Asthma is a common chronic airway disease affecting about 334 million people worldwide, and an estimated 7 million children globally. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids and other modifiers. Among these, are patients with severe neutrophilic asthma. Neutrophilic asthma is a phenotype of asthma that is very severe and persistent, with frequent exacerbations, and characterized by fixed airway obstruction. It is associated with comorbidities such as respiratory infections, obesity, gastroeosophageal reflux disease, and obstructive sleep apnoea. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the lungs and airways. Neutrophils and the interleukin-17 family of cytokines play a pivotal role in the pathogenesis of severe neutrophilic asthma. Most patients with the disease do not achieve control with high dose inhaled corticosteroids, and probably to novel IgE, interleukin and interleukin monoclonal antibodies. 

Keywords: neutrophilic asthma, neutrophils, inflammatory mediators, interleukins-17, monoclonal antibodies

IL, interleukin; TSLP, thymus stromal lymphopoietin; Th, T helper cells; FENO, fractional exhaled nitric oxide; FEV1, forced expired volume in 1 second, LABAs, long-acting β2-agonists; AERD, aspirin-exacerbated respiratory disease; EIA, exercise-induced asthma; ICSs, inhaled corticosteroids

Asthma is a complex chronic airway disease with several distinct phenotypes with different immunopathological pathways, clinical presentation, physiology, comorbidities, biomarker of allergic inflammation, and response to treatment.^1–4 There are several distinct clinical proposed asthma phenotypes, such as childhood-onset allergic asthma, adult-onset eosinophilic asthma, neutrophilic asthma, exercise-induced asthma (EIA), obesity-related asthma, and aspirin-exacerbated respiratory disease (AERD).^5–12 Among these phenotypes of asthma, there are patients whose asthma is very severe and refractory to the standard treatment including high doses of inhaled corticosteroids (ICSs), and long-acting β2- agonists (LABAs) and/or any other modifier.

Severe refractory asthma represents about 5-10% of patients with asthma.^9–11 The guidelines on the definition, evaluation and treatment of severe refractory asthma are discussed in detail by the American Thoracic Society, the European Respiratory Society, and the World Health Organization.^13–15

Severe refractory asthma encompasses several molecular phenotypes of asthma, including neutrophilic asthma phenotype. Neutrophilic asthma is characterized by severe refractory disease, with fixed airway obstruction, and poor response to standard treatment with inhaled corticosteroids (ICSs), long-acting β2-agonists (LABAs), and other modifiers. ^7,16–18

Eosinophilic asthma is adequately investigated and established phenotype of asthma.^{5, 6, 9, 10} By contrast, neutrophilic asthma has complex pathogenesis and is not fully understood phenotype of asthma. However, about 30%-50% of the patients with symptomatic asthma have this phenotype.¹⁹

Characterizing the phenotypes of severe asthma has clinical and therapeutic implications in the development of novel biologics for the personalized treatment of different phenotypes of asthma.^{5–7, 10, 14, 19} Approximately 50% of patients with asthma have Th2-driven eosinophilic asthma, whereas the remaining 50% have non-eosinophilic asthma phenotypes which can be subdivided into neutrophilic, and paucigranulocytic subtypes.^{5, 6, 20} Eosinophilic asthma is one of the well-characterized clinical phenotype of asthma,^{8,, 10, 20–24} whereas, neutrophilic asthma phenotype is less-well defined.^{25, 26}

The pathophysiology of neutrophilic asthma is complex and less clearly understood. Patients with neutrophilic asthma have high neutrophil count in the sputum ranging from 40% to 76% of sputum cells,^25–27 or a neutrophil count of 500 x 10⁴/ml.²⁶ Conversely, they have less sputum eosinophil count which has been quoted to be between less than 1.9% and 3% by various authors.^{6, 23}

Increased neutrophils in sputum have been associated with severe persistent asthma,^{6, 7, 14, 27, 28} fixed airway obstruction,^{27, 29, 30} with very low forced expired volume in 1 second (FEV1), and post-brochodilator FEV1.³⁰ Shaw and collagues³⁰ reported that both patients with eosinophilic asthma and neutrophilic asthma had low pre-bronchodilator FEV1, but only patients with neutrophilic asthma had lowest post-bronchodilator FEV1, indicating persistent airflow limitation.

