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Virus-induced wheezing and asthma: An overview

Sujani Kakumanu, MD
Section Editors
Gregory Redding, MD
Robert A Wood, MD
Deputy Editor
Elizabeth TePas, MD, MS


Viral respiratory infections are the most common causes of wheezing in infants and young children and are common triggers of asthma exacerbations in adult and pediatric patients with preexisting asthma [1-4]. In addition, wheezing with viral illnesses, particularly with respiratory syncytial virus (RSV) and human rhinovirus (HRV), in infants and young children is associated with an increased risk of developing childhood asthma [5-10].

The mechanisms by which viral respiratory infections trigger wheezing and asthma exacerbations are reviewed here. The influence of viral infection on both the development and perpetuation of asthma is also discussed. Other issues relating to the pathogenesis of asthma are reviewed elsewhere. Treatment of virus-induced wheezing and asthma is also discussed separately. (See "Pathogenesis of asthma" and "Risk factors for asthma" and "Natural history of asthma" and "Treatment of recurrent virus-induced wheezing in young children".)


Viral respiratory infections interact with host factors to promote recurrent virus-induced wheezing and the development of asthma (figure 1) [11]. Respiratory symptoms with viral infections most likely result from virus-induced damage of the airway epithelium, followed by airway inflammation in a predisposed individual. Immune responses triggered by viral respiratory tract infections include enhanced allergic inflammation, increased granulocyte recruitment, promotion of cytokine production, and upregulation of the parasympathetic response (table 1). These proinflammatory responses further influence the host responses to other microbial infections, allergens, stress, and pollutants.

Epithelial cells – Respiratory epithelial cells are the initial site of viral inoculation and serve as the primary site of viral replication. Respiratory viruses, such as influenza and respiratory syncytial virus (RSV), cause cytopathic damage to airway epithelium, and these changes can affect the function of the epithelium and airway smooth muscle. In addition, disturbing the integrity of the epithelial layer may enhance mucosal permeability and increase exposure of inflammatory and antigen-presenting cells to allergens, other infections, and irritants.

Approximately 90 percent of rhinovirus human rhinovirus-A (HRV-A) and human rhinovirus-B (HRV-B) serotypes bind to respiratory epithelial cells via the intercellular adhesion molecule 1 (ICAM-1, also called CD54 [cluster of differentiation 54]), while a minority, belonging to the HRV-A group, bind to the very low density lipoprotein (VLDL) receptor [12,13]. CDHR3, a human cadherin-related family member 3 protein, mediates human rhinovirus-C (HRV-C) entry into host cells [14]. The receptor for HRV-C strains has not yet been identified.


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  1. Carroll KN, Hartert TV. The impact of respiratory viral infection on wheezing illnesses and asthma exacerbations. Immunol Allergy Clin North Am 2008; 28:539.
  2. Tan WC. Viruses in asthma exacerbations. Curr Opin Pulm Med 2005; 11:21.
  3. MacDowell AL, Bacharier LB. Infectious triggers of asthma. Immunol Allergy Clin North Am 2005; 25:45.
  4. Le Souëf PN. Gene-environmental interaction in the development of atopic asthma: new developments. Curr Opin Allergy Clin Immunol 2009; 9:123.
  5. 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.
  6. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000; 161:1501.
  7. Sigurs N, Gustafsson PM, Bjarnason R, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 2005; 171:137.
  8. 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.
  9. Kusel MM, de Klerk NH, Kebadze T, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007; 119:1105.
  10. Holt PG, Sly PD. Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment. Nat Med 2012; 18:726.
  11. Gern JE. Viral respiratory infection and the link to asthma. Pediatr Infect Dis J 2008; 27:S97.
  12. Olenec JP, Kim WK, Lee WM, et al. Weekly monitoring of children with asthma for infections and illness during common cold seasons. J Allergy Clin Immunol 2010; 125:1001.
  13. Palmenberg AC, Rathe JA, Liggett SB. Analysis of the complete genome sequences of human rhinovirus. J Allergy Clin Immunol 2010; 125:1190.
  14. Bochkov YA, Watters K, Ashraf S, et al. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc Natl Acad Sci U S A 2015; 112:5485.
  15. Becker S, Quay J, Soukup J. Cytokine (tumor necrosis factor, IL-6, and IL-8) production by respiratory syncytial virus-infected human alveolar macrophages. J Immunol 1991; 147:4307.
  16. Subauste MC, Jacoby DB, Richards SM, Proud D. Infection of a human respiratory epithelial cell line with rhinovirus. Induction of cytokine release and modulation of susceptibility to infection by cytokine exposure. J Clin Invest 1995; 96:549.
