Early-life respiratory infections and asthma development

Beigelman, Avraham; Bacharier, Leonard B.

doi:10.1097/aci.0000000000000244

Cited by 74 publications

(41 citation statements)

References 48 publications

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“…38 Our findings contribute to an emerging body of evidence suggesting that viruses contribute to presumed bacterial pneumonia 39 and that bacteria seem to have an important role in the pathogenesis and severity of presumed viral bronchiolitis 9 and wheezing illness. 40 These findings show the inappropriateness of conventional single-bacteria and single-virus causation per Koch's postulates. Our findings also allude to the hypothesis that there is a universal pathway for the development of clinical LRTIs, linked to microbial dysbiosis, whereby clinical pheno types are driven more by host (eg age, anatomy, baseline mucosal inflammation, status of innate and adaptive immunity, genetic background) and environ mental characteristics rather than by single pathogen characteristics.…”

Section: (N=108) D (N=171) E (N=100) F (N=78)mentioning

confidence: 96%

Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study

Man

Houten

Mérelle

et al. 2019

The Lancet Respiratory Medicine

178

169

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Background Lower respiratory tract infections (LRTIs) are a leading cause of childhood morbidity and mortality. Potentially pathogenic organisms are present in the respiratory tract in both symptomatic and asymptomatic children, but their presence does not necessarily indicate disease. We aimed to assess the concordance between upper and lower respiratory tract microbiota during LRTIs and the use of nasopharyngeal microbiota to discriminate LRTIs from health.Methods First, we did a prospective study of children aged between 4 weeks and 5 years who were admitted to the paediatric intensive care unit (PICU) at Wilhelmina Children's Hospital (Utrecht, Netherlands) for a WHO-defined LRTI requiring mechanical ventilation. We obtained paired nasopharyngeal swabs and deep endotracheal aspirates from these participants (the so-called PICU cohort) between Sept 10, 2013, and Sept 4, 2016. We also did a matched case-control study (1:2) with the same inclusion criteria in children with LRTIs at three Dutch teaching hospitals and in age-matched, sex-matched, and time-matched healthy children recruited from the community. Nasopharyngeal samples were obtained at admission for cases and during home visits for controls. Data for child characteristics were obtained by questionnaires and from pharmacy printouts and medical charts. We used quantitative PCR and 16S rRNA-based sequencing to establish viral and bacterial microbiota profiles, respectively. We did sparse random forest classifier analyses on the bacterial data, viral data, metadata, and the combination of all three datasets to distinguish cases from controls.Findings 29 patients were enrolled in the PICU cohort. Intra-individual concordance in terms of viral microbiota profiles (96% agreement [95% CI 93-99]) and bacterial microbiota profiles (58 taxa with a median Pearson's r 0·93 [IQR 0·62-0·99]; p<0·05 for all 58 taxa) was high between nasopharyngeal and endotracheal aspirate samples, supporting the use of nasopharyngeal samples as proxy for lung microbiota during LRTIs. 154 cases and 307 matched controls were prospectively recruited to our case-control cohort. Individually, bacterial microbiota (area under the curve 0·77), viral microbiota (0·70), and child characteristics (0·80) poorly distinguished health from disease. However, a classification model based on combined bacterial and viral microbiota plus child characteristics distinguished children with LRTIs from their matched controls with a high degree of accuracy (area under the curve 0·92).Interpretation Our data suggest that the nasopharyngeal microbiota can serve as a valid proxy for lower respiratory tract microbiota in childhood LRTIs, that clinical LRTIs in children result from the interplay between microbiota and host characteristics, rather than a single microorganism, and that microbiota-based diagnostics could improve future diagnostic and treatment protocols.

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Section: (N=108) D (N=171) E (N=100) F (N=78)mentioning

confidence: 96%

Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study

Man

Houten

Mérelle

et al. 2019

The Lancet Respiratory Medicine

178

169

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“…However, the challenge to early life intranasal vaccination can be the induction of non-specific inflammation and/or the generation of tolerance to unknown or novel antigens (17). Such challenges may be a particular concern in early life, where the T-helper response is biased toward type-2 immunity, exacerbation of which may predispose individuals to eosinophilia and pulmonary disorders (18). Nevertheless, solutions to such challenges may be found in the use of precision adjuvants (19) which drive the appropriate activation of APCs and help in shaping the immune system (20,21).…”

Section: Introductionmentioning

confidence: 99%

The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

2020

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Intranasal mucosal vaccines are an attractive approach to induce protective mucosal immune responses. Activation of lung antigen presenting cells (APCs), a phenotypically and functionally heterogeneous cell population located at distinct mucosal sites, may be key to the immunogenicity of such vaccines. Understanding responsiveness of newborn lung APCs to adjuvants may the inform design of efficacious intranasal vaccines for early life, when most infections occur. Here, we characterized and phenotyped APCs from neonatal (7 days of life) and adult (6-8 weeks of age) mice. Neonatal mice demonstrated a relatively high abundance of alveolar macrophages (AMs), with lower percentages of plasmacytoid dendritic cells (pDCs), CD103 + (cDC1), and CD11b + (cDC2) DCs. Furthermore, neonatal CD103 + and CD11b + DC subsets demonstrated a significantly lower expression of maturation markers (CD40, CD80, and CD86) as compared to adult mice. Upon stimulation of lung APC subsets with a panel of pattern recognition receptor (PRR) agonists, including those engaging TLRs or STING, CD11c + enriched cells from neonatal and adult mice lungs demonstrated distinct maturation profiles. Of the agonists tested, the TLR5 ligand, flagellin, was most effective at activating neonatal lung APCs, inducing significantly higher expression of maturation markers on CD103 + (cDC1) and CD11b + (cDC2) subsets. Intranasal administration of flagellin induced a distinct migration of CD103 + and CD11b + DC subsets to the mediastinal lymph nodes (mLNs) of neonatal mice. Overall, these findings highlight age-specific differences in the maturation and responsiveness of lung APC subsets to different PRR agonists. The unique efficacy of flagellin in enhancing lung APC activity suggests that it may serve as an effective adjuvant for early life mucosal vaccines.

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“…An important and established factor for the later onset of asthma is the occurrence of respiratory viral infections, above all human rhinovirus (HRV) and respiratory syncytial virus (RSV) (11). Furthermore, respiratory viral infections play an important role in morbidity and early immune development during the first year of life in otherwise healthy infants (12)(13)(14)(15)(16). Despite recent data on the association between viral infections and changes in the microbiota in adults, data for young children are scarce (17)(18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Interactions of Respiratory Viruses and the Nasal Microbiota during the First Year of Life in Healthy Infants

Korten

Mika

Klenja

et al. 2016

mSphere

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Respiratory viral infections are very frequent in infancy and of importance in acute and chronic disease development. Infections with human rhinovirus (HRV) are, e.g., associated with the later development of asthma. We found that only symptomatic HRV infections were associated with acute changes in the nasal microbiota, mainly characterized by a loss of microbial diversity. Infants with more frequent symptomatic HRV infections had a lower bacterial diversity at the end of the first year of life. Whether the interaction between viruses and the microbiota is one pathway contributing to asthma development will be assessed in the follow-ups of these children. Independent of that, measurements of microbial diversity might represent a potential marker for risk of later lung disease or monitoring of early life interventions.

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Early-life respiratory infections and asthma development

Cited by 74 publications

References 48 publications

Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study

Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study

The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

Interactions of Respiratory Viruses and the Nasal Microbiota during the First Year of Life in Healthy Infants

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