Neutrophilic asthma is associated with more frequent exacerbations, although the exacerbations are not as severe as those encountered in patients with eosinophilic asthma.^{3, 31–33} On the sick note, patients with neutrophilic asthma have frequent urgent visits to emergence rooms, hospitalization and intubation.¹³ This phenotype of asthma has been associated with sudden-onset fatal asthma in about 23% of the patients.³⁴ Furthermore, patients with severe bronchial neutrophilia are more likely to be admitted to hospital for noninfectious status asthmaticus.³⁵ Intriguingly, the disease tends to be worse at night (nocturnal asthma).³⁶ Martin and collegues³⁶ found a greater than three-fold increase in the number of granulocytes in bronchoalveolar (BAL) fluid at 04:00 hr compared with 16:00 hr. This has clinical implication in the management of patients with neutrophilc asthma who may require chronotherapy for the treatment of their nocturnal symptoms.³⁷

Additionally, neutrophilic asthma is typically associated with a worse quality of life, and has a poor prognosis.^{7, 13, 14, 17, 21, 30, 38} Patients with neutrophilic asthma are unresponsive to high-dose ICSs,^39–41 and possibly to the newly introduced targeted biologics.^{11, 12, 16} Currently, no specific biomarkers are readily available to support the diagnosis and phenotyping of these patients,⁴² for personalized precision medicines.⁴³

Neutrophilic asthma phenotype is an adult-onset disease and usually starts after 12 years.⁹ Patients are less likely to be atopic,^{9, 22, 30, 44} and have less responsiveness to bronchoprovocation testing with methacholine.^{9, 22, 42} The underlying mechanisms of neutrophilic asthma are not fully understood. The clinical characteristics of neutrophilic asthma are summarized in Table 1.

Comorbidities and associated features of neutrophilic asthma

Neutrophilic asthma is associated with comorbidities and confounding factors which may contribute to the severity of the disease and exacerbations. These include: respiratory infections (viral, bacterial and fungal), rhinosinusitis, obesity, gastroeosophageal reflux disease, obstructive sleep apneas, and occupational asthma. Table 2 shows the comorbid and cofounder conditions associated with neutrophilic asthma.

Upper and lower respiratory tract infections including respiratory syncytial virus, and human rhinovirus have been associated with both the onset and exacerbations of asthma including the neutrophilic phenotype, especially in children.^45–47 Respiratory infection due to influenza can lead to severe refractory asthma exacerbation requiring intensive care unit (ICU) admission.⁴⁸

Bacterial infection has been associated with the pathogenesis of neutrophil corticosteroid-refractory severe asthma.^49–53 Refractory asthma is characterized by increased number of neutrophils, inflammasomes and pro-neutrophil biomarkers in the airways. The airway neutrophilia in this phenotype of asthma is unlikely to be due to bacterial infection or to corticosteroid use which is known to prevent apoptosis of neutrophils in favour of eosinophils. Wood et al⁵³ found several potentially pathogenic bacteria in the sputum from patients with stable asthma, as well as increased sputum counts, and IL-8 levels. This may suggest the presence of a specific lung microbiota and subsequent effect on immunity.⁵³

Fungal respiratory infection with Aspergillums fumigates and other fungi has been identified in severe asthma, with fungal sensitization and neutrophilic response in order to combat the infection.⁵⁴

Rhinosinusitis coexist with asthma in 34% of patients with different phenotypes of severe asthma.⁵⁵ However, patient with neutrophilic asthma have an increased prevalence of rhinosunisitis (>64%) compared to those with eosinophilic asthma.⁵⁶ Sinupulmonary infection is also reported to be high in patient with neutrophilic asthma.⁷ Patients with asthma should be investigated for chronic rhinosinusitis and nasal polyps. Medical and surgical therapy of chronic rhinosinusitis improve the clinical course of asthma, with medical treatment being superior to surgical procedures in patients with chronic rhinosinusitis and nasal polyps.⁵⁷

Obesity is extremely common in patients with asthma,^58–63 and the risk of severe asthma in obese patients appears stronger for central than for generalized adiposity.^64–66 Obesity is associated with more symptoms, more frequent severe exacerbations of asthma.^{60, 67} Patients with obesity-related asthma have less favourable response to reliever and controller medication compared to normal weight patients.^67–70 Similar to neutrophilic asthmatic patients, patients with obesity-related asthma have a poor response to corticosteroids,^71–75 and a worse quality of life.^67–69

Obesity-related asthma phenotype represent a distinct clinical phenotype,^{23, 61, 76} but with some identical clinical features and biomarkers as neutrophilic asthma (Table 1). It present with a particular set of characteristics that include late onset, predominantly female, severe asthma, less atopic to bronchoprovocation tests, lower pulmonary function, and poor responsiveness to corticosteroids.^{9, 23, 66}

Obesity-related asthma has been associated with increased airway neutrophilia.^{77, 78} Scott et al⁷⁸ have shown that neutrophils but not eosinophils were higher in the sputum of obese asthmatic than non-obese patients. The high levels of sputum neutrophil counts in obese patients has been confirmed by Marijsse and colleagues,⁷⁹ who also demonstrated higher levels of sputum neutrophils than eosinophils in obese versus lean subjects with poorly controlled asthma. This group also reported higher levels of IL-17A protein in obese asthmatic patients that in the lean patients.⁷⁹

The mechanisms and relationship between obesity-related asthma and severe steroid-resistant asthma are described in detail elsewhere,^{58, 60, 67, 79–83} however, the inflammatory cascade due to the activation of the Th17 cell/IL-17A axis may partly contribute to the pathogenesis of airway neutrophilic inflammation in patients with obesity-related asthma. It is important to investigate patients with asthma for comorbidities such as obesity and syndrome X.

