Re-estimation of the burden of serious fungal diseases in Uganda.

Background: It is of utmost importance to monitor any change in the epidemiology of fungal diseases that may arise from a change in the number of the at-risk population or the availability of local data. Objective: We sought to update the 2015 publication on the incidence and prevalence of serious fungal diseases in Uganda. Methods: Using the Leading International Fungal Education methodology, we reviewed published data on fungal diseases and drivers of fungal diseases in Uganda. Regional or global data were used where there were no Ugandan data. Results: With a population of ~45 million, we estimate the annual burden of serious fungal diseases at 4,099,357 cases (about 9%). We estimated the burden of candidiasis as follows: recurrent Candida vaginitis (656,340 cases), oral candidiasis (29,057 cases), and esophageal candidiasis (74,686 cases) in HIV-infected people. Cryptococcal meningitis annual incidence is estimated at 5553 cases, Pneumocystis pneumonia at 4604 cases in adults and 2100 cases in children. For aspergillosis syndromes, invasive aspergillosis annual incidence (3607 cases), chronic pulmonary aspergillosis (26,765 annual cases and 63,574 5-year-period prevalent cases), and prevalence of allergic bronchopulmonary aspergillosis at 75,931 cases, and severe asthma with fungal sensitization at 100,228 cases. Tinea capitis is common with 3,047,989 prevalent cases. For other mycoses, we estimate the annual incidence of histoplasmosis to be 646 cases and mucormycosis at 9 cases. Conclusion: Serious fungal diseases affect nearly 9% of Ugandans every year. Tuberculosis and HIV remain the most important predisposition to acute fungal infection necessitating accelerated preventive, diagnostic, and therapeutic interventions for the management of these diseases.

How common are serious fungal infections in Uganda? Why was the study done? This study was conducted to provide an updated understanding of the occurrence and impact of serious fungal diseases in Uganda. The aim was to monitor changes in the epidemiology of fungal diseases related to shifts in the at-risk population or the availability of local data. What did the researchers do? Utilizing the Leading International Fungal Education methodology, the research team systematically reviewed published data on fungal diseases in Uganda. In instances where Ugandan data was unavailable, regional, or global data were incorporated. This method allowed for a thorough examination of the incidence and prevalence of various serious fungal diseases, considering the local context. What did the researchers find? With a population of approximately 45 million, the study estimated that nearly 9% of Ugandans, totalling around 4,099,357 individuals, are affected by serious fungal diseases annually. Notable findings include the prevalence of recurrent Candida vaginitis, oral candidiasis, and oesophageal candidiasis in HIV-infected individuals. Cryptococcal meningitis and Pneumocystis pneumonia were identified as significant contributors, along with various aspergillosis syndromes and widespread cases of tinea capitis. What do the findings mean? These findings underscore the substantial impact of serious fungal diseases on the health of almost 9% of the Ugandan population each year. Recognizing tuberculosis and HIV as major predisposing factors, the study calls for urgent interventions to prevent, diagnose, and treat these diseases effectively. The identified targets, including improved access to essential antifungal medications, training of health care workers on fungal diseases, and increasing access to essential diagnostics. These interventions can significantly contribute to improving public health outcomes in Uganda.

Improving mycetoma case detection through the training of community health workers in Northern Uganda: protocol for a stepped-wedge cluster-randomized trial.

Introduction: The World Health Organization acknowledges the need for countries to incorporate neglected tropical disease care into their routine health care system. However, low detection rates and late presentation of mycetoma to health facilities have been observed in endemic countries, including Uganda. Objective: To empower community health workers (CHWs) in Northern Uganda to recognize and refer suspects of mycetoma to health facilities. Design: This will be a stepped-wedge cluster-randomized trial based in Gulu and Pader districts over a period of 9 months with sequential crossover from intervention phase to the control phase at different time points until both districts are exposed to the intervention. Methods and Analysis: The study will leverage on the ongoing partnership between Northern Uganda Medical Mission and the Uganda Ministry of Health that has trained over 300 CHWs in Gulu and Pader. The study evaluation will be done using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. The expected outcome of the study is increased detection and referral of suspects of mycetoma. Data will be analyzed using STATA 17.0 and Friedman statistics or Analysis of Variance to determine increase in case identifications and referrals. Ethics and Registration: The study was approved by Mulago Hospital Research and Ethics Committee (MHREC 2406) and registered with Pan African Clinical Trial Registry (PACTR202301534749787). Dissemination: The results from this trial will be published in a peer-reviewed journal. In addition, the findings will be shared at conferences, with funders, and at other research meetings.

