Skip to main content
SpringerLink
Log in

Scope of the Problem, Definition, and Pathophysiology

  • Chapter
  • First Online:
Difficult To Treat Asthma

Part of the book series: Respiratory Medicine ((RM))

  • 1400 Accesses

Abstract

The term asthma is now recognized as the common endpoint for a heterogeneous milieu of diverse inflammatory pathways. It is recognized as a public health issue in view of significant global morbidity and healthcare utilization. Despite progress in key outcomes such as asthma-related mortality, improvements have plateaued in the past decade in the face of escalating treatment costs. Similarly, advances in our understanding of pathogenesis have not translated into effective primary prevention strategies. This review seeks to highlight the risk factors identified for various asthma phenotypes as well as structural and inflammatory abnormalities associated with severe disease. We also describe the use of disease metrics to separate asthma phenotypes based on underlying mechanistic pathways that may facilitate the use of targeted therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention 2016.

    Google Scholar 

  2. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–25.

    Article  CAS  PubMed  Google Scholar 

  3. Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med. 2004;10(1):44–50.

    Article  PubMed  Google Scholar 

  4. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181(4):315–23.

    Article  PubMed  Google Scholar 

  5. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107–19.

    Article  PubMed  Google Scholar 

  6. Collaborators GBDCRD. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691–706.

    Article  Google Scholar 

  7. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355(21):2226–35.

    Article  CAS  PubMed  Google Scholar 

  8. Croisant S. Epidemiology of asthma: prevalence and burden of disease. Adv Exp Med Biol. 2014;795:17–29.

    Article  PubMed  CAS  Google Scholar 

  9. Wang D, Xiao W, Ma D, Zhang Y, Wang Q, Wang C, et al. Cross-sectional epidemiological survey of asthma in Jinan, China. Respirology. 2013;18(2):313–22.

    Article  PubMed  Google Scholar 

  10. Cabieses B, Uphoff E, Pinart M, Anto JM, Wright J. A systematic review on the development of asthma and allergic diseases in relation to international immigration: the leading role of the environment confirmed. PLoS One. 2014;9(8):e105347.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wang HY, Wong GW, Chen YZ, Ferguson AC, Greene JM, Ma Y, et al. Prevalence of asthma among Chinese adolescents living in Canada and in China. CMAJ. 2008;179(11):1133–42.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ebmeier S, Thayabaran D, Braithwaite I, Benamara C, Weatherall M, Beasley R. Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993-2012). Lancet. 2017;390(10098):935–45.

    Article  PubMed  Google Scholar 

  13. Ali Z, Dirks CG, Ulrik CS. Long-term mortality among adults with asthma: a 25-year follow-up of 1,075 outpatients with asthma. Chest. 2013;143(6):1649–55.

    Article  PubMed  Google Scholar 

  14. Guilbert T, Zeiger RS, Haselkorn T, Iqbal A, Alvarez C, Mink DR, et al. Racial disparities in asthma-related health outcomes in children with severe/difficult-to-treat asthma. J Allergy Clin Immunol Pract. 2019;7:568.

    Article  PubMed  Google Scholar 

  15. Rosser FJ, Forno E, Cooper PJ, Celedon JC. Asthma in Hispanics. An 8-year update. Am J Respir Crit Care Med. 2014;189(11):1316–27.

    Article  PubMed  PubMed Central  Google Scholar 

  16. El Burai FS, Bailey CM, Zahran HS. Asthma prevalence among Hispanic adults in Puerto Rico and Hispanic adults of Puerto Rican descent in the United States - results from two national surveys. J Asthma. 2015;52(1):3–9.

    Article  Google Scholar 

  17. Mushtaq A. Asthma in the USA: the good, the bad, and the disparity. Lancet Respir Med. 2018;6(5):335–6.

    Article  PubMed  Google Scholar 

  18. Sullivan PW, Ghushchyan VH, Slejko JF, Belozeroff V, Globe DR, Lin SL. The burden of adult asthma in the United States: evidence from the Medical Expenditure Panel Survey. J Allergy Clin Immunol. 2011;127(2):363-9 e1-3.

    Article  Google Scholar 

  19. Nunes C, Pereira AM, Morais-Almeida M. Asthma costs and social impact. Asthma Res Pract. 2017;3:1.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Nurmagambetov T, Kuwahara R, Garbe P. The economic burden of asthma in the United States, 2008-2013. Ann Am Thorac Soc. 2018;15(3):348–56.

    Article  PubMed  Google Scholar 

  21. Szefler SJ, Zeiger RS, Haselkorn T, Mink DR, Kamath TV, Fish JE, et al. Economic burden of impairment in children with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2011;107(2):110–9 e1.

    Article  PubMed  Google Scholar 

  22. Rutkowski K, Sowa P, Rutkowska-Talipska J, Sulkowski S, Rutkowski R. Allergic diseases: the price of civilisational progress. Postepy Dermatol Alergol. 2014;31(2):77–83.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Granell R, Henderson AJ, Timpson N, St Pourcain B, Kemp JP, Ring SM, et al. Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes. J Allergy Clin Immunol. 2013;131(3):685–94.

    Article  CAS  PubMed  Google Scholar 

  24. Bousquet J, Gern JE, Martinez FD, Anto JM, Johnson CC, Holt PG, et al. Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop. J Allergy Clin Immunol. 2014;133(6):1535–46.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu AH, Babineau DC, Krouse RZ, Zoratti EM, Pongracic JA, O'Connor GT, et al. Pathways through which asthma risk factors contribute to asthma severity in inner-city children. J Allergy Clin Immunol. 2016;138(4):1042–50.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rubner FJ, Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, et al. Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence. J Allergy Clin Immunol. 2017;139(2):501–7.

    Article  PubMed  Google Scholar 

  27. Kattan M, Mitchell H, Eggleston P, Gergen P, Crain E, Redline S, et al. Characteristics of inner-city children with asthma: the National Cooperative Inner-City Asthma Study. Pediatr Pulmonol. 1997;24(4):253–62.

    Article  CAS  PubMed  Google Scholar 

  28. Lodge CJ, Lowe AJ, Gurrin LC, Hill DJ, Hosking CS, Khalafzai RU, et al. House dust mite sensitization in toddlers predicts current wheeze at age 12 years. J Allergy Clin Immunol. 2011;128(4):782–8 e9.

    Article  PubMed  Google Scholar 

  29. Matsui EC, Wood RA, Rand C, Kanchanaraksa S, Swartz L, Curtin-Brosnan J, et al. Cockroach allergen exposure and sensitization in suburban middle-class children with asthma. J Allergy Clin Immunol. 2003;112(1):87–92.

    Article  CAS  PubMed  Google Scholar 

  30. Ownby DR. Will the real inner-city allergen please stand up? J Allergy Clin Immunol. 2013;132(4):836–7.

    Article  PubMed  Google Scholar 

  31. Stelmach I, Jerzynska J, Stelmach W, Majak P, Chew G, Kuna P. The prevalence of mouse allergen in inner-city homes. Pediatr Allergy Immunol. 2002;13(4):299–302.

    Article  PubMed  Google Scholar 

  32. Liccardi G, Salzillo A, Calzetta L, Piccolo A, Menna G, Rogliani P. Can the presence of cat/dog at home be considered the only criterion of exposure to cat/dog allergens? A likely underestimated bias in clinical practice and in large epidemiological studies. Eur Ann Allergy Clin Immunol. 2016;48(2):61–4.

    CAS  PubMed  Google Scholar 

  33. Takkouche B, Gonzalez-Barcala FJ, Etminan M, Fitzgerald M. Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis. Allergy. 2008;63(7):857–64.

    Article  CAS  PubMed  Google Scholar 

  34. Morgan WJ, Crain EF, Gruchalla RS, O'Connor GT, Kattan M, Evans R 3rd, et al. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med. 2004;351(11):1068–80.

    Article  CAS  PubMed  Google Scholar 

  35. Gern JE. The urban environment and childhood asthma study. J Allergy Clin Immunol. 2010;125(3):545–9.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrlander C, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011;364(8):701–9.

    Article  CAS  PubMed  Google Scholar 

  37. Wlasiuk G, Vercelli D. The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease. Curr Opin Allergy Clin Immunol. 2012;12(5):461–6.

    Article  PubMed  Google Scholar 

  38. Stein MM, Hrusch CL, Gozdz J, Igartua C, Pivniouk V, Murray SE, et al. Innate immunity and asthma risk in amish and hutterite farm children. N Engl J Med. 2016;375(5):411–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Genuneit J. Sex-specific development of asthma differs between farm and nonfarm children: a cohort study. Am J Respir Crit Care Med. 2014;190(5):588–90.

