Streptococcus pneumoniae colonization of the nasopharynx is associated with increased severity during respiratory syncytial virus infection in young children

Jaelle C Brealey, Keith J Chappell, Sally Galbraith, Emmanuelle Fantino, Jane Gaydon, Sarah Tozer, Paul R Young, Patrick G Holt, Peter D Sly, Jaelle C Brealey, Keith J Chappell, Sally Galbraith, Emmanuelle Fantino, Jane Gaydon, Sarah Tozer, Paul R Young, Patrick G Holt, Peter D Sly

Abstract

Background and objective: Respiratory syncytial virus (RSV) is the most significant cause of acute respiratory infection (ARI) in early life. RSV and other respiratory viruses are known to stimulate substantial outgrowth of potentially pathogenic bacteria in the upper airways of young children. However, the clinical significance of interactions between viruses and bacteria is currently unclear. The present study aimed to clarify the effect of viral and bacterial co-detections on disease severity during paediatric ARI.

Methods: Nasopharyngeal aspirates from children under 2 years of age presenting with ARI to the emergency department were screened by quantitative PCR for 17 respiratory viruses and the bacterial pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Associations between pathogen detection and clinical measures of disease severity were investigated.

Results: RSV was the most common virus detected, present in 29 of 58 samples from children with ARI (50%). Detection of S. pneumoniae was significantly more frequent during RSV infections compared to other respiratory viruses (adjusted effect size: 1.8, P: 0.03), and co-detection of both pathogens was associated with higher clinical disease severity scores (adjusted effect size: 1.2, P: 0.03).

Conclusion: Co-detection of RSV and S. pneumoniae in the nasopharynx was associated with more severe ARI, suggesting that S. pneumoniae colonization plays a pathogenic role in young children.

Keywords: co-infection; human respiratory syncytial virus; pneumococcus; respiratory tract infection; severity of illness index.

© 2017 Asian Pacific Society of Respirology.

Figures

Figure 1
Figure 1
Associations between pathogen detections in multivariable logistic regression models with adjustment for confounding factors and detection of Streptococcus pneumoniae (A), Haemophilus influenzae (B), Moraxella catarrhalis (C), multiple viruses per sample (D), RSV (E) and hRV (F). Effect size (penalised maximum likelihoods) and 95% CI are shown. Black points represent likelihoods significant at P < 0.05, dark grey points P < 0.1 and light grey points P > 0.1. ED, emergency department; Hi, H. influenzae;hRV, human rhinovirus; Mc, M. catarrhalis;PyV, polyomaviruses; RSV, respiratory syncytial virus; Sp, S. pneumoniae.
Figure 2
Figure 2
Interactions between viruses and bacteria in the upper respiratory tract during paediatric viral acute respiratory infection. Network built from output of partial correlation matrix analysis. Associations with P < 0.01 (solid line) and P < 0.05 (dashed line) are shown. Line thickness indicates magnitude of partial correlation. Positive (red lines) and negative (blue lines) correlations are shown. Age was the only confounding factor found to have a significant effect, indicated by arrow heads on edge lines. Hi, Haemophilus influenzae; hRV, human rhinovirus; Mc, Moraxella catarrhalis; RSV, respiratory syncytial virus; Sp, Streptococcus pneumoniae.
Figure 3
Figure 3
Clinical disease severity scores stratified by RSV and Sp co‐detection. Box and whisker plot with median and interquartile range is shown. + indicates positive detection of RSV or Sp, − indicates negative detection. RSV, respiratory syncytial virus; Sp, Streptococcus pneumoniae.