Investigating Metabolic and Molecular Ecological Evolution of Opportunistic Pulmonary Fungal Coinfections: Protocol for a Laboratory-Based Cross-Sectional Study.

BACKGROUND: Fungal-bacterial cocolonization and coinfections pose an emerging challenge among patients suspected of having pulmonary tuberculosis (PTB); however, the underlying pathogenic mechanisms and microbiome interactions are poorly understood. Understanding how environmental microbes, such as fungi and bacteria, coevolve and develop traits to evade host immune responses and resist treatment is critical to controlling opportunistic pulmonary fungal coinfections. In this project, we propose to study the coexistence of fungal and bacterial microbial communities during chronic pulmonary diseases, with a keen interest in underpinning fungal etiological evolution and the predominating interactions that may exist between fungi and bacteria. OBJECTIVE: This is a protocol for a study aimed at investigating the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections through determining and characterizing the burden, etiological profiles, microbial communities, and interactions established between fungi and bacteria as implicated among patients with presumptive PTB. METHODS: This will be a laboratory-based cross-sectional study, with a sample size of 406 participants. From each participant, 2 sputa samples (one on-spot and one early morning) will be collected. These samples will then be analyzed for both fungal and bacterial etiology using conventional metabolic and molecular (intergenic transcribed spacer and 16S ribosomal DNA-based polymerase chain reaction) approaches. We will also attempt to design a genome-scale metabolic model for pulmonary microbial communities to analyze the composition of the entire microbiome (ie, fungi and bacteria) and investigate host-microbial interactions under different patient conditions. This analysis will be based on the interplays of genes (identified by metagenomics) and inferred from amplicon data and metabolites (identified by metabolomics) by analyzing the full data set and using specific computational tools. We will also collect baseline data, including demographic and clinical history, using a patient-reported questionnaire. Altogether, this approach will contribute to a diagnostic-based observational study. The primary outcome will be the overall fungal and bacterial diagnostic profile of the study participants. Other diagnostic factors associated with the etiological profile, such as incidence and prevalence, will also be analyzed using univariate and multivariate schemes. Odds ratios with 95% CIs will be presented with a statistical significance set at P<.05. RESULTS: The study has been approved by the Mbarara University Research Ethic Committee (MUREC1/7-07/09/20) and the Uganda National Council of Science and Technology (HS1233ES). Following careful scrutiny, the protocol was designed to enable patient enrollment, which began in March 2022 at Mbarara University Teaching Hospital. Data collection is ongoing and is expected to be completed by August 2023, and manuscripts will be submitted for publication thereafter. CONCLUSIONS: Through this protocol, we will explore the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections among patients with presumptive PTB. Establishing key fungal-bacterial cross-kingdom synergistic relationships is crucial for instituting fungal bacterial coinfecting etiology. TRIAL REGISTRATION: ISRCTN Registry ISRCTN33572982; https://tinyurl.com/caa2nw69. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48014.

Prevalence of Histoplasma Antigenuria among Outpatient Cohort with Advanced HIV in Kampala, Uganda.

In sub-Saharan Africa, an estimated 25% of people with HIV present with advanced HIV and are at high risk of opportunistic infections. Whereas histoplasmosis has occasionally been seen in Uganda, the understanding of the local risk of acute infection is limited. We sought to determine the prevalence of Histoplasma antigenuria using an enzyme immunoassay (EIA, clarus Histoplasma GM EIA, IMMY; Norman, OK, USA) in a cohort of outpatients with advanced HIV disease in Kampala, Uganda. Among the persons with positive urine Histoplasma antigen tests, we assessed their clinical presentation and outcomes. The EIA was run on stored urine samples as per the manufacturer's instructions. Specimens ≥1 EIA units were considered positive. Among the 388 tested urine samples, 4 (1.2%) were positive for Histoplasma antigen. The histoplasmosis prevalence among participants with a CD4 < 100 cells/mcL was 2.5% (4/158). Three of the four participants with a positive Histoplasma antigen test reported systemic symptoms consistent with histoplasmosis. All four participants had a positive urine lipoarabinomannan test and were treated for tuberculosis. By the four-week follow-up visit, all participants were clinically improved, alive, and in care without antifungal therapy. In advanced HIV, the clinical presentations of tuberculosis and histoplasmosis overlap. The value of histoplasmosis screening and pre-emptive treatment is an area of future research.

Diagnostic options for pulmonary fungal diseases in Africa.

Background: Fungal lung diseases are global in distribution and require specific tests for diagnosis. We report a survey of diagnostic service provision in Africa. Methods: A written questionnaire was followed by a video conference call with each respondent(s) and external validation. To disseminate the questionnaire, a snowball sample was used. Results: Data were successfully collected from 50 of 51 African countries with populations >1 million. The questionnaire was completed by respondents affiliated with 72 health facilities. Of these 72 respondents, 33 (45.8%) reported data for the whole country while others reported data for a specific region/province within their country. In the public sector, chest X-ray and computed tomography are performed often in 49 countries (98%) and occasionally in 37 countries (74%), and less often in the private sector. Bronchoscopy and spirometry were done often in 28 countries (56%) and occasionally in 18 countries (36%) in the tertiary health facilities of public sector. The most conducted laboratory diagnostic assay was fungal culture (often or occasionally) in 29 countries (58%). In collaboration with the Africa Centre for Disease Control and Prevention, regional webinars and individual country profiles provided further data validation. Conclusion: This survey has found a huge disparity of diagnostic test capability across the African continent. Some good examples of good diagnostic provision and very high-quality care were seen, but this was unusual. The unavailability of essential testing such as spirometry was noted, which has a high impact in the diagnosis of lung diseases. It is important for countries to implement tests based on the World Health Organization Essential Diagnostics List.

Adherence of health workers to guidelines for screening and management of cryptococcal meningitis in Uganda.

INTRODUCTION: Health workers' failure to adhere to guidelines for screening, diagnosis and management of HIV-associated cryptococcal meningitis (CM) remains a significant public health concern. We aimed to assess adherence to the standards of care and management of HIV patients at risk of CM per the MoH guidelines and assess stock management of CM supplies in the period of January to June 2021 at selected public health facilities (HFs) in Uganda. METHODS: The study employed an observational cross-sectional design to assess the level of adherence of health workers to standards of clinical care and management of HIV positive patients at risk of CM as per the clinical guidelines for Uganda, and stock management of CM supplies in the period of January to June 2021in selected public health facilities. The study team used a survey guide designed by MoH to assess and score the screening, diagnosis and management practices of Health Facilities towards CM. Scoring was categorized as red (< 80%), light green (80%-95%), and dark green (˃95%) in the order from worst to best adherence. The data was transcribed into a spread sheet and analysed using STATA-v15. RESULTS: The study team visited a total of 15 public health facilities including 5 general hospitals, 9 regional referral hospitals (RRHs) and 1 National Referral hospital (NRH). The mean score for adherence to screening and management of CM for all the combined facilities was 15 (64.7%) classified as red. 10 (66.7%) HFs had not performed a baseline CD4 test for eligible patients within 2 weeks of ART initiation. With regards to treatment, 9 (60%) of the HFs were scored as light green on knowledge of the procedure for reconstituting intravenous Liposomal Amphotericin B. None of the HFs visited had potassium chloride tablets in stock. CONCLUSION: Major MoH guidelines are generally not being adhered to by health workers while managing cryptococcal meningitis. It is vital that government and implementing partners regularly support HFs with training, mentorship, and support supervision on CM management to improve adherence to CM screening and treatment guidelines.

Building clinical pharmacology laboratory capacity in low- and middle-income countries: Experience from Uganda.

Background: Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda. Intervention: Existing laboratory infrastructure was repurposed, and new equipment was acquired. Laboratory personnel were hired and trained to optimise, validate, and develop in-house methods for testing antiretroviral, anti-tuberculosis and other drugs, including 10 high-performance liquid chromatography methods and four mass spectrometry methods. We reviewed all research collaborations and projects for which samples were assayed in the laboratory from January 2006 to November 2020. We assessed laboratory staff mentorship from collaborative relationships and the contribution of research projects towards human resource development, assay development, and equipment and maintenance costs. We further assessed the quality of testing and use of the laboratory for research and clinical care. Lessons learnt: Fourteen years post inception, the clinical pharmacology laboratory had contributed significantly to the overall research output at the institute by supporting 26 pharmacokinetic studies. The laboratory has actively participated in an international external quality assurance programme for the last four years. For clinical care, a therapeutic drug monitoring service is accessible to patients living with HIV at the Adult Infectious Diseases clinic in Kampala, Uganda. Recommendations: Driven primarily by research projects, clinical pharmacology laboratory capacity was successfully established in Uganda, resulting in sustained research output and clinical support. Strategies implemented in building capacity for this laboratory may guide similar processes in other low- and middle-income countries.

