Rhinovirus-induced asthma exacerbations during childhood: The importance of understanding the atopic status of the host
2012; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2012.10.024
ISSN1097-6825
AutoresPeter W. Heymann, Joshua L. Kennedy,
Tópico(s)Respiratory and Cough-Related Research
ResumoRhinovirus is the most frequent infectious agent associated with exacerbations of wheezing during childhood and among young adults. Areas of investigation that have been improving our understanding for the strong association between rhinovirus infections and attacks of asthma include studies that have (1) examined the role of rhinovirus infections during infancy in promoting the development of asthma1Lemanske Jr., R.F. Jackson D.J. Gangnon R.E. Evans M.D. Li Z. Shult P.A. et al.Rhinovirus illnesses during infancy predict subsequent childhood wheezing.J Allergy Clin Immunol. 2005; 116: 571-577Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar, 2Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. et al.Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma.J Allergy Clin Immunol. 2007; 119: 1105-1110Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar, 3Jackson D.J. Evans M.D. Gangnon R.E. Tisler C.J. Pappas T.E. Lee W.M. et al.Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life.Am J Respir Crit Care Med. 2012; 185: 281-285Crossref PubMed Scopus (270) Google Scholar; (2) demonstrated the striking association between rhinovirus infections, allergic sensitization, and exposure to environmental allergens among children who wheeze during the preschool and school-age years4Rakes 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.Am J Respir Crit Care Med. 1999; 159: 785-790Crossref PubMed Scopus (396) Google Scholar, 5Murray C.S. Poletti G. Kebadze T. Morris J. Woodcock A. Johnston S.L. et al.Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children.Thorax. 2006; 61: 376-382Crossref PubMed Scopus (419) Google Scholar; and (3) examined the mechanisms of rhinovirus-induced exacerbations that will hopefully lead to new treatments. From birth through the school-age years, children are frequently exposed to a variety of respiratory tract pathogens, and controversies persist as to why rhinovirus stands out as the dominant pathogen linked to wheezing. Surprisingly, mechanisms to explain how rhinovirus provokes an attack of asthma remain poorly understood. However, an abundance of data from pediatric population-based studies indicate that rhinovirus-induced wheezing exacerbations after 3 years of age are most likely to occur among children who are atopic.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.Am J Respir Crit Care Med. 1999; 159: 785-790Crossref PubMed Scopus (396) Google Scholar, 5Murray C.S. Poletti G. Kebadze T. Morris J. Woodcock A. Johnston S.L. et al.Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children.Thorax. 2006; 61: 376-382Crossref PubMed Scopus (419) Google Scholar, 6Heymann P.W. Carper H.T. Murphy D.D. Platts-Mills T.A.E. Patrie J. McLaughlin A.P. et al.Viral infections in relation to age, atopy, and the season of admission among children hospitalized for wheezing.J Allergy Clin Immunol. 2004; 114: 239-247Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar More recently, data from adults with asthma indicate that innate antiviral responses (eg, the production of type I and type III interferons) might be deficient in the asthmatic airway and could be instrumental in explaining the susceptibility of the asthmatic population to wheezing attacks caused by rhinovirus and possibly other viral pathogens.7Wark P.A. Johnston S.L. Bucchieri F. Powell R. Puddicombe S. Laza-Stanca V. et al.Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.J Exp Med. 2005; 201: 937-947Crossref PubMed Scopus (1040) Google Scholar, 8Gill M.A. Bajwa G. George T.A. Dong C.C. Dougherty I.I. Jiang N. et al.Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells.J Immunol. 2010; 184: 5999-6006Crossref PubMed Scopus (250) Google Scholar Because asthma attacks provoked by rhinovirus are more common among children than adults,9Heymann P.W. Platts-Mills T.A. Johnston S.L. Role of viral infections, atopy and antiviral immunity in the etiology of wheezing exacerbations among children and young adults.Pediatr Infect Dis J. 2005; 24: S217-S222Crossref PubMed Scopus (80) Google Scholar the study in this issue of the Journal by Baraldo et al,10Baraldo S. Contolli M. Bazzan E. Turato G. Padovani A. Marku B. Calabrese F. Caramori G. Ballarin A. Snijders D. Barbato A. Saetta M. Papi A. Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma.J Allergy Clin Immunol. 