Association of endemic coronaviruses with nasopharyngeal metabolome and microbiota among infants with severe bronchiolitis: a prospective multicenter study

Fujiogi, Michimasa; Camargo, Carlos A.; Raita, Yoshihiko; Toivonen, Laura; Freishtat, Robert J.; Mansbach, Jonathan M.; Piedra, Pedro A.; Hasegawa, Kohei

doi:10.1038/s41390-020-01154-2

Cited by 4 publications

(19 citation statements)

References 22 publications

(30 reference statements)

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“…Indeed, current national guidelines for the diagnosis and management of bronchiolitis is based on this major assumption. 12 Nevertheless, concordant with the results of the present study, recent research has suggested the complexity of infant bronchiolitis, as reflected by the heterogeneity in clinical characteristics, 3,13,36,37 transcriptome, 38 microRNAome, 39 metabolome, [40][41][42][43][44] and microbiome. 21,[45][46][47][48][49][50] The proteomic approach adds to these previous reports through comprehensively profiling proteins that are the main effectors of cellular physiology.…”

Section: Discussionsupporting

confidence: 92%

Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma

Ooka

Raita

Fujiogi

et al. 2022

Allergy

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Background Bronchiolitis is the leading cause of hospitalization in U.S. infants and a major risk factor for childhood asthma. Growing evidence supports clinical heterogeneity within bronchiolitis. We aimed to identify endotypes of infant bronchiolitis by integrating clinical, virus, and serum proteome data, and examine their relationships with asthma development. Methods This is a multicenter prospective cohort study of infants hospitalized for physician‐diagnosis of bronchiolitis. We identified bronchiolitis endotypes by applying unsupervised machine learning (clustering) approaches to integrated clinical, virus (respiratory syncytial virus [RSV], rhinovirus [RV]), and serum proteome data measured at hospitalization. We then examined their longitudinal association with the risk for developing asthma by age 6 years. Results In 140 infants hospitalized with bronchiolitis, we identified three endotypes: (1) clinicalatopicvirusRVproteomeNFκB‐dysregulated, (2) clinicalnon‐atopicvirusRSV/RVproteomeTNF‐dysregulated, and (3) clinicalclassicvirusRSVproteomeNFκB/TNF‐regulated endotypes. Endotype 1 infants were characterized by high proportion of IgE sensitization and RV infection. These endotype 1 infants also had dysregulated NFκB pathways (FDR < 0.001) and significantly higher risks for developing asthma (53% vs. 22%; adjOR 4.04; 95% CI, 1.49–11.0; p = 0.006), compared with endotype 3 (clinically resembling “classic” bronchiolitis). Likewise, endotype 2 infants were characterized by low proportion of IgE sensitization and high proportion of RSV or RV infection. These endotype 2 infants had dysregulated tumor necrosis factor (TNF)‐mediated signaling pathway (FDR <0.001) and significantly higher risks for developing asthma (44% vs. 22%; adjOR 2.71; 95% CI, 1.03–7.11, p = 0.04). Conclusion In this multicenter cohort, integrated clustering of clinical, virus, and proteome data identified biologically distinct endotypes of bronchiolitis that have differential risks of asthma development.

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Section: Discussionsupporting

confidence: 92%

Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma

Ooka

Raita

Fujiogi

et al. 2022

Allergy

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“…For example, a recent analysis of three cohort studies of bronchiolitis in the USA and Finland has revealed that the phenotype characterised by a history of breathing problems, allergic predisposition and rhinovirus infection had a significantly increased risk for asthma12—which is in line with the present analysis. Additionally, previous reports using global metabolomics (ie, not lipidomics) have suggested pathobiological roles of complex lipids in the pathobiology of both acute respiratory infections17 38–42 and asthma 19 43 44. For example, concordant with the endotype B (clinical severe lipid sphingolipids-high ) observed in the current study, a metabolomic analysis of 144 infants with bronchiolitis has reported a positive association of sphingolipids in the upper airway with higher bronchiolitis severity 15.…”

