Rita O. Oladele

Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision

Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.

Chronic pulmonary aspergillosis as a cause of smear negative TB and or anti-TB treatment failure in Nigerians

OBJECTIVE To evaluate chronic pulmonary aspergillosis (CPA) as an alternative diagnosis of smear-negative tuberculosis (TB) and treatment failure in TB patients in Nigeria. METHODS We conducted a cross-sectional multicentre survey in human immunodeficiency virus (HIV) positive and negative adult patients at the end of their TB treatment in clinics in Lagos and Ilorin states. All were assessed using clinical examination, chest X-ray (CXR) and aspergillus immunoglobulin G (IgG) serology, and some for sputum fungal culture. CPA was defined as a positive Aspergillus fumigatus IgG titre with compatible CXR or a positive sputum culture of Aspergillus with a visible fungal ball on CXR with symptoms of underlying lung disease. RESULTS Of 208 patients recruited between June 2014 and May 2015, 153 (73.6%) were HIV-positive. The mean age was 39.8 years, 124 (59.6%) were female and 39 (18.8%) were unable to work. The median CD4 count was 169.5 cells/ml (range 4-593) in HIV-infected patients with positive Aspergillus IgG. Overall, 109 (52.4%) had documented TB, 140 (67.3%) had a productive cough and 50 had haemoptysis. CPA prevalence was 8.7%; 10 (6.5%) had HIV infection and 8 (14.5%) were HIV-negative (Fishers exact P = 0.092). CONCLUSION CPA is a neglected disease in Nigeria, and most cases match the World Health Organization diagnostic criteria for smear-negative TB.

Histoplasmosis in Africa: An emerging or a neglected disease?

Histoplasmosis in Africa has markedly increased since the advent of the HIV/AIDS epidemic but is under-recognised. Pulmonary histoplasmosis may be misdiagnosed as tuberculosis (TB). In the last six decades (1952–2017), 470 cases of histoplasmosis have been reported. HIV-infected patients accounted for 38% (178) of the cases. West Africa had the highest number of recorded cases with 179; the majority (162 cases) were caused by Histoplasma capsulatum var. dubuosii (Hcd). From the Southern African region, 150 cases have been reported, and the majority (119) were caused by H. capsulatum var. capsulatum (Hcc). There have been 12 histoplasmin skin test surveys with rates of 0% to 35% positivity. Most cases of Hcd presented as localised lesions in immunocompetent persons; however, it was disseminated in AIDS patients. Rapid diagnosis of histoplasmosis in Africa is only currently possible using microscopy; antigen testing and PCR are not available in most of Africa. Treatment requires amphotericin B and itraconazole, both of which are not licensed or available in several parts of Africa.

A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species

Fluconazole is the most commonly used antifungal agent for both the treatment of cryptococcal meningitis, and for prophylaxis against the disease. However, its prolonged use has the potential to exert selection pressure in favour of fluconazole‐resistant strains. We evaluated the prevalence of fluconazole resistance in Cryptococcus spp. clinical isolates in 29 studies from 1988 to May 2017 included in EMBASE and MEDLINE databases. A total of 4995 Cryptococcus isolates from 3210 patients constituted this study; 248 (5.0%) of the isolates from relapsed episodes of cryptococcosis were included in this analysis. Eleven (38%) of the studies used minimum inhibitory concentrations (MICs) breakpoints of ≥64 μg/mL to define fluconazole resistance, 6 (21%) used ≥32 μg/mL, 11 (38%) used ≥16 μg/mL and 1 (3%) used ≤20 μg/mL. Overall, mean prevalence of fluconazole resistance was 12.1% (95% confidence interval [CI]: 6.7‐17.6) for all isolates (n = 4995). Mean fluconazole resistance was 10.6% (95% CI: 5.5‐15.6) for the incident isolates (n = 4747) and 24.1% (95% CI: −3.1‐51.2) for the relapse isolates (n = 248). Of the 4995 isolates, 936 (18.7%) had MICs above the ecological cut‐off value. Fluconazole resistance appears to be an issue in Cryptococcus isolates from patients with relapses. It remains unclear whether relapses occur due to resistance or other factors. There is an urgent need to establish antifungal breakpoints for Cryptococcus spp.