2012; 130: 1307-1314Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar which examines whether innate antiviral responses to rhinovirus may be deficient in the airways of asthmatic children as previously reported in adults, is important. In addition, most pediatric data to date have been derived from studies using nasal washes to test for the presence of virus along with biomarkers of airway inflammation. Thus the study by Baraldo et al10Baraldo S. Contolli M. Bazzan E. Turato G. Padovani A. Marku B. Calabrese F. Caramori G. Ballarin A. Snijders D. Barbato A. Saetta M. Papi A. Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma.J Allergy Clin Immunol. 2012; 130: 1307-1314Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar is unique because of their evaluation of samples obtained by means of bronchoscopy from 4 groups of children (mean age, 5 years). These children included 2 groups with physician-diagnosed asthma (both atopic and nonatopic subjects), one group of atopic children without asthma, and nonatopic children without asthma who were enrolled as control subjects (12 in each group). The atopic status of these children was evaluated by using tests for total IgE and allergen-specific IgE antibodies in sera. Bronchoscopies were obtained when the children were asymptomatic, and samples sufficient for the analyses were available from 8 to 9 subjects in each group. During the bronchoscopies, bronchial brushings were obtained to grow epithelial cells in culture along with biopsy specimens for immunohistochemical analyses. The 2 asthmatic groups were well matched for previous hospitalizations, emergency department visits, and medication requirements. Only 6 of the children were being treated with low-dose inhaled corticosteroids, 3 in each group, and their results did not differ significantly from the results of those who were not using inhaled steroids. Before inoculation of the bronchoepithelial cells with virus, rhinovirus (strain 16) RNA was undetectable in all of the primary cell cultures. After inoculation, the expression of IFN-λ1 and IFN-β mRNA was evaluated at 8 hours, and the production of protein (ie, the quantities of IFN-β detected were sufficient for analysis) was evaluated at 48 hours. Similar to the data previously reported in adults, the authors found that the expression of mRNA for IFN-λ1 and IFN-β and the production of IFN-β protein from epithelial cells after infection with rhinovirus 16 was also decreased in cells from the atopic asthmatic children and also from the cells obtained from the nonatopic asthmatic children and the atopic children without asthma compared with samples from the control subjects. In addition, the production of these innate cytokines in vitro correlated inversely with rhinovirus replication, as judged by using quantitative PCR in supernatants from these cells at 8 hours. The authors conclude that the decreased expression of these cytokines observed within hours after viral inoculation might impart susceptibility to infections with rhinovirus in the asthmatic host. Whether this innate cytokine deficiency and the increased viral load observed by the authors reflect how bronchoepithelial cells would respond to a rhinovirus infection in the intact airway and whether this deficiency and increased viral load would persist throughout the course of the infection are important questions. In this regard significantly higher IFN-λ1 levels were recently reported in nasal washes from asthmatic children who had positive test results for rhinovirus during an episode of acute wheezing compared with those seen in nonwheezing asthmatic children with rhinovirus-induced rhinitis.11Miller E.K. Hernandez J.Z. Wimmenauer V. Shepherd B.E. Hijano D. Libster R. et al.A mechanistic role for type III IFN-λ1 in asthma exacerbations mediated by human rhinoviruses.Am J Respir Crit Care Med. 2012; 185: 508-516Crossref PubMed Scopus (92) Google Scholar Thus, although the expression of IFN-λ1 in response to rhinovirus might be reduced when bronchoepithelial cells from asthmatic patients are infected in vitro, the production of this cytokine during an attack of rhinovirus-induced asthma appears to be enhanced, at least in the upper airway where this virus replicates vigorously. The beauty of the biopsy results reported by Baraldo et al10Baraldo S. Contolli M. Bazzan E. Turato G. Padovani A. Marku B. Calabrese F. Caramori G. Ballarin A. Snijders D. Barbato A. Saetta M. Papi A. Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma.J Allergy Clin Immunol. 