References

    1. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, O'Brien KL, Roca A, Wright PF, Bruce N et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta‐analysis. Lancet 2010; 375: 1545–55.
    1. Nair H, Simoes EA, Rudan I, Gessner BD, Azziz‐Baumgartner E, Zhang JS, Feikin DR, Mackenzie GA, Moisi JC, Roca A et al; Severe Acute Lower Respiratory Infections Working Group . Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet 2013; 381: 1380–90.
    1. Chappell KJ, Brealey JC, Mackay IM, Bletchly C, Hugenholtz P, Sloots T, Sly PD, Young PR. Respiratory syncytial virus infection is associated with increased bacterial load in the upper respiratory tract in young children. J. Med. Microbiol. Diagn. 2013; S1: 005.
    1. O'Grady KF, Grimwood K, Sloots TP, Whiley DM, Acworth JP, Phillips N, Goyal V, Chang AB. Prevalence, codetection and seasonal distribution of upper airway viruses and bacteria in children with acute respiratory illnesses with cough as a symptom. Clin. Microbiol. Infect. 2016; 22: 527–34.
    1. Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, Holt BJ, Hales BJ, Walker ML, Hollams E et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 2015; 17: 704–15.
    1. de Steenhuijsen Piters WA, Heinonen S, Hasrat R, Bunsow E, Smith B, Suarez‐Arrabal MC, Chaussabel D, Cohen DM, Sanders EA, Ramilo O et al. Nasopharyngeal microbiota, host transcriptome and disease severity in children with respiratory syncytial virus infection. Am. J. Respir. Crit. Care Med. 2016; 194: 1104–15.
    1. Suarez‐Arrabal MC, Mella C, Lopez SM, Brown NV, Hall M, Hammond S, Shiels W, Groner J, Marcon M, Ramilo O et al. Nasopharyngeal bacterial burden and antibiotics: influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis. J. Infect. 2015; 71: 458–69.
    1. Thorburn K, Harigopal S, Reddy V, Taylor N, van Saene HKF. High incidence of pulmonary bacterial co‐infection in children with severe respiratory syncytial virus (RSV) bronchiolitis. Thorax 2006; 61: 611–5.
    1. Kneyber MC, Blusse van Oud‐Alblas H, van Vliet M, Uiterwaal CS, Kimpen JL, van Vught AJ. Concurrent bacterial infection and prolonged mechanical ventilation in infants with respiratory syncytial virus lower respiratory tract disease. Intensive Care Med. 2005; 31: 680–5.
    1. Resch B, Gusenleitner W, Mueller WD. Risk of concurrent bacterial infection in preterm infants hospitalized due to respiratory syncytial virus infection. Acta Paediatr. 2007; 96: 495–8.
    1. Vissers M, Ahout IM, van den Kieboom CH, van der Gaast de Jongh CE, Groh L, Cremers AJ, de Groot R, de Jonge MI, Ferwerda G. High pneumococcal density correlates with more mucosal inflammation and reduced respiratory syncytial virus disease severity in infants. BMC Infect. Dis. 2016; 16: 129.
    1. Vu HT, Yoshida LM, Suzuki M, Nguyen HA, Nguyen CD, Nguyen AT, Oishi K, Yamamoto T, Watanabe K, Vu TD. Association between nasopharyngeal load of Streptococcus pneumoniae, viral coinfection, and radiologically confirmed pneumonia in Vietnamese children. Pediatr. Infect. Dis. J. 2011; 30: 11–8.
    1. Wei L, Liu W, Zhang XA, Liu EM, Wo Y, Cowling BJ, Cao WC. Detection of viral and bacterial pathogens in hospitalized children with acute respiratory illnesses, Chongqing, 2009–2013. Medicine (Baltimore) 2015; 94: e742.
    1. Leung TF, Lam DS, Miu TY, Hon KL, Chau CS, Ku SW, Lee RS, Chow PY, Chiu WK, Ng DK; Hong Kong Society of Paediatric Respirology RSVCG . Epidemiology and risk factors for severe respiratory syncytial virus infections requiring pediatric intensive care admission in Hong Kong children. Infection 2014; 42: 343–50.
