pmc951642021005Clin Microbiol InfectClin Microbiol InfectClinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases1198-743X1469-0691394892921307600410.1016/j.cmi.2024.10.023HHSPA2156330ArticleEpidemiology of human metapneumovirus among children with severe or very severe pneumonia in high pneumonia burden settings: the Pneumonia Etiology Research for Child Health (PERCH) study experienceMiyakawaRyo1ZhangHaijun23*BrooksW. Abdullah45ProsperiChristine2BaggettHenry C.67FeikinDaniel R.28HammittLaura L.29HowieStephen R.C.101112KotloffKaren L.13LevineOrin S.2MadhiShabir A.1415MurdochDavid R.1617O’BrienKatherine L.2ScottJ. Anthony G.918TheaDonald M.19AntonioMartin1020AworiJuliet O.9BunthiCharatdao6DriscollAmanda J.221EbrukeBernard10FancourtNicholas S.2223HigdonMelissa M.2KarronRuth A.24MooreDavid P.141525MorpethSusan C.91821MulindwaJustin M.26ParkDaniel E.227RahmanMohammed Ziaur5RahmanMustafizur5SalaudeenRasheed A.1028SawatwongPongpun6SeidenbergPhil1929SowSamba O.30TapiaMilagritos D.13KnollMaria Deloria2Department of Pediatrics, Weill Cornell Medicine, New York, NY, USAInternational Vaccine Access Center, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USADepartment of Health Policy and Management, School of Public Health, Peking University, Beijing, ChinaDepartment of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USAInternational Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), Dhaka and Matlab, BangladeshDivision of Global Health Protection, Thailand Ministry of Public Health—U.S. Centers for Disease Control and Prevention Collaboration, Nonthaburi, ThailandDivision of Global Health Protection, Global Health Center, Centers for Disease Control and Prevention, Atlanta, GA, USADivision of Viral Diseases, National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USAKenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, KenyaMedical Research Council Unit at the London School of Hygiene and Tropical Medicine, Basse, The GambiaDepartment of Paediatrics: Child & Youth Health, University of Auckland, Auckland, New ZealandCollege of Medicine, Nursing and Health Sciences, Fiji National University, Suva, FijiDivision of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USASouth African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaWits Infectious Diseases and Oncology Research Institute, University of the Witwatersrand, Johannesburg, South AfricaDepartment of Pathology and Biomedical Sciences, University of Otago, Christchurch, New ZealandMicrobiology Unit, Canterbury Health Laboratories, Christchurch, New ZealandDepartment of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UKDepartment of Global Health, Boston University School of Public Health, Boston, MA, USADepartment of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, Microbiology and Infection Unit, Warwick Medical School, University of Warwick, Coventry, UKCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USAChildren’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, AustraliaMicrobiology Laboratory, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New ZealandDepartment of International Health, Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USADepartment of Paediatrics & Child Health, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg, South AfricaDepartment of Paediatrics and Child Health, University Teaching Hospital, Lusaka, ZambiaDepartment of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, USAMedical Microbiology Department, Lagos University Teaching Hospital, Lagos, NigeriaDepartment of Emergency Medicine, University of New Mexico, Albuquerque, NM, USACentre pour le Développement des Vaccins (CVD-Mali), Bamako, Mali

Author contributions

R.M. and M.D.K. participated in study conception and design (for subanalysis). W.A.B., H.C.B., D.R.F., L.L.H., S.R.C.H., K.L.K., O.S.L., S.A.M., D.R.M., K.L.O., J.A.G.S., D.M.T., R.A.K., P.S., S.O.S., M.D.T., and M.D.K. participated in study conception and design (for the parent PERCH study). W.A.B., C.P., H.C.B., D.R.F., L.L.H., S.R.C.H., K.L.K., O.S.L., S.A.M., D.R.M., K.L.O., J.A.G.S., D.M.T., M.A., J.O.A., C.B., A.J.D., B.E., N.S.F., M.M.H., R.A.K., D.P.M., S.C.M., J.M.M., D.E.P., M.Z.R., M.R., R.A.S., P Sawatwong, P Seidenberg, S.O.S., M.D.T., and M.D.K. participated in data collection. C.P. and M.D.K. participated in data curation for this subanalysis. R.M., H.Z., and M.D.K. participated in analysis of methods and materials and generation of figures. R.M., H.Z., W.A.B., and M.D.K. participated in interpretation of results and draft manuscript preparation. M.D.K. participated in funding acquisition for this subanalysis. All authors reviewed the results and approved the final version of the manuscript. R.M. and H.Z. contributed equally as co-first authors. M.D.K. contributed as the senior author.

Corresponding author. Haijun Zhang, Department of Health Policy and Management, School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China. zhanghj966@gmail.com (H. Zhang).253202632025011120241342026313441450Objectives:

After respiratory syncytial virus (RSV), human metapneumovirus (hMPV) was the second-ranked pathogen attributed to severe pneumonia in the PERCH study. We sought to characterize hMPV-positive cases in high-burden settings, which have limited data, by comparing with RSV-positive and other cases.

Methods:

Children aged 1–59 months hospitalized with suspected severe pneumonia and age/season-matched community controls in seven African and Asian countries had nasopharyngeal/oropharyngeal swabs tested by multiplex PCR for 32 respiratory pathogens, among other clinical and lab assessments at admission. Odds ratios adjusted for age and site (adjusted OR [aOR]) were calculated using logistic regression. Aetiologic probability was estimated using Bayesian nested partial latent class analysis. Latent class analysis identified syndromic constellations of clinical characteristics.

Results:

hMPV was detected more frequently among cases (267/3887, 6.9%) than controls (115/4976, 2.3%), among cases with pneumonia chest X-ray findings (8.5%) than without (5.5%), and among controls with respiratory tract illness (3.8%) than without (1.8%; all p ≤ 0.001). HMPV-positive cases were negatively associated with the detection of other viruses (aOR, 0.18), especially RSV (aOR, 0.11; all p < 0.0001), and positively associated with the detection of bacteria (aORs, 1.77; p 0.03). No single clinical syndrome distinguished hMPV-positive from other cases. Among hMPV-positive cases, 65.2% were aged <1 year and 27.5% had pneumonia danger signs; positive predictive value for hMPV aetiology was 74.5%; mortality was 3.9%, similar to RSV-positive (2.4%) and lower than that among other cases (9.6%).

