Infant respiratory syncytial virus prophylaxis and nasopharyngeal microbiota until 6 years of life: a subanalysis of the MAKI randomised controlled trial

Wing Ho Man, Nienke M Scheltema, Melanie Clerc, Marlies A van Houten, Elizabeth E Nibbelke, Niek B Achten, Kayleigh Arp, Elisabeth A M Sanders, Louis J Bont, Debby Bogaert

Research output: Contribution to journalArticlepeer-review

Abstract

Background Respiratory syncytial virus (RSV) infection during infancy is suggested to cause long-term wheeze. In turn, wheeze has been associated with bacterial dysbiosis of the respiratory tract. We investigated the effects of RSV prophylaxis by palivizumab during infancy in otherwise healthy preterms on respiratory microbiota composition at one year and six years of age in participants of the randomized, placebo-controlled MAKI trial. Methods 429 infants born between 32-35 weeks of gestation randomly received palivizumab or placebo during the RSV season of their first year of life. The trial is registered in the ISRCTN registry, number ISRCTN73641710. In total, 395/429 (92%) children were followed for clinical symptoms until six years of age. For this sub-analysis, the aim was to assess the impact of palivizumab during infancy on the respiratory microbiota composition of the available samples at age one and six years. We obtained nasopharyngeal swabs at age 12 months from 170/429 (40%) children and analyzed 145/170 of these by 16S-rRNA sequencing. At age six, 349 nasopharyngeal swabs were obtained of which 349/395 (88%) were analyzed by 16S-rRNA sequencing. At age six, also lung function (including reversible airway obstruction) was determined. Findings The overall microbiota composition was significantly different (p=0·0185, R2 1.2%) between the palivizumab and placebo group at 12 months of life, but not significant at 6 years of life (p=0·0575, R2 0.7%). At 12 months of life, a significant lower abundance of the Staphylococcus-dominated cluster, and increased abundance of biomarker species such as Klebsiella and a diverse set of oral taxa including Streptococcus spp. was observed in children who had received palivizumab early in life, whereas at age six years, a significant increased abundance of Haemophilus spp. and lower abundance of Moraxella and Neisseriaceae spp. was observed in the prophylaxis group. Absence of PCR-confirmed RSV infection in the first year of life was also significantly associated with a higher abundance of Haemophilus spp. at age 6 years and a significantly lower abundance of Moraxella and Neisseriaceae. Reversible airway obstruction (RAO) at age six was also positively associated with Haemophilus abundance and negatively associated with the abundance of health-associated taxa such as Moraxella, Corynebacterium, Dolosigranulum and Staphylococcus, even after correction for RSV immunoprophylaxis (all: p < 0.05). Additionally, RAO was associated with a significant increase in Streptococcus pneumoniae abundance. Interpretation Palivizumab in infancy in otherwise healthy preterm infants is associated with persistent effects on the abundance of specific potentially pathogenic microbial taxa in the respiratory tract. Several of the palivizumab-associated biomarker species were associated with reversible airway obstruction at age six. Together, our results warrant further studies to shed light on the long-term ecological effects and health consequences of palivizumab in infancy. Funding This study was funded by MedImmune (grant ESR-14-10006)
Original languageEnglish
Pages (from-to)1022-1031
JournalThe Lancet Respiratory Medicine
Volume8
Issue number10
Early online date20 Mar 2020
DOIs
Publication statusPublished - 1 Oct 2020

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