Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study

doi:10.3390/v13071249

. 2021 Jun 27;13(7):1249.

doi: 10.3390/v13071249.

Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study

Vicky L Baillie^{1

2}, David P Moore^{1

2

3}, Azwifarwi Mathunjwa^{1

2}, Henry C Baggett^{4

5}, Abdullah Brooks^{6

7}, Daniel R Feikin^{8

9}, Laura L Hammitt^{8

10}, Stephen R C Howie^{11

12}, Maria Deloria Knoll⁸, Karen L Kotloff¹³, Orin S Levine⁸, Katherine L O'Brien⁸, Anthony G Scott^{10

14}, Donald M Thea¹⁵, Martin Antonio^{11

16}, Juliet O Awori¹⁰, Amanda J Driscoll^{8

17}, Nicholas S S Fancourt⁸, Melissa M Higdon⁸, Ruth A Karron¹⁸, Susan C Morpeth^{10

14

19}, Justin M Mulindwa²⁰, David R Murdoch^{21

22}, Daniel E Park^{8

23}, Christine Prosperi⁸, Mohammed Ziaur Rahman⁷, Mustafizur Rahman⁷, Rasheed A Salaudeen^{11

24}, Pongpun Sawatwong⁴, Somwe Wa Somwe²⁰, Samba O Sow²⁵, Milagritos D Tapia¹³, Eric A F Simões^{1

26}, Shabir A Madhi^{1

2}

Affiliations

¹ South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa.
² Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases Unit, University of the Witwatersrand, Johannesburg 1864, South Africa.
³ Department of Paediatrics & Child Health, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg 1864, South Africa.
⁴ Division of Global Health Protection, Thailand Ministry of Public Health-U.S. Centers for Disease Control and Prevention Collaboration, Nonthaburi 11000, Thailand.
⁵ Division of Global Health Protection, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
⁶ Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁷ International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka and Matlab, Bangladesh.
⁸ Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁹ Division of Viral Diseases, National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
¹⁰ Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
¹¹ Medical Research Council Unit at the London School of Hygiene and Tropical Medicine, Basse 273, The Gambia.
¹² Department of Paediatrics: Child & Youth Health, University of Auckland, Park Rd, Auckland 1023, New Zealand.
¹³ Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21205, USA.
¹⁴ Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
¹⁵ Department of Global Health, Boston University School of Public Health, Boston, MA 02118, USA.
¹⁶ Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, Microbiology and Infection Unit, Warwick Medical School, University of Warwick, Coventry CV4 7JJ, UK.
¹⁷ Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21205, USA.
¹⁸ Department of International Health, Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
¹⁹ Microbiology Laboratory, Middlemore Hospital, Counties Manukau District Health Board, Auckland 1640, New Zealand.
²⁰ Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka 50110, Zambia.
²¹ Department of Pathology and Biomedical Sciences, University of Otago, Christchurch 8011, New Zealand.
²² Microbiology Unit, Canterbury Health Laboratories, Christchurch 8140, New Zealand.
²³ Milken Institute School of Public Health, Department of Epidemiology, George Washington University, Washington, DC 20052, USA.
²⁴ Medical Microbiology Department, Lagos University Teaching Hospital, Lagos 100254, Nigeria.
²⁵ Centre pour le Développement des Vaccins (CVD-Mali), Bamako 198, Mali.
²⁶ Department of Pediatrics, University of Colorado School of Medicine and Center for Global Health, Colorado School of Public Health, Aurora, CO 80309, USA.

PMID: 34198998
PMCID: PMC8310211
DOI: 10.3390/v13071249

Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study

Vicky L Baillie et al. Viruses. 2021.

. 2021 Jun 27;13(7):1249.

doi: 10.3390/v13071249.

