Comparison of risk factors for viral and nonviral asthma exacerbations
Authors: Amaziah T. Coleman, Daniel J. Jackson, Ronald E. Gangnon, Michael D. Evans, Robert F. Lemanske, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2015)

Asthma exacerbations secondary to viral illnesses are an important cause of morbidity among children with asthma, and allergy is a risk factor for virus-induced exacerbations. Although less frequent, some exacerbations of asthma occur independently of viral illnesses. The patterns and cause of asthma exacerbations have been investigated in cross-sectional studies,1Johnston S.L. Pattemore P.K. Sanderson G. Smith S. Lampe F. Josephs L. et al.Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.BMJ. 1995; 310: 1225-1229Crossref PubMed Scopus (1733) Google Scholar but longitudinal data are lacking. We sought to determine whether there are separate groups of children who have asthma exacerbations with viruses and children who have asthma exacerbations without viruses. In addition, we tested the hypothesis that there are distinct risk factors for virus-induced exacerbations and exacerbations not associated with viral infection. The Childhood Origins of Asthma (COAST) study followed 259 children prospectively from birth to age 6 years, and 217 were followed until age 11 years. Of those, 102 children met the criteria for asthma at 6, 8, and/or 11 years of age (Table I). This subset of COAST children was predominantly male (63%). Forty-nine percent had a family history of maternal asthma, and 34% had a history of paternal asthma. Forty-seven percent had aeroallergen sensitization at the age of 6 years and 52% at the age of 11 years. The majority (94%) lived in a home without smoke exposure. At year 6, 15% of children were taking a daily controller either seasonally or perennially compared with 35% of children by year 12.Table IFactors associated with asthma exacerbations between ages 6 and 11 years in the COAST cohort (n = 102)No.All exacerbationsViral exacerbationsNonviral exacerbationsMean ± SDP valueMean ± SDP valueMean ± SDP valueOverall no. of exacerbations2.1 ± 3.31.3 ± 2.40.6 ± 1.2Sex Female392.3 ± 3.9.611.4 ± 2.9.640.6 ± 1.4.91 Male632.0 ± 2.91.2 ± 2.00.6 ± 1.0Year 6 aeroallergen sensitization No351.7 ± 2.3.101.1 ± 1.8.270.4 ± 0.8.14 Yes472.9 ± 4.11.8 ± 3.10.8 ± 1.4Year 11 aeroallergen sensitization No231.3 ± 1.2.0080.8 ± 1.1.030.4 ± 0.6.11 Yes523.2 ± 4.11.9 ± 3.00.9 ± 1.5Maternal asthma No531.7 ± 2.4.171.0 ± 1.8.210.5 ± 0.9.37 Yes492.7 ± 4.01.6 ± 2.90.7 ± 1.4Paternal asthma No662.0 ± 2.9.411.2 ± 2.1.650.5 ± 1.0.17 Yes342.5 ± 4.01.5 ± 3.00.8 ± 1.5Smoke in home (year 6) No942.2 ± 3.4.491.4 ± 2.5.160.6 ± 1.2.62 Yes61.3 ± 1.50.3 ± 0.50.3 ± 0.5Dog in home (year 6) No642.1 ± 3.2.791.3 ± 2.2.800.6 ± 1.3.69 Yes362.3 ± 3.51.4 ± 2.90.7 ± 1.0Cat in home (year 6) No752.5 ± 3.6.031.5 ± 2.7.110.7 ± 1.3.10 Yes251.2 ± 1.90.8 ± 1.40.3 ± 0.7 Open table in a new tab An asthma exacerbation was defined as an illness in which a child required a step-up plan of care, use of oral corticosteroids, or both. A severe asthma exacerbation was defined by the use of oral corticosteroids. Nasal samples were collected during asthma exacerbations and analyzed for respiratory tract viruses. Respiratory tract viruses were identified by using multiplex PCR.2Lee W.M. Grindle K. Pappas T. Marshall D.J. Moser M.J. Beaty E.L. et al.High-throughput, sensitive, and accurate multiplex PCR-microsphere flow cytometry system for large-scale comprehensive detection of respiratory viruses.J Clin Microbiol. 2007; 45: 2626-2634Crossref PubMed Scopus (187) Google Scholar Allergen-specific IgE levels were measured by using ImmunoCAP (Phadia, Portage, Mich) performed at age 6 and 11 years, and positive results were defined as 0.35 kU/L or greater.3Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. et al.Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.Am J Respir Crit Care Med. 2008; 178: 667-672Crossref PubMed Scopus (1058) Google Scholar Of the 102 COAST children with asthma, 60% had at least 1 exacerbation between ages 6 and 11 years, and 38% had more than 1 exacerbation. When grouped by exacerbation cause, 40 (40%) children had no exacerbations, 23 (22%) had only viral exacerbations, 13 (13%) had only nonviral exacerbations, and 19 (19%) had a mixture of both viral and nonviral exacerbations. There were 7 (6%) children who each had 1 exacerbation but no nasal sample. Children who had only viral or only nonviral exacerbations had fewer exacerbations on average (mean, 2.4 [95% CI, 1.3-4.4] and 1.5 [95% CI, 0.6-3.4], respectively) than children who experienced both viral and nonviral exacerbations (mean, 6.9 [95% CI, 4.7-10.1]). Children with at least 2 exacerbations had the highest prevalence of allergic sensitization and total IgE levels at age 11 years (see Table E1 in this article's Online Repository at www.jacionline.org). There were a total of 217 exacerbations, of which 192 included nasal samples obtained for viral analysis. Viruses were identified in 69% of exacerbations, and rhinovirus was most commonly identified (34% of exacerbations, see Fig E1 in this article's Online Repository at www.jacionline.org). The total number of exacerbations was positively associated with total IgE levels at age 6 years (P = .009; incidence rate ratio (IRR) with respect to a 1-unit increase in log10 IgE, 1.74 [95% CI, 1.15-2.64]) and 11 years (P = .02; IRR, 1.64 [95% CI, 1.10-2.46]), and with aeroallergen sensitization at age 11 years (P = .008; IRR, 2.44 [95% CI, 1.27-4.70]; Fig 1). Having a cat in the home at year 6 was associated with a reduced number of exacerbations (IRR, 0.47 [95% CI, 0.24-0.91]; P = .03). Risk factors for viral and nonviral exacerbations were similar. For example, viral exacerbations were positively associated with total IgE levels at age 6 years (P = .04; IRR, 1.76 [95% CI, 1.02-3.02]) and aeroallergen sensitization at age 11 years (P = .03; IRR, 2.49 [95% CI, 1.08 5.73]), and nonviral exacerbations were positively associated with total IgE levels at age 6 years (P = .04; IRR, 1.77 [95% CI, 1.02-3.08]) and aeroallergen sensitization at age 11 years (trend: P = .11; IRR, 2.22 [95% CI, 0.83-5.94]; Fig 1). Finally, we compared the severity of viral versus nonviral exacerbations. Twenty-three percent (14/60) of nonviral exacerbations and 17% (23/132) of viral exacerbations were severe (P = .34). Of the 37 severe exacerbations, 14 (38%) were nonviral, 14 (38%) were associated with rhinovirus infection, and 9 (24%) were associated with other viruses. The greatest number of severe exacerbations, regardless of cause, occurred during the fall (October and November) and spring (March, see Figs E2 and E3 in this article's Online Repository at www.jacionline.org). This study provides new data about patterns of asthma exacerbation over a 6-year span in a cohort of suburban children. Notably, children who experienced multiple episodes had at least 1 viral exacerbation. Risk factors for having viral or nonviral asthma exacerbations were similar and consisted of indicators of atopy (ie, total IgE and aeroallergen sensitivity). Previous studies have established that atopy is a risk factor for virus-induced wheezing and exacerbations of asthma. For example, wheezing illnesses in children older than 2 years are most common in children who have rhinovirus infections together with allergic sensitization, nasal eosinophilia, or increased nasal eosinophil cationic protein levels.4Rakes G.P. Arruda E. Ingram J.M. Hoover G.E. Zambrano J.C. Hayden F.G. et al.Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. IgE and eosinophil analyses.Am J Respir Crit Care Med. 1999; 159: 785-790Crossref PubMed Scopus (397) Google Scholar Additional studies have identified increased expression of the FcεRI receptor on monocytes and dendritic cells during acute asthma exacerbations.5Holt P.G. Strickland D.H. Sly P.D. Virus infection and allergy in the development of asthma: what is the connection?.Curr Opin Allergy Clin Immunol. 2012; 12: 151-157Crossref PubMed Scopus (62) Google Scholar One potential mechanism by which IgE could affect viral exacerbations relates to effects of the FcεRI on interferon responses. In vitro experiments demonstrated that increased FcεRI expression on plasmacytoid dendritic cells and IgE cross-linking strongly inhibited rhinovirus-induced interferon production in cells from children with allergic asthma.6Durrani S.R. Montville D.J. Pratt A.S. Sahu S. DeVries M.K. Rajamanickam V. et al.Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children.J Allergy Clin Immunol. 2012; 130: 489-495Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Strengths of the current study include the longitudinal analysis of exacerbations over a 6-year period. Much of the current literature evaluates the cause of asthma exacerbations from a cross-sectional perspective and not prospectively over multiple years. The study is limited by the relatively small numbers of children in each group, particularly the groups with only viral and only nonviral exacerbations, and the fact that most of the children with asthma in this cohort study have relatively mild disease. In conclusion, our findings demonstrate that atopy is an important risk factor for both viral and nonviral exacerbations. These data are consistent with a clinical study of omalizumab, in which blocking IgE-mediated inflammation prevented both viral and nonviral exacerbations in children with moderate-to-severe asthma.7Busse W.W. Morgan W.J. Gergen P.J. Mitchell H.E. Gern J.E. Liu A.H. et al.Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children.N Engl J Med. 2011; 364: 1005-1015Crossref PubMed Scopus (746) Google Scholar One implication of these findings is that treatment aimed at reducing levels of IgE or perhaps other effectors of allergic inflammation could represent a common strategy to reduce morbidity caused by viral and nonviral asthma exacerbations. Fig E2Virology of exacerbations by month. AdV, Adenovirus; CoV, coronavirus; EV, enterovirus; MPV, metapneumovirus; Mult, multiple viruses; PIV, parainfluenza virus; RSV, respiratory syncytial virus; RV, rhinovirus.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Severity of exacerbations by month.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Characteristics of children with 0, 1, or 2 or more exacerbationsNo. of exacerbationsP value01≥20 vs ≥21 vs ≥2No. of children402339Sex17 F, 23 M7 F, 16 M15 F, 24 M.71.52Maternal asthma50%39%51%.91.35Paternal asthma33%36%33%1.00.81Maternal allergy90%83%84%.44.87Paternal allergy84%75%86%.78.30Aeroallergen sensitization (sIgE), year 6 (kU/L)60%41%63%.81.14Aeroallergen sensitization (sIgE), year 11 (kU/L)74%44%78%.73.02Total IgE, year 6 (kU/L)51 (25-126)46 (9-129)96 (25-280).62.09Total IgE, year 11 (kU/L)49 (26-460)59 (18-228)119 (44-472).53.04Positive skin test response, year 956%47%62%.60.29Feno, year 6 (ppb)9.1 (7.2-11.1)5.9 (4.7-11.0)7.9 (6.1-18.3).74.14Feno, year 8 (ppb)8.1 (7.0-10.1)8.9 (5.2-20.0)10.6 (7.6-28.7).14.28Feno, year 11 (ppb)15.0 (9.4-24.5)10.6 (8.8-24.6)15.7 (8.7-32.4).76.61Blood eosinophils (%), year 63.0 (1.0-5.0)2.5 (1.0-4.0)3.0 (1.0-5.2).71.96Blood eosinophils (%), year 84.0 (2.0-5.0)2.5 (1.0-5.0)4.0 (2.5-5.5).45.04Blood eosinophils (%), year 115.0 (2.0-6.0)4.0 (1.0-5.2)4.0 (2.0-6.0).69.18F, Female; Feno, fraction of exhaled nitric oxide; M, male; ppb, parts per billion. Open table in a new tab F, Female; Feno, fraction of exhaled nitric oxide; M, male; ppb, parts per billion.