Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study

Abstract

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.

Figure 1

Case (A) and control (B) enrolment and specimen availability profile CXR=chest x-ray. NP=nasopharyngeal. OP=oropharyngeal. WB=whole blood. LA=lung aspirate. PF=pleural fluid. IS=induced sputum. GA=gastric aspirate. *Of the 88 children not enrolled because of other reasons, 45 were not enrolled because of an enrolment cap at the Mali site, ten because of political unrest in Bangladesh, and 24 in Kenya and nine in Zambia because of reasons not stated. †Included in clinical descriptive analysis. ‡Lung aspirate and pleural fluid specimens were collected on a subset of cases eligible for the procedures; for samples with low volumes, only culture was done. §Measles testing was done on a subset of cases who met the study defined clinical criteria for measles. ¶Included in laboratory descriptive analysis and aetiology analysis; at least one of the following specimens was required for a child to be included in the aetiology analysis: blood culture, NP-OP PCR, WB PCR, or tuberculosis culture for cases; and NP-OP PCR or WB PCR for controls. ||Number contacted, screened, and eligible includes some extrapolated data for the Zambia and South Africa sites; data were available for 16 of 24 months for Zambia and 10·5 of 24 months for South Africa; for each of these sites, available data were used to extrapolate numbers for the months with missing data assuming that contact, participation, and eligibility rates were constant over time.**Not shown here are an additional 206 controls with HIV infection enrolled from HIV clinics at the South Africa and Zambia sites to ensure adequate sample size of children with HIV infection; these children will be described in forthcoming manuscripts devoted to the causes of severe and very severe pneumonia in children with HIV infection. ††Data for total number of children contacted and number of children who declined or did not show to clinic were not available for the Mali site. ‡‡Among sites with available data for total number of children contacted (ie, all sites except Mali), 8149 (73·9%) of 11 033 randomly selected children or households were contacted; the number of children or guardians contacted is used as the denominator for the percentage of children screened, eligible, and enrolled; because the denominator excludes Mali but the numerator does not, the percentages for screened, eligible, and enrolled are overestimated.

Figure 2

Blood culture results by study site in cases with positive chest x-ray and without HIV infection Enterobacteriaceae includes Escherichia coli, Enterobacter spp, and Klebsiella spp, excluding mixed Gram-negative rods. Other streptopcocci and enterococci include Streptococcus pyogenes and Enterococcus faecium. Mixed label includes Salmonella spp and other streptopcocci and enterococci. Contaminants, including those organisms deemed to be contaminants after clinical review, were excluded from the analysis. Figure is restricted to cases with available blood culture results. The numbers on the top of the bars refer to the total number of positive blood cultures. Two of the cases positive for pneumococcus in Kenya were pneumococcal conjugate vaccine (PCV) 13-type but not PCV10-type (serotypes 19A and 6A). Antibiotic pretreatment (defined as having a positive serum bioassay result, antibiotics administered at the referral facility, or antibiotic administration before whole-blood specimen collection at the study facility) varied by site: The Gambia (composite 10·6%, bioassay 7·6%), Mali (22·4%, 17·1%), Kenya (35·1%, 10·0%), Zambia (92·2%, 25·3%), South Africa (57·2%, 54·2%), Bangladesh (24·6%, 21·6%), and Thailand (30·6%, 19·4%).

Figure 3

Nasopharyngeal-oropharyngeal (NP-OP) pathogen prevalence* and adjusted odds ratios (OR) in cases with positive chest x-ray and without HIV infection and in controls without HIV infection Pathogens are ordered alphabetically among bacteria, followed by viruses and fungi. ORs adjusted for age (months), site, and presence of other pathogens detected by NP-OP PCR, but not adjusted for previous antibiotic use, which is known to influence bacterial positivity. *Prevalence defined by use of NP-OP PCR density thresholds for four pathogens: Pneumocystis jirovecii, 4 log₁₀ copies per mL; Haemophilus influenzae, 5·9 log₁₀ copies per mL; cytomegalovirus, 4·9 log₁₀ copies per mL; Streptococcus pneumoniae, 6·9 log₁₀ copies per mL; NP-OP PCR results based on positivity are in the appendix. PCV=pneumococcal conjugate vaccine.