Bariatric surgery, by either sleeve gastrectomy or Roux-en-Y gastric bypass has been reported to improve asthma control, lung function, and related-quality of life.^{84, 85} Bariatric surgery has also been shown to reduce airway hyperresponsiveness.⁸⁵ Hasegawa et al,⁸⁶ have reported that, bariatric surgery lead to nearly 60% reduction in the risk of asthma exacerbations.

Obese individuals usually have co-existing comorbidies such as hypertension, gatroeosophageal reflux disease (GERD), sleep obstructive apnoea (OA), type 2 diabetes mellitus, dyslipidaemia,^27,87–88 metabolic syndrome,⁶⁶ and depression (Table 3). These coexisting diseases may aggravate the symptoms of obesity-related asthma, and make it difficult to control.

Several studies have indicated that up to 50% of patients with asthma have either evidence of esophagitis or increased esophageal acid exposure assessed on a 24-hr ambulatory pH monitoring.^89–92 Gastroesophageal reflux disease has been found to be very common in patient with neutrophilic asthma.^{7, 86, 93, 94} Immunopathologically, GERD is characterized by airway neutrophilia.⁹³ Patients with GERD and neutrophilic asthma have severe refractory disease, lower lung function, and poor symptom control.^{7, 56, 86} Several reports have documented that medical treatment with prokinetics and H2-antagonists, proton-pump inhibitors, and antireflux surgery improve asthma symptom and reduce exacerbations in asthmatic patients with GERD.⁹⁵ Prokinetics and H2-receptor antagonists have been reported to reduce symptoms, ⁹⁶ and nocturnal asthma in patients with GERD.⁹⁷ Similarly, proton-pump inhibitors have been shown to improve symptom control and pulmonary function.^{98, 99} Antireflux surgery in patients with severe asthma and GERD has been documented to improve respiratory symptoms and peak expired flow rates (PEF),^{100, 101} and decrease the need or dose of systemic corticosteroids.¹⁰²

There is a high prevalence of obstructive sleep apnoea of about 80% in patients with severe asthma.^103,104 The frequency of severe asthma exacerbation is also reported to be higher is asthmatics with OSA than those without.¹⁰⁴ Teodeorescu and colleagues,¹⁰⁵ have reported that OSA is associated with severe asthma which is difficult to control. The same authors found that OSA was associated with neutrophilic airway inflammation.¹⁰⁸ Taillé et al¹⁰⁷ have also reported increased sputum neutrophil counts and airway remodeling in asthmatic patients with mild OSA.

Obstructive sleep apnea is treated with continuous positive airway pressure (CPAP). CPAP has been shown to reduce systemic inflammation and airway responsiveness.^85,109 Long-term use of CPAP has also been reported to decrease symptoms of asthma,¹¹⁰ and the use of rescue β2-agonists.¹⁰⁸ Noteworthy, the quadruple disease of obesity, obstructive sleep apnea, gastroesophageal reflux, and severe asthma has a worse clinical outcome.

Patients with neutrophilic asthma are at a higher risk of developing occupational asthma,¹¹¹ particularly due to low molecular weight (LMW) agents.¹¹² Patients who develop work-related asthma from LMW agents have bronchial neutrophilic inflammation.¹¹³ The mechanisms by which LMW sensitizers induce neutrophilic airway inflammation require further investigations. Patients with occupational asthma and comorbid conditions associated with neutrophilic airway inflammation should be suspected of having neutrophilic asthma, and at least be treated for the coexisting diseases.

Smoking is associated with severe asthma, frequent exacerbation, life-threatening asthma attacks, and worse asthma-specific quality of life.¹¹⁴ Shimoda et al.¹¹⁵ reported that smokers with asthma had very low FEV1/FVC ratio, lower fractional expired NO (FENO), and higher sputum neutrophil counts than eosinophils compared to non-smokers. Furthermore, smoking is associated with poor response to inhaled corticosteroids.^116,117 All these are typical characteristics of neutrophilic asthma. Siew et al¹¹⁸ have reported that the expression of IL-17A and IL-8, and neutrophil counts are significantly elevated in the bronchial mucosa of smokers compared to nonsmokers. Furthermore, IL-17A levels correlated with that of IL-8 and the neutrophil numbers.¹¹⁸ This emphasizes the importance of airway neutrophilic inflammation and IL-17A in the pathogenesis of severe asthma in smokers.

