Role of Viruses in the Development of Atopic Disease in Pediatric Patients
Pediatric Allergy and Immunology (JM Portnoy and CE Ciaccio, Section Editors)
First Online: 22 August 2012 DOI:
Cite this article as: Cheung, D.S. & Grayson, M.H. Curr Allergy Asthma Rep (2012) 12: 613. doi:10.1007/s11882-012-0295-y Abstract
The prevalence of atopic diseases continues to rise in modernized countries, without a clear explanation for this increase. One potential cause identified from epidemiologic studies of children is respiratory RNA viral infections leading to development of recurrent wheezing, asthma, and allergic sensitization. We review human epidemiologic data that both support and refute the role of viruses in this process. Exploring recent murine models, we document possible immunologic mechanisms that could translate a viral infection into atopic disease. We further discuss evidence for a post-viral “atopic cycle” that could explain the development of multiple allergen sensitization, and we explore available data to suggest a connection between viral infections of the gastrointestinal tract with the development of food allergy. Taken together, this review documents evidence to support the “viral hypothesis”, and, in particular, the role of RNA viruses in the development of atopic disease.
Keywords Virus Antiviral Immunology Atopy Asthma Food allergy IgE Atopic disease Pediatric Children References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Sly RM. Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol. 1999;82:233–48. quiz 248-252.
Hatice S. Zahran M, Cathy Bailey, MS, Paul Garbe, DVM. Vital Signs: Asthma Prevalence, Disease Characteristics, and Self-Management Education --- United States, 2001--2009. In: Morbidity and Mortality Weekly Report (MMWR). May 6, 2011. CDC; 2011. pp. 547-552.
Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–43.
Ben-Shoshan M, Turnbull E, Clarke A. Food allergy: temporal trends and determinants. Curr Allergy Asthma Rep 2012;12:346–72.
DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. 2012;33:227–34.
Sigurs N, Bjarnason R, Sigurbergsson F, et al. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics. 1995;95:500–5.
Sigurs N. A cohort of children hospitalised with acute RSV bronchiolitis: impact on later respiratory disease. Paediatr Respir Rev. 2002;3:177–83.
•• Sigurs N, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax. 2010;65:1045–52.
In this update of their original cohort, the authors showed that the increased risk for asthma and allergy after early life severe RSV bronchiolitis is sustained even over 18 years later.
Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178:667–72.
Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol 2010;125:1202–5.
Carroll KN, Hartert TV. The impact of respiratory viral infection on wheezing illnesses and asthma exacerbations. Immunol Allergy Clin North Am. 2008;28:539–61. viii.
Tan WC. Viruses in asthma exacerbations. Curr Opin Pulm Med. 2005;11:21–6.
Jartti T, Lehtinen P, Vuorinen T, Ruuskanen O. Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics. Pediatr Infect Dis J. 2009;28:311–7.
Lysholm F, Wetterbom A, Lindau C, et al. Characterization of the viral microbiome in patients with severe lower respiratory tract infections, using metagenomic sequencing. PLoS One. 2012;7:e30875.
Nair H, Brooks WA, Katz M, et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet. 2011;378:1917–30.
Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375:1545–55.
Gaunt ER, Harvala H, McIntyre C, et al. Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model. J Clin Virol. 2011;52:215–21.
Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354:541–5.
Stern DA, Morgan WJ, Halonen M, et al. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008;372:1058–64.
Henderson J, Hilliard TN, Sherriff A, et al. Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study. Pediatr Allergy Immunol. 2005;16:386–92.
• Escobar GJ, Ragins A, Li SX, et al. Recurrent wheezing in the third year of life among children born at 32 weeks' gestation or later: relationship to laboratory-confirmed, medically attended infection with respiratory syncytial virus during the first year of life. Arch Pediatr Adolesc Med. 2010;164:915–22.
This large cohort provided robust evidence that the severity of the RSV infection correlated positively with increased risk for recurrent wheezing.
Lee KK, Hegele RG, Manfreda J, et al. Relationship of early childhood viral exposures to respiratory symptoms, onset of possible asthma and atopy in high risk children: the Canadian Asthma Primary Prevention Study. Pediatr Pulmonol. 2007;42:290–7.
Kusel MM, de Klerk NH, Holt PG, et al. Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study. Pediatr Infect Dis J. 2006;25:680–6.
Lemanske Jr RF, Jackson DJ, Gangnon RE, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. The J Allergy Clin Immunol. 2005;116:571–7.
Jartti T, Kuusipalo H, Vuorinen T, et al. Allergic sensitization is associated with rhinovirus-, but not other virus-, induced wheezing in children. Pediatr Allergy Immunol. 2010;21:1008–14.
Frick OL, German DF, Mills J. Development of allergy in children. I. Association with virus infections. The J Allergy Clin Immunol. 1979;63:228–41.