Discussion:

HMPV-associated severe paediatric pneumonia in high-burden settings was predominantly in young infants and clinically indistinguishable from RSV. HMPV-positives had low case fatality, similar to that in RSV-positives.

AfricaAsiaHuman metapneumovirus (hMPV)PaediatricSevere pneumoniaIntroduction

Lower respiratory infections are the most common cause of hospitalization and death in children aged 1–59 months [1,2]. In contrast to respiratory syncytial virus (RSV), whose role in paediatric respiratory infections has long been recognized, human metapneumovirus (hMPV) was only identified in 2001 [3]. It is a member of the Pneumoviridae family along with RSV and consists of two genotypes (A and B) based on surface glycoprotein sequence variation in its attachment (G) and fusion (F) proteins, with further subdivisions in these genotypes [4].

HMPV has been shown to cause respiratory tract infections in all ages globally [1]. The clinical spectrum of hMPV infection ranges from mild upper respiratory symptoms, otitis media, bronchiolitis, bronchitis and pneumonia, and exacerbations of chronic lower airway diseases of asthma and chronic obstructive pulmonary disease (COPD) [1,5]. Treatment for hMPV-associated disease is currently supportive care and although no vaccines are available, several are under development [6], as are antiviral medications [1,7].

Although hMPV can infect all ages, infants <1 year have highest risk of severe hMPV-associated illness [8]. The droplet-spread virus infects most children (90–100%) by age 5–10 years and reinfection can occur [1,9]. In North America, the incidence of hMPV-associated severe hospitalized disease is similar to that of influenza and of parainfluenza 1, 2, and 3 combined [10]. In 2018, an estimated 14.2 million cases of hMPV acute lower respiratory infection occurred in children <5 years worldwide, including 643 000 hospitalizations and 7700 in-hospital deaths [8]. Children aged <12 months accounted for 71% of deaths and 64% of deaths were amongst children <6 months, of which 96% occurred in settings with high child mortality.

The Pneumonia Etiology Research for Child Health (PERCH) case-control study estimated the aetiology of pneumonia in children 1–59 months of age in five African and two Asian countries from 2011 to 2014. PERCH previously estimated that hMPV caused 6% of severe hospitalized radiographically confirmed pneumonia, the second most frequent viral pathogen after RSV [11]. Because of the high proportion of pneumonia cases attributed to hMPV, we further explored data from the PERCH study to evaluate the clinical and epidemiologic characteristics and outcomes of children infected with hMPV compared with other cases.

MethodsParticipants

Between August 2011 and January 2014, children aged 1–59 months were enrolled at nine study sites in seven countries: Dhaka and Matlab, Bangladesh; Basse, The Gambia; Kilifi, Kenya; Bamako, Mali; Soweto, South Africa; Sa Kaeo and Nakhon Phanom, Thailand; and Lusaka, Zambia. Sites represented a mix of urban and rural populations and different prevalences of HIV, malaria, and infant mortality rates [11]. Each site enrolled subjects for 24 consecutive months.

Cases, enrolled at hospital admission, had WHO-defined severe or very severe pneumonia (pre-2013 definition): cough or difficulty breathing and either lower chest wall indrawing or a pneumonia danger sign (indicating very severe), including central cyanosis, difficulty feeding, vomiting everything, convulsions, lethargy, reduced consciousness, or head nodding [11]. Cases hospitalized within 14 days preceding enrolment, discharged as a PERCH case in the past 30 days, residing outside the study catchment area, or whose lower chest wall indrawing resolved after bronchodilator therapy were excluded. Controls were selected randomly from communities within the catchment area of the cases and were frequency-matched to cases by enrolment date and age stratum (28 days–5 months, 6–11 months, 12–23 months, and 24–59 months). Controls meeting case-defining criteria were excluded but could have respiratory illness.

Data collection

Standardized assessment was performed for cases and controls at enrolment, including demographic information, medical history, clinical data, comorbidities, and risk factors, described in detail previously [11]. Mortality status of discharged cases was assessed 30–90 days after admission. Respiratory tract illness (RTI) in controls was defined as having any of cough, rhinorrhoea, fever, or sore throat, plus one or more of the following: ear discharge, wheezing, or difficulty breathing. Leucocytosis was defined as white blood cell count >15 × 109 cells/L for children aged 1–11 months and >13 × 109 cells/L for children aged 12–59 months. Chest X-rays (CXRs) taken within 72 hours of admission were read by two trained readers blinded to the clinical laboratory findings using WHO-standardized procedures [12]. Discordant readings were adjudicated by two other expert readers. Findings were classified as normal, other infiltrates only, consolidation with or without other infiltrates or uninterpretable. CXR-positive cases had either consolidation or other infiltrates identified.

Specimen collection and testing

Flocked nasopharyngeal (NP) and rayon oropharyngeal (OP) swabs collected from all participants were tested by multiplex PCR for 33 pathogens [13]. High density Streptococcus pneumoniae and Haemophilus influenzae were defined using thresholds associated with case status: >6.9 log10 copies/mL and >5.9 log10 copies/mL, respectively [14].

Blood from cases and controls was tested by lytA PCR; blood cultures were obtained from cases [15]. Cases had induced sputum and gastric aspirates tested for Mycobacterium tuberculosis by PCR and culture, respectively. Lung aspirates and pleural fluid were tested by multiplex PCR and cultured.

Statistical analysis

Cases and controls without HIV infection and with NP/OP test results were included in analyses. Odds ratios and 95% CIs were calculated using logistic regression adjusted for site and age in months. Cases with hMPV detected in NP/OP (‘hMPV-positive’), RSV-positive and cases negative for hMPV and RSV (‘hMPV-negative/RSV-negative’).

Aetiologic probability of hMPV as the cause of the pneumonia was estimated using the PERCH Integrated Analysis (PIA) adjusted for age and site, described elsewhere [11,16,17]. The PIA estimates the probability for each case; the mean across cases estimates the proportion of all cases attributed to hMPV. Briefly, PIA is a Bayesian nested partially latent class analysis that integrates laboratory evidence from multiple sources from both cases and controls to estimate both individual and population-level aetiology probabilities. Pathogens detected in invasive specimens and M. tuberculosis results from induced sputum were considered 100% specific and attributed 100% aetiology. PIA is a single-cause model; when evidence for multiple pathogens exists, aetiologic probability is divided among them. Positive predictive value was defined as the median (or mean) aetiologic probability among hMPV-positive cases.

