Elsevier

Journal of Infection

Volume 71, Issue 4, October 2015, Pages 458-469
Journal of Infection

Nasopharyngeal bacterial burden and antibiotics: Influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis

https://doi.org/10.1016/j.jinf.2015.06.010Get rights and content

Highlights

  • Eighty one percent of infants hospitalized with RSV bronchiolitis were colonized with potentially pathogenic bacteria.

  • Antibiotics were commonly used and associated with longer oxygen need and lobar consolidation in RSV-infected infants.

  • Overall and Gram-negative (GNB) NP bacterial colonization was more common in RSV-infected infants vs. healthy controls.

  • RSV-infected infants colonized with GNB had increased mucosal and blood neutrophil numbers, plasma IL-6 and IL-8 and duration of oxygen.

Summary

Objectives

Animal studies suggest that RSV increases nasopharyngeal (NP) bacterial colonization facilitating bacterial infections. We investigated the influence of antibiotic treatment and colonization with potentially pathogenic bacteria on inflammatory markers and disease severity in RSV-infected in infants.

Methods

Healthy young infants hospitalized with RSV bronchiolitis (n = 136) and age-matched healthy controls (n = 23) were enrolled and NP samples cultured for potentially pathogenic bacteria including: Gram-positive bacteria (GPB): Staphylococcus aureus, Streptococcus pneumoniae, β-hemolytic Streptococcus; and Gram-negative bacteria (GNB): Moraxella catarrhalis and Haemophilus influenzae. Clinical parameters and plasma IL-8, IL-6 and TNF-α concentrations were compared according to the bacterial class and antibiotic treatment.

Results

Antibiotic treatment decreased by 10-fold NP bacterial recovery. Eighty-one percent of RSV infants who did not receive antibiotics before sample collection were colonized with pathogenic bacteria. Overall, GNB were identified in 21% of patients versus 4% of controls who were mostly colonized with GPB. Additionally, in RSV patients NP white blood cell counts (p = 0.026), and blood neutrophils (p = 0.02) were higher in those colonized with potentially pathogenic bacteria versus respiratory flora. RSV patients colonized with GNB had higher plasma IL-8 (p = 0.01) and IL-6 (p < 0.01) concentrations than controls, and required longer duration of oxygen (p = 0.049).

Conclusions

Infants with RSV bronchiolitis colonized with potentially pathogenic bacteria had increased numbers of mucosal and systemic inflammatory cells. Specifically, colonization with GNB was associated with higher concentrations of proinflammatory cytokines and a trend towards increased disease severity.

Introduction

Respiratory syncytial virus (RSV) lower respiratory tract infections (LRTI) represent the leading cause of hospitalization in infants worldwide.1, 2 Epidemiologic studies have identified children at high risk for severe RSV disease and mortality.3, 4, 5, 6 Nevertheless, the majority of infants hospitalized with RSV LRTI are previously healthy with no known risk factors.7, 8 Of those, up to 15% require pediatric intensive care unit (PICU) treatment.9

A broad variety of bacteria colonize the children's nasopharynx, including commensal bacteria and potential pathogens such us Streptococcus pneumoniae, Staphylococcus aureus, non-typable Haemophilus influenzae and Moraxella catarrhalis.10, 11, 12 These potentially pathogenic bacteria usually colonize the nasopharynx without causing symptoms, however when the balance between the host and the pathogen is disrupted clinical disease may occur. Studies in vitro and in animal models suggest that respiratory viral infections, and specifically RSV, increase nasopharyngeal (NP) bacterial colonization promoting bacterial infections.11, 13, 14 The information in infants is limited. Epidemiologic studies have shown a temporal association between RSV infections and invasive pneumococcal disease.15, 16, 17, 18, 19, 20 In addition, studies mostly performed in older children with viral-induced wheezing or pneumonia suggest that colonization with pathogenic bacteria increases disease severity.15, 21, 22, 23 The potential role of NP colonization with PPB in modifying the severity of RSV LRTI remains to be defined. Although, antibiotics are not routinely recommended for the treatment of bronchiolitis, they are commonly used, likely reflecting physician concerns of an undetected bacterial infection in young infants.24 Whether antibiotic treatment impacts NP bacterial colonization, and whether infants with RSV LRTI receiving antibiotics represent a different subset of infants with enhanced disease severity has not been well characterized. The objectives of this study were: 1) to determine the frequency and type of NP colonization with potentially pathogenic bacteria in healthy infants hospitalized with RSV LRTI, and 2) to assess the impact of bacterial colonization on inflammatory cells in both the upper respiratory tract and blood; on plasma inflammatory cytokines; and on clinical disease severity after adjusting for antibiotic use.

Section snippets

Study design

This was a prospective, observational cohort study conducted in otherwise healthy infants hospitalized with a first episode of RSV bronchiolitis and a group of healthy age-matched controls during the 2010-11 RSV season. Patients were excluded if they were premature (gestational age < 35 weeks), had chronic medical conditions, were diagnosed with other respiratory viral infections (i.e. parainfluenza virus, human metapneumovirus), immunodeficiency, or had received systemic steroids or any

Study subjects

From December 2010 to July 2011, 154 children with bronchiolitis and 23 healthy controls were enrolled. RSV patients were enrolled from December to April, and controls from the beginning of March to July, 70% of them while there was RSV activity. Eighteen patients were excluded from the analyses for the reasons outlined in Fig. 1. Of the 136 infants with RSV LRTI, 104 were enrolled in the ward and 32 in the PICU at 24 h (1–3 days) of hospitalization. There were 84 (62%) males; and the median

Discussion

In this study we sought to define the frequency and type of nasopharyngeal bacterial colonization in infants hospitalized with severe RSV LRTI and its potential impact on the mucosal and systemic inflammatory response and clinical disease severity. We also evaluated the impact of antibiotic therapy on both NP bacterial colonization and clinical outcomes. We found that: 1) RSV-infected infants were colonized with pathogenic bacteria more frequently and with a higher proportion of Gram-negative

Disclosure

This work was supported in part by intramural grants to AM and OR and by the 2010 Ausonia & Arbora grant by the Asociación Española de Pediatría to MCSA.

This study was approved by the Institutional Review Board (IRB) at Nationwide Children's Hospital (IRB #10-00028), classified as a Level 1 risk clinical study – no greater than minimal risk (pursuant under 45 CFR 46.404; and 21 CFR 50.51). Informed consent procedures followed in compliance with Nationwide Children's Research Responsible Conduct

Conflict of interest

The authors do not declare any financial or commercial conflict of interest.

Acknowledgments

We would like to thank the Clinical Research Department at Nationwide Children's Hospital, in particular Gail Arthur, RN and Michael Lawson RN for their efforts with patient enrollment, Cynthia Burch for her help with bacterial cultures, Sara Mertz, BS for performing RSV loads determination, Lisa Hanson, BS for her help with cytokine processing and specially our patients and their families for agreeing to participate in the study.

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    This work was presented in part at the European Society for Pediatric Infectious Diseases 30th Annual Meeting. Thessaloniki, Greece, May 8–12, 2012.

    i

    Present address: Hospital General Universitario Gregorio Marañón, Madrid, Spain.

    j

    Present address: Section of Pediatric Critical Care, Baylor College of Medicine, 6621 Fannin St, W6006/Houston, TX 77030, USA.

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