Fungal diseases in Africa: Closing the gaps in diagnosis and treatment through implementation research and advocacy.

Fungal diseases impose an escalating burden on public health in Africa, exacerbated by issues such as delayed diagnosis, inadequate therapy, and limited access to healthcare resources, resulting in significant morbidity and mortality. Effectively tackling these challenges demands a comprehensive approach encompassing research, training, and advocacy initiatives. Recent clinical mycology surveys conducted by Global Action for Fungal Infection (GAFFI) and the European Confederation of Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) have underscored gaps in fungal diagnostics and the availability and accessibility of antifungal therapy in Africa. The World Health Organization (WHO) Fungal Priority Pathogens List (FPPL) identifies fungi of critical or high importance to human health, providing a roadmap for action and highlighting the urgent need for prioritizing fungal diseases and developing targeted interventions within the African context. To enhance diagnosis and treatment, it is imperative to invest in comprehensive training programs for healthcare workers across all levels and disciplines. Equipping them with the necessary knowledge and skills will facilitate early detection, accurate diagnosis, and appropriate management of fungal infections. Moreover, implementation science research in medical mycology assumes a pivotal role in bridging the gap between knowledge and practice. By identifying the barriers and facilitators that influence the adoption of diagnostic techniques and public health interventions, tailored strategies can be formulated to improve their implementation within healthcare settings. Advocacy plays a critical role in raising awareness regarding the profound impact of fungal diseases on public health in Africa. Engaging policymakers, healthcare providers, researchers, industry experts and communities underscore the importance of addressing these diseases and galvanize efforts for change. Substantial investment in surveillance, research and development specifically focused on fungal diseases is indispensable for advancing our understanding of local epidemiology, developing effective interventions, and ultimately improving patient outcomes. In conclusion, closing the gaps in diagnosing and treating fungal diseases in Africa demands concerted research and advocacy initiatives to ensure better healthcare delivery, reduced mortality rates, and improved public health outcomes.

Invasive Fungal Diseases in Africa: A Critical Literature Review.

Invasive fungal diseases (IFDs) are of huge concern in resource-limited settings, particularly in Africa, due to the unavailability of diagnostic armamentarium for IFDs, thus making definitive diagnosis challenging. IFDs have non-specific systemic manifestations overlapping with more frequent illnesses, such as tuberculosis, HIV, and HIV-related opportunistic infections and malignancies. Consequently, IFDs are often undiagnosed or misdiagnosed. We critically reviewed the available literature on IFDs in Africa to provide a better understanding of their epidemiology, disease burden to guide future research and interventions. Cryptococcosis is the most encountered IFD in Africa, accounting for most of the HIV-related deaths in sub-Saharan Africa. Invasive aspergillosis, though somewhat underdiagnosed and/or misdiagnosed as tuberculosis, is increasingly being reported with a similar predilection towards people living with HIV. More cases of histoplasmosis are also being reported with recent epidemiological studies, particularly from Western Africa, showing high prevalence rates amongst presumptive tuberculosis patients and patients living with HIV. The burden of pneumocystis pneumonia has reduced significantly probably due to increased uptake of anti-retroviral therapy among people living with HIV both in Africa, and globally. Mucormycosis, talaromycosis, emergomycosis, blastomycosis, and coccidiomycosis have also been reported but with very few studies from the literature. The emergence of resistance to most of the available antifungal drugs in Africa is yet of huge concern as reported in other regions. IFDs in Africa is much more common than it appears and contributes significantly to morbidity and mortality. Huge investment is needed to drive awareness and fungi related research especially in diagnostics and antifungal therapy.

Medical Mycology dissertation topics require prioritisation among Postgraduate Microbiology trainees of Makerere University, Uganda.

