Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: a systematic review and meta-analysis

Pneumocystis jirovecii is a ubiquitous opportunistic fungal pathogen that causes pneumocystis pneumonia (PCP) in patients with cellular immune defects. PCP heralded the onset of the global human immunodeficiency virus (HIV) pandemic [1], and prior to 1995 it was estimated that two-thirds of HIV-infected persons would eventually develop PCP [2]. Although the incidence has declined since the introduction of cotrimoxazole prophylaxis and combination antiretroviral therapy (ART), PCP remains the most important AIDS-defining opportunistic infection in the United States [3, 4]. By contrast, in sub-Saharan Africa the morbidity and mortality in HIV is dominated by tuberculosis [5], cryptococcal disease, and bacterial infections such as non-typhoidal salmonella and Streptococcus pneumoniae [6].

Early studies from African countries with high HIV prevalence reported PCP to be an uncommon OI [7‐9]. An overwhelmingly high burden of other opportunistic diseases, early exposure to P. jirovecii resulting in improved immunity, and immune modulation by other infections are putative explanations for the reduced prevalence of PCP in sub-Saharan Africa [10‐12]. A single recent study demonstrated an inverse relationship of PCP prevalence to gross domestic product [13].

In the context of late presentation at low CD4 T lymphocyte counts (CD4 count) [14] and limited ART coverage [15], there is potentially a large pool of individuals at high risk of presenting to health care facilities with PCP in sub-Saharan Africa. Local studies have revealed a high seroprevalence of P. jirovecii in healthy HIV-infected adults [16, 17], as well as high rates of clinical disease in African children [18‐20]. The reported increase in prevalence amongst adults in the 1990s, possibly as a result of better access to diagnostics and treatment [21], may reflect the true epidemiology of the disease, suggesting that PCP may be a more important cause of community-acquired pneumonia in Africa than was previously recognised.

A better understanding of PCP prevalence will help to inform empiric prescribing, the interpretation of diagnostic tests, and public health policy relating to the allocation of scarce resources such as intensive care unit beds, invasive procedures like bronchoscopy, and research funding. We therefore undertook a systematic review to more accurately determine the burden of PCP in sub-Saharan Africa in the ART era. Our primary aim was to determine the proportion of HIV-infected adults with confirmed PCP, stratified by clinical setting, method of diagnosis, and time. Secondary aims included attributable mortality and case fatality, a description of demographic profiles, and rates of co-infection with other pathogens.

Early studies conducted in sub-Saharan Africa suggested a lower PCP prevalence than in developed countries [25‐27], as well as a lower incidence (5 cases per 1000 person years) compared to the post-ART era estimate in the United States of 46 cases per 1000 person years [28]. These data have led a number of experts to question the importance of PCP in comparison to tuberculosis and other infections that dominate mortality and morbidity in sub-Saharan Africa [10‐12]. Our review of data collected predominantly after 1995 demonstrates a pooled prevalence of PCP comparable to that reported from developed countries [29], suggesting that it is more likely to have been missed or neglected in sub-Saharan Africa rather than being an uncommon opportunistic infection.

Previous reviews have shown time trend of increasing PCP prevalence in sub-Saharan Africa amongst comparable patient populations and diagnostic assessments. After crudely combining the data from these reports, seven out of ten studies conducted over the period 1986–1993 had prevalence rates ≤ 15 % while eight out of ten studies conducted between 1997 and 2005 had prevalence rates ≥ 30 % [21, 30]. We have shown the opposite, that the proportion of inpatients with PCP appears to be decreasing over time. This trend seems more realistic, and it is plausible that our observation of better exposure to ART and cotrimoxazole prophylaxis in more recent years can account for fewer diagnosed cases of PCP. Nonetheless, even after 2005, most patients in our included studies had not received these interventions and had low CD4 counts at presentation, reflecting the slow rollout of adequate HIV care in the region.

We noted a much higher prevalence of PCP amongst inpatients compared to outpatients. This is mainly a reflection of the superior performance of invasive diagnostic tests and that inpatients represent a selected denominator of patients that have failed empiric therapy for other causes of pneumonia in the community. However, the observation may also suggest something inherent about PCP itself, possibly that mild cases either resolve spontaneously or are an uncommon manifestation of the infection; these hypotheses require further study.

