key: cord-0001969-cmqo0nkb authors: Coleman, Amaziah T.; Jackson, Daniel J.; Gangnon, Ronald E.; Evans, Michael D.; Lemanske, Robert F.; Gern, James E. title: Comparison of risk factors for viral and nonviral asthma exacerbations date: 2015-07-17 journal: J Allergy Clin Immunol DOI: 10.1016/j.jaci.2015.05.038 sha: 1e1a90d1b157689b6a1e6b669162794586d7cbb9 doc_id: 1969 cord_uid: cmqo0nkb nan function decline. Given the close relationship between exacerbations and airway inflammation, interventions targeted at reducing exacerbations might also reduce airway inflammation. Limitations include the lack of biological specimens to confirm airway remodeling. A direct measure of medication compliance was also unavailable. Exacerbation data were collected semiannually by using patient recall for the prior 3 months and thus did not include the entire year or 6-month period from the data collection point. However, this might cause a potential underestimation of asthma exacerbation counts, thus biasing results toward the null hypothesis of no association between exacerbations and lung function decline. In summary, longitudinal data from the TENOR study suggest that asthma exacerbations accelerate lung function decline. The extent of possible structural changes in the airways caused by exacerbations and the subsequent risk of airway remodeling require further study. These findings emphasize the importance of preventing exacerbations to preserve lung function, particularly in younger populations. To the Editor: 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, 1 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. 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. 2 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. 3 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 5 .009; incidence rate ratio (IRR) with respect to a 1-unit increase in log 10 IgE, 1 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 5 .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. 4 Additional studies have identified increased expression of the FcεRI receptor on monocytes and dendritic cells during acute asthma exacerbations. 5 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. 6 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. 7 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. Does azithromycin modify viral load during severe respiratory syncytial virus bronchiolitis? To the Editor: Early life respiratory syncytial virus (RSV) bronchiolitis is a major risk factor for subsequent recurrent wheezing and asthma. 1, 2 The highest asthma risk occurs in infants with severe bronchiolitis requiring hospitalization 3 : up to 75% of hospitalized infants experience at least 3 additional wheezing episodes and almost 50% are diagnosed with asthma by the age of 7 years. 1 We recently reported the results of a proof-of-concept trial, ''Azithromycin for the Prevention of recurrent Wheezing following RSV bronchiolitis (APW-RSV),'' in which azithromycin (AZM) treatment of infants hospitalized with RSV bronchiolitis resulted in a lower likelihood of subsequent recurrent wheezing. 4 Anti-inflammatory effects of AZM were detected in that study: relative to placebo, AZM treatment resulted in a greater decline in nasal lavage IL-8 levels by day 15 (P 5 .03). 4 However, other mechanisms through which AZM may exert this protective effect remain uncertain. Previous laboratory investigations have suggested that macrolides have in vitro antiviral activity because pretreatment of ex vivo human respiratory epithelial cells with AZM 5 or clarithromycin 6 reduced replication and release of RSV 6 and rhinovirus. 5 In addition, AZM pretreatment reduces rhinovirus replication in cystic fibrosis bronchial epithelial cells. 7 However, potential in vivo antiviral effects of macrolides have not been investigated in humans infected with respiratory viruses. Therefore, we hypothesized that our finding of AZM's reduction in post-RSV recurrent wheeze 4 was mediated, at least in part, by antiviral activity. In this present study, we aimed to address 2 research questions. Does AZM have antiviral activity as demonstrated by lower RSV loads in serial nasal lavage samples obtained during RSV bronchiolitis? Does this potential antiviral activity mediate the reduction in recurrent wheeze detected in our proof-of-concept trial? A detailed description of the APW-RSV study has been reported elsewhere. 4 Briefly, this was a randomized, doublemasked, placebo-controlled, proof-of-concept trial involving 40 infants with RSV bronchiolitis. Eligible infants were aged 1 to 18 months, otherwise healthy, and hospitalized for the first episode of bronchiolitis with confirmed RSV infection. Infants with a history of prematurity were excluded. Study treatments were either AZM oral suspension 10 mg/kg once daily for 7 days, followed by 5 mg/kg once daily for 7 additional days, or an oral placebo suspension. 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