Background: As elsewhere worldwide, there is an increasing burden of fungal diseases in Uganda. However, expertise in medical mycology (the study of fungal diseases of medical importance) among clinicians and laboratory personnel remains low. Objective: This study sought to determine the proportion of dissertations on medical mycology among postgraduate medical microbiology trainees at the College of Health Sciences, Makerere University, Uganda. Methods: We retrospectively reviewed the topics of dissertations submitted to the Departments of Medical Microbiology and Immunology & Molecular Biology from 2011 through 2018. The proportion of dissertation topics on medical mycology was analysed using descriptive statistics. Results: A total of 152 dissertations were retrieved. Of these, only 5 (3.3%) were on medical mycology compared to bacteriology (50.7%, n = 77), virology (27.6%, n = 42), parasitology (14.5%, n = 22) and immunology (4.0%, n = 6). Of the 5 dissertations on fungal diseases, the distribution was as follows: cryptococcal meningitis (40%, n = 2), Candidiasis (20%, n = 1), superficial mycoses (20%, n = 1) and other invasive fungal diseases (20%, n = 1). The most common method that was used for studying the fungal diseases was culture 60%, n = 3. Conclusion: There is limited research on medical mycology among the postgraduate medical microbiology trainees of Makerere University, Uganda.

Chronic pulmonary aspergillosis in patients with active pulmonary tuberculosis with persisting symptoms in Uganda.

BACKGROUND: The occurrence of chronic pulmonary aspergillosis (CPA) among drug sensitive pulmonary tuberculosis (PTB) patients on optimal therapy with persistent symptoms was investigated. METHODS: We consecutively enrolled participants with PTB with persistent pulmonary symptoms after 2 months of anti-TB treatment at Mulago Hospital, Kampala, Uganda, between July 2020 and June 2021. CPA was defined as a positive Aspergillus-specific IgG/IgM immunochromatographic test (ICT), a cavity with or without a fungal ball on chest X-ray (CXR), and compatible symptoms >3 months. RESULTS: We enrolled 162 participants (median age 30 years; IQR: 25-40), 97 (59.9%) were male, 48 (29.6%) were HIV-infected and 15 (9.3%) had prior PTB. Thirty-eight (23.4%) sputum samples grew A. niger and 13 (8.0%) A. fumigatus species complexes. Six (3.7%) participants had intracavitary fungal balls and 52 (32.1%) had cavities. Overall, 32 (19.8%) participants had CPA. CPA was associated with prior PTB (adjusted odds ratio [aOR]: 6.61, 95% CI: 1.85-23.9, p = .004), and far advanced CXR changes (aOR: 4.26, 95% CI: 1.72-10.52, p = .002). The Aspergillus IgG/IgM ICT was positive in 10 (31.3%) participants with CPA. CONCLUSIONS: Chronic pulmonary aspergillosis may cause persistent respiratory symptoms in up to one-fifth of patients after intensive treatment for PTB. The Aspergillus IgG/IgM ICT positivity rate was very low and may not be used alone for the diagnosis of CPA in Uganda.

Evaluation of the initial 12 months of a routine cryptococcal antigen screening program in reduction of HIV-associated cryptococcal meningitis in Uganda.

BACKGROUND: Asymptomatic Cryptococcal Antigenemia (CrAg) patients develop meningitis within a month of testing positive. Pre-emptive antifungal therapy can prevent progression to Cryptococcal meningitis (CM). In April 2016, a national CrAg screening program was initiated in 206 high-volume health facilities that provide antiretroviral therapy in Uganda. We report the evaluation of the CrAg screening cascade focusing on linkage to care, fluconazole therapy for 10 weeks and 6 months follow up, and ART initiation in a subset of facilities. METHODS: We conducted a retrospective, cross-sectional survey of patients with CD4 < 100 at seven urban and seven rural facilities after 1 year of program implementation. We quantified the number of patients who transitioned through the steps of the CrAg screening cascade over six-months follow-up. We defined cascade completion as a pre-emptive fluconazole prescription for the first 10 weeks. We conducted semi-structured interviews with lab personnel and clinic staff to assess functionality of the CrAg screening program. Data was collected using REDCap. RESULTS: We evaluated 359 patient records between April 2016 to March 2017; the majority (358/359, 99.7%) were from government owned health facilities and just over half (193/359, 53.8%) had a median baseline CD4 cell count of < 50 cell/µL. Overall, CrAg screening had been performed in 255/359 (71.0, 95% CI, 66.0-75.7) of patients' records reviewed, with a higher proportion among urban facilities (170/209 (81.3, 95% CI, 75.4-86.4)) than rural facilities (85/150 (56.7, 95% CI, 48.3-64.7)). Among those who were CrAg screened, 56/255 (22.0, 95% CI, 17.0-27.5%) had cryptococcal antigenemia, of whom 47/56 (83.9, 95% CI, 71.7-92.4%) were initiated on pre-emptive therapy with fluconazole and 8/47 (17.0, 95% CI, 7.6-30.8%) of these were still receiving antifungal therapy at 6 months follow up. At least one CNS symptom was present in 70% (39/56) of those with antigenemia. In patients who had started ART, almost 40% initiated ART prior to CrAg screening. Inadequacy of equipment/supplies was reported by 15/26 (58%) of personnel as a program barrier, while 13/26 (50%) reported a need for training about CM and CrAg screening. CONCLUSION: There was a critical gap in the follow-up of patients after initiation on fluconazole therapy. ART had been initiated in almost 40% of patients prior to CrAg screening.. Higher antigenemia patients presenting with CNS symptoms could be related to late presentation. There is need to address these gaps after a more thorough evaluation.