Latent class analysis (LCA) was used to identify constellations of clinical characteristics among hMPV-positive and RSV-positive cases. We evaluated 3- to 6-class LCA models of cough, fever, CXR consolidation, C-reactive protein (CRP) ≥40 mg/L, leucocytosis, and wheeze. Sensitivity analyses restricted to CXR-positive cases, cases with high aetiologic probability and controls with RTI were conducted.

Two-sided p < 0.05 was considered statistically significant. Analyses were performed using Stata version 15.1 (StataCorp LLC, College Station, TX), and R Statistical Software 4.3.1 (The R Development Core Team, Vienna, Austria). PIA was performed using Bayesian inference software JAGS 4.2.0 (http://mcmc-jags.sourceforge.net/) and the publicly available R package Bayesian Analysis Kit for Etiology Research (website: https://github.com/zhenkewu/baker).

Ethical considerations

The study protocol was approved by the institutional review board or ethical review committee overseeing each site and at the Johns Hopkins Bloomberg School of Public Health. Written informed consent was obtained from parents or legal guardians of participants.

Results

We analysed 3887 of 4232 (91.9%) cases and 4976 of 5325 (93.4%) controls who were not infected with HIV and had hMPV results. HMPV was detected in NP/OP of 267 (6.9%) cases and 115 (2.3%) controls (adjusted OR [aOR], 3.0; 95% CI, 2.42–3.80; p < 0.0001; Fig. 1 and Table 1) [18]. hMPV positivity was higher among CXR-positive cases (8.5% vs. 5.5% CXR-negative; aOR, 1.62; p 0.001) and among controls with RTI (3.8% vs. 1.8% in controls without RTI; aOR, 2.81; p < 0.0001). Although cases aged 6–11 months (8.8%) and 12–23 months (7.4%) had the highest proportion of hMPV-positive cases (vs. 6.1% in younger and 5.2% in older age groups, p=0.03; Table S1), most (65.2%) hMPV-positive cases were <1 year of age and 16.5% were aged 1–2 months. HMPV was detected in one of 37 lung aspirate specimens, which was also positive for H. influenzae (non-type b) and Moraxella catarrhalis, in a 6-month-old child.

NP/OP hMPV positivity ranged from 3.6% in Thailand to 8.9% in Zambia for cases and 1.2% in Mali to 3.3% in South Africa for controls (Table 1 and S1). HMPV seasonal and annual patterns and co-circulation with RSV also differed within and across sites (Fig. 2). Detection of other viruses was negatively associated with hMPV positivity (cases: aOR, 0.18; 95% CI, 0.14–0.23; controls: aOR, 0.47; 95% CI, 0.32–0.69), particularly for RSV (cases: aOR, 0.11; 95% CI, 0.06–0.20) (Table 1). Conversely, bacteria were detected in NP/OP more frequently among hMPV-positive than hMPV-negative cases (aOR, 1.77; p 0.03) and controls (aOR, 1.93; p 0.16).Results for CXR-positive cases were similar (Table S2).

PIA analyses estimated that 6.0% (range, 2.1–7.6% across sites) of all pneumonia cases (6.4% among severe, 5.4% among very severe) and 7.5% (range, 2.5–11.6%) of CXR-positive cases were caused by hMPV (Fig. S1), which decreased in older age groups (Fig. S1B). Among all hMPV-positive cases, 39.0% (n = 104) had high (≥80%) probability that hMPV was the cause of the pneumonia and 70.0% (n = 187) had ≥50% probability (Fig. 3). The positive predictive value (median probability among hMPV-positive cases) of hMPV as the sole cause was 74.5% (mean, 65.6%).

Among all cases, 27.5% of hMPV-positive cases were very severe, similar to RSV-positive cases (26.7%) but lower than hMPV-negative/RSV-negative cases (34.7%, aOR, 0.70; p 0.02; Table 2). Results were similar when restricted to high (>=80%) probability hMPV-positive and RSV-positives cases (Table S3); however, among CXR-positive cases, the proportion very severe was similar between hMPV-positive (30.5%) and hMPV-negative/RSV-negative cases (31.1%, Table S4). Ten hMPV-positive cases died (Table S5). Case fatality among hMPV-positive cases (3.9%) was similar to that of RSV-positive cases (2.4%; p 0.58) but lower than hMPV-negative/RSV-negative cases (9.6%, aOR, 0.36; p 0.003; Table 2).

Compared with RSV-positive cases, fewer hMPV-positive cases had wheeze (29.8% vs. 38.6%) and rhinorrhoea (41.6% vs. 47.1%), and more had vomiting (4.3% vs. 1.6%), consolidation on CXR (26.3% vs. 20.4%) and CRP ≥40 mg/L (31.8% vs. 17.4%; all p ≤ 0.05, Table 2). Compared with hMPV-negative/RSV-negative cases, more hMPV-positive cases had cough, fever, chest wall retraction, hypoxemia, abnormal CXR (both consolidation and other infiltrates), and CRP ≥40 mg/L (all p < 0.05, Table 2). Among hMPV-positive cases, characteristics were generally similar regardless of aetiologic probability (Table S6). Latent class analyses assessing cough, fever, CXR consolidation, CRP ≥40 mg/L, leucocytosis, and wheeze and other stratified evaluations showed hMPV-positive cases exhibited no predominant constellations of clinical features (Tables S7A and S8).

Among controls, RTI (39.1% vs. 23.4%, p < 0.0001) and diarrhoea (4.4% vs. 1.9%, p 0.03) was more common among hMPV-positive than hMPV-negative (Table S9), and hMPV prevalence was similar across age groups (range, 2.0–2.7%; p 0.76; Table S1).

Discussion

This study characterized children ages 28 days to <5 years hospitalized with hMPV-associated severe pneumonia in seven African and Asian countries before the SARS-CoV-2 pandemic. Six percent of cases were estimated to be caused by hMPV in our single-cause aetiologic probability model and 70% of hMPV-positive cases had hMPV attributed as the most likely cause. Although less frequently detected than RSV, hMPV-positive cases had comparable severity and mortality with RSV-positive cases. Consolidation on CXR, leucocytosis, and high CRP were common among hMPV-positive cases, but, as observed previously [1], no single constellation of clinical findings at admission characterized them. The role hMPV plays in both upper and lower respiratory infections at our high pneumonia burden sites was supported by finding significantly greater hMPV positivity amongst cases than controls and amongst controls with RTI vs. those without, in addition to finding hMPV in a lung aspirate specimen.