Cryptococcal Antigenemia in Nigerian Patients With Advanced Human Immunodeficiency Virus: Influence of Antiretroviral Therapy Adherence

Background. Cryptococcal meningitis has a high mortality in human immunodeficiency virus (HIV)-infected persons in Africa. This is preventable with early screening and preemptive therapy. We evaluated the prevalence of cryptococcal disease by antigen testing, possible associated factors, and outcomes in HIV-infected patients being managed in a tertiary hospital in Lagos, Nigeria. Methods. Sera were collected from 214 consenting HIV-infected participants with CD4+ counts <250 cells/mm3, irrespective of their antiretroviral therapy (ART) status, between November 2014 and May 2015. A cryptococcal antigen (CrAg) lateral flow assay was used for testing. Pertinent clinical data were obtained from patients and their case notes. Results. Of the 214 participants, females (124; 57.9%) outnumbered males. Mean age was 41.3 ± 9.4 (standard deviation) years. The majority (204; 95.3%) were ART experienced. The median CD4+ cell count was 160 cells/mm3 (interquartile range, 90–210). The overall seroprevalence of cryptococcal antigenemia was 8.9% (19 of 214); 6 of 61 (9.8%) in those with CD4+ cell counts <100 cells/mm3, 4 of 80 (5.0%) in the 100–200 group, and 9 of 73 (12.3%) in 200–250 cells/mm3 group. Among ART-naive patients, 1 of 10 (10%) was CrAg positive. Twenty-seven of 214 (12.6%) had associated oral thrush. Potential baseline meningitis symptoms (3 of 214 [1.4%] experienced neck pain or stiffness and 21 of 214 [9.8%] experienced headache) were common in the study group, but the result was not statistically significant in relation to CrAg positivity. Two of 19 (10.5%) CrAg-positive patients died, 10 of 19 (52.6%) were lost to follow up, and 7 of 19 (36.8%) were alive. Empirical fluconazole was routinely given to those with low CD4 counts <100 cells/mm3, which was unrelated to CrAg positivity (P = .018). Conclusions. We report a prevalence of 8.9% cryptococcal antigenemia in a setting where first-line antifungals are not readily available. We recommend CrAg screening for HIV-infected patients, even for patients on ART.

Case Definition of Chronic Pulmonary Aspergillosis in Resource-Constrained Settings

Chronic pulmonary aspergillosis (CPA) is a recognized complication of pulmonary tuberculosis (TB). In 2015, the World Health Organization reported 2.2 million new cases of nonbacteriologically confirmed pulmonary TB; some of these patients probably had undiagnosed CPA. In October 2016, the Global Action Fund for Fungal Infections convened an international expert panel to develop a case definition of CPA for resource-constrained settings. This panel defined CPA as illness for >3 months and all of the following: 1) weight loss, persistent cough, and/or hemoptysis; 2) chest images showing progressive cavitary infiltrates and/or a fungal ball and/or pericavitary fibrosis or infiltrates or pleural thickening; and 3) a positive Aspergillus IgG assay result or other evidence of Aspergillus infection. The proposed definition will facilitate advancements in research, practice, and policy in lower- and middle-income countries as well as in resource-constrained settings.

Fluconazole Resistance among Oral Candida Isolates from People Living with HIV/AIDS in a Nigerian Tertiary Hospital

Oropharyngeal candidiasis, a common fungal infection in people living with HIV/AIDS (PLWHA), arises from Candida species colonizing the oral cavity. Fluconazole is the preferred treatment and is often used empirically. Few studies have investigated the prevalence of fluconazole resistance in Nigeria. This study aimed at determining the burden of fluconazole resistance among Candida species in the oral cavities of PLWHA. We sampled the oral cavities of 350 HIV-infected adults and an equal number of HIV-negative controls. Candida isolates were identified using germ tube tests, CHROMagar Candida (CHROMagar, Paris, France), and API Candida yeast identification system (BioMérieux, Marcy-l’Étoile, France). Fluconazole susceptibility was determined using the Clinical and Laboratory Standards Institute disc diffusion method. Data were analysed using SPSS version 21 (IBM, New York, NY, USA). The significance level was set at p ≤ 0.05. The isolation rates for Candida amongst HIV-infected subjects and controls were 20.6% and 3.4%, respectively (p < 0.001). In PLWHA, Candida albicans was most frequently isolated (81.3%) and fluconazole resistance was present in 18 (24%) of the 75 Candida isolates. Resistance to fluconazole was present in half of the non-albicans Candida isolates. Fluconazole resistance is prevalent among oral Candida isolates in PLWHA in the study area with a significantly higher rate among non-albicans Candida spp.