Authors

Affiliations

¹ South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa.
² Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases Unit, University of the Witwatersrand, Johannesburg 1864, South Africa.
³ Department of Paediatrics & Child Health, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg 1864, South Africa.
⁴ Division of Global Health Protection, Thailand Ministry of Public Health-U.S. Centers for Disease Control and Prevention Collaboration, Nonthaburi 11000, Thailand.
⁵ Division of Global Health Protection, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
⁶ Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁷ International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka and Matlab, Bangladesh.
⁸ Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁹ Division of Viral Diseases, National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
¹⁰ Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi 80108, Kenya.
¹¹ Medical Research Council Unit at the London School of Hygiene and Tropical Medicine, Basse 273, The Gambia.
¹² Department of Paediatrics: Child & Youth Health, University of Auckland, Park Rd, Auckland 1023, New Zealand.
¹³ Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21205, USA.
¹⁴ Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
¹⁵ Department of Global Health, Boston University School of Public Health, Boston, MA 02118, USA.
¹⁶ Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, Microbiology and Infection Unit, Warwick Medical School, University of Warwick, Coventry CV4 7JJ, UK.
¹⁷ Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21205, USA.
¹⁸ Department of International Health, Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
¹⁹ Microbiology Laboratory, Middlemore Hospital, Counties Manukau District Health Board, Auckland 1640, New Zealand.
²⁰ Department of Paediatrics and Child Health, University Teaching Hospital, Lusaka 50110, Zambia.
²¹ Department of Pathology and Biomedical Sciences, University of Otago, Christchurch 8011, New Zealand.
²² Microbiology Unit, Canterbury Health Laboratories, Christchurch 8140, New Zealand.
²³ Milken Institute School of Public Health, Department of Epidemiology, George Washington University, Washington, DC 20052, USA.
²⁴ Medical Microbiology Department, Lagos University Teaching Hospital, Lagos 100254, Nigeria.
²⁵ Centre pour le Développement des Vaccins (CVD-Mali), Bamako 198, Mali.
²⁶ Department of Pediatrics, University of Colorado School of Medicine and Center for Global Health, Colorado School of Public Health, Aurora, CO 80309, USA.

PMID: 34198998
PMCID: PMC8310211
DOI: 10.3390/v13071249

Abstract

Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1-59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3-1.6). This association was driven by the children aged 12-59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8-2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4-2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability (>75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing.

Keywords: PERCH; childhood; epidemiology; pneumonia; rhinovirus.

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Conflict of interest statement

S.A.M. has received honoraria for advisory board participation from Bill & Melinda Gates Foundation, Pfizer, Medimmune, and Novartis and institutional grants from GSK, Novartis, Pfizer, Minervax, and Bill & Melinda Gates Foundation and has served on speakers’ bureaus for Sanofi Pasteur and GSK. M.D.K. has received funding for consultation from Merck, Pfizer, and Novartis and grant funding from Merck. C.P. has received grant funding from Merck. K.L.O. has received grant funding from GlaxoSmithKline and Pfizer and participates on technical advisory boards for Merck, Sanofi-Pasteur, PATH, Affinivax, and ClearPath. K.L.K. has received grant funding from Merck Sharp & Dohme. W.A.B. reported funding from Sanofi, PATH, and Bill & Melinda Gates Foundation (BMGF) and contributed to contemporaneous studies from Serum Institute of India, LTD, Roche, and Sanofi. All other authors: No reported conflicts. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

**Figure 1**
The number of cases and controls enrolled per country and overall.

**Figure 2**
Individual Case Etiological Probability of rhinovirus-Associated Pneumonia Based the PERCH Integrated Analysis, Stratified by Age Group (A) and Study Site (B). The figures display the distribution of the individual case probability that rhinovirus was the cause of pneumonia based on the PERCH integrated etiology analysis [26]. Cases with an etiologic probability <5% for rhinovirus were excluded to scale the y axis and better visualize the cases with higher probability (>75%) of disease associated with rhinovirus. Cases testing positive for rhinovirus by nasopharyngeal/oropharyngeal RT-PCR are displayed in pink. Cases who tested negative by RT-PCR for rhinovirus are displayed in blue. Cases with missing nasopharyngeal/oropharyngeal PCR data are shown in gray.

**Figure 3**
Prevalence of rhinovirus among Cases and Controls by PERCH overall (A), Age Group (B), and Site of enrolment (C–E). The * denotes groups where rhinovirus prevalence differs significantly (adjusted for site of enrolment and age where necessary) between cases and controls. Mono-infections refers to when rhinovirus was the only respiratory virus detected in the nasopharyngeal/oropharyngeal samples, and mixed infections refers to any viral co-infection with rhinovirus and RSV (A,B), HMPV, AdV, InFV (A–C), PIV type 1–4, or HCoV (OC43, NL63, 229E, and HKU1). By age group, RV detection was associated with control status in infants 1- to < 6-months of age, and RV detection was associated with case status in children >12–59 months of age. By site, RV detection was associated with case status in Bangladesh and Kenya but only in children >12 months of age.