An estimated 96% of in-hospital hMPV-associated mortality in children <6 months of age occurs in high child mortality settings [8]. Only a few previous studies assessed the role of hMPV in pneumonia in high-burden African and Asian countries. Sites in the GABRIEL study (Cambodia, China, Haiti, India, Madagascar, Mali, Mongolia, and Paraguay) that conducted surveillance for 1–3 years found similar prevalences among hospitalized pneumonia cases with consolidation on CXR (8.6% vs. 8.5% in PERCH CXR-positive) and among controls who were restricted to children without RTI (1.1% vs. 1.8% in PERCH), estimating the population attributable fraction to be 7.8% [19]. The South African Drakenstein study, a 12-month longitudinal nested case-control study, observed 10% positivity among predominantly non-severe pneumonia cases; when restricted to severe cases as in PERCH, positivity (5%) was similar to PERCH South African cases (6.6%) [20]. Although this study found higher positivity in controls than in PERCH South African controls (11% vs. 3.3%), which was also higher than positivity in their cases resulting in no increased risk with case status, viral load among hMPV-positives was higher in Drakenstein cases than controls, as was similarly observed in a previous PERCH analysis of viral load [21]. However, another South African study, a pneumococcal conjugate vaccine trial, found that 11.1% of children hospitalized with clinical pneumonia or bronchiolitis in the placebo group were hMPV-positive [22]. Some variability in hMPV prevalence between studies may be expected due to annual and geographic variability, as was seen in PERCH, but the high positivity in Drakenstein asymptomatic controls was unusual.

As with all pneumonia cases, the absolute number of hMPV-positive cases was largest for younger children and decreased with age. Although cases aged 6–11 months had the highest proportion hMPV-positive, the proportion among children <6 months was restricted by the higher burden of RSV infection in that age group relative to other ages. Children aged 1–2 months represented 16.5% of hMPV-positive cases, and 4 of 10 hMPV-associated deaths were in children <6 months of age, data that could inform discussions on the role of maternal immunization. HMPV vaccines are currently under development, including combination vaccines with RSV and parainfluenza virus type 3 [6,23], as are neutralizing monoclonal antibodies for hMPV similar to those for RSV [1,7].

The negative association between detection of hMPV and other viruses, especially RSV, has been reported elsewhere [24]. Previous studies suggested different seasonality and responses to relative humidity [25,26], but three PERCH sites had hMPV and RSV co-circulation (South Africa, Kenya, and Bangladesh). In this context, immune responses such as interferon production may interfere with subsequent secondary infection [27]. Epidemiological surveillance of respiratory virus infection to understand dynamics between hMPV, RSV, SARS-CoV-2, and other viruses will continue to be important.

The diversity of clinical constellations among hMPV-positive cases may imply diverse aetiology among hMPV-associated illnesses, with some cases having hMPV as the sole aetiology, whereas others may be mixed infection with bacteria and still others may be due to another pathogen altogether because hMPV was detected in asymptomatic controls. Clinical characteristics traditionally considered consistent with bacterial pneumonia, including consolidation on CXR, leucocytosis, and high CRP, were common among many hMPV-positive cases (although finding all three was rare, 5.5%). Along with association with bacterial co-carriage and evidence from other studies [28–30], these findings support that some hMPV-positive cases are likely hMPV-bacterial co-infections that may increase risk of progression to severe disease.

Our study has several limitations. Importantly, hMPV detection does not confirm aetiology because hMPV was detected among asymptomatic community controls. However, analyses accounted for specificity, sensitivity, and other pathogens, and most hMPV-positive cases had ≥75% probability of hMPV being the aetiologic agent. Poor sensitivity and specificity of bacterial microbiologic data limited ability to identify children with bacterial disease, likely underestimating bacterial-viral co-infection. Clinical characteristics were assessed at admission, likely underestimating very severe and CXR-positive cases whose disease progressed during hospitalization. Additionally, the study added physicians and provided oxygen, CXRs and microbiological testing that likely reduced mortality to all aetiologies compared with non-study conditions, but relative mortality between pathogens was likely unaffected.

Conclusions

HMPV-associated severe pneumonia among children aged <5 years in high-burden African and Asian settings was predominantly in young infants but occurred in all ages, and likely included some cases with bacterial co-infection. HMPV-positive case fatality was low, similar to that of RSV. HMPV-positive cases were characterized by a range of clinical constellations and were indistinguishable from RSV-positive cases. Moderately high NP/OP hMPV PCR test positive predictive value implies testing can distinguish most hMPV cases for evaluating disease burden and interventions.