Ishizaka K, Ishizaka T. Identification of gamma-E-antibodies as a carrier of reaginic activity. J Immunol. 1967;99:1187–98.
Nordbring F, Johansson SG, Espmark A. Raised serum levels of IgE in infectious mononucleosis. Scand J Infect Dis. 1972;4:119–24.
Perelmutter L, Phipps P, Potvin L. Viral infections and IgE levels. Ann Allergy. 1978;41:158–9.
Welliver RC, Wong DT, Sun M, et al. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med. 1981;305:841–6.
Soto ME, Sly PD, Uren E, et al. Bronchodilator response during acute viral bronchiolitis in infancy. Pediatr Pulmonol. 1985;1:85–90.
Russi JC, Delfraro A, Borthagaray MD, et al. Evaluation of immunoglobulin E-specific antibodies and viral antigens in nasopharyngeal secretions of children with respiratory syncytial virus infections. J Clin Microbiol. 1993;31:819–23.
Welliver RC, Sun M, Rinaldo D, Ogra PL. Respiratory syncytial virus-specific IgE responses following infection: evidence for a predominantly mucosal response. Pediatr Res. 1985;19:420–4.
Bui RH, Molinaro GA, Kettering JD, et al. Virus-specific IgE and IgG4 antibodies in serum of children infected with respiratory syncytial virus. J Pediatr. 1987;110:87–90.
Rabatic S, Gagro A, Lokar-Kolbas R, et al. Increase in CD23+ B cells in infants with bronchiolitis is accompanied by appearance of IgE and IgG4 antibodies specific for respiratory syncytial virus. J Infect Dis. 1997;175:32–7.
Aberle JH, Aberle SW, Dworzak MN, et al. Reduced interferon-gamma expression in peripheral blood mononuclear cells of infants with severe respiratory syncytial virus disease. Am J Respir Crit Care Med. 1999;160:1263–8.
Schwarze J, Hamelmann E, Bradley KL, et al. Respiratory syncytial virus infection results in airway hyperresponsiveness and enhanced airway sensitization to allergen. J Clin Invest. 1997;100:226–33.
Zhou W, Hashimoto K, Moore ML, et al. IL-13 is associated with reduced illness and replication in primary respiratory syncytial virus infection in the mouse. Microbes Infect. 2006;8:2880–9.
Moore ML, Newcomb DC, Parekh VV, et al. STAT1 negatively regulates lung basophil IL-4 expression induced by respiratory syncytial virus infection. J Immunol. 2009;183:2016–26.
Newcomb DC, Boswell MG, Huckabee MM, et al. IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner. J Immunol. 2012;188:1027–35.
Lukacs NW, Tekkanat KK, Berlin A, et al. Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms. J Immunol. 2001;167:1060–5.
Tekkanat KK, Maassab H, Berlin AA, et al. Role of interleukin-12 and stat-4 in the regulation of airway inflammation and hyperreactivity in respiratory syncytial virus infection. Am J Pathol. 2001;159:631–8.
Lukacs NW, Moore ML, Rudd BD, et al. Differential immune responses and pulmonary pathophysiology are induced by two different strains of respiratory syncytial virus. Am J Pathol. 2006;169:977–86.
Lukacs NW, Smit JJ, Schaller MA, Lindell DM. Regulation of immunity to respiratory syncytial virus by dendritic cells, toll-like receptors, and notch. Viral Immunol. 2008;21:115–22.
Grayson MH, Cheung D, Rohlfing MM, et al. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med. 2007;204:2759–69.
Walter MJ, Morton JD, Kajiwara N, et al. Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. J Clin Invest. 2002;110:165–75.
• Cheung DS, Ehlenbach SJ, Kitchens RT, et al. Cutting edge: CD49d+ neutrophils induce FcepsilonRI expression on lung dendritic cells in a mouse model of postviral asthma. J Immunol. 2010;185:4983–7.
This is the first report to document a subset of neutrophils specific to an RNA viral infection that drives the antiviral response toward the atopic pathway.
Stephens R, Randolph DA, Huang G, et al. Antigen-nonspecific recruitment of Th2 cells to the lung as a mechanism for viral infection-induced allergic asthma. J Immunol. 2002;169:5458–67.
• Cheung DS, Ehlenbach SJ, Kitchens T, et al. Development of atopy by severe paramyxoviral infection in a mouse model. Ann Allergy Asthma Immunol. 2010;105:437–443 e431.
This is the first report to document how a viral infection led to IgE against a nonviral antigen, which in turn exacerbated the post-viral airway disease upon re-exposure to the nonviral antigen.
Kumar A, Grayson MH. The role of viruses in the development and exacerbation of atopic disease. Ann Allergy Asthma Immunol. 2009;103:181–6. quiz 186-187, 219.