Airway neutrophilic inflammation in neurophilic asthma

The pathogenesis and immunopathology is complex and is not fully understood. The hallmark of neutrophilic asthma and its coexisting diseases such as obesity, GERD and OSA is infiltration of the airway with activated neutrophils. The driving mechanism for neutrophilic asthma has been associated with altered innate immune response and activation of Th17 cells.^119–121 Unlike eosinophilic asthma, which has clearly been identified as a Th2-driven phenotype,^{20, 21, 24} and associated with IL-3, IL-4, IL-5, IL-13, IL-25, IL-33, and TSLP,^122–128 the relationship between Th17 cells and its family of cytokines is becoming much clear. Interleukin 17A (synonymous to IL-17) and IL-17F are the signature cytokines implicated in neutrophilic airway inflammation and in the pathogenesis of neutrophilic asthma. There are also other surrogate cytokines such as IL-6, IL-8, IL-23, IL-1β, TNF-α, TGF-β and many more other cytokines, chemokines and inflammasomes which aid IL-17A in orchestrating neutrophilic airway inflammation in patients with severe neutrophilic asthma.^129–132 This review has just discussed briefly IL-17A, but this kingpin cytokine and its other five siblings are implicated in a myriad of autoimmune and inflammatory diseases. Table 4 lists the several diseases implicated by activation of the Th17 cells/IL-17A axis. It is hoped in future to find a suitable IL-17 A and/or IL-17RA monoclonal antibody specific for the targeted personalized treatment of neutrophilic asthma, similar to the other phenotypes of asthma.^{43, 132, 133}

Neutrophilic asthma is a complex phenotype of asthma characterized by high levels of neutrophils in sputum, BAL fluid, and bronchial biopsy specimen. Th17 cells and IL-17A and IL-17F cytokines play an important role in the pathogenesis of neutrophilic airway inflammation. Neutrophilic asthma is characterized by severe disease, frequent exacerbations, near-fatal asthma, fixed airflow obstruction with low FEV1. Patients with neutrophilic asthma have poor response to corticosteroids, and have worse quality of life. Cormobid disease coexisting with NA, such as respiratory infections, rhinosinusitis, obesity, gastroesophageal reflux disease, obstructive sleep apnoeas aggravate the symptoms, and contribute to the poor response of neutrophilic asthma to controller and modifier medications. Treatment of of some of these coexisting diseases improve the symptoms, lung function, reduce frequent use of rescue medication, and improve the quality of life. There are no readily available biomarkers for the diagnosis of neutrophilic asthma for targeted precision medicines.

None.

The author declares there is no conflicts of interest.

None.