Supplementary MaterialAcknowledgements

We thank the study participants and their families and recognize the efforts of the following groups during the study development, conduct, and analysis phases: Pneumonia Methods Working Group, Pneumonia Etiology Research for Child Health (PERCH) Expert Group, PERCH contributors and the PERCH Chest Radiograph Reading Panel. We also acknowledge the substantial contributions of all members of the PERCH Study Group: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland: Katherine L. O’Brien (PI), Orin S. Levine (Initial PI), Maria Deloria Knoll (co-PI), Daniel R. Feikin (joint affiliation with Centers for Disease Control and Prevention, Atlanta, Georgia), Andrea N. DeLuca, Amanda J. Driscoll, Nicholas Fancourt, Wei Fu, Meredith Haddix, Laura L. Hammitt, Melissa M. Higdon, E. Wangeci Kagucia, Ruth A. Karron, Mengying Li, Daniel E. Park, Christine Prosperi, Qiyuan Shi, Zhenke Wu, and Scott L. Zeger; The Emmes Corporation, Rockville, Maryland: Nora L. Watson; Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom: Jane Crawley; University of Otago, Christchurch, New Zealand: David R. Murdoch; ICDDR, b, Dhaka and Matlab, Bangladesh: W. Abdullah Brooks (site PI), Hubert P. Endtz, Khalequ Zaman, Doli Goswami, Lokman Hossain, Yasmin Jahan, and Mohammod Jobayer Chisti; Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine: Stephen R. C. Howie (site PI), Bernard E. Ebruke, Martin Antonio, Jessica McLellan, Eunice Machuka, Arifin Shamsul, Syed M.A. Zaman, and Grant Mackenzie; KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya: J. Anthony G. Scott (site PI and PERCH co-PI, joint affiliation with London School of Hygiene and Tropical Medicine, London, United Kingdom), Juliet O. Awori, Susan C. Morpeth, Alice Kamau, Sidi Kazungu, and Micah Silaba Ominde; Department of Pediatrics and Department of Medicine, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland and Centre pour le Développement des Vaccins (CVD-Mali), Bamako, Mali: Karen L. Kotloff (site PI), Milagritos D. Tapia, Samba O. Sow (site co-PI), Mamadou Sylla, Boubou Tamboura, Uma Onwuchekwa, Nana Kourouma, Aliou Toure, Seydou Sissoko; Medical Research Council: Respiratory and Meningeal Pathogens Research Unit and Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa: Shabir A. Madhi (site PI), David P. Moore, Peter V. Adrian, Vicky L. Baillie, Locadiah Kuwanda, Azwifarwi Mudau, Michelle J. Groome, Nasreen Mahomed, and Eric A.F. Simões; Thailand Ministry of Public Health—U.S. CDC Collaboration, Nonthaburi, Thailand: Henry C. Baggett (site PI), Somsak Thamthitiwat, Susan A. Maloney (former site PI), Charatdao Bunthi, Julia Rhodes, Pongpun Sawatwong, and Pasakorn Akarasewi (site co-PI, Ministry of Public Health); Department of Global Health and Development, Boston University School of Public Health, Boston, Massachusetts and University Teaching Hospital, Lusaka, Zambia: Donald M. Thea (site PI), Lawrence Mwananyanda (site co-PI), James Chipeta (site co-PI), Phil Seidenberg (site co-PI), James Mwansa, Somwe wa Somwe, and Geoffrey Kwenda; Canterbury Health Laboratories, Christchurch, New Zealand: Trevor P. Anderson, Joanne Mitchell, Shalika Jayawardena, and Rose Watt.

Financial report

The conduct of the Pneumonia Etiology Research for Child Health study was supported by a grant from the Bill & Melinda Gates Foundation to the International Vaccine Access Center, Department of International Health, Johns Hopkins Bloomberg School of Public Health (grant 48968). Icosavax provided funding for this analysis. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Potential conflict of interest

The authors declare that they have no conflicts of interest.

Disclaimer

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention.

Data availability

The Pneumonia Etiology Research for Child Health dataset is publicly available at the ClinEpiDB website (University of Pennsylvania, Philadelphia, USA; https://clinepidb.org).

Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.cmi.2024.10.023.

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Case and control enrolment and eligibility for analysis and hMPV positivity by site and age. CXR, chest X-ray; hMPV, human metapneumovirus; PERCH, Pneumonia Etiology Research for Child Health. aHIV-infection was determined using either positive HIV PCR at any age, or positive HIV serology for those >18 months of age. HIV antibody testing was performed for cases from all sites except Bangladesh and for controls from Kenya, Mali, and Zambia. bRespiratory tract illness defined as having any of the following: (a) cough, (b) rhinorrhoea, or (c) fever or sore throat and one or more of following: the ear discharge, wheeze, or difficulty breathing.

Distribution of hMPV-positive, RSV-positive, and hMPV/RSV-negative cases across the enrolment period, by site. The proportion for the blue bars is determined using the denominator of all hMPV + cases, and for orange bars the denominator is all RSV + cases. The 12 cases positive for both hMPV and RSV (eight South Africa, two Kenya, two Bangladesh) are shown twice, included in both the hMPV + case distribution and the RSV + case distribution. Thailand is not shown due to few (n = 8) hMPV + cases. hMPV, human metapneumovirus; RSV, respiratory syncytial virus.

Cumulative probability that pneumonia aetiology was hMPV, estimated using the PERCH Integrated Analysis (PIA) among all NP/OP hMPV-positive cases. These are all cases that tested positive for hMPV in NP/OP, including the 12 that were positive for both hMPV and RSV. The PIA used all available data (e.g. blood cultures, NP/OP testing for other pathogens, etc.) and accounted for measurement error (sensitivity and specificity for each test/pathogen) to inform aetiology. The PIA assumed that a single pathogen was the cause of the pneumonia. Pathogens detected in normally sterile specimens (e.g. blood tested by culture, lung aspirates tested by PCR or culture and pleural fluid tested by PCR or culture) are assumed to be the cause and ignore data from other specimens (e.g. NP/OP, blood PCR, and gastric aspirate tested for Myco-bacterium tuberculosis (Mtb)). Low aetiology probability for a particular pathogen can mean either that that pathogen is not likely the cause, or that it is a co-cause with one or more other pathogen(s) because this single-cause model splits the probability in mixed-cause pneumonia between the pathogens (e.g. pneumonia confirmed to be both H. influenzae and hMPV will be attributed at 50% to H. influenzae and 50% to hMPV). A case with a bacterial pathogen detected in blood by culture and hMPV detected in NP/OP will have 0% hMPV probability of aetiology in this single-cause model. Most cases that tested negative for hMPV in NP/OP have low (<10%) but non-zero aetiologic probability (not shown). hMPV, human metapneumovirus; NP/OP, nasopharyngeal/oropharyngeal swab specimen; PERCH, Pneumonia Etiology Research for Child Health; RSV, respiratory syncytial virus.

Characteristics associated with hMPV detection in NP/OP among severe pneumonia cases and community controls