  17. Becker S, Koren HS, Henke DC. Interleukin-8 expression in normal nasal epithelium and its modulation by infection with respiratory syncytial virus and cytokines tumor necrosis factor, interleukin-1, and interleukin-6. Am J Respir Cell Mol Biol 1993; 8:20.
  18. Einarsson O, Panusak J, Zhu Z, et al. Respiratory syncytial virus stimulation of interleukin-11 production by airway epithelial cells and lung fibroblasts. Am J Respir Crit Care Med 1994; 149:47.
  19. Noah TL, Becker S. Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line. Am J Physiol 1993; 265:L472.
  20. Garofalo R, Mei F, Espejo R, et al. Respiratory syncytial virus infection of human respiratory epithelial cells up-regulates class I MHC expression through the induction of IFN-beta and IL-1 alpha. J Immunol 1996; 157:2506.
  21. Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol 2010; 125:1178.
  22. Papi A, Stanciu LA, Papadopoulos NG, et al. Rhinovirus infection induces major histocompatibility complex class I and costimulatory molecule upregulation on respiratory epithelial cells. J Infect Dis 2000; 181:1780.
  23. Holt PG, Strickland DH, Hales BJ, Sly PD. Defective respiratory tract immune surveillance in asthma: a primary causal factor in disease onset and progression. Chest 2014; 145:370.
  24. Durrani SR, Montville DJ, Pratt AS, 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.
  25. 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.
  26. 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.
  27. Douglas RG Jr, Alford BR, Couch RB. Atraumatic nasal biopsy for studies of respiratory virus infection in volunteers. Antimicrob Agents Chemother (Bethesda) 1968; 8:340.
  28. Winther B, Farr B, Turner RB, et al. Histopathologic examination and enumeration of polymorphonuclear leukocytes in the nasal mucosa during experimental rhinovirus colds. Acta Otolaryngol Suppl 1984; 413:19.
  29. Fraenkel DJ, Bardin PG, Sanderson G, et al. Immunohistochemical analysis of nasal biopsies during rhinovirus experimental colds. Am J Respir Crit Care Med 1994; 150:1130.
  30. Calhoun WJ, Dick EC, Schwartz LB, Busse WW. A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects. J Clin Invest 1994; 94:2200.
  31. Lemanske RF Jr, Dick EC, Swenson CA, et al. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J Clin Invest 1989; 83:1.
  32. Avila PC, Abisheganaden JA, Wong H, et al. Effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold. J Allergy Clin Immunol 2000; 105:923.
  33. Fraenkel DJ, Bardin PG, Sanderson G, et al. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med 1995; 151:879.
  34. Gern JE, Galagan DM, Jarjour NN, et al. Detection of rhinovirus RNA in lower airway cells during experimentally induced infection. Am J Respir Crit Care Med 1997; 155:1159.
  35. Folkerts G, Busse WW, Nijkamp FP, et al. Virus-induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med 1998; 157:1708.
  36. Jarjour NN, Gern JE, Kelly EA, et al. The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin Immunol 2000; 105:1169.
  37. Denlinger LC, Sorkness RL, Lee WM, et al. Lower airway rhinovirus burden and the seasonal risk of asthma exacerbation. Am J Respir Crit Care Med 2011; 184:1007.
  38. Arnold R, Humbert B, Werchau H, et al. Interleukin-8, interleukin-6, and soluble tumour necrosis factor receptor type I release from a human pulmonary epithelial cell line (A549) exposed to respiratory syncytial virus. Immunology 1994; 82:126.
  39. Grünberg K, Timmers MC, Smits HH, et al. Effect of experimental rhinovirus 16 colds on airway hyperresponsiveness to histamine and interleukin-8 in nasal lavage in asthmatic subjects in vivo. Clin Exp Allergy 1997; 27:36.
  40. Teran LM, Johnston SL, Schröder JM, et al. Role of nasal interleukin-8 in neutrophil recruitment and activation in children with virus-induced asthma. Am J Respir Crit Care Med 1997; 155:1362.
  41. Zhou S, Stark JM, Leikauf GD. Leukotriene B4 formation: human neutrophil-airway epithelial cell interactions. J Appl Physiol (1985) 1995; 78:1396.
  42. Fiedler MA, Wernke-Dollries K, Stark JM. Respiratory syncytial virus increases IL-8 gene expression and protein release in A549 cells. Am J Physiol 1995; 269:L865.
