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Asthma

Nature Reviews Disease Primers volume 1, Article number: 15025 (2015) Cite this article

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Abstract

Asthma is the most common inflammatory disease of the lungs. The prevalence of asthma is increasing in many parts of the world that have adopted aspects of the Western lifestyle, and the disease poses a substantial global health and economic burden. Asthma involves both the large-conducting and the small-conducting airways, and is characterized by a combination of inflammation and structural remodelling that might begin in utero. Disease progression occurs in the context of a developmental background in which the postnatal acquisition of asthma is strongly linked with allergic sensitization. Most asthma cases follow a variable course, involving viral-induced wheezing and allergen sensitization, that is associated with various underlying mechanisms (or endotypes) that can differ between individuals. Each set of endotypes, in turn, produces specific asthma characteristics that evolve across the lifecourse of the patient. Strong genetic and environmental drivers of asthma interconnect through novel epigenetic mechanisms that operate prenatally and throughout childhood. Asthma can spontaneously remit or begin de novo in adulthood, and the factors that lead to the emergence and regression of asthma, irrespective of age, are poorly understood. Nonetheless, there is mounting evidence that supports a primary role for structural changes in the airways with asthma acquisition, on which altered innate immune mechanisms and microbiota interactions are superimposed. On the basis of the identification of new causative pathways, the subphenotyping of asthma across the lifecourse of patients is paving the way for more-personalized and precise pathway-specific approaches for the prevention and treatment of asthma, creating the real possibility of total prevention and cure for this chronic inflammatory disease.

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Figure 1: Selected asthma subphenotypes.
Figure 2: Changing trends in the prevalence of asthma according to gross domestic product.
Figure 3: Proportions of children and adolescents with asthma in the Isle of Wight birth cohort.
Figure 4: Histopathology of the asthmatic airway.
Figure 5: Involvement of various T cell subtypes in asthma pathogenesis and asthma endotypes.
Figure 6: Allergen sensitization of the airways during the induction of allergic-type asthma.
Figure 7: Epithelial–mesenchymal trophic unit in asthma.
Figure 8: Asthma as a developmental disease.
Figure 9: Contribution of risk factors to the development and/or exacerbation of asthma.
Figure 10: Biomarkers for the assessment of T2-type asthma.
Figure 11: Global Initiative for Asthma-based steps for treatment of asthma at all stages of severity.
Figure 12: Overall goals of asthma management.

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References

  1. Global Initiative for Asthma. Global strategy for asthma management and prevention GINA[online], (2015).

  2. Lange, P., Parner, J., Vestbo, J., Schnohr, P. & Jensen, G. A 15-year follow-up study of ventilatory function in adults with asthma. N. Engl. J. Med. 339, 1194–1200 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Porsbjerg, C., Lange, P. & Ulrik, C. S. Lung function impairment increases with age of diagnosis in adult onset asthma. Respir. Med. 109, 821–827 (2015).

    Article  PubMed  Google Scholar 

  4. Custovic, A. To what extent is allergen exposure a risk factor for the development of allergic disease? Clin. Exp. Allergy 45, 54–62 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Amelink, M. et al. Severe adult-onset asthma: a distinct phenotype. J. Allergy Clin. Immunol. 132, 336–341 (2013).

    Article  PubMed  Google Scholar 

  6. Ledford, D. K. & Lockey, R. F. Asthma and comorbidities. Curr. Opin. Allergy Clin. Immunol. 13, 78–86 (2013).

    Article  PubMed  Google Scholar 

  7. Custovic, A. et al. EAACI position statement on asthma exacerbations and severe asthma. Allergy 68, 1520–1531 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Fu, L. et al. Natural progression of childhood asthma symptoms and strong influence of sex and puberty. Ann. Am. Thorac. Soc. 11, 939–944 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Soyka, M. B., van de Veen, W., Holzmann, D., Akdis, M. & Akdis, C. A. Scientific foundations of allergen-specific immunotherapy for allergic disease. Chest 146, 1347–1357 (2014).

    Article  PubMed  Google Scholar 

  10. Murray, C. S., Woodcock, A., Langley, S. J., Morris, J. & Custovic, A. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet 368, 754–762 (2006). This longitudinal birth-cohort study, along with similar studies, failed to show that regular ICSs administered to high-risk infants with viral-associated wheeze before they fully developed asthma had any effect in protecting children from developing asthma by 5 years of age.

    Article  CAS  PubMed  Google Scholar 

  11. Murray, C. S. Can inhaled corticosteroids influence the natural history of asthma? Curr. Opin. Allergy Clin. Immunol. 8, 77–81 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Moore, W. C. et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 181, 315–323 (2010).

    Article  PubMed  Google Scholar 

  13. World Health Organization. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. WHO[online], (2007).

  14. Wang, D. et al. Cross-sectional epidemiological survey of asthma in Jinan, China. Respirology 18, 313–322 (2013).

    Article  PubMed  Google Scholar 

  15. Jackson, D. J., Hartert, T. V., Martinez, F. D., Weiss, S. T. & Fahy, J. V. Asthma: NHLBI workshop on the primary prevention of chronic lung diseases. Ann. Am. Thorac. Soc. 11, S139–S145 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yunginger, J. W. et al. A community-based study of the epidemiology of asthma. Incidence rates,1964–1983. Am. Rev. Respir. Dis. 146, 888–894 (1992). This population-based survey showed that the median age of onset of asthma was 3 years for males and 8 years for females. These findings demonstrated that asthma begins in early childhood, with a higher incidence and earlier onset in males, and that the increase in incidence rates from 1964 to 1983 occurred only in children and adolescents.

    Article  CAS  PubMed  Google Scholar 

  17. Butland, B. K. & Strachan, D. P. Asthma onset and relapse in adult life: the British 1958 birth cohort study. Ann. Allergy Asthma Immunol. 98, 337–343 (2007).

    Article  PubMed  Google Scholar 

  18. Arshad, S. H. et al. Pathophysiological characterization of asthma transitions across adolescence. Respir. Res. 15, 153 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Szefler, S. J. Advances in pediatric asthma in 2014: moving toward a population health perspective. J. Allergy Clin. Immunol. 135, 644–652 (2015).

    Article  PubMed  Google Scholar 

  20. Dumas, O. et al. Occupational irritants and asthma: an Estonian cross-sectional study of 34,000 adults. Eur. Respir. J. 44, 647–656 (2014).

    Article  PubMed  Google Scholar 

  21. Simpson, A. et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am. J. Respir. Crit. Care Med. 181, 1200–1206 (2010).

    Article  PubMed  Google Scholar 

  22. Tai, A. et al. Outcomes of childhood asthma to the age of 50 years. J. Allergy Clin. Immunol. 133, 1572–1578.e3 (2014).

