Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study
Pneumonia Etiology Research for Child Health Study Group
BACKGROUND: Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. METHODS: We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1-59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. FINDINGS: Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41.8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99.7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31.7%) of 1752 cases (range by site 10.6-97.3%). 30-day case-fatality ratio was 6.4% (114 of 1769 cases). Blood cultures were positive in 56 (3.2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33.9%] of 56). Almost all cases (98.9%) and controls (98.0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61.4% (95% credible interval [CrI] 57.3-65.6) of causes, whereas bacteria accounted for 27.3% (23.3-31.6) and Mycobacterium tuberculosis for 5.9% (3.9-8.3). Viruses were less common (54.5%, 95% CrI 47.4-61.5 vs 68.0%, 62.7-72.7) and bacteria more common (33.7%, 27.2-40.8 vs 22.8%, 18.3-27.6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31.1%, 95% CrI 28.4-34.2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus-enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. INTERPRETATION: In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. FUNDING: Bill & Melinda Gates Foundation.