2012; 130: 1307-1314Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar is the discovery of increased tissue eosinophilia and IL-4–expressing cells, along with epithelial cell damage, not only in samples from the atopic asthmatic patients but also in biopsy specimens from nonatopic asthmatic children and atopic children without asthma. These results were also inversely related to the expression of IFN-λ1 and IFN-β mRNA in the bronchoepithelial cells infected in vitro. The results from the children with asthma who were not atopic are of interest because there is little information about this phenotypic group in the literature and because the presence of TH2-driven immunopathology in their lower airways might, as the authors note, also impart a greater risk for acute asthma symptoms provoked by rhinovirus, even in the absence of allergic sensitization. Of interest, however, is that compared with the atopic asthmatic children in this study, the nonatopic asthmatic children had significantly lower levels of blood eosinophilia and a trend toward lower tissue eosinophilia in their biopsy specimens. This might suggest a better prognosis for these children; however, a larger longitudinally based study is needed, which might be difficult because nonatopic asthmatic children at this age represent a minority (<20%) of those who need hospitalization or treatment in the emergency department for acute wheezing.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.Am J Respir Crit Care Med. 1999; 159: 785-790Crossref PubMed Scopus (396) Google Scholar, 6Heymann P.W. Carper H.T. Murphy D.D. Platts-Mills T.A.E. Patrie J. McLaughlin A.P. et al.Viral infections in relation to age, atopy, and the season of admission among children hospitalized for wheezing.J Allergy Clin Immunol. 2004; 114: 239-247Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 12Soto-Quiros M. Avila L. Platts-Mills T.A. Hunt J.E. Erdman D.D. Carper H. et al.High titers of IgE antibody to dust mite allergen and risk for wheezing among asthmatic children infected with rhinovirus.J Allergy Clin Immunol. 2012; 129: 1499-1505Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Among the atopic children without physician-diagnosed asthma, the authors also discovered TH2-associated immunopathology in their biopsy samples along with reduced IFN-λ1 and IFN-β expression in their bronchoepithelial cells after rhinovirus 16 inoculation. However, like other children in this study, the 8 children in this group had clinical indications for their bronchoscopies, including 5 who were being evaluated for recurrent pneumonias, 2 for chronic cough, and 1 for middle-lobe syndrome. Therefore these children differ from the majority of children with allergic rhinitis who do not require bronchoscopic evaluations for reasons that might be consistent with asthmatic changes in their lower airways. More directly related to the relevance of atopy, the authors found a positive correlation between total IgE levels in sera from the children in the study and an increased viral load detected in their epithelial cell supernatants at 8 hours and an inverse correlation between total IgE levels and the expression of IFN-λ1. These results are in keeping with a recent study of school-age asthmatic children demonstrating that increasing serum titers of allergen-specific IgE antibody (eg, to dust mite allergen) substantially increase the probability of wheeze provoked by rhinovirus.12Soto-Quiros M. Avila L. Platts-Mills T.A. Hunt J.E. Erdman D.D. Carper H. et al.High titers of IgE antibody to dust mite allergen and risk for wheezing among asthmatic children infected with rhinovirus.J Allergy Clin Immunol. 2012; 129: 1499-1505Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Taken together, the data from the study by Baraldo et al10Baraldo S. Contolli M. Bazzan E. Turato G. Padovani A. Marku B. Calabrese F. Caramori G. Ballarin A. Snijders D. Barbato A. Saetta M. Papi A. Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma.J Allergy Clin Immunol. 2012; 130: 1307-1314Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar provide important information relevant to the pediatric population and help to highlight the importance of defining the atopic status of asthmatic patients in studies to decipher the mechanisms of wheezing induced by rhinovirus. Deficient antiviral immune responses in childhood: Distinct roles of atopy and asthmaJournal of Allergy and Clinical ImmunologyVol. 130Issue 6PreviewImpaired immune response to viral infections in atopic asthmatic patients has been recently reported and debated. Whether this condition is present in childhood and whether it is affected by atopy per se deserves further investigation. Full-Text PDF
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