    Article  PubMed  Google Scholar 

  23. Wu, W. et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J. Allergy Clin. Immunol. 133, 1280–1288 (2014). In this study, unsupervised clustering approaches were applied to clinical, physiological and inflammatory variables from 378 individuals with asthma. Ten variable clusters and six subject clusters were identified, which differed and overlapped with previous clusters.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sporik, R., Holgate, S. T., Platts-Mills, T. A. & Cogswell, J. J. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood — a prospective study. N. Engl. J. Med. 323, 502–507 (1990). This highly cited study of 67 children from south England carried out in 1989 showed that the level of exposure in early childhood to household dust mite allergens is an important determinant of the subsequent development of asthma.

    Article  CAS  PubMed  Google Scholar 

  25. Permaul, P. et al. Allergens in urban schools and homes of children with asthma. Pediatr. Allergy Immunol. 23, 543–549 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Olivieri, M. et al. Risk factors for new-onset cat sensitization among adults: a population-based international cohort study. J. Allergy Clin. Immunol. 129, 420–425 (2012).

    Article  PubMed  Google Scholar 

  27. Djukanovic, R. et al. Mucosal inflammation in asthma. Am. Rev. Respir. Dis. 142, 434–457 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Fajt, M. L. & Wenzel, S. E. Mast cells, their subtypes, and relation to asthma phenotypes. Ann. Am. Thorac. Soc. 10, S158–S164 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Brightling, C. E. et al. Mast-cell infiltration of airway smooth muscle in asthma. N. Engl. J. Med. 346, 1699–1705 (2002). Asthma and eosinophilic bronchitis are characterized by similar inflammatory infiltrates in the submucosa of the lower airway. In this airway biopsy study, the main differentiating feature between the two conditions was the presence in asthma of MCTs between muscle bundles, whereas the location and number of eosinophils and T cells were similar in the two diseases.

    Article  PubMed  Google Scholar 

  30. Balzar, S. et al. Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 183, 299–309 (2011).

    Article  PubMed  Google Scholar 

  31. Holgate, S. T. Innate and adaptive immune responses in asthma. Nat. Med. 18, 673–683 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Fahy, J. V. Type 2 inflammation in asthma — present in most, absent in many. Nat. Rev. Immunol. 15, 57–65 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Truyen, E. et al. Evaluation of airway inflammation by quantitative Th1/Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax 61, 202–208 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chesné, J. et al. IL-17 in severe asthma. Where do we stand? Am. J. Respir. Crit. Care Med. 190, 1094–1101 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010). This important publication shows that nuocyte (ILC2) numbers expand in vivo in response to the T2-type-inducing cytokines IL-25 and IL-33, and represent the predominant early source of IL-13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL-25 and IL-33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro-cultured wild-type, but not IL-13-deficient, nuocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim, H. Y., DeKruyff, R. H. & Umetsu, D. T. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat. Immunol. 11, 577–584 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martinez-Gonzalez, I., Steer, C. A. & Takei, F. Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol. 36, 189–195 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Jain, V. V., Perkins, D. L. & Finn, P. W. Costimulation and allergic responses: immune and bioinformatic analyses. Pharmacol. Ther. 117, 385–392 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Lambrecht, B. N. & Hammad, H. The immunology of asthma. Nat. Immunol. 16, 45–56 (2014).

    Article  CAS  Google Scholar 

  40. Kay, A. B. The role of T lymphocytes in asthma. Chem. Immunol. Allergy 91, 59–75 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Jacquet, A. Interactions of airway epithelium with protease allergens in the allergic response. Clin. Exp. Allergy 41, 305–311 (2011). This excellent review draws attention to the interactions of protease allergens with the respiratory epithelium in facilitating their antigen presentation through epithelial barrier degradation, activating airway mucosal surfaces to recruit inflammatory cells and initiating airway remodelling. The authors suggest that a greater understanding of the effects of protease allergens on airway inflammation and on the relevant targets could define novel therapeutic strategies for the treatment of allergic asthma.

    Article  CAS  PubMed  Google Scholar 

  42. Lambrecht, B. N. & Hammad, H. Biology of lung dendritic cells at the origin of asthma. Immunity 31, 412–424 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Kemeny, D. M. The role of the T follicular helper cells in allergic disease. Cell. Mol. Immunol. 9, 386–389 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Perros, F., Hoogsteden, H. C., Coyle, A. J., Lambrecht, B. N. & Hammad, H. Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy 64, 995–1002 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Bradding, P., Walls, A. F. & Holgate, S. T. The role of the mast cell in the pathophysiology of asthma. J. Allergy Clin. Immunol. 117, 1277–1284 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Ma, L. L. & O'Byrne, P. M. The pharmacological modulation of allergen-induced asthma. Inflammopharmacology 21, 113–124 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Hargreave, F. E., Dolovich, J., O'Byrne, P. M., Ramsdale, E. H. & Daniel, E. E. The origin of airway hyperresponsiveness. J. Allergy Clin. Immunol. 78, 825–832 (1986).

    Article  CAS  PubMed  Google Scholar 

  48. Diamant, Z. et al. Inhaled allergen bronchoprovocation tests. J. Allergy Clin. Immunol. 132, 1045–1055.e6 (2013). This is a comprehensive review of the allergen provocation tests used to measure allergen-related bronchial hyper-responsiveness.

    Article  CAS  PubMed  Google Scholar 

  49. Barnig, C. et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma.Sci. Transl. Med. 5, 174ra26 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Barbers, R. G. et al. Near fatal asthma: clinical and airway biopsy characteristics. Pulm. Med. 2012, 829608 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Al-Muhsen, S., Johnson, J. R. & Hamid, Q. Remodeling in asthma. J. Allergy Clin. Immunol. 128, 451–462 (2011).

    Article  PubMed  Google Scholar 

  52. Bjermer, L. The role of small airway disease in asthma. Curr. Opin. Pulm. Med. 20, 23–30 (2014). This is a review summarizing the literature showing that inflammation and remodelling occur from the central to peripheral airways in asthma.

    Article  PubMed  Google Scholar 

  53. Boucherat, O., Boczkowski, J., Jeannotte, L. & Delacourt, C. Cellular and molecular mechanisms of goblet cell metaplasia in the respiratory airways. Exp. Lung Res. 39, 207–216 (2013).

    Article  PubMed  Google Scholar 

  54. Roche, W. R., Beasley, R., Williams, J. H. & Holgate, S. T. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1, 520–524 (1989).

    Article  CAS  PubMed  Google Scholar 

  55. Kanemitsu, Y. et al. Osteopontin and periostin are associated with a 20-year decline of pulmonary function in patients with asthma. Am. J. Respir. Crit. Care Med. 190, 472–474 (2014).

    Article  PubMed  Google Scholar 

  56. Liesker, J. J. W. et al. Reticular basement membrane in asthma and COPD: similar thickness, yet different composition. Int. J. Chron. Obstruct. Pulmon. Dis. 4, 127–135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Holgate, S. T. et al. Epithelial–mesenchymal communication in the pathogenesis of chronic asthma. Proc. Am. Thorac. Soc. 1, 93–98 (2004). This review proposes the hypothesis that epithelial damage in patients with asthma initiates aberrant communication, mediated by growth factors, between the epithelium and the underlying myofibroblast sheath to drive airway remodelling, which is termed activation of the epithelial–mesenchymal trophic unit.

    Article  CAS  PubMed  Google Scholar 

  58. Chanez, P. et al. Platelet-derived growth factor in asthma. Allergy 50, 878–883 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Puddicombe, S. M. et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 14, 1362–1374 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Olgart Höglund, C. et al. Nerve growth factor levels and localisation in human asthmatic bronchi. Eur. Respir. J. 20, 1110–1116 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Lopez-Guisa, J. M. et al. Airway epithelial cells from asthmatic children differentially express proremodeling factors. J. Allergy Clin. Immunol. 129, 990.e6–997.e6 (2012). Using nasal epithelial cells, these investigators showed that, in asthma, such cells cultured in vitro differentially express the growth factors TGFβ2, vascular endothelial growth factor and periostin when compared with cells from atopic non-asthmatic and healthy children. They suggest that nasal epithelial cells might be a suitable surrogate for bronchial cells that could facilitate investigation of the airway epithelium in future longitudinal paediatric studies.

    Article  CAS  Google Scholar 

  62. Harkness, L. M., Ashton, A. W. & Burgess, J. K. Asthma is not only an airway disease, but also a vascular disease. Pharmacol. Ther. 148, 17–33 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Puddicombe, S. M. et al. Increased expression of p21waf cyclin-dependent kinase inhibitor in asthmatic bronchial epithelium. Am. J. Respir. Cell. Mol. Biol. 28, 61–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Alcala, S. E. et al. Mitotic asynchrony induces transforming growth factor-β1 secretion from airway epithelium. Am. J. Respir. Cell. Mol. Biol. 51, 363–369 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Johnson, J. R. et al. Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L658–L671 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Descalzi, D. et al. Importance of fibroblasts–myofibroblasts in asthma-induced airway remodeling. Recent Pat. Inflamm. Allergy Drug Discov. 1, 237–241 (2007).

    Article  PubMed  Google Scholar 

  67. Pepe, C. et al. Differences in airway remodeling between subjects with severe and moderate asthma. J. Allergy Clin. Immunol. 116, 544–549 (2005).

    Article  PubMed  Google Scholar 

  68. Glezen, W. P., Taber, L. H., Frank, A. L. & Kasel, J. A. Risk of primary infection and reinfection with respiratory syncytial virus. Am. J. Dis. Child. 140, 543–546 (1986).

    CAS  PubMed  Google Scholar 

  69. Turner, S. et al. A longitudinal study of lung function from 1 month to 18 years of age. Thorax 69, 1015–1020 (2014). This article describes longitudinal tracking of lung function from birth to young adult life. This comes from the family of studies linking lung function and airway responsiveness in infancy to asthma risk in later life.

    Article  PubMed  Google Scholar 

  70. Morgan, W. J. et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am. J. Respir. Crit. Care Med. 172, 1253–1258 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Robertson, C. F. Long-term outcome of childhood asthma. Med. J. Aust. 177, S42–S44 (2002).

    PubMed  Google Scholar 

  72. Van Putte-Katier, N. et al. Relationship between parental lung function and their children's lung function early in life. Eur. Respir. J. 38, 664–671 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Soler Artigas, M. et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat. Genet. 43, 1082–1090 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Young, S. et al. The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy. N. Engl. J. Med. 324, 1168–1173 (1991). This landmark paper demonstrated airway responsiveness in infancy related to a family history of asthma. Subsequent studies in this cohort have shown this responsiveness to be highly predictive of persistent asthma in later life.

    Article  CAS  PubMed  Google Scholar 

  75. Latzin, P., Röösli, M., Huss, A., Kuehni, C. E. & Frey, U. Air pollution during pregnancy and lung function in newborns: a birth cohort study. Eur. Respir. J. 33, 594–603 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Stick, S. M., Burton, P. R., Gurrin, L., Sly, P. D. & LeSouëf, P. N. Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 348, 1060–1064 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Sly, P. D., Soto-Quiros, M. E., Landau, L. I., Hudson, I. & Newton-John, H. Factors predisposing to abnormal pulmonary function after adenovirus type 7 pneumonia. Arch. Dis. Child. 59, 935–939 (1984). This study links infections to reduced lung function in childhood, a factor that was later shown to be associated with the development of asthma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sly, P. D. & Hibbert, M. E. Childhood asthma following hospitalization with acute viral bronchiolitis in infancy. Pediatr. Pulmonol. 7, 153–158 (1989).

    Article  CAS  PubMed  Google Scholar 

  79. Guilbert, T. W. et al. Decreased lung function after preschool wheezing rhinovirus illnesses in children at risk to develop asthma. J. Allergy Clin. Immunol. 128, 532–538.e10 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Jackson, D. J. et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am. J. Respir. Crit. Care Med. 178, 667–672 (2008). This study highlights the major risk for asthma in children who continue to wheeze with acute rhinovirus infections into their third year of life.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Jackson, D. J. et al. Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life. Am. J. Respir. Crit. Care Med. 185, 281–285 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wark, P. A. B. et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201, 937–947 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Edwards, M. R. et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol. 6, 797–806 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Belsky, D. W. & Sears, M. R. The potential to predict the course of childhood asthma. Expert Rev. Respir. Med. 8, 137–141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chan, K. N. et al. Airway responsiveness in low birthweight children and their mothers. Arch. Dis. Child. 63, 905–910 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sonnenschein-van der Voort, A. M. et al. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. J. Allergy Clin. Immunol. 133, 1317–1329 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kennedy, J. D. Lung function outcome in children of premature birth. J. Paediatr. Child Health 35, 516–521 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Renz, H. et al. Gene–environment interactions in chronic inflammatory disease. Nat. Immunol. 12, 273–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Litonjua, A. A. & Weiss, S. T. Is vitamin D deficiency to blame for the asthma epidemic? J. Allergy Clin. Immunol. 120, 1031–1035 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Weiss, S. T. Bacterial components plus vitamin D: the ultimate solution to the asthma (autoimmune disease) epidemic? J. Allergy Clin. Immunol. 127, 1128–1130 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Sundar, I. K. & Rahman, I. Vitamin D and susceptibility of chronic lung diseases: role of epigenetics. Front. Pharmacol. 2, 50 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Shaheen, S. O. & Adcock, I. M. The developmental origins of asthma: does epigenetics hold the key? Am. J. Respir. Crit. Care Med. 180, 690–691 (2009).

    Article  PubMed  Google Scholar 

  94. Huang, Y. J. & Boushey, H. A. The microbiome in asthma. J. Allergy Clin. Immunol. 135, 25–30 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Holt, P. G., Strickland, D. H., Hales, B. J. & Sly, P. D. Defective respiratory tract immune surveillance in asthma: a primary causal factor in disease onset and progression. Chest 145, 370–378 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Holt, P. G. Prevention — what is the most promising approach? Pediatr. Allergy Immunol. 25, 12–14 (2014). This editorial summarizes a substantial body of evidence gained from longitudinal studies of birth cohorts that suggest that a balanced immune response to bacteria resident on airway mucosal surfaces might limit the risk of asthma.