1. The Global Asthma Network. The Global Asthma Report 2014. 2018.
2. Masoli M, Fabian D, Holt D, et al. The global burden of asthma:executive summary of the GINA Dissemination Committee report. Allergy. 2004;59(5):469–478.
3. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR 3):Guidelines for the Diagnosis and Management of Asthma – A Summary Report 2007. J Allergy Clin Immunol. 2007;120(5 Suppl):S94–S138.
4. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood:ISAAC Phase One and Three repeat multi–country cross–sectional surveys. Lancet. 2006;368:733–743.
5. Wenzel SE, Schwartz LB,  Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160:1001–1008.
6. Simpson JL, Scott R, Boyle MJ, et al. Inflammatory subtypes in asthma:assessment and identification using induced sputum. Respirology. 2006;11(1):54–61.
7. Moore W, Bleecker E, Curren–Everett D, et al. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Characterization of the severe asthma phenotypes by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119:405–413.
8. Anderson GP. Endotypying asthma:new insights into key pathogenic mechanism in a heterogenous disease. Lancet. 2008;372:1107–1119.
9.  Moore WC, Meyer DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315–323.
10. Wenzel SE. Asthma phenotypes:the evolution from clinical to molecular approach. Nat Med. 2012;18(5):716–725.
11. Siroux V, González JR, Bouzigon E, et al. Genetic heterogenicity of asthma phenotypes identified by a clustering approach. Eur Resp J. 2014;43:439–452.
12. Sutherland ER, Goleva E, King TS, et al. Cluster analysis of obesity and asthma phenotypes. PLoS One. 2012;7(5):e36631.
13. Proceeding of the ATS workshop on refractory asthma:current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000;162(6):2341–2351.
14. Chung K, Godard P, Adelroth E, et al. Difficult/therapy–resistant asthma:the need for integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. Eur Respir J. 1999;13(5):1198–1208.
15. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations:document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126:926–238.
16.  Chanez P, Wenzel SE, Anderson GP, et al. Severe asthma in adults:what are the important questions?. J Allergy Clin Immunl. 2007;119:1337–1348.
17. Bel EH, Sousa A, Fleming L, et al. Diagnosis of severe refractory asthma:an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax. 2011;66:910–917.
18.  Wener RL, Bel EH. Severe refractory asthma:an update. Eur Respir Rev. 2013;22:196–201.
19.  Chung KF. Asthma phenotyping:a necessity for improved therapeutic precision and new targeted therapies. J Intern Med. 2016;279:192–204.
20. Pavord ID. Eosinophilic phenotypes of airway disease. Ann Am Thorac Soc. 2013;10(Suppl):S143–S149.
21.  Buhl R, Humbert M, Bjermer L, et al. Severe eosinophilic asthma:a roadmap to consensus. Eur Respir J. 2017;49(5):1700634.
22.  Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes:role of onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113:101–108.
23.  Harder P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am Rev Respir Crit Care Med. 2008;178:218–224.
24. Groot JC, Ten Brinke A, Bel EHD. Management of patients with eosinophilic asthma:a new era begins. ERJ Open Res. 2015;1(1):00024–2015.
25. Chung KF. Neutrophilic asthma:a distinct target for treatment. Lancet Respir Med. 2016;(10):765–767.
26. Nair P, Aziz–Ur–Rehman A, Radford K. Therapeutic implication of ‘neutrophilic asthma’. Curr Opin Pulm Med. 2005;21(1):33–38.
27. Ray A, Kolls JK.  Neutrophilic inflammation in asthma is associated with disease severity. Trends Immunol. 2017;38(12):948–954.
28. Moore WC, Hasle A, Shaw, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557–1563.
29. Little SA, Macleod KJ, Chalmers GW, et al. Association of forced expired volume with disease duration and sputum neutrophils in chronic asthma. Am J Med. 2002;112:446–452.
30. Shaw DE, Berry MA, Hargadon B, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest. 2007;132(6):1871–1875.
31. Fahy JV, Kim KW, Liu J, et al. Prominent neutrophil inflammation in sputum from subjects with asthma exacerbations. J Allergy Clin Immunol. 1995;95:843–852.
32. Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts:effect on exacerbations. Eur Repir J. 2006;27(3);483–494.
33. Haldar P, Pavord ID. Noneosinophilic asthma:A distinct clinical and pathologic phenotype. J Allergy Clin Immunol. 2007;119(5):1043–1052.
34. Sur S, Crotty TB, Kephart GM, et al. Sudden–onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway mucosa?. Am Rev Respir Dis. 1993;148:713–719.