Aspergillus-specific IgM/IgG antibody serostatus of patients hospitalized with moderate-critical COVID-19 in Uganda.

Invasive pulmonary aspergillosis is known to complicate the coronavirus diseases-2019 (COVID-19), especially those with critical illness. We investigated the baseline anti-Aspergillus antibody serostatus of patients with moderate-critical COVID-19 hospitalized at 3 COVID-19 Treatment Units in Uganda. All 46 tested patients, mean age 30, and 11% with underlying respiratory disease had a negative serum anti-Aspergillus IgM/IgG antibody immunochromatographic test on day 3 (mean) of symptom onset (range 1-26), but follow up specimens to assess seroconversion were not available.

Aspergillus-specific IgM/IgG antibody serostatus of patients hospitalized with moderate-critical COVID-19 in Uganda

Invasive pulmonary aspergillosis is known to complicate the coronavirus diseases-2019 (COVID-19), especially those with critical illness. We investigated the baseline anti Aspergillus antibody serostatus of patients with moderate-critical COVID-19 hospitalized at 3 COVID-19 Treatment Units in Uganda. All 46 tested patients, mean age 30, and 11% with underlying respiratory disease had a negative serum anti-Aspergillus IgM/IgG antibody immunochromatographic test on day 3 (mean) of symptom onset (range 1-26), but follow up specimens to assess seroconversion were not available

Mapping of Chronic Pulmonary Aspergillosis in Africa.

Africa has a high burden of tuberculosis, which is the most important risk factor for chronic pulmonary aspergillosis (CPA). Our goal was to systematically evaluate the burden of CPA in Africa and map it by country. We conducted an extensive literature search for publications on CPA in Africa using the online databases. We reviewed a total of 41 studies published between 1976 and 2021, including a total of 1247 CPA cases from 14 African countries. Most of the cases came from Morocco (n = 764, 62.3%), followed by South Africa (n = 122, 9.9%) and Senegal (n = 99, 8.1%). Seventeen (41.5%) studies were retrospective, 12 (29.3%) were case reports, 5 case series (12.2%), 5 prospective cohorts, and 2 cross-sectional studies. The majority of the cases (67.1%, n = 645) were diagnosed in men, with a median age of 41 years (interquartile range: 36-45). Active/previously treated pulmonary tuberculosis (n = 764, 61.3%), human immunodeficiency virus infection (n = 29, 2.3%), diabetes mellitus (n = 19, 1.5%), and chronic obstructive pulmonary disease (n = 10, 0.8%) were the common co-morbidities. Haemoptysis was the most frequent presenting symptom, reported in up to 717 (57%) cases. Smoking (n = 69, 5.5%), recurrent lung infections (n = 41, 3%) and bronchorrhea (n = 33, 3%) were noted. This study confirms that CPA is common in Africa, with pulmonary tuberculosis being the most important risk factor.

Symptomatic Cryptococcal Meningitis with Negative Serum and Cerebrospinal Fluid Cryptococcal Antigen Tests.