    1. McCullers JA. The co‐pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 2014; 12: 252–62.
    1. Brealey JC, Sly PD, Young PR, Chappell KJ. Viral bacterial co‐infection of the respiratory tract during early childhood. FEMS Microbiol. Lett. 2015; 10.1093/femsle/fnv062
    1. Avadhanula V, Wang Y, Portner A, Adderson E. Nontypeable Haemophilus influenzae and Streptococcus pneumoniae bind respiratory syncytial virus glycoprotein. J. Med. Microbiol. 2007; 56: 1133–7.
    1. Hament JM, Aerts PC, Fleer A, van Dijk H, Harmsen T, Kimpen JL, Wolfs TF. Direct binding of respiratory syncytial virus to pneumococci: a phenomenon that enhances both pneumococcal adherence to human epithelial cells and pneumococcal invasiveness in a murine model. Pediatr. Res. 2005; 58: 1198–203.
    1. Smith CM, Sandrini S, Datta S, Freestone P, Shafeeq S, Radhakrishnan P, Williams G, Glenn SM, Kuipers OP, Hirst RA et al. RSV increases the virulence of Streptococcus pneumoniae by binding to PBP1a: a new paradigm in respiratory infection. Am. J. Respir. Crit. Care Med. 2014; 190: 196–207.
    1. Stark JM, Stark MA, Colasurdo GN, LeVine AM. Decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection. J. Med. Virol. 2006; 78: 829–38.
    1. Nguyen DT, Louwen R, Elberse K, van Amerongen G, Yuksel S, Luijendijk A, Osterhaus AD, Duprex WP, de Swart RL. Streptococcus pneumoniae enhances human respiratory syncytial virus infection in vitro and in vivo . PLoS One 2015; 10: e0127098.
    1. Ishizuka S, Yamaya M, Suzuki T, Takahashi H, Ida S, Sasaki T, Inoue D, Sekizawa K, Nishimura H, Sasaki H. Effects of rhinovirus infection on the adherence of Streptococcus pneumoniae to cultured human airway epithelial cells. J. Infect. Dis. 2003; 188: 1928–39.
    1. Wang JH, Kwon HJ, Jang YJ. Rhinovirus enhances various bacterial adhesions to nasal epithelial cells simultaneously. Laryngoscope 2009; 119: 1406–11.
    1. Paynter S. Humidity and respiratory virus transmission in tropical and temperate settings. Epidemiol. Infect. 2015; 143: 1110–8.
    1. Martinon‐Torres F, Rodriguez‐Nunez A, Martinon‐Sanchez JM. Heliox therapy in infants with acute bronchiolitis. Pediatrics 2002; 109: 68–73.
    1. O'Grady KA, Torzillo PJ, Rockett RJ, Whiley DM, Nissen MD, Sloots TP, Lambert SB. Successful application of a simple specimen transport method for the conduct of respiratory virus surveillance in remote Indigenous communities in Australia. Trop. Med. Int. Health 2011; 16: 766–72.
    1. Greiner O, Day PJ, Bosshard PP, Imeri F, Altwegg M, Nadal D. Quantitative detection of Streptococcus pneumoniae in nasopharyngeal secretions by real‐time PCR. J. Clin. Microbiol. 2001; 39: 3129–34.
    1. Dunne EM, Manning J, Russell FM, Robins‐Browne RM, Mulholland EK, Satzke C. Effect of pneumococcal vaccination on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Fijian children. J. Clin. Microbiol. 2012; 50: 1034–8.
    1. Wang X, Mair R, Hatcher C, Theodore MJ, Edmond K, Wu HM, Harcourt BH, Carvalho Mda G, Pimenta F, Nymadawa P et al. Detection of bacterial pathogens in Mongolia meningitis surveillance with a new real‐time PCR assay to detect Haemophilus influenzae . Int. J. Med. Microbiol. 2011; 301: 303–9.
    1. Carvalho Mda G, Tondella ML, McCaustland K, Weidlich L, McGee L, Mayer LW, Steigerwalt A, Whaley M, Facklam RR, Fields B et al. Evaluation and improvement of real‐time PCR assays targeting lytA, ply, and psaA genes for detection of pneumococcal DNA. J. Clin. Microbiol. 2007; 45: 2460–6.