35. Lamblin C, Gosset P, Tillie–Leblond I, et al. Bronchial neutrophilia in patients with noninfectious status astmaticus. Am J Respir Crit Care Med. 1998;157(2):394–402.
36.  Martin RJ, Cicutto LC, Smith HR, et al. Airway inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143(2):351–357.
37. Syabbalo NC. Chronobiology and chronopathophysiology of nocturnal asthma. Int J Clin Pract. 1997;51 (7), 455–462.
38.  Wenzel SE, Szefler SJ, Leung DY,  et al. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med. 1997;156:737–743.
39.  Pavord ID, Brightling CE,  Woltmann  G, et al. Non–eosinophilic asthma corticosteroid unresponsive asthma. Lancet. 1999;353:2213–2214.
40.   Green RH, Brightling CE, Wolmann G, et al. Analysis of induced sputum in adults with asthma identification of a subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57(10):875–879.
41. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45–56.
42. Fahy JV. Type 2 inflammation in asthma – present in most, absent in many. Nat Rev Immunol. 2015;15(1):57–65.
43. Chung KF. Personalised medicine in asthma:time for action:Number 1 in the Series "Personalised medicine in respiratory diseases" Edited by Renaud Louis and Nicolas Roche. Eur Respir Rev. 2017;26:170064.
44. Woodruff PG, Khashayar R, Lazarus SC, et al. Relationship between airway inflammation, hyperresponsiveness, and obstructive asthma. J Allergy Clin Immunol. 2001;108:753–758.
45.  Busse WW, Lemanske RFJ, Gern JE. Role of viral respiratory infection in asthma and asthma exacerbations. Lancet. 2010;376(9743):826–834.
46.  Feldman AS, He Y, More ML, et al. Towards primary prevention of asthma. Reviewing he evidence for early–life respiratory viral infections as modifiable risk factors to prevent childhood asthma. Am J Respir Crit Care Med. 2015;19(1):34–44.
47.  Openshaw PJM, Chiu C, Culley FJ. Protective and harmful immunity to RSV infection. Annu Rev Immunol. 2017;35:501–532.
48.  Wark PAB, Johnston SL, Moric I, et al. Neutrophil degranulation and cell lysis associated with clinical severity in virus–induced asthma. Eur Respir J. 2010;19(1):68–75.
49.  Zhang Q, Illing R, Hui CK, et al. Bacteria in sputum of stable severe asthma and increased airway wall thickness. Respir Res. 2012;18;13:35.
50.  Green BJ, Wiriyachaiporn S, Grainge C, et al. Potentially pathogenic airway bacteria and neutrophil inflammation in treatment resistant severe asthma. PLoS One. 2014;23;9(6):100645.
51. Horvat JC, Starkey MR, Kim RY, et al. Chlamydial respiratory infection during allergen sensitization drives neutrophilic allergic airways disease. J Immunol. 2010;184:4159–4169.
52. Essilfie AT, Simpson JC, Dunkley ML, et al. Combined Haemophilus influenzae respiratory infection and allergic airway disease drives chronic inflammation and neutrophilic asthma. Thorax. 2012;67:588–599.
53. Wood LG, Simpson JL, Hansbro PM, et al. Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8–isoprostane and airway neutrophilia. Free Radic Res. 2010;44(2):146–154.
54. Brown GD. Innate fungal immunity:the key role of phagocytosis. Annu Rev Immunol. 2011;29:1–21.
55. Annesi–Maesano I. Epidemiological evidence of the occurrence of rhinitis and sinusitis in asthmatics. Allergy. 1999;54(Suppl. 57):7–13.
56. Simpson JL, Baines KL, Ryan N, et al. Neutrophil asthma is characterised by increased rhinosunisitis and sleep disturbance and GERD. Asian Pac J Allergy Immunol. 2014;32(1):66–74.
57.  Ragab S, Scadding GK, Lund VY, et al. Treatment of chronic rhinosinusitis and its effects on asthma. Eur Respir J. 2006;28:68–74.
58.  Ford ES. Epidemiology of obesity and asthma. J Allergy Clin Immunol. 2005;115(5):897–909.
59. Beuther DA, Sunderland ER. Overweight, obesity, and incident asthma:a meta–analysis of prospective epidemiological studies. Am J Respir Crit Care Med. 2007;175:661–666.
60. Dixon AE, Holguin F, Sood A, et al. An Official American Thoracic Society Workshop report:obesity and asthma. Proc Am Thorac Soc. 2010;7(5):325–335.
61. Gibeon D, Batuwita K, Osmond M, et al. Obesity–associated severe asthma represent a distinct clinical phenotype:analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort according to BMI. Chest. 2013;143(2):406–414.
62. Schatz M, Hsu J, Zeiger RS, et al. Phenotypes determined by cluster analysis in severe or difficult–to–treat asthma. J Allergy Clin Immunol. 2014;133:1549–1556.
63. Wood LG. Asthma in the obese:a big and growing problem. Am J Respir Crit Care Med. 2017;195(1):4–5.
64. Kronander UN, Falkenberg M, Zetterman O. Prevalence and incidence of asthma related to waist circumference and BMI in Swedish community sample. Respir Med. 2004;98(11):1108–1116.
