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. 2019 Nov;144(5):1187-1197.
doi: 10.1016/j.jaci.2019.05.035. Epub 2019 Jun 13.

Distinct nasal airway bacterial microbiotas differentially relate to exacerbation in pediatric patients with asthma

Kathryn McCauley  1 , Juliana Durack  1 , Ricardo Valladares  1 , Douglas W Fadrosh  1 , Din L Lin  1 , Agustin Calatroni  2 , Petra K LeBeau  2 , Hoang T Tran  2 , Kei E Fujimura  1 , Brandon LaMere  1 , Geil Merana  1 , Kole Lynch  1 , Robyn T Cohen  3 , Jacqueline Pongracic  4 , Gurjit K Khurana Hershey  5 , Carolyn M Kercsmar  5 , Michelle Gill  6 , Andrew H Liu  7 , Haejin Kim  8 , Meyer Kattan  9 , Stephen J Teach  10 , Alkis Togias  11 , Homer A Boushey  1 , James E Gern  12 , Daniel J Jackson  13 , Susan V Lynch  14 ; National Institute of Allergy and Infectious Diseases–sponsored Inner-City Asthma Consortium
Affiliations

Distinct nasal airway bacterial microbiotas differentially relate to exacerbation in pediatric patients with asthma

Kathryn McCauley et al. J Allergy Clin Immunol. 2019 Nov.

Abstract

Background: In infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development.

Objective: We hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes.

Methods: Nasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses.

Results: Six nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species-dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species-dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species-dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested.

Conclusion: Distinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season.

Keywords: 16S rRNA; Microbiota; Moraxella species; Staphylococcus species; airway; asthma; exacerbation; rhinovirus.

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Conflict of interest statement

Disclosure of potential conflict of interest: All authors, with the exception of A. Togias, report grants from the National Institutes of Health (NIH) during the conduct of study. R. Valladares reports personal fees for employment with Siolta Therapeutics outside the submitted work. H. T. Tran reports personal fees from GlaxoSmithKline outside the submitted work. J. Pongracic reports provision of study drug for other asthma and allergy studies from GlaxoSmithKline, Boehringer Ingelheim, and Genentech/Novartis outside the submitted work. C. M. Kercsmar reports personal fees from GlaxoSmithKline for service on a DSMB and royalties from UpToDate outside the submitted work. M. Gill reports honoraria and support for travel from the American Academy of Allergy, Asthma & Immunology (AAAAI), as well as payment for lectures from the American Academy of Pediatrics outside the submitted work. A.H. Liu reports personal fees from Merck Sharp & Dohme and Phadia Thermo-Fisher and membership on a Data Monitoring Committee for GlaxoSmithKline outside the submitted work. M. Kattan reports personal feed from Novartis Pharma and Regeneron for service on advisory boards outside the submitted work. S. J. Teach reports grants from Patient-Centered Outcomes Research Institute (PCORI), EJF, and the NIH/National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work and personal fees from UpToDate outside the submitted work. H. A. Boushey serves as a compensated member of a Scientific Advisory Committee for Siolta Therapeutics. J. E. Gern reports personal fees from PREP Biopharm, Regeneron, Meissa Vaccines, MedImmune, and Ena Pharmaceuticals, as well as stock options from Meissa Vaccines outside the submitted work and has a patent “Methods of Propagating Rhinovirus C in Previously Unsusceptible Cell Lines” issued and a patent “Adapted Rhinovirus C” pending outside the submitted work. D. J. Jackson reports personal fees from Novartis, Boehringer Ingelheim, Pfizer, Commense, and Sanofi/Genzyme outside the submitted work, as well as grants from GlaxoSmithKline and the NIH/NHLBI. S.V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases (NIAID), NIH/National Institute on Drug Abuse (NIDA), NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH/Office of the Director, and the Crohn’s and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a startup developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

FIG 1.
FIG 1.
A, Study design and distribution of microbiota profiles from children in the PROSE study (10) used in the current study. ICS, Inhaled corticosteroid. B, Frequency and timing of sample collection. Blue bars depict the first postrandomization (baseline) sample collected from participants, and all subsequent longitudinal samples collected are indicated by red bars. Green, blue, and red dots indicate exacerbation, rhinovirus infection (RV), and respiratory illness events, respectively.
FIG 2.
FIG 2.
Compositionally distinct nasal airway microbiotas exist in children with asthma. A, Six compositionally distinct microbiotas are evident in the nasal airway samples of children with asthma (P = .001, bootstrapped permutational multivariate ANOVA). B, Moraxella and Staphylococcus most frequently dominate nasal samples from pediatric patients with asthma, with Streptococcus, Alloiococcus, Corynebacterium, Haemophilus and a number of additional genera dominating smaller proportions of samples.
FIG 3.
FIG 3.
Network analysis identifies 3 distinct modules of coassociated nasal airway bacterial taxa. Taxa identified as differentially enriched in taxon comparisons of exacerbation versus nonexacerbation and rhinovirus infection versus non–rhinovirus infection comparisons are indicated and color coded according to the dominant microbiota colors defined in Fig 2. Hub operational taxonomic units (OTUs; triangles) exhibit greater intermodule connectivity, whereas connector OTUs (circles) exhibit a higher frequency of intramodule connectivity. The size of the node (triangles or circles) scales with the total number of connections with other OTUs. Genus classification and OTU numbers are indicated.
FIG 4.
FIG 4.
Staphylococcus and Moraxella species–dominated nasal airway microbiotas exhibit temporal stability in children with asthma. The heat map indicates the frequency with which a specific microbiota at a given time point (y axis) remains the same or transitions to a distinct microbiota assemblage in the subsequent patient sample (time point 2; x-axis). Frequencies of these events are provided within each square and proportions are indicated by the color intensity (eg, 74% of Moraxella species–dominated microbiotas remain Moraxella species–dominated in the subsequent sample). The diagonal represents transitions that resulted in maintenance of the same microbiota assemblage over time. Data were generated from longitudinally collected sample transitions (n = 2709) from all participants (n = 413).
FIG 5.
FIG 5.
Biofilm-derived products of bacterial isolates dominating nasal airway microbiotas differentially influence epithelial responses in vitro. Comparative analysis of airway epithelial immune gene expression (relative to PBS) and lactate dehydrogenase (LDH) release (relative to LPS stimulation) after exposure to sterile biofilm supernatants of Moraxella catarrhalis (2 strains, see the Methods section in this article’s Online Repository for more information), Staphylococcus aureus, Staphylococcus epidermidis, and Corynebacterium propinquum. M catarrhalis strains consistently induce increased epithelial damage (LDH) and inflammation (IL-8 and IL-33) compared with S epidermidis, C propinquum, and Lactobacillus sakei. Statistical significance was determined by using Kruskal-Wallis (KW) tests. Results were obtained from 2 or more independent experiments using 3 biological replicates.
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