    Article  PubMed  Google Scholar 

  40. Lukkarinen M, Koistinen A, Turunen R, Lehtinen P, Vuorinen T, Jartti T. Rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age. J Allergy Clin Immunol. 2017;140(4):988–95.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Phan JA, Kicic A, Berry LJ, Fernandes LB, Zosky GR, Sly PD, et al. Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice. PLoS One. 2014;9(3):e92163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Bacharier LB, Cohen R, Schweiger T, Yin-Declue H, Christie C, Zheng J, et al. Determinants of asthma after severe respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2012;130(1):91–100 e3.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Bernstein JA, Alexis N, Barnes C, Bernstein IL, Bernstein JA, Nel A, et al. Health effects of air pollution. J Allergy Clin Immunol. 2004;114(5):1116–23.

    Article  PubMed  Google Scholar 

  44. Hernandez ML, Dhingra R, Burbank AJ, Todorich K, Loughlin CE, Frye M, et al. Low-level ozone has both respiratory and systemic effects in African American adolescents with asthma despite asthma controller therapy. J Allergy Clin Immunol. 2018;142:1974.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Gehring U, Wijga AH, Brauer M, Fischer P, de Jongste JC, Kerkhof M, et al. Traffic-related air pollution and the development of asthma and allergies during the first 8 years of life. Am J Respir Crit Care Med. 2010;181(6):596–603.

    Article  PubMed  Google Scholar 

  46. Lau N, Norman A, Smith MJ, Sarkar A, Gao Z. Association between traffic related air pollution and the development of asthma phenotypes in children: a systematic review. Int J Chronic Dis. 2018;2018:4047386.

    PubMed  PubMed Central  Google Scholar 

  47. Godtfredsen NS, Lange P, Prescott E, Osler M, Vestbo J. Changes in smoking habits and risk of asthma: a longitudinal population based study. Eur Respir J. 2001;18(3):549–54.

    Article  CAS  PubMed  Google Scholar 

  48. Teague WG. Up in smoke: accelerated loss of lung function in two clusters of smokers identified in a longitudinal cohort study of adult-onset asthma. J Allergy Clin Immunol Pract. 2017;5(4):979–80.

    Article  PubMed  Google Scholar 

  49. Dinakar C, O'Connor GT. The health effects of electronic cigarettes. N Engl J Med. 2016;375(26):2608–9.

    Article  PubMed  Google Scholar 

  50. Ghosh A, Coakley RC, Mascenik T, Rowell TR, Davis ES, Rogers K, et al. Chronic E-Cigarette exposure alters the human bronchial epithelial proteome. Am J Respir Crit Care Med. 2018;198(1):67–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Spindel ER, McEvoy CT. The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of E-Cigarettes. Am J Respir Crit Care Med. 2016;193(5):486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. The September epidemic of asthma hospitalizations...and do antibiotics in infancy lead to asthma?. Child Health Alert. 2006;24:3.

    Google Scholar 

  53. Gaga M, Papageorgiou N, Yiourgioti G, Karydi P, Liapikou A, Bitsakou H, et al. Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire. Clin Exp Allergy. 2005;35(7):954–9.

    Article  CAS  PubMed  Google Scholar 

  54. Jarjour NN, Erzurum SC, Bleecker ER, Calhoun WJ, Castro M, Comhair SA, et al. Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Am J Respir Crit Care Med. 2012;185(4):356–62.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Peters U, Dixon AE, Forno E. Obesity and asthma. J Allergy Clin Immunol. 2018;141(4):1169–79.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Newson RB, Jones M, Forsberg B, Janson C, Bossios A, Dahlen SE, et al. The association of asthma, nasal allergies, and positive skin prick tests with obesity, leptin, and adiponectin. Clin Exp Allergy. 2014;44(2):250–60.

    Article  CAS  PubMed  Google Scholar 

  57. Zein JG, Erzurum SC. Asthma is Different in Women. Curr Allergy Asthma Rep. 2015;15(6):28.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Vink NM, Postma DS, Schouten JP, Rosmalen JG, Boezen HM. Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents' Individual Lives Survey (TRAILS) study. J Allergy Clin Immunol. 2010;126(3):498–504 e1-6.

    Article  PubMed  Google Scholar 

  59. Fu L, Freishtat RJ, Gordish-Dressman H, Teach SJ, Resca L, Hoffman EP, et al. Natural progression of childhood asthma symptoms and strong influence of sex and puberty. Ann Am Thorac Soc. 2014;11(6):939–44.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Smith AM. The epidemiology of work-related asthma. Immunol Allergy Clin N Am. 2011;31(4):663–75, v.