    Article  PubMed  Google Scholar 

  97. Hales, B. J. et al. Antibacterial antibody responses associated with the development of asthma in house dust mite-sensitised and non-sensitised children. Thorax 67, 321–327 (2012).

    Article  PubMed  Google Scholar 

  98. Hales, B. J. et al. Differences in the antibody response to a mucosal bacterial antigen between allergic and non-allergic subjects. Thorax 63, 221–227 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Holt, P. G. & Sly, P. D. Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment. Nat. Med. 18, 726–735 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Hollams, E. M. et al. Th2-associated immunity to bacteria in teenagers and susceptibility to asthma. Eur. Respir. J. 36, 509–516 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Saglani, S. et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am. J. Respir. Crit. Care Med. 176, 858–864 (2007).

    Article  PubMed  Google Scholar 

  102. Malmström, K. et al. Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years. Thorax 66, 157–162 (2011).

    Article  PubMed  Google Scholar 

  103. Sonnappa, S., Bastardo, C. M., Saglani, S., Bush, A. & Aurora, P. Relationship between past airway pathology and current lung function in preschool wheezers. Eur. Respir. J. 38, 1431–1436 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. O'Reilly, R. et al. Increased airway smooth muscle in preschool wheezers who have asthma at school age. J. Allergy Clin. Immunol. 131, 1024–1032.e16 (2013). This is one of only a few studies on airway tissue from preschool-aged children with asthma that shows increased airway smooth muscle in these children. The results led the authors to the conclusion that a focus on early changes in smooth muscle might be important in understanding the subsequent development of childhood asthma.

    Article  PubMed  Google Scholar 

  105. Regamey, N. et al. Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis. Am. J. Respir. Crit. Care Med. 177, 837–843 (2008).

    Article  PubMed  Google Scholar 

  106. An, S. S. & Fredberg, J. J. Biophysical basis for airway hyperresponsiveness. Can. J. Physiol. Pharmacol. 85, 700–714 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Grainge, C. L. et al. Effect of bronchoconstriction on airway remodeling in asthma. N. Engl. J. Med. 364, 2006–2015 (2011). This landmark study provides proof of principle for the concept that the mechanical stress on the airways imposed by bronchoconstriction might contribute to airway remodelling.

    Article  CAS  PubMed  Google Scholar 

  108. Grainge, C. et al. Resistin-like molecule-β is induced following bronchoconstriction of asthmatic airways. Respirology 17, 1094–1100 (2012).

    Article  PubMed  Google Scholar 

  109. Chu, E. K. et al. Induction of the plasminogen activator system by mechanical stimulation of human bronchial epithelial cells. Am. J. Respir. Cell. Mol. Biol. 35, 628–638 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Park, J.-A., Drazen, J. M. & Tschumperlin, D. J. The chitinase-like protein YKL-40 is secreted by airway epithelial cells at base line and in response to compressive mechanical stress. J. Biol. Chem. 285, 29817–29825 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Holgate, S. T. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol. Rev. 242, 205–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Bedke, N. et al. Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response. PLoS ONE 7, e44580 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Djukanovic, R. et al. The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial. Am. J. Respir. Crit. Care Med. 190, 145–154 (2014). Following the discovery that in moderate-to-severe asthma there is a deficiency in epithelial interferon production upon infection with common respiratory viruses, this randomized controlled trial showed that, in such individuals, inhaled IFNβ at the start of an upper respiratory tract infection can protect against exacerbation of asthma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Vink, N. M., Postma, D. S., Schouten, J. P., Rosmalen, J. G. & Boezen, H. M. Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents' Individual Lives Survey (TRAILS) study. J. Allergy Clin. Immunol. 126, 498–504.e6 (2010).

    Article  PubMed  Google Scholar 

  115. Van den Toorn, L. M. et al. Airway inflammation is present during clinical remission of atopic asthma. Am. J. Respir. Crit. Care Med. 164, 2107–2113 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Wood, R. A., Laheri, A. N. & Eggleston, P. A. The aerodynamic characteristics of cat allergen. Clin. Exp. Allergy 23, 733–739 (1993).

    Article  CAS  PubMed  Google Scholar 

  117. Vonk, J. M. et al. Childhood factors associated with asthma remission after 30 year follow up. Thorax 59, 925–929 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Broekema, M. et al. Airway eosinophilia in remission and progression of asthma: accumulation with a fast decline of FEV1 . Respir. Med. 104, 1254–1262 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Broekema, M. et al. Persisting remodeling and less airway wall eosinophil activation in complete remission of asthma. Am. J. Respir. Crit. Care Med. 183, 310–316 (2011).

    Article  PubMed  Google Scholar 

  120. Volbeda, F. et al. Can AMP induce sputum eosinophils, even in subjects with complete asthma remission? Respir. Res. 11, 106 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Shaaban, R. et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet 372, 1049–1057 (2008).

    Article  PubMed  Google Scholar 

  122. Platts-Mills, T., Vaughan, J., Squillace, S., Woodfolk, J. & Sporik, R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357, 752–756 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Torrent, M. et al. Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age. Am. J. Respir. Crit. Care Med. 176, 446–453 (2007).

    Article  PubMed  Google Scholar 

  124. Scott, M. et al. Multifaceted allergen avoidance during infancy reduces asthma during childhood with the effect persisting until age 18 years. Thorax 67, 1046–1051 (2012). This longitudinal randomized controlled trial on babies considered at high risk of asthma owing to heredity showed that, within the first 12 months of life, intervention with either breastfeeding with the mother on a low-allergen diet or an extensively hydrolysed formula combined with reduced exposure to house dust mite allergen prevented the onset of asthma. The effect occurred in the early years but persisted through to adulthood.

    Article  PubMed  Google Scholar 

  125. Kovac, K., Dodig, S., Tjesic-Drinkovic, D. & Raos, M. Correlation between asthma severity and serum IgE in asthmatic children sensitized to Dermatophagoides pteronyssinus. Arch. Med. Res. 38, 99–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Adgate, J. L., Ramachandran, G., Cho, S. J., Ryan, A. D. & Grengs, J. Allergen levels in inner city homes: baseline concentrations and evaluation of intervention effectiveness. J. Expo. Sci. Environ. Epidemiol. 18, 430–440 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. MacDonald, C., Sternberg, A. & Hunter, P. R. A systematic review and meta-analysis of interventions used to reduce exposure to house dust and their effect on the development and severity of asthma. Environ. Health Perspect. 115, 1691–1695 (2007). This meta-analysis of 14 studies concluded that there was not sufficient evidence to support implementing hygiene measures to improve outcomes in existing atopic disease. However, interventions from birth in those at high risk of atopy were found to be useful in preventing diagnosed asthma but not parental-reported wheeze.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Van Schayck, O. C., Maas, T., Kaper, J., Knottnerus, A. J. & Sheikh, A. Is there any role for allergen avoidance in the primary prevention of childhood asthma? J. Allergy Clin. Immunol. 119, 1323–1328 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Braun-Fahrländer, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).