  43. Garofalo R, Kimpen JL, Welliver RC, Ogra PL. Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection. J Pediatr 1992; 120:28.
  44. Rakes GP, Arruda E, Ingram JM, et al. Assessment of viral pathogens and eosinophilic cationic protein in nasal washes form wheezing infants and children. Am J Respir Crit Care Med 1995; 151:A362.
  45. Seminario MC, Squillace D, Bardin PG, et al. Increased levels of eosinophil major basic protein in nasal secretions in rhinovirus infection. J Allergy Clin Immunol 1995; 95:259.
  46. Volovitz B, Welliver RC, De Castro G, et al. The release of leukotrienes in the respiratory tract during infection with respiratory syncytial virus: role in obstructive airway disease. Pediatr Res 1988; 24:504.
  47. Proud D, Gwaltney JM Jr, Hendley JO, et al. Increased levels of interleukin-1 are detected in nasal secretions of volunteers during experimental rhinovirus colds. J Infect Dis 1994; 169:1007.
  48. Noah TL, Henderson FW, Wortman IA, et al. Nasal cytokine production in viral acute upper respiratory infection of childhood. J Infect Dis 1995; 171:584.
  49. Gern JE, Dick EC, Lee WM, et al. Rhinovirus enters but does not replicate inside monocytes and airway macrophages. J Immunol 1996; 156:621.
  50. Roberts NJ Jr, Prill AH, Mann TN. Interleukin 1 and interleukin 1 inhibitor production by human macrophages exposed to influenza virus or respiratory syncytial virus. Respiratory syncytial virus is a potent inducer of inhibitor activity. J Exp Med 1986; 163:511.
  51. Johnston SL, Papi A, Monick MM, Hunninghake GW. Rhinoviruses induce interleukin-8 mRNA and protein production in human monocytes. J Infect Dis 1997; 175:323.
  52. Gern JE, Busse WW. Role of T cells in virus-induced asthma. In: The Genetics of Asthma, Liggett SB, Meyers DA (Eds), Marcel Dekker, New York 1996. p.39.
  53. Gern JE, Vrtis R, Kelly EA, et al. Rhinovirus produces nonspecific activation of lymphocytes through a monocyte-dependent mechanism. J Immunol 1996; 157:1605.
  54. Riese RJ, Finn PW, Shapiro SD. Influenza and asthma: adding to the respiratory burden. Nat Immunol 2004; 5:243.
  55. Proud D, Naclerio RM, Gwaltney JM, Hendley JO. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis 1990; 161:120.
  56. Hsia J, Goldstein AL, Simon GL, et al. Peripheral blood mononuclear cell interleukin-2 and interferon-gamma production, cytotoxicity, and antigen-stimulated blastogenesis during experimental rhinovirus infection. J Infect Dis 1990; 162:591.
  57. Linden M, Greiff L, Andersson M, et al. Nasal cytokines in common cold and allergic rhinitis. Clin Exp Allergy 1995; 25:166.
  58. Levandowski RA, Horohov DW. Rhinovirus induces natural killer-like cytotoxic cells and interferon alpha in mononuclear leukocytes. J Med Virol 1991; 35:116.
  59. Wark PA, Johnston SL, Bucchieri F, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med 2005; 201:937.
  60. Gern JE, Vrtis R, Grindle KA, et al. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection. Am J Respir Crit Care Med 2000; 162:2226.
  61. Brooks GD, Buchta KA, Swenson CA, et al. Rhinovirus-induced interferon-gamma and airway responsiveness in asthma. Am J Respir Crit Care Med 2003; 168:1091.
  62. Contoli M, Message SD, Laza-Stanca V, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med 2006; 12:1023.
  63. Miller EK, Hernandez JZ, Wimmenauer V, 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.
  64. Allakhverdi Z, Comeau MR, Jessup HK, et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 2007; 204:253.
  65. Kato A, Favoreto S Jr, Avila PC, Schleimer RP. TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol 2007; 179:1080.
  66. Fryer AD, Jacoby DB. Parainfluenza virus infection damages inhibitory M2 muscarinic receptors on pulmonary parasympathetic nerves in the guinea-pig. Br J Pharmacol 1991; 102:267.
  67. Sorkness R, Clough JJ, Castleman WL, Lemanske RF Jr. Virus-induced airway obstruction and parasympathetic hyperresponsiveness in adult rats. Am J Respir Crit Care Med 1994; 150:28.
  68. Skoner DP, Doyle WJ, Tanner EP, et al. Effect of rhinovirus 39 (RV-39) infection on immune and inflammatory parameters in allergic and non-allergic subjects. Clin Exp Allergy 1995; 25:561.