    Article  Google Scholar 

  61. Baur X, Bakehe P. Allergens causing occupational asthma: an evidence-based evaluation of the literature. Int Arch Occup Environ Health. 2014;87(4):339–63.

    Article  CAS  PubMed  Google Scholar 

  62. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–25. https://doi.org/10.1038/nm.2678.

    Article  CAS  PubMed  Google Scholar 

  63. Georas SN, Guo J, De Fanis U, Casolaro V. T-helper cell type-2 regulation in allergic disease. Eur Respir J. 2005;26(6):1119–37.

    Article  CAS  PubMed  Google Scholar 

  64. Barnes PJ. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2018;18(7):454–66.

    Article  CAS  PubMed  Google Scholar 

  65. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136(7):2348–57.

    CAS  PubMed  Google Scholar 

  66. Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K, Tumes DJ, Okamoto Y. Th2 cells in health and disease. Annu Rev Immunol. 2017;35:53–84.

    Article  CAS  PubMed  Google Scholar 

  67. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E. Innate lymphoid cells--a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13(2):145–9. https://doi.org/10.1038/nri3365.

    Article  CAS  PubMed  Google Scholar 

  68. Stier MT, Peebles RS Jr. Innate lymphoid cells and allergic disease. Ann Allergy Asthma Immunol. 2017;119(6):480–8.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Peters MC, Kerr S, Dunican EM, Woodruff PG, Fajt ML, Levy BD, et al. Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol. 2019;143(1):104–113.e14.

    Article  CAS  PubMed  Google Scholar 

  71. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Raundhal M, Morse C, Khare A, Oriss TB, Milosevic J, Trudeau J, et al. High IFN-γ and low SLPI mark severe asthma in mice and humans. J Clin Invest. 2015;125(8):3037–50.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Wisniewski JA, Muehling LM, Eccles JD, Capaldo BJ, Agrawal R, Shirley DA, et al. TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J Allergy Clin Immunol. 2018;141(6):2048–2060.e13.

    Article  CAS  PubMed  Google Scholar 

  74. Iwanaga N, Kolls JK. Updates on T helper type 17 immunity in respiratory disease. Immunology. 2019;156(1):3–8.

    Article  CAS  PubMed  Google Scholar 

  75. Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, Lin SL. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188(11):1294–302.

    Article  CAS  PubMed  Google Scholar 

  76. Snelgrove RJ, Patel DF, Patel T, Lloyd CM. The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent? Clin Exp Allergy. 2018;48(10):1275–85.

    Article  CAS  PubMed  Google Scholar 

  77. O’Byrne PM, Metev H, Puu M, Richter K, Keen C, Uddin M. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(10):797–806.

    Article  PubMed  CAS  Google Scholar 

  78. den Dekker HT, Sonnenschein-van der Voort AMM, de Jongste JC, Anessi-Maesano I, Arshad SH, Barros H. Early growth characteristics and the risk of reduced lung function and asthma: a meta-analysis of 25,000 children. J Allergy Clin Immunol. 2016;137(4):1026–35.

    Article  Google Scholar 

  79. James A, Elliot JG, Jones RL, Carroll ML, Mauad T, Bai TR, et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med. 2012;185(10):1058–64.

    Article  PubMed  Google Scholar 

  80. Regamey N, Ochs M, Hilliard TN, Mühlfeld C, Cornish N, Fleming L, et al. Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2008;177(8):837–43.

    Article  PubMed  Google Scholar 

  81. Berair R, Hollins F, Brightling C. Airway smooth muscle hypercontractility in asthma. J Allergy (Cairo). 2013;2013:185971.

    PubMed Central  Google Scholar 

  82. Deshpande DA, Dogan S, Walseth TF, Miller SM, Amrani Y, Panettieri RA, Kannan MS. Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway. Am J Respir Cell Mol Biol. 2004;31(1):36–42.

    Article  CAS  PubMed  Google Scholar 

  83. Risse PA, Jo T, Suarez F, Hirota N, Tolloczko B, Ferraro P, et al. Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype. Am J Physiol Lung Cell Mol Physiol. 2011;300(6):L958–66.

    Article  CAS  PubMed  Google Scholar 

  84. Sundaram A, Chen C, Khalifeh-Soltani A, Atakilit A, Ren X, Qiu W, et al. Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest. 2017;127(1):365–74.