Characteristics, n (%)All cases
Community controls
hMPV A/B positive (n = 267)hMPV A/B negative (n = 3620)Adjusted OR (95% CI)apahMPV A/B positive (n = 115)hMPV A/B negative (n = 4861)Adjusted OR (95% CI)apa
Demographic
 Site0.310.08
  Kenya46 (17.2)582 (16.1)Reference22 (19.1)833 (17.1)Reference
  Gambia40 (15.0)569 (15.7)0.88 (0.57–1.37)13 (11.3)611 (12.6)0.81 (0.40–1.61)
  Mali41 (15.4)609 (16.8)0.84 (0.54–1.30)9 (7.8)715 (14.7)0.48 (0.22–1.05)
  Zambia41 (15.4)419 (11.6)1.21 (0.78–1.89)10 (8.7)519 (10.7)0.74 (0.34–1.58)
  South Africa52 (19.5)742 (20.5)0.87 (0.57–1.32)27 (23.5)796 (16.4)1.29 (0.73–2.29)
  Thailand8 (3.0)213 (5.9)0.48 (0.22–1.04)10 (8.7)640 (13.1)0.59 (0.28–1.25)
  Bangladesh39 (14.6)486 (13.4)1.02 (0.65–1.58)24 (20.9)747 (15.4)1.22 (0.68–2.19)
 Age group0.030.25
  28 d–2 mo44 (16.5)760 (21.0)Reference4 (3.5)421 (8.7)Reference
  3–5 mo52 (19.5)724 (20.0)1.28 (0.84–1.96)31 (26.9)1096 (22.5)2.89 (1.01–8.32)
  6–11 mo78 (29.2)806 (22.3)1.85 (1.17–2.93)24 (20.9)1158 (23.8)2.28 (0.76–6.83)
  12–23 mo65 (24.3)818 (22.6)1.70 (0.86–3.38)33 (28.7)1199 (24.7)3.39 (1.03–11.14)
  24–59 mo28 (10.5)512 (14.1)1.48 (0.40–5.55)23 (20.0)987 (20.3)3.46 (0.62–19.41)
  Female118 (44.2)1522 (42.0)1.09 (0.85–1.40)0.4960 (52.2)2410 (49.6)1.10 (0.76–1.59)0.62
Pneumonia risk factors
 Underweightb84 (31.5)1280 (35.4)0.83 (0.63–1.09)0.1714 (12.2)707 (14.5)0.78 (0.44–1.38)0.39
 Day care attendance37 (14.0)606 (16.9)0.85 (0.53–1.36)0.5016 (14.0)886 (18.3)1.13 (0.55–2.32)0.74
 Smoker in household82 (31.1)1229 (34.1)0.93 (0.69–1.24)0.6136 (31.3)1873 (38.7)0.70 (0.46–1.06)0.09
 Never breastfed21 (7.9)340 (9.4)0.88 (0.53–1.45)0.6113 (11.3)328 (6.8)1.44 (0.71–2.90)0.31
 Premature birthc33 (12.7)382 (10.8)1.27 (0.85–1.88)0.2410 (8.9)497 (10.4)0.67 (0.34–1.34)0.26
 Low birth weightd56 (21.4)718 (20.0)1.07 (0.78–1.45)0.6917 (14.8)587 (12.1)1.21 (0.71–2.04)0.48
 Prematurec or low birth weightd66 (25.2)853 (23.7)1.07 (0.80– 1.44)0.6522 (19.1)874 (18.0)0.96 (0.59–1.55)0.87
 HIV-exposed, uninfectede33 (36.3)381 (34.2)1.07 (0.85 – 1.34)0.5610 (27.8)364 (28.2)0.99 (0.68–1.43)0.96
 Prior antibiotics131 (49.1)1599 (44.2)0.95 (0.76–1.20)0.682 (1.7)81 (1.7)0.88 (0.46–1.66)0.69
 DTP vaccine (≥1 dose)225 (84.3)2861 (79.0)1.69 (1.13–2.52)0.01105 (91.3)4435 (91.2)1.18 (0.53–2.62)0.68
 PCV vaccine (≥1 dose)142 (53.2)1854 (51.2)1.23 (0.84–1.81)0.2956 (48.7)2442 (50.2)0.69 (0.36–1.32)0.27
Microbiologic findings
 Microbiologically confirmed infection in sterile specimen hMPV (in lung aspirates)f1 (0.4)0 (0.0)N/AN/AN/AN/AN/AN/A
 Any viruses (in lung aspirates, other than hMPV)g3 (1.1)0 (0.0)N/AN/AN/AN/AN/AN/A
 Non contaminant bacteria
  Blood culture positivity7 (2.7)110 (3.1)0.85 (0.39–1.86)0.69N/AN/AN/AN/A
  Any invasive specimen positivityh9 (3.4)121 (3.3)1.01 (0.50–2.02)0.98N/AN/AN/AN/A
   S. pneumoniaeh2 (0.8)42 (1.2)0.67 (0.16–2.78)0.58N/AN/AN/AN/A
   H. influenzaeh2 (0.8)19 (0.5)1.41 (0.32–6.10)0.65N/AN/AN/AN/A
S. pneumoniae PCR positive in whole blood
 Any positivity14 (5.2)234 (6.5)0.82 (0.47–1.43)0.498 (7.0)245 (5.0)1.31 (0.62–2.76)0.48
 Positivity >2.2 log10 copies/mL12 (4.5)160 (4.4)1.05 (0.57–1.92)0.884 (3.5)139 (2.9)1.18 (0.43–3.29)0.75
Detection in NP/OP
 Any organism positive (other than hMPV)258 (96.6)3496 (96.6)1.01 (0.51 –2.02)0.98111 (96.5)4624 (95.1)1.31 (0.47–3.60)0.61
  Restricted to high density for S. pneumoniae and H. influenzaei182 (68.2)3084 (85.2)0.37 (0.28–0.48)<0.000167 (58.3)3349 (68.9)0.59 (0.40–0.87)0.008
Viral detection in NP/OP
 Any NP viral positive (other than hMPV)93 (34.8)2687 (74.2)0.18 (0.14–0.23)<0.000140 (34.8)2538 (52.2)0.47 (0.32–0.69)<0.0001
 Respiratory syncytial virus12 (4.5)1024 (28.3)0.11 (0.06–0.20)<0.00012 (1.7)159 (3.3)0.54 (0.13–2.19)0.39
 Adenovirus18 (6.7)387 (10.7)0.63 (0.38–1.02)0.069 (7.8)606 (12.5)0.60 (0.30–1.19)0.14
 Human bocavirus24 (9.0)489 (13.5)0.64 (0.42–0.99)0.04514 (12.2)643 (13.2)0.92 (0.52–1.63)0.79
 Human rhinovirus27 (10.1)874 (24.2)0.34 (0.23–0.52)<0.000119 (16.5)1017 (20.9)0.72 (0.43–1.18)0.19
 Parainfluenza virus11 (4.1)429 (11.9)0.32 (0.17–0.58)<0.00015 (4.4)290 (6.0)0.69 (0.28–1.70)0.42
 Human coronavirus10 (3.8)280 (7.7)0.47 (0.24–0.89)0.029 (7.8)492 (10.1)0.73 (0.37–1.45)0.37
 Influenza virus8 (3.0)171 (4.7)0.62 (0.30–1.28)0.191 (0.9)113 (2.3)0.35 (0.05–2.50)0.29
Bacterial detection in NP/OP
 Any bacteria positive250 (93.6)3225 (89.1)1.77 (1.07–2.93)0.03110 (95.7)4453 (91.6)1.93 (0.77–4.79)0.16
  Restricted to high density for S. pneumoniae and H. influenzaei138 (51.7)1708 (47.2)1.22 (0.94–1.57)0.1446 (40.0)1879 (38.7)1.04 (0.70–1.53)0.86
 S. pneumoniae220 (82.4)2738 (75.6)1.49 (1.07–2.08)0.02100 (87.0)3976 (81.8)1.47 (0.84–2.57)0.18
  S. pneumoniae >6.9 log10 copies/mL36 (13.5)456 (12.6)1.10 (0.76–1.60)0.605 (4.4)374 (7.7)0.54 (0.22–1.34)0.18
 H. influenzae166 (62.2)1922 (53.1)1.48 (1.14–1.92)0.00365 (56.5)2500 (51.4)1.24 (0.84–1.83)0.28
  H. influenzae >5.9 log10 copies/mL87 (32.6)965 (26.7)1.38 (1.05–1.82)0.0219 (16.5)1058 (21.8)0.70 (0.42–1.16)0.16
 S. aureus48 (18.0)577 (15.9)1.16 (0.83–1.61)0.4020 (17.4)656 (13.5)1.28 (0.78–2.12)0.33
 B. pertussis1 (0.4)31 (0.9)0.42 (0.06–3.12)0.400 (0.0)14 (0.3)N/A
 C. pneumoniae1 (0.4)34 (0.9)0.40 (0.05–2.91)0.363 (2.6)63 (1.3)1.89 (0.58–6.17)0.29
 M. pneumoniae4 (1.5)40 (1.1)1.57 (0.55–4.47)0.396 (5.2)46 (1.0)6.23 (2.55–15.20)<0.0001
 Salmonella species3 (1.1)25 (0.7)1.61 (0.48–5.42)0.440 (0.0)25 (0.5)N/A
Fungi detection in NP/OP
 P. jirovecii16 (6.0)293 (8.1)0.69 (0.40–1.16)0.165 (4.4)376 (7.7)0.54 (0.22–1.35)0.19
  P. jirovecii >4 log10 copies/mL9 (3.4)130 (3.6)0.89 (0.44–1.78)0.731 (0.9)105 (2.2)0.39 (0.05–2.87)0.36