  69. 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.
  70. Welliver RC, Wong DT, Middleton E Jr, et al. Role of parainfluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection. J Pediatr 1982; 101:889.
  71. Welliver RC, Kaul TN, Ogra PL. The appearance of cell-bound IgE in respiratory-tract epithelium after respiratory-syncytial-virus infection. N Engl J Med 1980; 303:1198.
  72. Pyle DM, Yang VS, Gruchalla RS, et al. IgE cross-linking critically impairs human monocyte function by blocking phagocytosis. J Allergy Clin Immunol 2013; 131:491.
  73. Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ 1995; 310:1225.
  74. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993; 307:982.
  75. Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 1999; 282:1440.
  76. Centers for Disease Control and Prevention (CDC). Bronchiolitis-associated outpatient visits and hospitalizations among American Indian and Alaska Native children--United States, 1990-2000. MMWR Morb Mortal Wkly Rep 2003; 52:707.
  77. Stark JM, Busse WW. Respiratory virus infection and airway hyperreactivity in children. Pediatr Allergy Immunol 1991; 2:95.
  78. Rakes GP, Arruda E, Ingram JM, 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.
  79. Jackson DJ. The role of rhinovirus infections in the development of early childhood asthma. Curr Opin Allergy Clin Immunol 2010; 10:133.
  80. Lemanske RF Jr, Jackson DJ, Gangnon RE, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 2005; 116:571.
  81. Roberg KA, Sullivan-Dillie KT, Evans MD, et al. Wheezing severe rhinovirus illnesses during infancy predict childhood asthma at age 6 years. J Allergy Clin Immunol 2007; 119:S157 (Abstract).
  82. Rosenthal LA, Avila PC, Heymann PW, et al. Viral respiratory tract infections and asthma: the course ahead. J Allergy Clin Immunol 2010; 125:1212.
  83. Miller EK, Edwards KM, Weinberg GA, et al. A novel group of rhinoviruses is associated with asthma hospitalizations. J Allergy Clin Immunol 2009; 123:98.
  84. Lee WM, Kiesner C, Pappas T, et al. A diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants. PLoS One 2007; 2:e966.
  85. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001; 7:719.
  86. Boivin G, Abed Y, Pelletier G, et al. Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus responsible for acute respiratory-tract infections in all age groups. J Infect Dis 2002; 186:1330.
  87. Edwards KM, Thompson J, Paolini J, Wright PF. Adenovirus infections in young children. Pediatrics 1985; 76:420.
  88. Esper F, Weibel C, Ferguson D, et al. Evidence of a novel human coronavirus that is associated with respiratory tract disease in infants and young children. J Infect Dis 2005; 191:492.
  89. Foulongne V, Rodière M, Segondy M. Human Bocavirus in children. Emerg Infect Dis 2006; 12:862.
  90. Mansbach JM, Camargo CA Jr. Respiratory viruses in bronchiolitis and their link to recurrent wheezing and asthma. Clin Lab Med 2009; 29:741.
  91. Pattemore PK, Johnston SL, Bardin PG. Viruses as precipitants of asthma symptoms. I. Epidemiology. Clin Exp Allergy 1992; 22:325.
  92. Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse association between tuberculin responses and atopic disorder. Science 1997; 275:77.
  93. Bardin PG, Johnston SL, Pattemore PK. Viruses as precipitants of asthma symptoms. II. Physiology and mechanisms. Clin Exp Allergy 1992; 22:809.
  94. Sterk PJ. Virus-induced airway hyperresponsiveness in man. Eur Respir J 1993; 6:894.
  95. Gern JE, Rosenthal LA, Sorkness RL, Lemanske RF Jr. Effects of viral respiratory infections on lung development and childhood asthma. J Allergy Clin Immunol 2005; 115:668.
  96. Duff AL, Pomeranz ES, Gelber LE, et al. Risk factors for acute wheezing in infants and children: viruses, passive smoke, and IgE antibodies to inhalant allergens. Pediatrics 1993; 92:535.
  97. Martinez FD, Morgan WJ, Wright AL, et al. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med 1988; 319:1112.
  98. 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.
  99. Stern DA, Morgan WJ, Wright AL, et al. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 2007; 370:758.
  100. Chong Neto HJ, Rosario N, Solé D, Mallol J. Associated factors for recurrent wheezing in infancy. Allergy 2010; 65:406.
  101. Kotaniemi-Syrjänen A, Vainionpää R, Reijonen TM, et al. Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma? J Allergy Clin Immunol 2003; 111:66.
