Browsing by Author "Denning, David W."

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    Burden of Fungal Asthma in Africa: A Systematic Review and Meta-Analysis
    (PloS one, 2019) Kwizera, Richard; Musaazi, Joseph; Meya, David B.; Worodria, William; Bwanga, Freddie; Kajumbula, Henry; Fowler, Stephen J.; Kirenga, Bruce J.; Gore, Robin; Denning, David W.
    Asthma is one of the neglected diseases in Africa with a high prevalence. Allergic fungal diseases have been reported to complicate asthma progression and treatment outcomes. However, data about fungal asthma and its associated complications are limited in Africa. We aimed to estimate the burden of fungal asthma among adults and children in Africa using a systematic review.We first engaged the Institute for Health Metrics and Evaluation (IHME) to highlight the trend in morbidity and mortality attributed to asthma in Africa. We then searched PubMed, HINARI and Google Scholar for all studies of any design focusing on fungal asthma in any African country. Languages were restricted to English and French, but not year of publication. We estimated the weighted prevalence of allergic fungal infections among asthmatics with a 95% CI and pooled the results using a random effects model. This study is registered with PROSPERO, number CRD42019117319.The IHME data showed that there has been a gradual increase in morbidity and mortality due to asthma in African adults with a prevalence of 4%. Our search retrieved 5233 citations. We retained 20 studies that met our selection criteria. These were from 13 African countries published between 1967 and 2018. There were eight cross-sectional studies and twelve review articles. The average asthma prevalence in Africa was 6% from these studies. The prevalence of fungal sensitisation was relatively high (3–52%) in the asthmatic population with an average of 28% and a pooled estimate of 23.3%, mostly due to Aspergillus species. Prevalence of Allergic bronchopulmonary apsergillosis was estimated at 1.6–21.2%. Diagnosis of fungal allergy was mostly made by skin prick tests. There was no data on the use of medication to manage fungal asthma. None of the studies evaluated the association between fungal allergy and asthma severity. Data were lacking in children.There is a high prevalence of fungal sensitization among Africans with asthma. Fungal asthma is a significant problem in Africa but there remains a paucity of data on the epidemiology and associated complications. There is urgent need for national epidemiological studies to estimate the actual burden of fungal asthma in Africa.
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    Comment on: Susceptibility Breakpoints and Target Values for Therapeutic Drug Monitoring of Voriconazole and Aspergillus Fumigatus in an in Vitro Pharmacokinetic/Pharmacodynamic Model
    (Journal of Antimicrobial Chemotherapy, 2015) Denning, David W.; Ghnan, Nesrin; Kwizera, Richard; Osmanov, Ali
    Siopi et al.1 are to be congratulated on a superb paper with convincing results using a combination of resistant isolates and sophisticated pharmacodynamic modelling to demonstrate the strong relationship between voriconazole serum concentrations and outcome. Three different MIC determinations yielded similar although numerically slightly different results. The authors propose slightly different breakpoints for resistance using the EUCAST method and breakpoints can now be set for Aspergillus fumigatus for the other two methods.
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    Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis
    (BMC Pulmonary Medicine, 2017) Kwizera, Richard; Parkes-Ratanshi, Rosalind; Wiltshire, Christine Sekaggya; Musaazi, Joseph; Castelnuovo, Barbara; Kambugu, Andrew; Denning, David W.
    The incidence of tuberculosis (TB) is high among human immunodeficiency virus (HIV) infected Ugandans. Recent evidence suggests that Chronic Pulmonary Aspergillosis and Aspergillus sensitisation might be responsible for significant mortality in patients treated for tuberculosis in Uganda. We retrieved and tested paired serum aliquots for 101 HIV-TB co-infected patients at the beginning and week 24 of TB treatment. We tested samples for Aspergillus-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) using ImmunoCAP®; and Aspergillus-specific IgG and total serum IgE using Immulite® immunoassays. We compared antibody levels between baseline and week 24, relating them to selected baseline characteristics.10% of the patients had elevated Aspergillus-specific IgE (Aspergillus sensitization) and Aspergillus-specific IgG antibodies were elevated in 9% of the patients at the end of TB treatment. There was a significant fall in the Aspergillus-specific IgG antibody levels between baseline and week 24 (P = 0.02). Patients with cluster of differentiation 4 (CD4) T-cell count <100 cells/μl and those who were not on anti-retroviral therapy at baseline had more elevated Aspergillus-specific IgG antibodies (P = 0.01, P = 0.03). The ImmunoCAP® Aspergillus-specific IgG antibody titres were higher at week 24 than baseline with more positives at week 24; even though the difference in means was small. However, this difference was statistically significant (P = 0.02). Pulmonary infiltrates were the commonest x-ray abnormality and only 5% of the patients had pulmonary cavities on chest x-ray at week 24.These results suggest that Aspergillus infection may complicate active pulmonary TB and further studies including fungal culture and thoracic imaging may now be indicated to measure the prevalence of pulmonary aspergillosis complicating tuberculosis.
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    Getting Histoplasmosis on the Map of International Recommendations for Patients with Advanced HIV Disease
    (Journal of Fungi, 2019) Bongomin, Felix; Kwizera, Richard; Denning, David W.
    Progressive disseminated histoplasmosis, caused by H. capsulatum, is a life-threatening illness and is an AIDS-defining opportunistic infection. It is neglected, worryingly under-diagnosed, and often misdiagnosed as cancer or tuberculosis with fatal consequences. Globally, over 100,000 cases of disseminated histoplasmosis have been estimated. In 2017, the World Health Organization (WHO) noted that disseminated histoplasmosis is a significant cause of mortality in AIDS patients. Through the rigorous efforts of the Global Action Fund for Fungal Infections (GAFFI) and partners, in 2019, the Histoplasma antigen test was included on the 2nd Edition of the WHO List of Essential Diagnostics. The drugs used in the treatment of histoplasmosis (amphotericin B and itraconazole) are on the WHO Essential Medicine List. The Manaus Declaration on histoplasmosis in the Americas and the Caribbean, where histoplasmosis kills more people with HIV than tuberculosis, advocates for universal access to rapid testing for histoplasmosis and availability of essential drugs for the treatment of histoplasmosis in every country by 2025. Hyperendemic areas are present in the Americas, Caribbean, Southeast Asia, and Latin America. In conclusion, histoplasmosis remains an important clinical and public health problem. To reduce HIV-associated mortality, disseminated histoplasmosis must be addressed through advocacy, increased awareness, and universal access to essential diagnostics and antifungal agents
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    Intravenous Therapy for Chronic Pulmonary Aspergillosis: A Systematic Review and Meta-analysis
    (Mycoses, 2020) Bongomin, Felix; Asio, Lucy Grace; Olum, Ronald; Denning, David W.
    Chronic pulmonary aspergillosis (CPA) is a potentially life-threatening debilitating lung disease necessitating long-term oral antifungal treatment. However, development of antifungal resistant isolates of Aspergillus and major toxicities requiring discontinuation of treatment limit their use. Intravenous (IV) antifungals are an option in this group of patients. We comprehensively evaluate the response rates to IV antifungals in the management of CPA. We searched Medline and Embase databases to select clinical studies providing information about IV amphotericin B or an echinocandin for the treatment of CPA from inception to May 2020. Reviews, single case reports and case series reporting less than 10 patients were excluded. We evaluated 12 eligible studies. A total of 380 patients received amphotericin B (n =143) or an echinocandin (n=237) and were included in the meta-analysis. In a pooled analysis, overall response to IV antifungals was 61% ((95% confidence interval (CI): 52-70%; I2=73.3%; p<0.001), to amphotericin B was 58% (95% CI: 36-80%; I2=86.6%; p<0.001) and to echinocandins was 62% (95% CI: 53-72%; I2=63.6%; p<0.001). Amphotericin B courses were usually doses at slightly less that 1mg/Kg (deoxycholate) or 3mg/Kg (liposomal) for 2-3 weeks. Micafungin doses varied from 12.5 to 300mg (frequently, 150mg) daily for at least 3 weeks, and sometimes much longer. Liposomal amphotericin B was well tolerated, but led to renal function loss in 25% of patients. Adverse events were observed in 5 – 35.3% of patients receiving echinocandins, none of which was considered major. Intravenous antifungals have a place in the management of CPA. A head-to-head comparison of amphotericin B and echinocandins is lacking, and future studies should look at evaluating short and longer-term outcomes of these agents.
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    Prevalence of Aspergillus Fumigatus Skin Positivity in Adults without an apparent/known Atopic Disease in Uganda
    (Therapeutic advances in infectious disease, 2021) Kwizera, Richard; Bongomin, Felix; Olum, Ronald; Worodria, William; Meya, David B.; Kirenga, Bruce J.; Gore, Robin; Denning, David W.
    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. 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. 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].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.