Prior subclinical histoplasmosis revealed in Nigeria using histoplasmin skin testing

Objectives Disseminated histoplasmosis is an AIDS-defining illness. Histoplasmosis is commonly misdiagnosed as tuberculosis. Nigeria has the second highest number of people living with HIV/AIDS in Africa. The present study was carried out to investigate the prevalence of skin sensitivity amongst Nigerians to histoplasmin. Design A cross-sectional study was conducted in six centres across five geopolitical zones of Nigeria. Methods We recruited both healthy non-HIV and HIV-positive adults with CD4 count ≥ 350 cells/mm3 regardless of their ART status from March to May 2017. Skin tests were performed intradermally; induration ≥5 mm were considered to be histoplasmin positive. Results 750 participants were recruited from Lagos (n = 52), Yola (n = 156), Ilorin (n = 125), Calabar (n = 120), Ibadan (n = 202) and Benin (n = 95). 467 (62.3%) were HIV negative, 247 (32.9%) were HIV positive and 36 (4.8%) did not know their HIV status. A total of 32/735 (4.4%) participants had a positive skin test. Study centre (p<0.001), education (p = 0.002) and age (p = 0.005) appeared to be significantly associated with positive skin reactivity at the 0.5% significance level, while sex (p = 0.031) and occupation (p = 0.031) would have been significant at the 5% significance level. Males had a higher rate of reactivity than females (p = 0.031, 7% vs 3%). The highest positive rates were recorded from Benin City (13/86 (15%)) and Calabar (7/120 (6%)) and no positives were recorded in Lagos (p<0.001). HIV status was not statistically significant (p = 0.70). Conclusion Histoplasmosis diagnostics should be included in the Nigerian HIV guidelines. Epidemiological vigilance of progressive disseminated histoplasmosis should be considered by local health authorities.

Diagnosis and Management of Pneumocystis Pneumonia in Resource-poor Settings

Abstract:Globally, Pneumocystis pneumonia (PCP) remains a common and lethal infection in both HIV-positive and HIV-negative patients, particularly in developing countries where rates of PCP increases with rising GDP. Pneumocystis jirovecii cannot be cultured in routine clinical laboratories; thus diagnosis relies on microscopy, histology, serology and/or polymerase chain reaction (PCR) of the Pneumocystis DNA. Most of these methods are expensive and require training. Accessing lower respiratory tract specimens in young children is often challenging and only PCR testing of nasopharyngeal aspirates is useful. Early treatment with high-dose co-trimoxazole is effective therapy; however, adverse reactions are common along with reports of emerging resistance. Improved outcomes are associated with adding corticosteroid to treatment in those with moderate/severe PCP, although this has not been studied in resource-poor settings. This review compares the available diagnostic techniques in relation to their suitability for use in resource-poor settings. We also addressed the non-availability of the alternative medications in these regions.

Incidence, Clinical Outcome and Risk Factors of Intensive Care Unit Infections in the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria

Background Infections are common complications in critically ill patients with associated significant morbidity and mortality. Aim This study determined the prevalence, risk factors, clinical outcome and microbiological profile of hospital-acquired infections in the intensive care unit of a Nigerian tertiary hospital. Materials and Methods This was a prospective cohort study, patients were recruited and followed up between September 2011 and July 2012 until they were either discharged from the ICU or died. Antimicrobial susceptibility testing of isolates was done using CLSI guidelines. Results Seventy-one patients were recruited with a 45% healthcare associated infection rate representing an incidence rate of 79/1000 patient-days in the intensive care unit. Bloodstream infections (BSI) 49.0% (22/71) and urinary tract infections (UTI) 35.6% (16/71) were the most common infections with incidence rates of 162.9/1000 patient-days and 161.6/1000 patient-days respectively. Staphylococcus aureus was the most common cause of BSIs, responsible for 18.2% of cases, while Candida spp. was the commonest cause of urinary tract infections, contributing 25.0% of cases. Eighty percent (8/10) of the Staphylococcus isolates were methicillin-resistant. Gram-negative multidrug bacteria accounted for 57.1% of organisms isolated though they were not ESBL-producing. Use of antibiotics (OR = 2.98; p = 0.03) and surgery (OR = 3.15, p< 0.05) in the month preceding ICU admission as well as urethral catheterization (OR = 5.38; p<0.05) and endotracheal intubation (OR = 5.78; p< 0.05) were risk factors for infection. Conclusion Our findings demonstrate that healthcare associated infections is a significant risk factor for ICU-mortality and morbidity even after adjusting for APACHE II score.