    Article  PubMed  Google Scholar 

  130. Ege, M. J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Heederik, D. & von Mutius, E. Does diversity of environmental microbial exposure matter for the occurrence of allergy and asthma? J. Allergy Clin. Immunol. 130, 44–50 (2012).

    Article  PubMed  Google Scholar 

  132. Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat. Rev. Immunol. 12, 9–23 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Carroll, K. N. et al. Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma. J. Allergy Clin. Immunol. 123, 964–966 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Jackson, D. J. & Lemanske, R. F. The role of respiratory virus infections in childhood asthma inception. Immunol. Allergy Clin. North Am. 30, 513–522 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Durrani, S. R. et al. Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J. Allergy Clin. Immunol. 130, 489–495 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mortensen, L. J., Kreiner-Møller, E., Hakonarson, H., Bønnelykke, K. & Bisgaard, H. The PCDH1 gene and asthma in early childhood. Eur. Respir. J. 43, 792–800 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Bønnelykke, K. et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat. Genet. 46, 51–55 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Klaassen, E. M. et al. An ADAM33 polymorphism associates with progression of preschool wheeze into childhood asthma: a prospective case–control study with replication in a birth cohort study. PLoS ONE 10, e0119349 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Huang, S.-K., Zhang, Q., Qiu, Z. & Chung, K. F. Mechanistic impact of outdoor air pollution on asthma and allergic diseases. J. Thorac. Dis. 7, 23–33 (2015).

    PubMed  PubMed Central  Google Scholar 

  140. Guarnieri, M. & Balmes, J. R. Outdoor air pollution and asthma. Lancet 383, 1581–1592 (2014). This recent review confirms the link between outdoor air pollution and exacerbations of pre-existing asthma. It also suggests that air pollution contributes to new-onset asthma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Chan, J. K. et al. Combustion-derived flame generated ultrafine soot generates reactive oxygen species and activates Nrf2 antioxidants differently in neonatal and adult rat lungs. Part. Fibre Toxicol. 10, 34 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wang, P., Thevenot, P., Saravia, J., Ahlert, T. & Cormier, S. A. Radical-containing particles activate dendritic cells and enhance Th17 inflammation in a mouse model of asthma. Am. J. Respir. Cell. Mol. Biol. 45, 977–983 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nadeau, K. et al. Ambient air pollution impairs regulatory T-cell function in asthma. J. Allergy Clin. Immunol. 126, 845–852.e10 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Gowers, A. M. et al. Does outdoor air pollution induce new cases of asthma? Biological plausibility and evidence; a review. Respirology 17, 887–898 (2012).

    Article  PubMed  Google Scholar 

  145. Goodman, J. E., Chandalia, J. K., Thakali, S. & Seeley, M. Meta-analysis of nitrogen dioxide exposure and airway hyper-responsiveness in asthmatics. Crit. Rev. Toxicol. 39, 719–742 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Gauderman, W. J. et al. Association of improved air quality with lung development in children. N. Engl. J. Med. 372, 905–913 (2015). Levels of air pollution have been trending progressively downward over the past several decades in southern California, as a result of the implementation of air quality-control policies. Here, the authors show that long-term reductions in air pollution were associated with improvements in lung growth and respiratory health among children.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yang, I. A., Fong, K. M., Zimmerman, P. V., Holgate, S. T. & Holloway, J. W. Genetic susceptibility to the respiratory effects of air pollution. Postgrad. Med. J. 85, 428–436 (2009).

    CAS  PubMed  Google Scholar 

  148. Esposito, S. et al. Possible molecular mechanisms linking air pollution and asthma in children. BMC Pulm. Med. 14, 31 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Vork, K. L., Broadwin, R. L. & Blaisdell, R. J. Developing asthma in childhood from exposure to secondhand tobacco smoke: insights from a meta-regression. Environ. Health Perspect. 115, 1394–1400 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Burke, H. et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 129, 735–744 (2012).

    Article  PubMed  Google Scholar 

  151. Feleszko, W. et al. Parental tobacco smoking is associated with augmented IL-13 secretion in children with allergic asthma. J. Allergy Clin. Immunol. 117, 97–102 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Li, Y.-F., Langholz, B., Salam, M. T. & Gilliland, F. D. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest 127, 1232–1241 (2005). In this key study on generational influences on asthma, a case–control study nested within the Children's Health Study in southern California comprising 338 children with asthma that had been diagnosed in the first 5 years of life, and 570 control individuals, was conducted. The study showed that maternal and grandmaternal smoking during pregnancy might increase the risk of childhood asthma, possibly through epigenetic mechanisms.

    PubMed  Google Scholar 

  153. Mebrahtu, T. F., Feltbower, R. G., Greenwood, D. C. & Parslow, R. C. Childhood body mass index and wheezing disorders: a systematic review and meta-analysis. Pediatr. Allergy Immunol. 26, 62–72 (2015).

    Article  PubMed  Google Scholar 

  154. Forno, E., Young, O. M., Kumar, R., Simhan, H. & Celedon, J. C. Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma. Pediatrics 134, e535–e546 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Torday, J. S. et al. Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L405–L410 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Shore, S. A. et al. Effect of leptin on allergic airway responses in mice. J. Allergy Clin. Immunol. 115, 103–109 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. McLachlan, C. R. et al. Adiposity, asthma, and airway inflammation. J. Allergy Clin. Immunol. 119, 634–639 (2007).

    Article  PubMed  Google Scholar 

  158. Kattan, M. et al. Asthma control, adiposity, and adipokines among inner-city adolescents. J. Allergy Clin. Immunol. 125, 584–592 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Aaron, S. D. et al. Overdiagnosis of asthma in obese and nonobese adults. CMAJ 179, 1121–1131 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  160. [No authors listed.] Statement on standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am. Rev. Respir. Dis. 136, 225–244 (1987).

  161. National Institute for Health and Care Excellence. Asthma: diagnosis and monitoring of asthma in adults, children and young people. NICE[online], (2015).

  162. Pavord, I. D., Bush, A. & Holgate, S. Asthma diagnosis: addressing the challenges. Lancet Respir. Med. 3, 339–341 (2015). This editorial highlights the lack of uptake of diagnostic tests to identify inflammation of the airways in patients with asthma in both diagnosis and long-term management, which leads to suboptimal disease control.

    Article  PubMed  Google Scholar 

  163. Wenzel, S. E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 18, 716–725 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Woodruff, P. G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Green, R. H. et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360, 1715–1721 (2002). This landmark study demonstrated that control of asthma using sputum eosinophil numbers to titre ICS use as an adjunct to symptoms and lung function produced better disease control and less overall corticosteroid use. On the basis of these findings, the authors concluded that an asthma treatment strategy directed at normalization of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.

    Article  PubMed  Google Scholar 

  167. Jayaram, L. et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur. Respir. J. 27, 483–494 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Bel, E. H. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 371, 1189–1197 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Pavord, I. D. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380, 651–659 (2012).

    Article  CAS  PubMed  Google Scholar 

  170. Guo, F. H. et al. Interferon γ and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J. Clin. Invest. 100, 829–838 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Modena, B. D. et al. Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways. Am. J. Respir. Crit. Care Med. 190, 1363–1372 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Smith, A. D. et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am. J. Respir. Crit. Care Med. 169, 473–478 (2004).