BACKGROUND: Cryptococcal meningitis is a leading cause of mortality in advanced HIV disease. A positive cerebrospinal fluid cryptococcal antigen (CrAg) test defines cryptococcal meningitis. Herein, we present a patient with serum and cerebrospinal fluid CrAg negative cryptococcal meningitis, despite a positive cerebrospinal fluid India ink examination and quantitative culture. CASE DETAILS: A 56-year-old HIV-positive Ugandan woman, with an undetectable HIV RNA viral load and CD4+ T-cell count of 766 cells per microlitre presented with signs and symptoms consistent with cryptococcal meningitis. Her serum and cerebrospinal fluid CrAg tests were negative despite having a positive cerebrospinal fluid India ink and quantitative culture. On day 1, she was commenced on intravenous amphotericin B deoxycholate (1mg/kg) for 3 days (considering 10 CFU growth of Cryptococcus spp) in combination with oral flucytosine (100mg/kg) for 7 days and then fluconazole 1200mg once daily for the next 11 days. By day 7, she was symptom free and quantitative cerebrospinal fluid culture was negative for Cryptococcus spp. She was discharged on day 9. At 10 weeks (day +40) and 18 weeks (day +72), she was well and adherent to her antiretroviral therapy and on maintenance phase of cryptococcal meningitis on fluconazole at a dose of 400mg once daily. CONCLUSION: This report alerts clinicians managing patients with HIV-associated cryptococcal meningitis to four uncommon clinical scenarios; first, the possibility of negative serum and cerebrospinal fluid CrAg lateral flow assay results in the context of low cerebrospinal fluid fungal burden in a symptomatic patient. Second, possible occurrence of cryptococcal meningitis in a patient with high CD4 T-cell lymphocyte counts. Third, an early seroconversion of cryptococcal antigenaemia following effective fluconazole therapy. Fourth, an early symptomatic relapse of cryptococcal meningitis albeit negative serum CrAg.

Prevalence of Aspergillus fumigatus skin positivity in adults without an apparent/known atopic disease in Uganda.

BACKGROUND: Skin prick testing (SPT) is an important investigation in the evaluation of allergy to fungal pathogens. However, the background sensitivity to fungal allergens among healthy people in Uganda is unknown. Our aim was to assess the background prevalence of Aspergillus fumigatus SPT positivity in apparently healthy adults without known atopic disease in Uganda. METHODS: For this pilot study, we recruited 50 healthy volunteers using convenience sampling, 56% of whom were health workers. We performed the SPT for A. fumigatus according to manufacturer's instructions. A wheal diameter of ⩾3 mm was considered positive. RESULTS: The prevalence of A. fumigatus skin positivity was 60% (30/50). Participants with a positive A. fumigatus SPT were significantly younger than those with a negative result [median age (years): 28 versus 35; p = 0.005]. CONCLUSION: There is a high skin positivity against A. fumigatus among non-atopic healthy Ugandan adults. There is an urgent need to establish a normal wheal cut-off value for this population. SPT alone may be an unreliable test for the diagnosis of A. fumigatus associated allergic syndromes. More studies are needed to define the prevalence of A. fumigatus skin positivity among non-atopic healthy population in Africa.

Surgical management of chronic pulmonary aspergillosis in Africa: A systematic review of 891 cases.

Chronic pulmonary aspergillosis (CPA) is an emerging fungal infectious disease of public health importance. We conducted a systematic review of studies reporting the outcomes of patients with CPA managed surgically in Africa. A search of Medline, Embase, Web of Science, Google Scholar and African Journals Online was conducted to identify studies indexed from inception to June 2021 that examined surgical management of CPA in Africa. All articles that presented primary data, including case reports and case series, were included. We excluded review articles. A total of 891 cases (557 males (62.5%), mean age 39.3 years) extracted from 27 eligible studies published between 1976 and 2020 from 11 African countries were included. Morocco (524, 59%) and Senegal (99, 11%) contributed the majority of cases. Active or previous pulmonary tuberculosis was reported in 677 (76.0%) cases. Haemoptysis was reported in 682 (76.5%) cases. Lobectomy (either unilateral or bilateral, n = 493, 55.3%), pneumonectomy (n = 154, 17.3%) and segmentectomy (n = 117, 13.1%) were the most frequently performed surgical procedures. Thirty (4.9%) cases from South Africa received bronchial artery embolisation. Empyema (n = 59, 27.4%), significant haemorrhage (n = 38, 173.7%), incomplete lung expansion (n = 26, 12.1%) and prolonged air leak (n = 24, 11.2%) were the most frequent complications. Overall, 45 (5.1%) patients died. The causes of death included respiratory failure (n = 14), bacterial superinfection/sepsis (n = 10), severe haemorrhage (n = 5), cardiopulmonary arrest (n = 3) and complications of chronic obstructive pulmonary disease (n = 3). The cause of death was either unknown or unspecified in 9 cases. We conclude that surgical treatment had very low mortality rates and maybe considered as first-line management option in centres with experience and expertise in Africa.