  102. Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol 2010; 125:1202.
  103. Carroll KN, Wu P, Gebretsadik T, et al. Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma. J Allergy Clin Immunol 2009; 123:964.
  104. Rantala AK, Jaakkola MS, Mäkikyrö EM, et al. Early Respiratory Infections and the Development of Asthma in the First 27 Years of Life. Am J Epidemiol 2015; 182:615.
  105. Wu P, Dupont WD, Griffin MR, et al. Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am J Respir Crit Care Med 2008; 178:1123.
  106. Bartlett NW, McLean GR, Chang YS, Johnston SL. Genetics and epidemiology: asthma and infection. Curr Opin Allergy Clin Immunol 2009; 9:395.
  107. Gern JE. Rhinovirus and the initiation of asthma. Curr Opin Allergy Clin Immunol 2009; 9:73.
  108. 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.
  109. Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013; 368:1791.
  110. Shaheen SO. Changing patterns of childhood infection and the rise in allergic disease. Clin Exp Allergy 1995; 25:1034.
  111. Cypcar D, Busse WW. Role of viral infections in asthma. Immunol Allergy Clin North Am 1993; 13:745.
  112. 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.
  113. Cogswell JJ, Halliday DF, Alexander JR. Respiratory infections in the first year of life in children at risk of developing atopy. Br Med J (Clin Res Ed) 1982; 284:1011.
  114. Welliver RC. RSV and chronic asthma. Lancet 1995; 346:789.
  115. Bacharier LB, Cohen R, Schweiger T, et al. Determinants of asthma after severe respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol 2012; 130:91.
  116. Simões 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.
  117. 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.
  118. Calışkan M, Bochkov YA, Kreiner-Møller E, et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med 2013; 368:1398.
  119. Bønnelykke K, Sleiman P, Nielsen K, et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 2014; 46:51.
  120. von Mutius E, Martinez FD, Fritzsch C, et al. Skin test reactivity and number of siblings. BMJ 1994; 308:692.
  121. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989; 299:1259.
  122. Strachan DP, Harkins LS, Johnston ID, Anderson HR. Childhood antecedents of allergic sensitization in young British adults. J Allergy Clin Immunol 1997; 99:6.
  123. Tan WC, Xiang X, Qiu D, et al. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med 2003; 115:272.
  124. Bates DV, Baker-Anderson M, Sizto R. Asthma attack periodicity: a study of hospital emergency visits in Vancouver. Environ Res 1990; 51:51.
  125. Johnston SL, Bardin PG, Pattemore PK. Viruses as precipitants of asthma symptoms. III. Rhinoviruses: molecular biology and prospects for future intervention. Clin Exp Allergy 1993; 23:237.
  126. Bizzintino J, Lee WM, Laing IA, et al. Association between human rhinovirus C and severity of acute asthma in children. Eur Respir J 2011; 37:1037.
  127. Mak RK, Tse LY, Lam WY, et al. Clinical spectrum of human rhinovirus infections in hospitalized Hong Kong children. Pediatr Infect Dis J 2011; 30:749.
  128. Iwane MK, Prill MM, Lu X, et al. Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis 2011; 204:1702.
  129. Weiss KB. Seasonal trends in US asthma hospitalizations and mortality. JAMA 1990; 263:2323.
  130. Kimes D, Levine E, Timmins S, et al. Temporal dynamics of emergency department and hospital admissions of pediatric asthmatics. Environ Res 2004; 94:7.
  131. Johnston NW, Johnston SL, Norman GR, et al. The September epidemic of asthma hospitalization: school children as disease vectors. J Allergy Clin Immunol 2006; 117:557.
  132. Maffey AF, Barrero PR, Venialgo C, et al. Viruses and atypical bacteria associated with asthma exacerbations in hospitalized children. Pediatr Pulmonol 2010; 45:619.
  133. Corne JM, Marshall C, Smith S, et al. Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study. Lancet 2002; 359:831.
  134. Beasley R, Clayton T, Crane J, et al. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6-7 years: analysis from Phase Three of the ISAAC programme. Lancet 2008; 372:1039.
  135. Beasley RW, Clayton TO, Crane J, et al. Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. Am J Respir Crit Care Med 2011; 183:171.
  136. Wickens K, Beasley R, Town I, et al. The effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Clin Exp Allergy 2011; 41:399.
  137. Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics 2002; 109:E20.
  138. Sheehan WJ, Mauger DT, Paul IM, et al. Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. N Engl J Med 2016; 375:619.