A systematic review and meta-analysis of the aetiological agents of non-malarial febrile illnesses in Africa

Background: The awareness of non-malarial febrile illnesses (NMFIs) has been on the rise over the last decades. Therefore, we undertook a systematic literature review and meta-analysis of causative agents of non-malarial fevers on the African continent. Methodology: We searched for literature in African Journals Online, EMBASE, PubMed, Scopus, and Web of Science databases to identify aetiologic agents that had been reported and to determine summary estimates of the proportional morbidity rates (PMr) associated with these pathogens among fever patients. Findings: A total of 133 studies comprising 391,835 patients from 25 of the 54 African countries were eligible. A wide array of aetiologic agents were described with considerable regional differences among the leading agents. Overall, bacterial pathogens tested from blood samples accounted for the largest proportion. The summary estimates from the meta-analysis were low for most of the agents. This may have resulted from a true low prevalence of the agents, the failure to test for many agents or the low sensitivity of the diagnostic methods applied. Our meta-regression analysis of study and population variables showed that diagnostic methods determined the PMr estimates of typhoidal Salmonella and Dengue virus. An increase in the PMr of Klebsiella spp. infections was observed over time. Furthermore, the status of patients as either inpatient or outpatient predicted the PMr of Haemophilus spp. infections. Conclusion: The small number of epidemiological studies and the variety of NMFI agents on the African continent emphasizes the need for harmonized studies with larger sample sizes. In particular, diagnostic procedures for NMFIs should be standardized to facilitate comparability of study results and to improve future meta-analyses. Reliable NMFI burden estimates will inform regional public health strategies. Author summary: Previous systematic reviews have highlighted the research priorities of causative agents for non-malarial febrile illnesses by counting the number of publications attributed to an agent. However, proportional morbidity rates are calculated by dividing the number of cases with a specific disease (numerator) by the total number of diagnosed fever cases (denominator) and are better indicators of the relative importance of aetiological agents in a population. Therefore, we present the leading causes of non-malarial febrile illnesses in African patients in both healthcare and community settings. Preference is given to HIV-negative patients when data could be found. We also determined summary estimates of Brucella spp., Chikungunya virus, Dengue virus, Haemophilus spp., Klebsiella spp., Leptospira spp., non-typhoidal Salmonella spp., typhoidal Salmonella spp., Staphylococcus spp., and Streptococcus spp.