Al-Garawi AA, Fattouh R, Walker TD, et al. Acute, but not resolved, influenza A infection enhances susceptibility to house dust mite-induced allergic disease. J Immunol. 2009;182:3095–104.
Vasudev M, Cheung DS, Pincsak H, et al. Expression of high-affinity IgE receptor on human peripheral blood dendritic cells in children. PLoS One. 2012;7:e32556.
•• Subrata LS, Bizzintino J, Mamessier E, et al. Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children. J Immunol. 2009;183:2793–800.
This report demonstrated that FcεRI expression on human dendritic cells can be upregulated by an active viral respiratory infection and return to a baseline level during convalescence.
Khan SH, Grayson MH. Cross-linking IgE augments human conventional dendritic cell production of CC chemokine ligand 28. J Allergy Clin Immunol. 2010;125:265–7.
Tversky JR, Le TV, Bieneman AP, et al. Human blood dendritic cells from allergic subjects have impaired capacity to produce interferon-alpha via Toll-like receptor 9. Clin Exp Allergy. 2008;38:781–8.
Schroeder JT, Bieneman AP, Chichester KL, et al. Pulmonary allergic responses augment interleukin-13 secretion by circulating basophils yet suppress interferon-alpha from plasmacytoid dendritic cells. Clin Exp Allergy. 2010;40:745–54.
Schroeder JT, Bieneman AP, Xiao H, et al. TLR9- and FcepsilonRI-mediated responses oppose one another in plasmacytoid dendritic cells by down-regulating receptor expression. J Immunol. 2005;175:5724–31.
Gill MA, Bajwa G, George TA, et al. Counterregulation between the FcepsilonRI pathway and antiviral responses in human plasmacytoid dendritic cells. J Immunol. 2010;184:5999–6006.
Chen CH, Lin YT, Yang YH, et al. Ribavirin for respiratory syncytial virus bronchiolitis reduced the risk of asthma and allergen sensitization. Pediatr Allergy Immunol. 2008;19:166–72.
Simoes EA, Groothuis JR, Carbonell-Estrany X, et al. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr. 2007;151:34–42. 42 e31.
Simoes EA, Carbonell-Estrany X, Rieger CH, et al. The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol. 2010;126:256–62.
•• Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364:1005–15.
This report showed that anti-IgE therapy is beneficial not just for atopic asthma during the pollen seasons but also for viral-induced asthma exacerbations.
• Stensballe LG, Simonsen JB, Thomsen SF, et al. The causal direction in the association between respiratory syncytial virus hospitalization and asthma. J Allergy Clin Immunol. 2009;123:131–137 e131.
Utilizing mathematical modeling, this study argued that the pre-asthmatic phenotype was at a higher risk for severe RSV bronchiolitis instead of RSV infection causing any increased risk for asthma.
Thomsen SF, van der Sluis S, Stensballe LG, et al. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. Am J Respir Crit Care Med. 2009;179:1091–7.
Stein RT, Martinez FD. Respiratory syncytial virus and asthma: still no final answer. Thorax. 2010;65:1033–4.
Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332:133–8.
Chawes BL, Poorisrisak P, Johnston SL, Bisgaard H. Neonatal bronchial hyperresponsiveness precedes acute severe viral bronchiolitis in infants. The J Allergy Clin Immunol 2012;130:354–61.
Poorisrisak P, Halkjaer LB, Thomsen SF, et al. Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins. Chest. 2010;138:338–44.
Jackson DJ, Evans MD, Gangnon RE, et al. Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life. Am J Respir Crit Care Med. 2012;185:281–5.
Heymann PW, Carper HT, Murphy DD, et al. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. The J Allergy Clin Immunol. 2004;114:239–47.
Vince JD. Diarrhoea in children in Papua New Guinea. P N G Med J. 1995;38:262–71.
Guerra-Godinez JC, Larrosa-Haro A, Coello-Ramirez P, et al. Changing trends in prevalence, morbidity, and lethality in persistent diarrhea of infancy during the last decade in Mexico. Arch Med Res. 2003;34:209–13.
Fischer TK, Viboud C, Parashar U, et al. Hospitalizations and deaths from diarrhea and rotavirus among children <5 years of age in the United States, 1993-2003. J Infect Dis. 2007;195:1117–25.
Chen X, Leach D, Hunter DA, et al. Characterization of intestinal dendritic cells in murine norovirus infection. Open Immunol J. 2011;4:22–30.
Fecek RJ, Marcondes Rezende M, Busch R, et al. Enteric reovirus infection stimulates peanut-specific IgG2a responses in a mouse food allergy model. Immunobiology. 2010;215:941–8.
Payne DC, Staat MA, Edwards KM, et al. Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States. Pediatrics. 2008;122:1235–43.
Yen C, Tate JE, Wenk JD, et al. Diarrhea-associated hospitalizations among US children over 2 rotavirus seasons after vaccine introduction. Pediatrics. 2011;127:e9–e15.
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