    1. R Core Team . R: A Language and Environment for Statistical Computing. Vienna, R Foundation for Statistical Computing, 2013.
    1. Chongsuvivatwong V. Analysis of Epidemiological Data Using R and Epicalc. Hat Yai, Epidemiology Unit, Prince of Songkla University, 2008. [Accessed 27 Jun 2016.] Available from URL: .
    1. Heinze G, Schemper M. A solution to the problem of separation in logistic regression. Stat. Med. 2002; 21: 2409–19.
    1. Kim S. ppcor: an R package for a fast calculation to semi‐partial correlation coefficients. Commun. Stat. Appl. Methods 2015; 22: 665–74.
    1. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13: 2498–504.
    1. van den Bergh MR, Biesbroek G, Rossen JW, de Steenhuijsen Piters WA, Bosch AA, van Gils EJ, Wang X, Boonacker CW, Veenhoven RH, Bruin JP et al. Associations between pathogens in the upper respiratory tract of young children: interplay between viruses and bacteria. PLoS One 2012; 7: e47711.
    1. Duttweiler L, Nadal D, Frey B. Pulmonary and systemic bacterial co‐infections in severe RSV bronchiolitis. Arch. Dis. Child. 2004; 89: 1155–7.
    1. Lehtinen P, Jartti T, Virkki R, Vuorinen T, Leinonen M, Peltola V, Ruohola A, Ruuskanen O. Bacterial coinfections in children with viral wheezing. Eur. J. Clin. Microbiol. Infect. Dis. 2006; 25: 463–9.
    1. Kloepfer KM, Lee WM, Pappas TE, Kang TJ, Vrtis RF, Evans MD, Gangnon RE, Bochkov YA, Jackson DJ, Lemanske RF Jr et al. Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations. J. Allergy Clin. Immunol. 2014; 133: 1301–7.e3.
    1. Greer RM, McErlean P, Arden KE, Faux CE, Nitsche A, Lambert SB, Nissen MD, Sloots TP, Mackay IM. Do rhinoviruses reduce the probability of viral co‐detection during acute respiratory tract infections? J. Clin. Virol. 2009; 45: 10–5.
    1. Karppinen S, Toivonen L, Schuez‐Havupalo L, Waris M, Peltola V. Interference between respiratory syncytial virus and rhinovirus in respiratory tract infections in children. Clin. Microbiol. Infect. 2016; 22: 208.e1‐6.
    1. Martin ET, Fairchok MP, Stednick ZJ, Kuypers J, Englund JA. Epidemiology of multiple respiratory viruses in childcare attendees. J. Infect. Dis. 2013; 207: 982–9.
    1. Mansbach JM, Piedra PA, Teach SJ, Sullivan AF, Forgey T, Clark S, Espinola JA, Camargo CA, Jr. ; MARC‐30 Investigators . Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch. Pediatr. Adolesc. Med.. 2012;166:700–6.
    1. Kouni S, Karakitsos P, Chranioti A, Theodoridou M, Chrousos G, Michos A. Evaluation of viral co‐infections in hospitalized and non‐hospitalized children with respiratory infections using microarrays. Clin. Microbiol. Infect. 2013; 19: 772–7.
    1. Chiu C, Dey A, Wang H, Menzies R, Deeks S, Mahajan D, Macartney K, Brotherton J, Jardine A, Quinn H et al. Vaccine preventable diseases in Australia, 2005 to 2007. Commun. Dis. Intell. Q. Rep. 2010; 34(Supp.): S1–167.
    1. Simoes EA. Environmental and demographic risk factors for respiratory syncytial virus lower respiratory tract disease. J. Pediatr. 2003; 143: S118–26.
    1. Jacoby P, Carville KS, Hall G, Riley TV, Bowman J, Leach AJ, Lehmann D; Kalgoorlie Otitis Media Research Project Team . Crowding and other strong predictors of upper respiratory tract carriage of otitis media‐related bacteria in Australian Aboriginal and non‐Aboriginal children. Pediatr. Infect. Dis. J. 2011; 30: 480–5.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe