Current Allergy and Asthma Reports

, Volume 12, Issue 6, pp 613–620

Role of Viruses in the Development of Atopic Disease in Pediatric Patients

Pediatric Allergy and Immunology (JM Portnoy and CE Ciaccio, Section Editors)


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.


Virus Antiviral Immunology Atopy Asthma Food allergy IgE Atopic disease Pediatric Children 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Sly RM. Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol. 1999;82:233–48. quiz 248-252.PubMedCrossRefGoogle Scholar
  2. 2.
    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.Google Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Ben-Shoshan M, Turnbull E, Clarke A. Food allergy: temporal trends and determinants. Curr Allergy Asthma Rep 2012;12:346–72.Google Scholar
  5. 5.
    DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. 2012;33:227–34.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedGoogle Scholar
  7. 7.
    Sigurs N. A cohort of children hospitalised with acute RSV bronchiolitis: impact on later respiratory disease. Paediatr Respir Rev. 2002;3:177–83.PubMedCrossRefGoogle Scholar
  8. 8.
    •• 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. PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol 2010;125:1202–5.Google Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Tan WC. Viruses in asthma exacerbations. Curr Opin Pulm Med. 2005;11:21–6.PubMedGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    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.PubMedCrossRefGoogle Scholar
  21. 21.
    • 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. PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    Ishizaka K, Ishizaka T. Identification of gamma-E-antibodies as a carrier of reaginic activity. J Immunol. 1967;99:1187–98.PubMedGoogle Scholar
  28. 28.
    Nordbring F, Johansson SG, Espmark A. Raised serum levels of IgE in infectious mononucleosis. Scand J Infect Dis. 1972;4:119–24.PubMedGoogle Scholar
  29. 29.
    Perelmutter L, Phipps P, Potvin L. Viral infections and IgE levels. Ann Allergy. 1978;41:158–9.PubMedGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    Soto ME, Sly PD, Uren E, et al. Bronchodilator response during acute viral bronchiolitis in infancy. Pediatr Pulmonol. 1985;1:85–90.PubMedCrossRefGoogle Scholar
  32. 32.
    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.PubMedGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedGoogle Scholar
  37. 37.
    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.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    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.PubMedCrossRefGoogle Scholar
  40. 40.
    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.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    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.PubMedCrossRefGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    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.PubMedGoogle Scholar
  47. 47.
    • 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. PubMedCrossRefGoogle Scholar
  48. 48.
    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.PubMedGoogle Scholar
  49. 49.
    • 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. PubMedCrossRefGoogle Scholar
  50. 50.
    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.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar
  53. 53.
    •• 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. PubMedCrossRefGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    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.PubMedGoogle Scholar
  57. 57.
    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.PubMedGoogle Scholar
  58. 58.
    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.PubMedCrossRefGoogle Scholar
  59. 59.
    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.PubMedCrossRefGoogle Scholar
  60. 60.
    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.PubMedCrossRefGoogle Scholar
  61. 61.
    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.PubMedCrossRefGoogle Scholar
  62. 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. PubMedCrossRefGoogle Scholar
  63. 63.
    • 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. PubMedCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    Stein RT, Martinez FD. Respiratory syncytial virus and asthma: still no final answer. Thorax. 2010;65:1033–4.PubMedCrossRefGoogle Scholar
  66. 66.
    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.PubMedCrossRefGoogle Scholar
  67. 67.
    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.Google Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    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.CrossRefGoogle Scholar
  71. 71.
    Vince JD. Diarrhoea in children in Papua New Guinea. P N G Med J. 1995;38:262–71.PubMedGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    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.PubMedCrossRefGoogle Scholar
  74. 74.
    Chen X, Leach D, Hunter DA, et al. Characterization of intestinal dendritic cells in murine norovirus infection. Open Immunol J. 2011;4:22–30.PubMedCrossRefGoogle Scholar
  75. 75.
    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.PubMedCrossRefGoogle Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of PediatricsMedical College of WisconsinMilwaukeeUSA

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