65. J von  Behren J, Lipsett M, Horn–Ross PL, et al. Obesity, waist size and prevalence of current asthma in California Teacher Study cohort. Thorax. 2009;64:889–893.
66.  Brumpton B, Langhammer A, Romundstad P, et al. General and abdominal obesity and incident asthma in adults:the HUNT study. Eur Respir J. 2013;41:323–329.
67. Peters U, Dixon AE, Forno E. Obesity and asthma. J Allergy Clin Immunol. 2018;141(4):1169–1179.
68. Farah CS, Kermode JA, Downie SR, et al. Obesity is a determinant of asthma control independent of inflammation and lung mechanics. Chest. 2011;140(3):659–666.
69. Lv N, Xiao L, Camargo CA, et al. Abdominal and general adiposity and level of asthma control in adults with uncontrolled asthma. Ann Am Thorac Soc. 2014;11(8):1218–1224.
70. Ulrik CS. Asthma symptoms in obese adults:the challenge of achieving control. Exp Rev Clin Pharmacol. 2015;9(1):5–8.
71. Peters–Golden M, Swern A, Bird SS, et al. Influence of body mass index on the response to controller agents. Eur Respir J. 2006;27(3):495–503.
72. Boulet LP, Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med. 2007;101(11):2240–2247.
73. Sutherland ER, Goleva E, Strand M, et al. Body mass and glucocorticoid response in asthma.  Am J Respir Crit Care Med. 2008;27(3):682–687.
74. Taylor B, Mannino D, Brown C, et al. Body mass index and asthma severity in the national survey. Thorax. 2008;63(1):14–20.
75.  Pradeepan S, Garrison G, Dixon AE. Obesity in asthma:approaches to treatment. Curr Allergy Asthma Rep. 2013;13:434–442.
76. Schatz M, Hsu JW, Zeiger RS, et al. Phenotypes determined by cluster analysis in severe or difficult–to–treat asthma. J Allergy Clin Immunol. 2014;133(6):1549–1556.
77. Telenga ED, Tideman, SW, Kersjens HK, et al. Obesity in asthma:more neutrophil inflammation as a possible explanation for a reduced treatment response. Allergy. 2012;67(8):1060–1068.
78. Scott HA, Gibson PG, Gard ML, et al. Airway inflammation is augmented by obesity and fatty acids in asthma. Eur Respir J. 2011;38:594–602.
79.  Marijsse GS, Seys SF, Schelpe AS, et al. Obese individuals with asthma preferentially have a high IL–5/IL–17A/IL–25 sputum inflammatory pattern. Am J Respir Crit Care Med. 2014;189(10):1284–1285.
80. Baffi CW, Winicca DE, Holguin F. Asthma and obesity:mechanisms and clinical implications. Asthma Res Prac. 2015;4(1):1.
81. Gibson PG. Obesity and asthma. Ann Am Thorac Soc. 2013;10(Supl):S38–S142.
82. Scott HA, Wood LG, Gibson PG. Role of obesity in asthma:mechanisms and management strategies. Curr Allergy Asthma Rep. 2017;17(8):53.
83. Wood LG, Li Q, Scot HA, et al. Saturated fatty acids, obesity, and the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome in asthmatic patients. J Allergy Clin Immunol. 2019;143(1):303–315.
84. Dixon AE, Pratley RE, Forgione PM, et al. Effect of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol. 2011;128(3):508–515.
85. Boulet LP, Turcotte H, Martin J, et al. Effect of bariatric surgery on airway response and lung function in obese subjects with asthma. Respir Med. 2012;106(5):651–660.
86. Shaw DE, Sousa AR, Fowler SJ, et al. Clinical and inflammatory characteristics of the European U–BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46:1308–1321.
87. Hasegawa K, Tsugawa Y, Chang Y, et al. Risk of an asthma exacerbation after bariatric surgery in adults. J Allergy Clin Immnol. 2015;136(2):288–294.
88. Tashiro H, Shore SA. Obesity and severe asthma. Allergol Intern. 2019;68(2):135–142.
89. May EE. Intrinsic asthma in adults  associated with gastroesophageal reflux. JAMA. 1976;236(23):2626–2628.
90. Sontag SJ, O’Connell S, Khandelwal S, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology. 1990;99(3):613–620.
91. Gustafsson BB, Kjelmann NI, Tibbing L. Bronchial asthma and acid reflux into the distal and proximal esophagus. Arch Dis Child. 1990;65(11):1255–1259.
92.  Vincent D, Cohn–Jonathan AM Leport J, et al. Gastro–oesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur Respir J. 1997;10(10):2255–2259.
93.  Simpson JL, Baines KJ, Ryan N, et al. Netrophilic asthma is characterised by increased rhinosinusitis with sleep disturbances and GERD. Asian Pac J Allergy Immunol. 2014;32(1):66–74.
94. Maio S, Baldacci S, Bresciani M, et al. RItA:the Italian severe/uncontrolled asthma registry. Allergy. 2018;73(3):683–695.
95. Bowrey DS, Peters JH, DeMester TR. Gastroesophageal reflux disease in asthma. Ann Surg. 2000;23(2):161–172.
96.  Tucci F, Resti M, Fontana R, et al. Gastroesophageal reflux and bronchial asthma:prevalence of effect of cisapride therapy. J Pediatr Gastroenterol Nutr. 1993;17(3):265–270.
