely diagnosis as the reference standard., Results: The Aspergillus PCR assay demonstrated the highest agreement with the diagnostic reference standard, with 31.25% (10/32) sensitivity and 97.17% (206/212) specificity. Positive and negative predictive values were 62.50% (10/16) and 90.35% (206/228), respectively. No Mucorales or Nocardia infections were identified by the diagnostic reference standard, so the sensitivity could not be calculated. The specificity of Mucorales and Nocardia targets was 98.35% and 96.69%, respectively., Conclusions: Our data demonstrated relatively poor clinical sensitivity for all 3 constituent PCR assays in our patient population, suggesting a limited role for this test in the diagnosis of Aspergillus , Mucorales, or Nocardia ., Competing Interests: Potential conflicts of interest. The listed authors have no conflicts of interest. Individual authors receive the following sources of funding: Liesman: receives funding from Acenxion, which has no conflict with the data presented in this study. Bahr: receives research support from the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (K23 NS110470), which has no conflicts of interest with the data presented in this study. All other authors report no outside funding or potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Tuberculosis is a leading cause of death among women of reproductive age. However, tuberculous meningitis, the most severe form of extrapulmonary tuberculosis, is rarely discussed in pregnancy despite this being a unique period of immune modulation that may predispose women to active disease., Methods: We identified and described cases of tuberculous meningitis among pregnant or postpartum women screened during meningitis clinical trials in Uganda from 2018 to 2022. We conducted a systematic literature review via PubMed/Medline and Embase for all English-language publications from 1970 to 10 July 2022, to identify additional cases., Results: We identified 8 cases of pregnancy-related tuberculous meningitis in Ugandan women living with human immunodeficiency virus (HIV) and 40 additional cases via systematic literature review (none HIV-positive). Of all combined cases, 50% (24/48) were diagnosed postpartum; 50% (24/48) had initial onset during pregnancy, of which 38% (9/24) had worsening of symptoms or disease relapse following pregnancy cessation. Diagnosis was missed or delayed in 33% (16/48) of cases. For those with known outcomes, maternal mortality was 23% (11/48) and fetal/neonatal mortality was 30% (13/44). Of maternal survivors, 30% (11/37) had residual neurologic deficits., Conclusions: The true incidence of tuberculous meningitis in pregnancy or the postpartum period is unclear but likely underappreciated. To date, nearly all published cases have occurred in HIV-negative or otherwise immunocompetent women. Given the well-described physiological immunosuppression during pregnancy and subsequent reconstitution postpartum, physicians must be aware of tuberculous meningitis and pregnancy-related immune reconstitution inflammatory syndrome, especially in countries with a high burden of tuberculosis and in women living with HIV., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The Infectious Diseases Society of America (IDSA) guidelines for the management of histoplasmosis were last revised 15 years ago. Since those guidelines were compiled, new antifungal treatment options have been developed. Furthermore, the ongoing development of immunomodulatory therapies has increased the population at increased risk to develop histoplasmosis., Methods: An electronic survey about the management practices of histoplasmosis was distributed to the adult infectious disease (ID) physician members of the IDSA's Emerging Infections Network., Results: The survey response rate was 37% (551/1477). Only 46% (253/551) of respondents reported seeing patients with histoplasmosis. Regions considered endemic had 82% (158/193) of physicians report seeing patients with histoplasmosis compared to 27% (95/358) of physicians in regions not classically considered endemic ( P  < 0.001). Most ID physicians follow IDSA treatment guidelines recommending itraconazole for acute pulmonary (189/253 [75%]), mild-moderate disseminated (189/253 [75%]), and as step-down therapy for severe disseminated histoplasmosis with (232/253 [92%]) and without (145/253 [57%]) central nervous system involvement. There were no consensus recommendations observed for survey questions regarding immunocompromised patients., Conclusions: Though there are increased reports of histoplasmosis diagnoses outside regions classically considered endemic, a majority of ID physicians reported not seeing patients with histoplasmosis. Most respondents reported adherence to IDSA guidelines recommending itraconazole in each clinical situation. New histoplasmosis guidelines need to reflect the growing need for updated general guidance, particularly for immunocompromised populations., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults., Methods: We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018-2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing., Results: We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13-102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%-30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83-2.49; P  = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13-28.5; P  = .04)., Conclusions: In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Increased antiretroviral therapy (ART) availability has been associated with more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis in those already receiving ART are limited. We compared clinical presentations and outcomes among ART-naïve and ART-experienced Ugandans., Methods: We prospectively enrolled 605 HIV-infected persons with first-episode cryptococcal meningitis from August 2013 to May 2017 who received amphotericin-based combination therapy. We classified participants by ART status and ART duration and compared groups for 2-week survival., Results: Overall, 46% (281/605) of participants were receiving ART at presentation. Compared with those not receiving ART, those receiving ART had higher CD4 counts ( P < .001) and lower cerebrospinal fluid fungal burdens ( P < .001). Of those receiving ART, 56% (156/281) initiated ART within 6 months, and 18% (51/281) initiated ART within 14 days. Two-week mortality did not differ by ART status (27% in both ART-naïve and ART-experienced%; P > .99). However, 47% (24/51) of those receiving ART for ≤14 days died within 2 weeks, compared with 19% (20/105) of those receiving ART for 15-182 days and 26% (32/125) of those receiving ART for >6 months ( P < .001). Among persons receiving ART for >6 months, 87% had HIV viral loads >1000 copies/mL., Conclusions: Cryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of central nervous system infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent cryptococcal meningitis after ART initiation.