    Article  PubMed  Google Scholar 

  173. Wenzel, S. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 368, 2455–2466 (2013). In this paper, which describes one of several biologic interventions in severe asthma, the authors investigated the efficacy and safety of dupilumab, a fully human monoclonal antibody raised against the α-subunit of the IL-4 receptor, in patients with persistent, moderate-to-severe asthma and increased eosinophil counts. Patients received the study drug or placebo for 12 weeks or until a protocol-defined asthma exacerbation occurred. The results showed that dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and ICSs were withdrawn accompanied by improved lung function and reduced levels of TH2-associated inflammatory markers.

    Article  CAS  PubMed  Google Scholar 

  174. Hanania, N. A. et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am. J. Respir. Crit. Care Med. 187, 804–811 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Takayama, G. et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J. Allergy Clin. Immunol. 118, 98–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  176. Sidhu, S. S. et al. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. Proc. Natl Acad. Sci. USA 107, 14170–14175 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Conway, S. J. et al. The role of periostin in tissue remodeling across health and disease. Cell. Mol. Life Sci. 71, 1279–1288 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. Jia, G. et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J. Allergy Clin. Immunol. 130, 647–654.e10 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Izuhara, K. et al. Periostin in allergic inflammation. Allergol. Int. 63, 143–151 (2014). Periostin is an extracellular matrix protein involved in remodelling during tissue and/or organ development or repair that is under the control of IL-4 and IL-13 in the airways. In this review, not only do the authors point to the usefulness of serum periostin as a TH2 biomarker but they also suggest that, at least in skin, periostin is crucial for amplification and persistence of allergic inflammation by communicating between fibroblasts and keratinocytes. In addition, they suggest that blocking the interaction between periostin and its receptor, αv integrin, or downregulating periostin expression might be a novel asthma intervention.

    Article  CAS  PubMed  Google Scholar 

  180. Schulman, E. S. & Pohlig, C. Rationale for specific allergen testing of patients with asthma in the clinical pulmonary office setting. Chest 147, 251–258 (2015).

    Article  PubMed  Google Scholar 

  181. Ortega, H. G. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371, 1198–1207 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Choy, D. F. et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci. Transl. Med. 7, 301ra129 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Mauri, P. et al. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol. Lett. 162, 2–10 (2014).

    Article  CAS  PubMed  Google Scholar 

  184. Duncan, J. M. & Sears, M. R. Breastfeeding and allergies: time for a change in paradigm? Curr. Opin. Allergy Clin. Immunol. 8, 398–405 (2008).

    Article  PubMed  Google Scholar 

  185. Kramer, M. S. Breastfeeding and allergy: the evidence. Ann. Nutr. Metab. 59, S20–S26 (2011).

    Article  CAS  Google Scholar 

  186. Oddy, W. H., Peat, J. K. & de Klerk, N. H. Maternal asthma, infant feeding, and the risk of asthma in childhood. J. Allergy Clin. Immunol. 110, 65–67 (2002).

    Article  PubMed  Google Scholar 

  187. Sears, M. R. et al. Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study. Lancet 360, 901–907 (2002).

    Article  PubMed  Google Scholar 

  188. Dogaru, C. M., Nyffenegger, D., Pescatore, A. M., Spycher, B. D. & Kuehni, C. E. Breastfeeding and childhood asthma: systematic review and meta-analysis. Am. J. Epidemiol. 179, 1153–1167 (2014). Although controversial for many years, this systematic review and meta-analysis of studies published between 1983 and 2012 on breastfeeding and asthma in children from the general population found a positive association between breastfeeding and reduced asthma and/or wheezing, and is supported by the combined evidence of existing studies.

    Article  PubMed  Google Scholar 

  189. Ramos, G. F. et al. Cost-effectiveness of primary prevention of paediatric asthma: a decision-analytic model. Eur. J. Health Econ. 15, 869–883 (2014).

    Article  PubMed  Google Scholar 

  190. Litonjua, A. A. et al. The Vitamin D Antenatal Asthma Reduction Trial (VDAART): rationale, design, and methods of a randomized, controlled trial of vitamin D supplementation in pregnancy for the primary prevention of asthma and allergies in children. Contemp. Clin. Trials 38, 37–50 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Yang, H., Xun, P. & He, K. Fish and fish oil intake in relation to risk of asthma: a systematic review and meta-analysis. PLoS ONE 8, e80048 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Anandan, C., Nurmatov, U. & Sheikh, A. Omega 3 and 6 oils for primary prevention of allergic disease: systematic review and meta-analysis. Allergy 64, 840–848 (2009).

    Article  CAS  PubMed  Google Scholar 

  193. Von Mutius, E. & Vercelli, D. Farm living: effects on childhood asthma and allergy. Nat. Rev. Immunol. 10, 861–868 (2010).

    Article  CAS  PubMed  Google Scholar 

  194. Elazab, N. et al. Probiotic administration in early life, atopy, and asthma: a meta-analysis of clinical trials. Pediatrics 132, e666–e676 (2013).

    Article  PubMed  Google Scholar 

  195. West, C. E., Hammarströ m, M.-L. & Hernell, O. Probiotics in primary prevention of allergic disease — follow-up at 8–9 years of age. Allergy 68, 1015–1020 (2013).

    Article  CAS  PubMed  Google Scholar 

  196. Bengmark, S. Gut microbiota, immune development and function. Pharmacol. Res. 69, 87–113 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Nieto, A. et al. Allergy and asthma prevention 2014. Pediatr. Allergy Immunol. 25, 516–533 (2014).

    Article  PubMed  Google Scholar 

  198. Heine, R. G. Preventing atopy and allergic disease. Nestle Nutr. Inst. Workshop Ser. 78, 141–153 (2014).

    Article  PubMed  Google Scholar 

  199. Tamblyn, R. et al. Evaluating the impact of an integrated computer-based decision support with person-centered analytics for the management of asthma in primary care: a randomized controlled trial. J. Am. Med. Inform. Assoc. 22, 773–783 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Griffiths, C. & Levy, M. L. Preventing avoidable asthma deaths. Practitioner 258, 27–31 (2014).

    PubMed  Google Scholar 

  201. Toelle, B. G. & Ram, F. S. Written individualised management plans for asthma in children and adults. Cochrane Database Syst. Rev. 2, CD002171 (2004).

    Google Scholar 

  202. Depner, M. et al. Clinical and epidemiologic phenotypes of childhood asthma. Am. J. Respir. Crit. Care Med. 189, 129–138 (2014).

    PubMed  Google Scholar 

  203. Pedersen, S. E. et al. Global strategy for the diagnosis and management of asthma in children 5 years and younger. Pediatr. Pulmonol. 46, 1–17 (2011).

    Article  PubMed  Google Scholar 

  204. Roberts, N. J. et al. The development and comprehensibility of a pictorial asthma action plan. Patient Educ. Couns. 74, 12–18 (2009).