Evaluation of the BioFire® FilmArray® Meningitis/Encephalitis panel in an adult and pediatric Ugandan population.

BACKGROUND: Meningitis causes significant mortality in sub-Saharan Africa and limited diagnostics exist. We evaluated the utility of the BioFire® FilmArray® Meningitis/Encephalitis multiplex PCR panel (BioFire ME) in HIV-infected adults and HIV-infected and uninfected children presenting with suspected meningitis in Uganda. METHODS: We tested cerebrospinal fluid (CSF) using a stepwise meningitis diagnostic algorithm including BioFire ME. We determined the diagnostic performance of BioFire ME for cryptococcal meningitis, using cryptococcal antigen (CrAg) and CSF culture as reference standards, and assessed other central nervous system (CNS) pathogens identified by the panel. RESULTS: We evaluated 328 adult and 42 pediatric CSF specimens using BioFire ME. Of the adult CSF samples tested, 258 were obtained at baseline, and 70 were obtained from repeat lumbar punctures in cryptococcal meningitis. For Cryptococcus, sensitivity was 82%, specificity was 98%, PPV was 98%, and NPV was 79% in baseline specimens using CSF CrAg as the reference standard. Among follow-up specimens, a negative BioFire ME for Cryptococcus predicted CSF culture sterility with 84% NPV. Overall sensitivity was decreased at low fungal burdens: 29% for 0-99 Cryptococcus CFU/mL compared to 94% for ≥100 CFU/mL in baseline specimens. Other pathogens detected included E. Coli, H. influenzae, S. pneumoniae, CMV, enterovirus, HSV, HHV-6, and VZV. Two specimens tested positive for S. pneumoniae and one for Cryptococcus in the pediatric population. CONCLUSIONS: Multiplex PCR is a promising rapid diagnostic test for meningitis in adults and children in resource-limited settings. Cryptococcus at low fungal burdens in CSF may be missed by BioFire ME.

Evaluation of the Diagnostic Performance of a Semiquantitative Cryptococcal Antigen Point-of-Care Assay among HIV-Infected Persons with Cryptococcal Meningitis.

A newly developed cryptococcal antigen (CrAg) semiquantitative (SQ) lateral flow assay (LFA) provides a semiquantitative result in a rapid one-step test instead of performing serial dilutions to determine CrAg titer. We prospectively compared the diagnostic performance of the CrAgSQ assay (IMMY) with the CrAg LFA (IMMY) on cerebrospinal fluid (CSF) samples collected from persons with HIV-associated meningitis. The CrAgSQ grades (1+ to 5+) were compared with CrAg LFA titers and quantitative CSF fungal cultures. Among 87 participants screened for HIV-associated meningitis, 60 had cryptococcal meningitis (59 CrAg positive [CrAg+] by LFA and 1 false negative due to prozone with CrAg LFA titer of 1:1,310,000 and culture positivity), and 27 had no cryptococcal meningitis by CrAg LFA or culture. The CrAgSQ on CSF had 100% (60/60) sensitivity and 100% specificity (27/27). CSF CrAg titers ranged from 1:5 to 1:42 million. CrAgSQ grades of 1+, 2+, 3+, 4+, and 5+ corresponded to median CrAg LFA titers of 1:<10, 1:60, 1:7,680, 1:81,920, and 1:1,474,000, respectively. CSF CrAgSQ grades 3+ or higher were always CSF culture positive. Mortality at 14 days for those with low CrAgSQ grade (1+ to 3+) was 5% (1/22) versus 21% (8/38) with high CrAgSQ grades (4+ to 5+) (P = 0.084). The CrAgSQ demonstrates excellent diagnostic performance, maintaining both the sensitivity and specificity of the CrAg LFA, and counters false-negative prozone effects. The CrAgSQ assay reading is more complex but does provide useful clinical information about disease burden and probability of culture positivity in a single rapid diagnostic test.