The diagnosis of blastomycosis is often delayed. We identified 28 cases of pulmonary blastomycosis in a retrospective chart review. Most patients received multiple antibiotic courses before being diagnosed, and the sputum KOH smear was rarely used. Diagnostic delay can be decreased with higher suspicion for pulmonary blastomycosis and early use of the sputum KOH smear.

Background.  Cerebrospinal fluid (CSF) cryptococcal glucuronoxylomannan antigen (CrAg) titers generally correlate with quantitative fungal culture burden; however, correlation is not precise. Some patients have higher CrAg titers with lower fungal burdens and vice versa. We hypothesized that the relative discordancy between CrAg titer and quantitative culture burden reflects the relative degree of CrAg shedding by Cryptococcus neoformans and is associated with human immune responses. Methods.  One hundred ninety human immunodeficiency virus-infected individuals with cryptococcal meningitis were enrolled in Uganda and South Africa. We compared initial CSF CrAg titers relative to their CSF quantitative cultures to determine low (n = 58), intermediate (n = 68), or high (n = 64) CrAg shedders. We compared cytokines measured by Luminex multiplex assay on cryopreserved CSF and 10-week mortality across shedding groups using linear and logistic regression and distribution of genotypes by multilocus sequence typing. Results.  The relative degree of CrAg shedding was positively associated with increasing CSF levels of the following: interleukin (IL)-6, IL-7, IL-8, and tumor necrosis factor-α (each P < 0.01), which are all secreted by antigen-presenting cells and negatively associated with vascular endothelial growth factor (P = .01). In addition, IL-5, IL-13, granulocyte colony-stimulating factor, and macrophage chemotactic protein were decreased in low-CrAg shedders compared with intermediate shedders (each P ≤ .01). Type 1 T-helper cells (Th1) cytokine responses and 10-week mortality did not differ between the shedding groups. Cryptococcal genotypes were equally distributed across shedding groups. Conclusions.  Discordancy between CrAg shedding and expected shedding based on quantitative fungal burden is associated with detectable immunologic differences in CSF, primarily among secreted cytokines and chemokines produced by antigen-presenting cells and Th2.

Background: (1→3)-β-d-Glucan (BDG) is a helpful diagnostic marker for many invasive fungal infections. However, BDG is not thought to be useful in diagnosing cryptococcosis. We evaluated the utility of BDG as an adjunct diagnostic tool for patients infected with human immunodeficiency virus (HIV) and presenting with suspected cryptococcal meningitis., Methods: The Fungitell assay was used to measure BDG concentrations in cerebrospinal fluid (CSF) (n = 177) and serum (n = 109) of HIV-infected Ugandans and South Africans with suspected meningitis. Correlations between BDG concentrations and quantitative CSF cryptococcal cultures, CSF cryptococcal antigen (CRAG) titers, and 18 different CSF cytokine concentrations were assessed using non-parametric tests. Mixed models evaluated longitudinal changes in CSF BDG concentrations. Survival analyses were used to evaluate BDG's relationship with mortality., Results: The Fungitell BDG assay provided 89% sensitivity and 85% specificity in CSF for cryptococcal meningitis. Serum sensitivity was suboptimal (79%). Cerebrospinal fluid BDG concentrations at diagnosis were median (interquartile range) 343 (200-597) pg/mL in cryptococcal patients and 37 (23-46) pg/mL in patients without cryptococcosis. Sensitivity in CSF improved to 98% (53 of 54) when initial fungal burdens were ≥10 000 colony-forming units/mL. (1→3)-β-d-Glucan normalized rapidly after initiating antifungal therapy. Baseline BDG concentrations correlated with CSF fungal burden (rho = 0.820; P < .001), CSF CRAG lateral flow assay titers (rho = 0.780, P < .001), and monocyte chemotactic protein-1 levels in CSF (P = .047). In patients with cryptococcal meningitis, BDG ≥500 pg/mL at diagnosis was associated with increased 10-week mortality., Conclusions: (1→3)-β-d-Glucan is detectable in the CSF of HIV-infected patients with Cryptococcus, and it may provide useful prognostic information. Sensitivity is less than CRAG; however, BDG normalizes rapidly, unlike CRAG, making BDG potentially useful in diagnosing recurrent episodes.

Background: Cryptococcal meningitis is associated with increased intracranial pressure (ICP). Therapeutic lumbar puncture (LP) is recommended when the initial ICP is >250 mm H2O, yet the availability of manometers in Africa is limited and not always used where available. We assessed whether intraocular pressure could be a noninvasive surrogate predictor to determine when additional therapeutic LPs are necessary., Methods: Ninety-eight human immunodeficiency virus-infected Ugandans with suspected meningitis (81% Cryptococcus) had intraocular pressure measured using a handheld tonometer (n = 78) or optic nerve sheath diameter (ONSD) measured by ultrasound (n = 81). We determined the diagnostic performance of these methods for predicting ICP vs a standard manometer., Results: The median ICP was 225 mm H2O (interquartile range [IQR], 135-405 mm H2O). The median intraocular pressure was 28 mm Hg (IQR, 22-37 mm Hg), and median ultrasound ONSD was 5.4 mm (IQR, 4.95-6.1 mm). ICP moderately correlated with intraocular pressure (ρ = 0.45, P < .001) and with ultrasound ONSD (ρ = 0.44, P < .001). There were not discrete threshold cutoff values for either tonometry or ultrasound ONSD that provided a suitable cutoff diagnostic value to predict elevated ICP (>200 mm H2O). However, risk of elevated ICP >200 mm H2O was increased with an average intraocular pressure >28 mm Hg (relative risk [RR] = 3.03; 95% confidence interval [CI], 1.55-5.92; P < .001) or an average of ONSD >5 mm (RR = 2.39; 95% CI, 1.42-4.03; P = .003). As either intraocular pressure or ONSD increased, probability of elevated ICP increased (ie, positive predictive value increased)., Conclusions: Noninvasive intraocular pressure measurements by tonometry or ultrasound correlate with cerebrospinal fluid opening pressure, but both are a suboptimal replacement for actual ICP measurement with a manometer.

Background: Amphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa., Methods: Human immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001-2002, and universal in 2006-2012. In 2001-2009, serum potassium (K(+)) was monitored on days 1, 7, and 14 of treatment with replacement (K(+), Mg(2+)) per clinician discretion. In 2011-2012, K(+) was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K(+), Mg(2+)) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies., Results: With limited intravenous fluids, the 14-day survival was 49% in 2001-2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006-2010 (P = .003). In 2011-2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006-2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011-2012 with universal supplementation (P < .001)., Conclusions: Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K(+), Mg(2+)), as part of comprehensive amphotericin-based cryptococcal therapy.