hMPV, human metapneumovirus; NP/OP, nasopharyngeal/oropharyngeal swab specimen; PCV, pneumococcal conjugate vaccine; DTP, Diphtheria-Tetanus-Pertussis; N/A, Not Applicable.

Adjusted for age in months and study site.

Underweight defined as weight for age less than −2 standard deviations of the median age-sex specific WHO reference [18].

Premature birth defined as gestational age <37 weeks.

Birth weight <2.5 kg.

HIV-exposed but uninfected defined as having had a negative HIV PCR test but either HIV seropositive for those <12 months ofage or seronegative with maternal history of HIV infection. For HIV seronegative infants <7 months ofage, perinatal exposure was defined as positive maternal serology. Positive maternal status based on self-report was accepted, except for seronegative children <7 months of age where documented positive maternal status was required. Analyses were limited to Zambia and South Africa, where were high HIV prevalence sites.

One case had hMPV detected in the lung aspirate (aged 6 months) with two other bacteria co-detected, Haemophilus influenzae and Moraxella catarrhalis. Human cytomegalovirus, H. influenzae and hMPV were detected in NP/OP specimen but not Moraxella catarrhalis. Blood culture was negative.

One case (aged 9 months) had adenovirus detected and other two cases (aged 4 and 7 months) had human cytomegalovirus detected in the lung aspirates.

Detected by blood culture, by PCR or culture of lung aspirate, or by PCR, culture, or pneumococcal antigen detection (BinaxNOW) of pleural fluid.

Restricted to high density for S. pneumoniae (>6.9 log10 copies/mL) and H. influenzae (>5.9 log10 copies/mL).

Comparison of clinical and laboratory findings by hMPV and RSV status in NP/OP swabs among all cases