More cases of PCP were diagnosed using BAL (21 %) compared with sputum (7–11 %). This reflects a selection bias of patients with a higher likelihood of PCP being referred for bronchoscopy but also the enhanced sensitivity of BAL for diagnosis. Unfortunately, access to bronchoscopy is extremely limited in most African countries, and clinicians must rely on a combination of knowledge of disease prevalence, unvalidated clinical case definitions and insensitive non-invasive tests to diagnose PCP. In the context of a prevalence of > 20 % and poor diagnostic tools, there should be a low threshold to initiate empiric PCP therapy for HIV-infected inpatients with pneumonia. This may lead to overtreatment, with the attendant risks of unnecessary exposure to high dose cotrimoxazole and concerns about using corticosteroids in patients with undiagnosed tuberculosis or Kaposi sarcoma. Our finding of a high frequency of PCP with the use of bronchoscopy therefore emphasises the need for more accurate non-invasive diagnostic tests such as PCR, which has been shown to be sensitive, specific and cost effective when used on sputum and BAL [31], with a potentially important role as a rule-out test for PCP in resource-limited settings [32]. Only ten studies included in our review used PCR assays to diagnose PCP, and similar numbers of cases were identified by this method and staining techniques on all specimen types. Our study was not designed to assess the performance of diagnostic tests for PCP, and prospective cohort studies are needed to evaluate the role of PCR, and other non-invasive tests such as plasma beta-glucan [33], in the diagnosis of PCP in sub-Saharan Africa.

Our calculated case fatality of almost 19 % is higher than the mortality from other common respiratory infections in Africa [34, 35] as well as from PCP in developed countries [36]. This contributes to the overall burden of PCP and adds impetus to more investment in prevention strategies and effective diagnostic tests.

Similarly to a recent review [13], a substantial number of patients with PCP were found to have coexistent bacterial pneumonia and other opportunistic infections, particularly tuberculosis. This is an important consideration when evaluating patients with inadequate responses to empiric or confirmed PCP therapy, and co-infections should be excluded before attributing a poor treatment response to PCP infection alone.

This review has a number of important limitations. First, most included studies were conducted in highly selected cohorts, such as patients with suspected PCP, exclusion of patients with tuberculosis and other illnesses, and the performance of BAL only in cases where the diagnosis remained elusive. This increases the risk of selection bias and of overestimating true disease prevalence. However, the clinical burden of PCP in a population is influenced almost exclusively by those who are ill with respiratory symptoms and our chosen denominator therefore allows an assessment that is probably close to the true prevalence.

Second, missing or unreported data was common. With regard to disease prevalence, bronchoscopy studies frequently excluded a substantial proportion of patients with possible PCP on the basis of medical contraindications for the procedure, and five studies excluded patients with either advanced HIV or severe respiratory illness. If anything, this may result in an underestimate of PCP prevalence because the outcomes of otherwise eligible patients with respiratory symptoms not enrolled were rarely reported and over half of the included studies did not specifically evaluate participants for PCP.

The third limitation was the high degree of heterogeneity in the prevalence findings from different studies. This is not unusual in prevalence reviews, and reflects differences in methodology and aims, diagnostic methods and the chosen population denominator. We attempted to minimise this effect by analysing data by clinical setting to include patients with similar risk for PCP and by scoring the quality of each study, and found no significant difference in prevalence on the basis of study quality (data not shown). It is also possible that some undefined environmental or biological differences exist across geographic locations to explain the observed heterogeneity, but our study was not designed to address this.

We have performed a systematic review of PCP prevalence using diagnostic criteria with high specificity, a well-defined population denominator and clinically relevant categorisation of cases. The overall impression from our pooled data is that PCP is an important cause of community-acquired pneumonia in HIV-infected adults living in sub-Saharan Africa. This has implications for clinical guidelines in resource poor settings where indications for empiric therapy and referral need to be clearly defined. The contribution of PCP to mortality in the region suggests that cases are unrecognised, and highlights the need for the development of a reliable clinical case definition and the evaluation of sensitive non-invasive diagnostic tests, such as PCR. The observed trend of decreasing PCP prevalence is encouraging, but there is much work to be done to expand access to ART and cotrimoxazole prophylaxis so that ultimately this sentinel AIDS-defining infection achieves the status of a rare disease it was once erroneously ascribed.