Figure 4

Aetiological fraction unstratified (A), stratified by age (B), and stratified by severity (C) for cases with a positive chest x-ray and without HIV infection from all PERCH sites combined Lines represent 95% credible interval; the darker region of the line represents the IQR. The size of the symbol is scaled on the basis of the ratio of the estimated aetiological fraction to its SE. Of two identical aetiological fraction estimates, the estimate associated with a larger symbol is more informed by the data than the priors. Positive chest x-rays defined as consolidation or other infiltrate on the x-ray. The following pathogens contributed less than 1% to the aetiological fraction (overall and after stratifying by age and severity) and were excluded from the figure: Coronavirus, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. Other streptococci and enterococci includes Streptococcus pyogenes and Enterococcus faecium. Non-fermentative Gram-negative rods (NFGNR) includes Acinetobacter spp and Pseudomonas spp. Enterobacteriaceae includes Escherichia coli, Enterobacter spp, and Klebsiella spp, excluding mixed Gram-negative rods. Pathogens that were estimated at the subspecies level, but grouped to the species level for display include parainfluenza virus type 1, 2, 3 and 4; Streptococcus pneumoniae PCV 13 and S pneumoniae non-PCV 13 types; Haemophilus influenzae type b and H influenzae non-type b; and influenza A, B, and C. Exact figures, including subspecies and serotype disaggregation (eg, PCV13 type and non-PCV13 type), are given in the appendix. NOS=not otherwise specified (ie, pathogens we did not test for).

Figure 5

Site-specific aetiology results for ten focus pathogens in cases with a positive chest x-ray and without HIV infection The size of the symbol is scaled on the basis of the ratio of the estimated aetiological fraction to its SE. Of two identical aetiological fraction estimates, the estimate associated with a larger symbol is more informed by the data than the priors. Positive chest x-rays defined as consolidation or other infiltrate on the x-ray. Graph restricted to the ten focus pathogens from the all-site analysis, which include those with aetiology estimate higher than 5% (n=7) or higher than 2% that were of epidemiological interest (defined as treatable by antibiotics [Pneumocystis jirovecii and Staphylococcus aureus] or having an available vaccine [influenza virus]). The 95% credibility intervals for the aetiological fractions of these three pathogens overlap with some non-focus pathogens, hence our use of the term focus pathogen rather than labelling these ten as the most common pathogens. Other pathogens category represents the sum of the aetiological fraction for all remaining pathogens tested for, but not presented in this figure. Site-specific results were standardised to the following case mix: 40% younger than 1 year with severe pneumonia, 20% younger than 1 year with very severe pneumonia, 30% aged 1 year or older with severe pneumonia, and 10% aged 1 year or older with very severe pneumonia. Pathogens estimated at the subspecies level, but grouped to the species level for display include parainfluenza virus types 1, 2, 3, and 4; Streptococcus pneumoniae PCV13 and S pneumoniae non-PCV13 types; Haemophilus influenzae type b and H influenzae non-type b; and influenza virus A, B, and C. Exact figures are given in the appendix. NOS=not otherwise specified (ie, pathogens we did not test for). *The summary for bacteria excludes Mycobacterium tuberculosis.

Figure 6

Cumulative contribution of site-specific ten most common pathogens in cases with a positive chest x-ray and without HIV infection Positive chest x-rays defined as consolidation or other infiltrate on the x-ray. Site-specific results were standardised to the following case mix: 40% younger than 1 year with severe pneumonia, 20% younger than 1 year with very severe pneumonia, 30% aged 1 year or older with severe pneumonia, and 10% aged 1 year or older with very severe pneumonia. Ranks correspond to the site-specific rank from the top ten pathogens of each site; the pathogen corresponding to each rank varies by site (see inset panel). Other strep category includes Streptococcus pyogenes and Enterococcus faecium. Non-fermentative Gram-negative rods (NFGNR) includes Acinetobacter spp and Pseudomonas spp. Enterobacteriaceae category (Entrb) includes Escherichia coli, Enterobacteriaceae spp, and Klebsiella spp, excluding mixed Gram-negative rods. Pathogens estimated at the subspecies level, but grouped to the species level for display include parainfluenza virus types 1, 2, 3, and 4; Streptococcus pneumoniae PCV13 and S pneumoniae non-PCV13 types; Haemophilus influenzae type b and H influenzae non-type b; and influenza virus A, B, and C. Boca=human bocavirus. Cand sp=Candida spp. CMV=cytomegalovirus. Flu=influenza virus A, B and C. H inf=H influenzae. HMPV=human metapneumovirus A or B. Mtb=Mycobacterium tuberculosis. M cat=Moraxella catarrhalis. NOS=not otherwise specified (ie, pathogens we did not test for). P jirov=Pneumocystis jirovecii. Para=parainfluenza virus type 1, 2, 3 and 4. PV-EV=parechovirus–enterovirus. Rhino=human rhinovirus. RSV=respiratory syncytial virus A or B. S aur=Staphylococcus aureus. S pneu=S pneumoniae. Salm sp=Salmonella spp.