Characteristics, n (%)hMPV-positivea [A] (n = 255)RSV-positivea [B] (n = 1024)Negative for hMPV and RSV [C] (n = 2596)A vs. B Adjusted OR (95% CI)bpbA vs. C Adjusted OR (95% CI)bpb
Clinical
 Tachypneac216 (84.7)863 (84.3)2090 (80.5)0.92 (0.61 – 1.38)0.681.38 (0.95–2.00)0.09
 Rhinorrhoea106 (41.6)482 (47.1)1112 (42.8)0.69 (0.51–0.95)0.021.01 (0.76–1.34)0.95
 Cough188 (73.7)777 (75.9)1730 (66.6)0.90 (0.64–1.26)0.541.51 (1.11 –2.06)0.008
 Feverd100 (39.2)297 (29.0)777 (29.9)1.29 (0.94–1.77)0.111.60 (1.20–2.13)0.001
 Diarrhoea30 (11.8)137 (13.4)405 (15.6)0.89 (0.57–1.37)0.590.70 (0.46–1.04)0.08
 Wheeze76 (29.8)395 (38.6)845 (32.6)0.62 (0.42–0.91)0.020.86 (0.60–1.23)0.42
 Stridor4 (1.6)8 (0.8)84 (3.2)1.77 (0.50–6.22)0.380.51 (0.18–1.41)0.19
 Nasal flaring148 (58.0)613 (59.9)1494 (57.6)0.98 (0.70–1.36)0.891.08 (0.80–1.46)0.62
 Grunting48 (18.8)178 (17.4)458 (17.6)1.05 (0.68–1.62)0.831.09 (0.73–1.62)0.68
 Chest wall retraction245 (96.1)1002 (97.9)2310 (89.0)0.59 (0.26–1.31)0.192.88 (1.48–5.60)0.002
 Tachycardiae128 (50.2)525 (51.3)1304 (50.2)0.94 (0.70–1.25)0.660.98 (0.75–1.28)0.88
 Very severe pneumonia70 (27.5)273 (26.7)902 (34.7)1.01 (0.73–1.42)0.930.70 (0.52–0.95)0.02
  Vomiting11 (4.3)16 (1.6)89 (3.4)2.52 (1.12–5.70)0.031.40 (0.72–2.72)0.32
  Inability to feed19 (7.5)72 (7.0)209 (8.1)1.11 (0.64–1.94)0.710.88 (0.54–1.46)0.63
  Lethargy24 (9.4)51 (5.0)325 (12.5)1.64 (0.96–2.80)0.070.73 (0.47–1.14)0.17
  Multiple convulsions12 (4.7)21 (2.1)211 (8.1)1.74 (0.80–3.76)0.160.62 (0.33–1.14)0.13
  Nodding38 (14.9)204 (19.9)397 (15.3)0.77 (0.52–1.16)0.210.98 (0.67–1.42)0.90
  Cyanosis5 (2.0)10 (1.0)64 (2.5)2.53 (0.82–7.82)0.110.80 (0.32–2.04)0.64
 Hypoxemiaf101 (39.6)380 (37.1)900 (34.7)1.28 (0.91 – 1.81)0.161.40 (1.03–1.89)0.03
 Supplemental oxygen110 (43.1)426 (41.6)1064 (41.0)1.33 (0.92–1.94)0.131.26 (0.90–1.76)0.19
Radiographic findingsg
 Abnormalh141 (55.3)500 (48.8)1078 (41.5)1.29 (0.97–1.71)0.081.76 (1.36–2.28)<0.0001
 Consolidation67 (26.3)209 (20.4)538 (20.7)1.41 (1.01 – 1.97)0.041.38 (1.02–1.86)0.04
 Other infiltrates74 (29.0)291 (28.4)540 (20.8)1.01 (0.74–1.38)0.941.58 (1.18–2.12)0.002
Laboratory findings
 Leucocytosisi90 (35.3)285 (27.8)1206 (46.5)1.27 (0.93–1.73)0.130.66 (0.50–0.87)0.003
 Leukopenia6 (2.4)30 (2.9)63 (2.4)0.79 (0.31–2.01)0.621.00 (0.42–2.36)1.00
CRP (mg/mL)
 <562 (24.3)281 (27.4)629 (24.2)Reference0.02Reference0.22
 5–<1024 (9.4)112 (10.9)286 (11.0)0.98 (0.58–1.67)0.90 (0.55–1.48)
 10–<2029 (11.4)121 (11.8)319 (12.3)1.01 (0.61 – 1.67)1.00 (0.63–1.60)
 20–<4030 (11.8)135 (13.2)351 (13.5)0.98 (0.59–1.61)0.96 (0.60–1.52)
 40–<6019 (7.5)61 (6.0)168 (6.5)1.38 (0.76–2.51)1.27 (0.73–2.19)
 ≥6062 (24.3)117 (11.4)468 (18.0)2.01 (1.29–3.13)1.49 (1.01–2.20)
 CRP ≥40 mg/mL81 (31.8)178 (17.4)636 (24.5)1.80 (1.29–2.52)0.0011.47 (1.09–1.98)0.01
 Prior antibiotics123 (48.2)458 (44.7)1141 (44.0)1.07 (0.82–1.38)0.630.97 (0.76–1.23)0.77
Microbiologic findings in NP/OP
 Any organism positive (other than hMPV and RSV)247 (96.9)957 (93.5)2509 (96.7)2.06 (0.97–4.40)0.061.08 (0.52–2.27)0.84
 Any viral positive (other than hMPV and RSV)81 (31.8)362 (35.4)1663 (64.1)0.81 (0.60–1.10)0.180.26 (0.19–0.34)<0.0001
 Any bacteria positivej133 (52.2)502 (49.0)1206 (46.5)1.29 (0.97–1.73)0.081.24 (0.95–1.62)0.11
 S. pneumoniae >6.9 log10 copies/mL36 (14.1)139 (13.6)317 (12.2)1.12 (0.74–1.70)0.591.18 (0.81–1.73)0.39
 H. influenzae >5.9 log10 copies/mL84 (32.9)275 (26.9)690 (26.6)1.47 (1.07–2.01)0.021.36 (1.03–1.82)0.03
Microbiologically confirmed infection in sterile specimen
 Any pathogen10 (3.9)10 (1.0)124 (4.8)3.65 (1.46–9.13)0.0060.80 (0.41–1.55)0.51
 Any bacteria9 (3.5)10 (1.0)111 (4.3)3.18 (1.24–8.16)0.020.80 (0.40–1.60)0.52
Outcomes
 Hospital stay >3 dk167 (65.5)572 (55.9)1441 (55.5)1.76 (1.28–2.41)0.0011.65 (1.24–2.20)0.001
 Hospital duration (median, IQR)4.0 (3.0–7.0)4.0 (3.0–6.0)4.0 (3.0–7.0)1.05 (1.02–1.08)0.0011.00 (0.98–1.02)0.65
 Mortality within 30 d of admission10 (3.9)l25 (2.4)248 (9.6)1.25 (0.57–2.71)0.580.36 (0.19–0.71)0.003

CRP, C-reactive protein; CXR, chest X-ray; hMPV, human metapneumovirus; IQR, interquartile range; NP/OP, nasopharyngeal/oropharyngeal swab specimen; RSV, respiratory syncytial virus.

Excludes 12 cases that were positive for both hMPV and RSV.

Adjusted for study sites and age in months.

Tachypnea defined as respiratory rate ≥60 breaths/min if aged <2 months, respiratory rate ≥50 breaths/min if aged 2–12 months, respiration rate ≥40 breaths/min if aged >12 months.

Fever defined as measured temperature ≥38°C or reported history of fever.

Tachycardia defined as heart rate >160 beats per minute (bpm) if aged <11 months, heart rate >150 bpm if aged 12–35 months, heart rate >140 bpm if aged 36–59 months.

Children were considered to have hypoxemia if: (a) a room air pulse-oximetry reading indicated oxygen saturation <90% at the two sites at elevation (Zambia and South Africa) or <92% at all other sites, or (b) supplemental oxygen used if a room air oxygen saturation reading was not available.

Excluding missing or uninterpretable CXRs.

Defined as findings of consolidation or other infiltrates on chest radiographs.

Leucocytosis defined as white blood cell count >15 000 cells/μL if age <12 months, or >13 000 cells/μL if age >12 months.

Restricting to high density for S. pneumoniae (>6.9 log10 copies/mL) and H. influenzae (>5.9 log10 copies/mL).

Excluding cases with inpatient mortality.

See Table S10 for characteristics of the 10 hMPV cases that died.