Section: Discussionsupporting

confidence: 82%

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

Fujiogi

Zhu

Raita

et al. 2022

Thorax

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BackgroundBronchiolitis is the leading cause of hospitalisation of US infants and an important risk factor for childhood asthma. Recent evidence suggests that bronchiolitis is clinically heterogeneous. We sought to derive bronchiolitis endotypes by integrating clinical, virus and lipidomics data and to examine their relationship with subsequent asthma risk.MethodsThis is a multicentre prospective cohort study of infants (age <12 months) hospitalised for bronchiolitis. We identified endotypes by applying clustering approaches to clinical, virus and nasopharyngeal airway lipidomic data measured at hospitalisation. We then determined their longitudinal association with the risk for developing asthma by age 6 years by fitting a mixed-effects logistic regression model. To account for multiple comparisons of the lipidomics data, we computed the false discovery rate (FDR). To understand the underlying biological mechanism of the endotypes, we also applied pathway analyses to the lipidomics data.ResultsOf 917 infants with bronchiolitis (median age, 3 months), we identified clinically and biologically meaningful lipidomic endotypes: (A) cinicalclassiclipidmixed (n=263), (B) clinicalseverelipidsphingolipids-high (n=281), (C) clinicalmoderatelipidphospholipids-high (n=212) and (D) clinicalatopiclipidsphingolipids-low (n=161). Endotype A infants were characterised by ‘classic’ clinical presentation of bronchiolitis. Profile D infants were characterised by a higher proportion of parental asthma, IgE sensitisation and rhinovirus infection and low sphingolipids (eg, sphingomyelins, ceramides). Compared with endotype A, profile D infants had a significantly higher risk of asthma (22% vs 50%; unadjusted OR, 3.60; 95% CI 2.31 to 5.62; p<0.001). Additionally, endotype D had a significantly lower abundance of polyunsaturated fatty acids (eg, docosahexaenoic acid; FDR=0.01). The pathway analysis revealed that sphingolipid metabolism pathway was differentially expressed in endotype D (FDR=0.048).ConclusionsIn this multicentre prospective cohort study of infants with bronchiolitis, integrated clustering of clinical, virus and lipidomic data identified clinically and biologically distinct endotypes that have a significantly differential risk for developing asthma.Delete

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“…Findings are presented as described in the original publications, as data to re-calculate the associations was not available in many publications. 2017;Hasegawa et al, 2017;Kelly et al, 2017;Lu et al, 2017;Peŕez-Losada et al, 2017;Stewart et al, 2017;Dai et al, 2018;Kelly et al, 2018;Luna et al, 2018;Peŕez-Losada et al, 2018;Rosas-Salazar et al, 2018;Teo et al, 2018;Toivonen et al, 2018;Wen et al, 2018;Man et al, 2019a;Mansbach et al, 2019;Stewart et al, 2019;Toivonen et al, 2019;Mansbach et al, 2020;Zhou et al, 2020;Fujiogi et al, 2021;Raita et al, 2021;Reyman et al, 2021;Xu et al, 2021b;Xu et al, 2021a;Tan et al, 2023). Counting these studies only once, the following study designs were used: randomised placebo-controlled trial (2), prospective birth cohort study (6), prospective cohort study (17), retrospective cohort study (4), prospective case-control study (5), and cross-sectional study (17) (one study had two sub-studies with different study designs).…”

Section: Study Selectionmentioning

confidence: 99%

“…• Non-Hispanic White children more frequently Haemophilus-dominated profile than children from other ethnicities (Hasegawa et al, 2016;Hasegawa et al, 2017;Toivonen et al, 2018;Toivonen et al, 2019;Fujiogi et al, 2021) • ↑Diversity in Fijian children of Indian descent than Fijian Indigenous children (Boelsen et al, 2019) • Fijian Indigenous children ↑Moraxella, ↑Haemophilus, ↑Helococcus, ↓Staphylococcus, ↑Dolosigranulum, ↑Corynebacterium than Fijian children of Indian descent (Boelsen et al, 2019) • Association without specifying further details (McCauley et al, 2021) • No association (Shilts et al, 2016;Chonmaitree et al, 2017)…”

Section: Ethnicitymentioning

confidence: 99%

“…• PCV: ↑diversity (Biesbroek et al, 2014c;Henares et al, 2021) • Hib/PCV10: ↑richness (Salgado et al, 2020) • PCV7/PCV13: ↓S. pneumoniae (Boelsen et al, 2019;Kelly et al, 2022) • PCV7: ↑Haemophilus (Biesbroek et al, 2014c), ↑Staphylococcus (Biesbroek et al, 2014c), ↑Veilonella (Biesbroek et al, 2014c), ↑Prevotella (Biesbroek et al, 2014c), ↑Bacteroidetes (Biesbroek et al, 2014c), ↑Leptorichia (Biesbroek et al, 2014c), ↑Streptococcus (Biesbroek et al, 2014c) ↓Streptococcaceae (Hilty et al, 2012), ↓Corynebacteriacea (Hilty et al, 2012) • PCV7 (Hilty et al, 2012;Biesbroek et al, 2014b;Henares et al, 2021) or Hib/PCV10 (Feazel et al, 2015): no association with diversity or composition Antibiotics • ↑Diversity (Chonmaitree et al, 2017) • ↑Bifidobacterium (Chonmaitree et al, 2017), ↑Brachybacterium (Salter et al, 2017), ↑Dolosigranulum (Salter et al, 2017), ↑Firmicutes incertae sedis (Salter et al, 2017), ↑Haemophilus (Teo et al, 2015;Hasegawa et al, 2016;Thapa et al, 2020;Hasegawa et al, 2017;Luna et al, 2018;Toivonen et al, 2018;Toivonen et al, 2019;Fujiogi et al, 2021;Raita et al, 2021;Kelly et al, 2022), ↑Moraxella (Teo et al, 2015;Kelly et al, 2022), ↑Pasteurellaceae (Hilty et al, 2012), ↑Streptococcus (Teo et al, 2015;Salter et al, 2017;Kelly et al, 2022), • ↓Dolosigranulum…”

Section: Vaccinationmentioning

confidence: 99%

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Exploring the microbial landscape of the nasopharynx in children: a systematic review of studies using next generation sequencing

Zimmermann

2023

Front. Microbiomes

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IntroductionThe nasopharynx harbours a diverse and dynamic microbial community, which plays an important role in maintaining the health and homeostasis of the respiratory tract, as well as in immune system development. Understanding factors that influence the composition of the nasopharyngeal microbiome in children and its association with diseases is of particular importance, as children are at a heightened risk for respiratory infections and other adverse health outcomes.ObjectivesThis review systematically summarises studies which investigated the nasopharyngeal microbiome in children, including its dynamics, stability over time, and the influence of intrinsic and extrinsic factors on its composition.MethodsMEDLINE was searched using the OVID interface. Original studies which investigated the nasopharyngeal microbiome using next generation sequencing in children were summarised.ResultsThe search identified 736 studies, of which 77 were included. The studies show that the nasopharyngeal microbiome in children is dynamic and influenced by many external factors. A high abundance of Haemophilus, Moraxella, and Streptococcus and a low abundance of Corynebacterium and Dolosigranlum are associated with adverse health outcomes such as respiratory tract infections, wheezing and asthma exacerbations. Factors which have been identified as risk factors for these adverse health outcomes, such as being born by Caesarean section, not being breast-fed, having siblings, day-care attendance, and antibiotic exposure have been shown to be associated with the aforementioned features in the nasopharyngeal microbiome.ConclusionThe association between specific nasopharyngeal microbial profiles and adverse health outcomes highlights the potential of the nasopharyngeal microbiome as a marker for identifying children at risk for disease and even more importantly, as an avenue for targeted interventions and preventive strategies.

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Association of endemic coronaviruses with nasopharyngeal metabolome and microbiota among infants with severe bronchiolitis: a prospective multicenter study

Cited by 4 publications

References 22 publications

Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma

Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study

Exploring the microbial landscape of the nasopharynx in children: a systematic review of studies using next generation sequencing

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