    Article  PubMed  Google Scholar 

  205. National Heart Lung and Blood Advisory Council Asthma Expert Working Group. Draft needs assessment report for potential update of the expert panel report-3 (2007): guidelines for the diagnosis and management of asthma January 2015. NIH [online], (2015).

  206. British Thoracic Society & Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 69, S1–S192 (2014).

    Google Scholar 

  207. Papi, A. et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir. Med. 1, 23–31 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Lipworth, B. J. Emerging role of long acting muscarinic antagonists for asthma. Br. J. Clin. Pharmacol. 77, 55–62 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Matera, M. G. & Cazzola, M. Ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs 67, 503–515 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. Loymans, R. J. B. et al. Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: network meta-analysis. BMJ 348, g3009 (2014). In this comprehensive study, 64 trials with 59,622 patient years of follow-up comparing 15 strategies and placebo were evaluated for the prevention of severe exacerbations, combined ICSs and LABAs as maintenance and reliever treatment and combined ICSs alone. It found that LABAs in a fixed daily dose performed equally well and were ranked first for effectiveness. The overall conclusion was that strategies with combined ICSs and long-acting β-adrenergic agonists are most effective and safe in preventing severe exacerbations of asthma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Abramson, M. J., Puy, R. M. & Weiner, J. M. Injection allergen immunotherapy for asthma. Cochrane Database Syst. Rev. 8, CD001186 (2010).

  212. Mosbech, H. et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J. Allergy Clin. Immunol. 134, 568–575.e7 (2014).

    Article  CAS  PubMed  Google Scholar 

  213. Kelly, W., Massoumi, A. & Lazarus, A. Asthma in pregnancy: physiology, diagnosis, and management. Postgrad. Med. 127, 349–358 (2015).

    Article  PubMed  Google Scholar 

  214. Price, D. et al. Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness. Curr. Allergy Asthma Rep. 11, 526–538 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Qamar, N., Pappalardo, A. A., Arora, V. M. & Press, V. G. Patient-centered care and its effect on outcomes in the treatment of asthma. Patient Relat. Outcome Meas. 2, 81–109 (2011).

    PubMed  PubMed Central  Google Scholar 

  216. Hinks, T. S. C. et al. Innate and adaptive T cells in asthmatic patients: relationship to severity and disease mechanisms. J. Allergy Clin. Immunol. 136, 323–333 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Holgate, S. T. Stratified approaches to the treatment of asthma. Br. J. Clin. Pharmacol. 76, 277–291 (2013).

    Article  PubMed  Google Scholar 

  218. Campo, P. et al. Phenotypes and endotypes of uncontrolled severe asthma: new treatments. J. Investig. Allergol. Clin. Immunol. 23, 76–88 (2013).

    CAS  PubMed  Google Scholar 

  219. Krug, N. et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N. Engl. J. Med. 372, 1987–1995 (2015).

    Article  PubMed  Google Scholar 

  220. Hambly, N. & Nair, P. Monoclonal antibodies for the treatment of refractory asthma. Curr. Opin. Pulm. Med. 20, 87–94 (2014).

    Article  CAS  PubMed  Google Scholar 

  221. Lima, J. J. Do genetic polymorphisms alter patient response to inhaled bronchodilators? Expert Opin. Drug Metab. Toxicol. 10, 1231–1240 (2014).

    Article  CAS  PubMed  Google Scholar 

  222. Zuurhout, M. J. L. et al. Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting β2-agonists: results of the PACMAN cohort. Pharmacogenomics 14, 1965–1971 (2013).

    Article  CAS  PubMed  Google Scholar 

  223. Manoharan, A. et al. β2-adrenergic receptor Gly16Arg polymorphism and impaired asthma control in corticosteroid-treated asthmatic adults. Ann. Allergy. Asthma Immunol. 114, 421–423 (2015).

    Article  CAS  PubMed  Google Scholar 

  224. Ortega, V. E. et al. Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during longacting β agonist treatment in a multiethnic asthma population: a genetic study. Lancet Respir. Med. 2, 204–213 (2014). Although polymorphisms of the β2-adrenergic receptor especially, at amino acids 16 and 27, have been associated with more-active asthma and impaired β-agonist treatment responsiveness, this comprehensive genotypic analysis has shown that the rare adrenoceptor β2 gene (ADRB2) variants Ile164 and -376ins are associated with severe adverse events during LABA therapy. It is suggested that they should be evaluated in large clinical trials, including in the current FDA-mandated safety study.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Meyers, D. A., Bleecker, E. R., Holloway, J. W. & Holgate, S. T. Asthma genetics and personalised medicine. Lancet Respir. Med. 2, 405–415 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Miller, R. J. & Murgu, S. D. Interventional pulmonology for asthma and emphysema: bronchial thermoplasty and bronchoscopic lung volume reduction. Semin. Respir. Crit. Care Med. 35, 655–670 (2014).

    Article  PubMed  Google Scholar 

  227. Castro, M., Cox, G., Wechsler, M. E. & Niven, R. M. Bronchial thermoplasty: ready for prime time — the evidence is there! Chest 147, e73–e74 (2015).

    Article  PubMed  Google Scholar 

  228. Pretolani, M. et al. Reduction of airway smooth muscle mass by bronchial thermoplasty in patients with severe asthma. Am. J. Respir. Crit. Care Med. 190, 1452–1454 (2014).

    Article  PubMed  Google Scholar 

  229. Sheshadri, A., McKenzie, M. & Castro, M. Critical review of bronchial thermoplasty: where should it fit into asthma therapy? Curr. Allergy Asthma Rep. 14, 470 (2014).

    Article  PubMed  Google Scholar 

  230. Iyer, V. N. & Lim, K. G. Bronchial thermoplasty: reappraising the evidence (or lack thereof). Chest 146, 17–21 (2014).

    Article  PubMed  Google Scholar 

  231. Ducharme, F. M., Tse, S. M. & Chauhan, B. Diagnosis, management, and prognosis of preschool wheeze. Lancet 383, 1593–1604 (2014).

    Article  PubMed  Google Scholar 

  232. Guilbert, T. W. et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med. 354, 1985–1997 (2006).

    Article  CAS  PubMed  Google Scholar 

  233. Busse, W. W. et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N. Engl. J. Med. 364, 1005–1015 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Wasfi, Y. S. et al. Onset and duration of attenuation of exercise-induced bronchoconstriction in children by single-dose of montelukast. Allergy Asthma Proc. 32, 453–459 (2011).

    Article  CAS  PubMed  Google Scholar 

  235. Schultz, A. & Brand, P. L. Phenotype-directed treatment of pre-school-aged children with recurrent wheeze. J. Paediatr. Child Health 48, E73–E78 (2012).

    Article  PubMed  Google Scholar 

  236. Lemanske, R. F. et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N. Engl. J. Med. 362, 975–985 (2010). The Best Add-on Therapy Giving Effective Responses (BADGER) study demonstrated that there is not a single ‘best’ add-on therapy for children whose asthma is not controlled by first-line therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Martinez, F. D. The connection between early life wheezing and subsequent asthma: the viral march. Allergol. Immunopathol. (Madr.) 37, 249–251 (2009).