    Article  PubMed  Google Scholar 

  85. Lauzon AM, Martin JG. Airway hyperresponsiveness; smooth muscle as the principal actor. F1000Res. 2016;5. pii: F1000 Faculty Rev-306.

    Article  Google Scholar 

  86. Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002;8(8):885–9.

    Article  CAS  PubMed  Google Scholar 

  87. Bonser LR, Zlock L, Finkbeiner W, Erle DJ. Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma. J Clin Invest. 2016;126(6):2367–71.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, Fitzgerald JM. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med. 1998;157(6 Pt 1):1804–9.

    Article  CAS  PubMed  Google Scholar 

  89. Miller MK, Lee JH, Miller DP, Wenzel SE, Group TS. Recent asthma exacerbations: a key predictor of future exacerbations. Respiratory medicine. 2007;101(3):481–9.

    Article  PubMed  Google Scholar 

  90. Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, et al. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018;128(3):997–1009.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Kuyper LM, Paré PD, Hogg JC, Lambert RK, Ionescu D, Woods R, Bai TR. Characterization of airway plugging in fatal asthma. Am J Med. 2003;115(1):6–11.

    Article  PubMed  Google Scholar 

  92. Bossé Y, Riesenfeld EP, Paré PD, Irvin CG. It’s not all smooth muscle: non-smooth-muscle elements in control of resistance to airflow. Ann Rev Physiol. 2010;72:437–62.

    Article  CAS  Google Scholar 

  93. Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol. 2014;134(3):509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Saatian B, Rezaee F, Desando S, Emo J, Chapman T, Knowlden S, Georas SN. Interleukin-4 and interleukin-13 cause barrier dysfunction in human airway epithelial cells. Tissue Barriers. 2013;1(2):e24333.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Soyka MB, Wawrzyniak P, Eiwegger T, Holzmann D, Treis A, Wanke K, et al. Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4. J Allergy Clin Immunol. 2012;130(5):1087–1096.e10.

    Article  CAS  PubMed  Google Scholar 

  96. Busse WW, Pedersen S, Pauwels RA, Tan WC, Chen YZ, Lamm CJ, et al. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol. 2008;121(5):1167–74.

    Article  CAS  PubMed  Google Scholar 

  97. Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest. 1995;108(5):1228–34.

    Article  CAS  PubMed  Google Scholar 

  98. Selroos O. Effect of disease duration on dose-response of inhaled budesonide in asthma. Respir Med. 2008;102(7):1065–72.

    Article  PubMed  Google Scholar 

  99. Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154(9):573–82.

    Article  PubMed  Google Scholar 

  100. Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804–11.

    Article  CAS  PubMed  Google Scholar 

  101. Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med. 2015;3(11):849–58.

    Article  PubMed  Google Scholar 

  102. Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4(7):549–56.

    Article  CAS  PubMed  Google Scholar 

  103. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.

    Article  CAS  PubMed  Google Scholar 

  104. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–207.

    Article  PubMed  CAS  Google Scholar 

  105. Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of Reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799–810.

    Article  PubMed  Google Scholar 

  106. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–27.

    Article  CAS  PubMed  Google Scholar 

  107. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128–41.

    Article  CAS  PubMed  Google Scholar 

  108. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and safety of Dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475–85.

    Article  CAS  PubMed  Google Scholar 

  109. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–96.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pulmonary Diseases and Critical Care, University of Rochester Medical Center, Rochester, NY, USA

    Steve N. Georas

  2. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, Atlanta, GA, USA

    F. Eun-Hyung Lee & Merin Kuruvilla

Authors
  1. Steve N. Georas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Eun-Hyung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Merin Kuruvilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steve N. Georas .

Editor information

Editors and Affiliations

  1. Mary Parkes Center for Asthma, Allergy & Pulmonary Care, University of Rochester School of Medicine, Rochester, NY, USA

    Sandhya Khurana

  2. Asthma Clinical & Research Programs Pulmonary Sciences and Critical Care, University of Colorado, Denver, CO, USA

    Fernando Holguin

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Georas, S.N., Lee, F.EH., Kuruvilla, M. (2020). Scope of the Problem, Definition, and Pathophysiology. In: Khurana, S., Holguin, F. (eds) Difficult To Treat Asthma. Respiratory Medicine. Humana, Cham. https://doi.org/10.1007/978-3-030-20812-7_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-20812-7_1

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-20811-0

  • Online ISBN: 978-3-030-20812-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation