Abstract
Pneumocystis jirovecii pneumonia (PCP) is an important opportunistic infection in patients infected with HIV, but its burden is incompletely characterized in those areas of sub-Saharan Africa where HIV is prevalent. We explored the prevalence of both PCP in HIV-infected adults admitted with pneumonia to a tertiary-care hospital in Uganda and of putative P. jirovecii drug resistance by mutations in fungal dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr). In 129 consecutive patients with sputum smears negative for mycobacteria, 5 (3.9%) were diagnosed with PCP by microscopic examination of Giemsa-stained bronchoalveolar lavage fluid. Concordance was 100% between Giemsa stain and PCR (dhps and dhfr). PCP was more prevalent in patients newly-diagnosed with HIV (11.4%) than in patients with known HIV (1.1%; p = 0.007). Mortality at 2 months after discharge was 29% overall: 28% among PCP-negative patients, and 60% (3 of 5) among PCP-positive patients. In these 5 fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation. No non-synonymous dhfr mutations were detected. PCP is an important cause of pneumonia in patients newly-diagnosed with HIV in Uganda, is associated with high mortality, and putative molecular evidence of drug resistance is prevalent. Given the reliability of field diagnosis in our cohort, future studies in sub-Saharan Africa can investigate the clinical impact of these genotypes.
Highlights
Pneumocystis jirovecii pneumonia (PCP) is a major opportunistic infection in people with HIV and AIDS
In sub-Saharan Africa, access to these interventions remains limited for the 23 million people living with HIV infection; recent estimates indicate that the prevalence of PCP amongst HIV-infected patients with pneumonia may be as high as 27% in some African countries [1]
Antifolate drugs target two enzymes that are necessary for the fungus to synthesize folate – dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) – and mutations in the genes encoding these proteins are associated with reduced in vitro drug efficacy. [3,4] Because drug efficacy cannot be directly assessed in the absence of a reliable P. jirovecii cultivation system, and because the presence of several mutations is consistently associated with exposure to antifolates, [5] these mutations may represent a genetic signature of clinical drug resistance
Summary
Pneumocystis jirovecii pneumonia (PCP) is a major opportunistic infection in people with HIV and AIDS. In the United States and Europe, its incidence has decreased dramatically among HIVinfected patients owing to the twin interventions of antimicrobial prophylaxis of high-risk patients and combination antiretroviral (ARV) therapy. In sub-Saharan Africa, access to these interventions remains limited for the 23 million people living with HIV infection; recent estimates indicate that the prevalence of PCP amongst HIV-infected patients with pneumonia may be as high as 27% in some African countries [1]. [2] putative P. jirovecii drug resistance threatens the durability of PCP prophylaxis with antifolate antibiotics, which are the mainstay of PCP prevention amongst high-risk patients. In the United States and Europe, the prevalence of two of the most common dhps mutations (those at codons 55 and 57) in patients with PCP has been reported between 23–81% (in the USA) and 7–57% (in Europe). In the United States and Europe, the prevalence of two of the most common dhps mutations (those at codons 55 and 57) in patients with PCP has been reported between 23–81% (in the USA) and 7–57% (in Europe). [6] Estimates of the independent effect of P. jirovecii mutants upon clinical outcomes have been conflicting: some studies report their association with increased mortality or antifolate-based treatment failure, [7,8,9,10] while others have not [11,12,13]
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