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References

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1. Esposito S., Daleno C., Prunotto G., Scala A., Tagliabue C., Borzani I., Fossali E., Pelucchi C., Principi N. Impact of viral infections in children with community-acquired pneumonia: Results of a study of 17 respiratory viruses. Influenza Other Respir. Viruses. 2012;7:18–26. doi: 10.1111/j.1750-2659.2012.00340.x. - DOI - PMC - PubMed
1. Piotrowska Z., Vázquez M., Shapiro E.D., Weibel C., Ferguson D., Landry M.L., Kahn J.S. Rhinoviruses are a major cause of wheezing and hospitalization in children less than 2 years of age. Pediatr. Infect. Dis. J. 2009;28:25–29. doi: 10.1097/INF.0b013e3181861da0. - DOI - PMC - PubMed

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[1] Price W.H. The isolation of a new virus associated with respiratory clinical disease in humans. Proc. Natl. Acad. Sci. USA. 1956;42:892–896. doi: 10.1073/pnas.42.12.892. - DOI - PMC - PubMed

[2] Price W.H. The isolation of a new virus associated with respiratory clinical disease in humans. Proc. Natl. Acad. Sci. USA. 1956;42:892–896. doi: 10.1073/pnas.42.12.892. - DOI - PMC - PubMed

[3] Papadopoulos N.G. Do rhinoviruses cause pneumonia in children? Paediatr. Respir. Rev. 2004;5:S191–S195. doi: 10.1016/S1526-0542(04)90036-X. - DOI - PubMed

[4] Papadopoulos N.G. Do rhinoviruses cause pneumonia in children? Paediatr. Respir. Rev. 2004;5:S191–S195. doi: 10.1016/S1526-0542(04)90036-X. - DOI - PubMed

[5] Louie J.K., Roy-Burman A., Guardia-LaBar L., Boston E.J., Kiang D., Padilla T., Yagi S., Messenger S., Petru A.M., Glaser C.A., et al. Rhinovirus associated with severe lower respiratory tract infections in children. Pediatr. Infect. Dis. J. 2009;28:337–339. doi: 10.1097/INF.0b013e31818ffc1b. - DOI - PubMed

[6] Louie J.K., Roy-Burman A., Guardia-LaBar L., Boston E.J., Kiang D., Padilla T., Yagi S., Messenger S., Petru A.M., Glaser C.A., et al. Rhinovirus associated with severe lower respiratory tract infections in children. Pediatr. Infect. Dis. J. 2009;28:337–339. doi: 10.1097/INF.0b013e31818ffc1b. - DOI - PubMed

[7] Esposito S., Daleno C., Prunotto G., Scala A., Tagliabue C., Borzani I., Fossali E., Pelucchi C., Principi N. Impact of viral infections in children with community-acquired pneumonia: Results of a study of 17 respiratory viruses. Influenza Other Respir. Viruses. 2012;7:18–26. doi: 10.1111/j.1750-2659.2012.00340.x. - DOI - PMC - PubMed

[8] Esposito S., Daleno C., Prunotto G., Scala A., Tagliabue C., Borzani I., Fossali E., Pelucchi C., Principi N. Impact of viral infections in children with community-acquired pneumonia: Results of a study of 17 respiratory viruses. Influenza Other Respir. Viruses. 2012;7:18–26. doi: 10.1111/j.1750-2659.2012.00340.x. - DOI - PMC - PubMed

[9] Piotrowska Z., Vázquez M., Shapiro E.D., Weibel C., Ferguson D., Landry M.L., Kahn J.S. Rhinoviruses are a major cause of wheezing and hospitalization in children less than 2 years of age. Pediatr. Infect. Dis. J. 2009;28:25–29. doi: 10.1097/INF.0b013e3181861da0. - DOI - PMC - PubMed

[10] Piotrowska Z., Vázquez M., Shapiro E.D., Weibel C., Ferguson D., Landry M.L., Kahn J.S. Rhinoviruses are a major cause of wheezing and hospitalization in children less than 2 years of age. Pediatr. Infect. Dis. J. 2009;28:25–29. doi: 10.1097/INF.0b013e3181861da0. - DOI - PMC - PubMed

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Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study

Affiliations

Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study

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