    Article  CAS  Google Scholar 

  238. Martinez, F. D. & Vercelli, D. Asthma. Lancet 382, 1360–1372 (2013).

    Article  PubMed  Google Scholar 

  239. Van Asperen, P. P., Mellis, C. M., Sly, P. D. & Robertson, C. F. Evidence-based asthma management in children — what's new? Med. J. Aust. 194, 383–384 (2011). This study reviewed the evidence-base for asthma treatment in children and concluded that early-life intervention is crucial to prevent asthma from evolving over the lifecourse.

    PubMed  Google Scholar 

  240. Zeiger, R. S. et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N. Engl. J. Med. 365, 1990–2001 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Beigelman, A. et al. Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing? J. Allergy Clin. Immunol. 131, 1518–1525 (2013).

    Article  CAS  PubMed  Google Scholar 

  242. Pelkonen, A. S. et al. The effect of montelukast on respiratory symptoms and lung function in wheezy infants. Eur. Respir. J. 41, 664–670 (2013).

    Article  CAS  PubMed  Google Scholar 

  243. Wechsler, M. E. Getting control of uncontrolled asthma. Am. J. Med. 127, 1049–1059 (2014).

    Article  PubMed  Google Scholar 

  244. Worth, A. et al. Patient-reported outcome measures for asthma: a systematic review. NPJ Prim. Care Respir. Med. 24, 14020 (2014). This systematic review of the literature identified the AQLQ and mini-AQLQ for adults and PAQLQ as PROMs that were found to be sufficiently well validated to offer promise for use in clinical settings. Rhinasthma was also considered promising in simultaneously assessing the impact of asthma and rhinitis.

    Article  PubMed  PubMed Central  Google Scholar 

  245. Juniper, E. Measurement of health-related quality of life and asthma control. Quoltech[online],

  246. Chen, H. et al. Asthma control, severity, and quality of life: quantifying the effect of uncontrolled disease. J. Allergy Clin. Immunol. 120, 396–402 (2007).

    Article  PubMed  Google Scholar 

  247. Lurie, A., Marsala, C., Hartley, S., Bouchon-Meunier, B. & Dusser, D. Patients' perception of asthma severity. Respir. Med. 101, 2145–2152 (2007).

    Article  PubMed  Google Scholar 

  248. Haselkorn, T. et al. Effect of weight change on asthma-related health outcomes in patients with severe or difficult-to-treat asthma. Respir. Med. 103, 274–283 (2009).

    Article  PubMed  Google Scholar 

  249. Hanania, N. A. et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann. Intern. Med. 154, 573–582 (2011).

    Article  PubMed  Google Scholar 

  250. Castro, M. et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am. J. Respir. Crit. Care Med. 181, 116–124 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Earnshaw, V. A. & Quinn, D. M. The impact of stigma in healthcare on people living with chronic illnesses. J. Health Psychol. 17, 157–168 (2012).

    Article  PubMed  Google Scholar 

  252. Comer, B. S., Ba, M., Singer, C. A. & Gerthoffer, W. T. Epigenetic targets for novel therapies of lung diseases. Pharmacol. Ther. 147, 91–110 (2015).

    Article  CAS  PubMed  Google Scholar 

  253. Boutin, H. & Boulet, L.-P. L'asthme au Quotidien (Press Universite Laval, 2005).

    Google Scholar 

  254. Bousquet, J., Bousquet, P. J., Godard, P. & Dyres, J.-P. The public health implications of asthma.Bull. World Health Organ. 93, 548–554 (2005).

    Google Scholar 

  255. Holgate, S. T. et al. A new look at the pathogenesis of asthma. Clin. Sci. 118, 439–450 (2009).

    Article  CAS  Google Scholar 

  256. Bateman, E. D. et al. Overall asthma control: the relationship between current control and future risk. J. Allergy Clin. Immunol. 125, 600–608.e6 (2010).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Clinical and Experimental Sciences, Mail Point 810, Level F, Sir Henry Wellcome Building

    Stephen T. Holgate

  2. Southampton General Hospital, Southampton, SO16 6YD, UK

    Stephen T. Holgate

  3. Subsection Chief of Allergy, Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Asthma Institute at UPMC/UPSOM, Pittsburgh, Pennsylvania, USA

    Sally Wenzel

  4. Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Dirkje S. Postma

  5. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Scott T. Weiss

  6. Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, University Hospital Giessen and Marburg GmbH, Campus Marburg, Marburg, Germany

    Harald Renz

  7. Queensland Children's Medical Research Institute and Centre for Child Health Research, University of Queensland, Brisbane, Australia

    Peter D. Sly

Authors
  1. Stephen T. Holgate
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  2. Sally Wenzel
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  3. Dirkje S. Postma
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  4. Scott T. Weiss
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  6. Peter D. Sly
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Contributions

Introduction (S.T.H.); Epidemiology (S.T.W.); Mechanisms/pathophysiology (P.D.S. and S.T.H.); Diagnosis, screening and prevention (D.S.P., H.R., S.T.H. and S.W.); Management (D.S.P., P.D.S. and S.T.H.); Quality of life (D.S.P.); Outlook (D.S.P., H.R., P.D.S., S.T.H., S.T.W. and S.W.); Overview of Primer (S.T.H.).

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Correspondence to Stephen T. Holgate.

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Competing interests

S.T.H. is a non-executive director and a consultant for Synairgen, and a consultant for AstraZeneca and Novartis. He is in receipt of a UK Medical Research Council (MRC) programme grant and receives salary support as an MRC clinical professor. S.W. has served as a consultant for Aerocrine, GlaxoSmithKline and AstraZeneca. She has received research funding (paid to her institution) from GlaxoSmithKline, AstraZeneca, Genentech and Sanofi-Aventis. She has also received research support from the NIH National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID), which provides her salary support. D.S.P. has received an unrestricted educational grant for research (paid to the University of Groningen) from AstraZeneca. Her travel to the European Respiratory Society (ERS) and/or the American Thoracic Society (ATS) meetings has been partially funded by AstraZeneca, Chiesi, GlaxoSmithKline and Takeda. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda and Teva. Her travel and lectures in China have been funded by Chiesi. S.T.W. is funded by the NIH NHLBI and is a consultant for the TENOR study for Novartis. H.R. has received research support from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the European Union, Land Hessen, the German Academic Exchange Service (DAAD), ALK, Stiftung Pathobiochemie, Ernst-Wendt-Stiftung, Mead Johnson Nutritional and Beckman Coulter. He has also received speakers honoraria from Allergopharma, Novartis, Thermo Fisher Scientific, Danone, Mead Johnson Nutritional and Bencard Allergie. H.R. also serves as a consultant for Bencard Allergie and Sterna Biologicals (for which he is also a cofounder). P.D.S. declares no competing interests.

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Holgate, S., Wenzel, S., Postma, D. et al. Asthma. Nat Rev Dis Primers 1, 15025 (2015). https://doi.org/10.1038/nrdp.2015.25

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