97.  Ekstrom T, Lingren RR, Tibbing L. Effect of ranitidine treatment on patients with a history of gastro–oesophageal reflux:a double–blind cross–over study. Thorax. 1989;44(1):19–23.
98. Meier JH, McNally, PR, Punja M, et al. Does omepraxole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double–blind, placebo–controlled crossover study. Dig Dis Sci. 1994;39:2127–2133.
99.  Harding SM, Ritcher JE, Guzzo MR, et al. Asthma and gastroesophageal reflux:acid suppressive therapy improves outcome. Am J Med. 1996;100(4):395–405.
100. Sontag S, O’Connell S, Greenlee H, et al. Is gastroesophageal reflux a factor in some asthmatics. Am J Gastroenterol. 1987;82(2):119–126.
101. Perrin–Fayolle M, Gormand F, Braillon G, et al. Long–term results of surgical treatment for gastroesophageal reflux in asthmatic patients. Chest. 1989;96(1):40–45.
102. Spivak, H, Smith CD, Phichith A, et al. Asthma and gastroesophageal reflux:fundoplication decreases the need for corticosteroids. J Gastrointest Surg. 1999;3(5):477–482.
103. Davis SE, Bishopp A, Wharton S, et al. The association between asthma and IL–17 and IL–17 and IL–17 and IL–17 and obstructive sleep apnea (OSA):a systemic review. J Asthma. 2018;56(2):118–129.
104. Wang Y, Liu K, Hu K, et al. Impact of obstructive sleep apnea on severe asthma exacerbations. Sleep Med. 2016;26:1–5.
105. Teodorescu M, Polomis DA, Hall SV, et al. Association of obstructive sleep apnea risk with asthma control in adults. Chest. 2010;138(3):543–550.
106. Teodorescu C, Broytman O, Curran–Everett D, et al. Obstructive sleep apnea risk, asthma burden and lower airway inflammation in adults in the Severe Asthma Research Program (SARP) II. J Allergy Clin Immunol Pract. 2015;3(4):566–575.
107. Taillé C, Rouvel–Tallec, Stoica M, et al. Obstructive sleep apnea modulates airway inflammation and remodeling in severe asthma. PLoS One. 2016;11(3):e0150042.
108. Thomson NC, Spear SM. The influence of smoking on the treatment response in patents with asthma Current Opinion in Allergy and Clinical Immunology. 2005;5(1):57–63.
109. Karamanli O, Ozol D, Ugur KS, et al. Influence of CPAP treatment on airway and systemic inflammation in OSA patients. Sleep Breath. 2014;18(2):251–256.
110. Kauppi P, Bachour P, Maasilta P, et al. Long–term CPAP treatment improve asthma control in patients with asthma and obstructive sleep apnea. Sleep Breath. 2016;20(4):1217–1224.
111. Quirce S, Campos P, Dominguez–Ortega J, et al. New development in work–related asthma. Expert Rev Clin Immunol. 2017;13(3):271–281.
112.  Anees W, Huggins V, Pavord ID, et al. Occupational asthma due to low molecular agents:eosinophilic and neutrophilic variants. Thorax. 2002;57:231–236.
113. Tarlo SM, Lemiré C. Occupational asthma.  N Engl J Overseas Ed. 2014;370(7):640–649.
114. Polosa R, Thomson NC. Smoking and asthma:dangerous liaisons. Eur Respir J. 2013;41(3):716–726.
115. Shimoda T, Obase Y, Kishikawa R, et al. Influence of cigarette smoking on airway inflammation and inhaled corticosteroids treatment in patients with asthma. Allergy Asthma Proc. 2016;37(4):50–58.
116. Lazarus SC, Chinchilli VM, Rolling NJ, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;175:783–790.
117. Siew LQC, Wu S–Y, Ying S, et al. Cigarette smoking increases bronchial mucosal IL–17A expression in asthmatics, which act in concert with environmental aeroallergens to engender neutrophilic inflammation. Clin Exp Allergy. 2017;47(6):740–750.
118. Doe C, Bafadhel M, Siddiqui S, et al. Expression of T helper 17–associated cytokines IL–17A and IL–17F in asthma and COPD. Chest. 2010;138:1140–1147.
119. Kuo CS, Pavlidis S, Loza M, et al. T–helper cell type 2 (Th2) and non–Th2 molecular phenotypes of asthma using sputum transcriptomics in U–BIPRED. Eur Respir J. 2017;49(2):1602135.
120. Cosmi L, Liotta F, Maggi E, et al. Th17 cells:new players in asthma pathogenesis. Allergy. 2011;66(8):989–998.
121. Pavord ID, Korns S, Howarth P, et al. Mepolizumab for severe asthma (DREAM):a multicenter, double–blind, placebo–controlled trial. Lancet. 2012;380:651–659.
122. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–1207.
123. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil count:result from two multicenter, parallel, double–blind, randomized, placebo–controlled phase 3 trial. Lancet Respir Med. 2015;3(5):355–366.
124. Bleeker ER, Fizgerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high–dose inhaled corticosteroids and long–acting β–agonists (SIROCCO): a randomized multi–centre, placebo–controlled phase 3 trial. Lancet. 2016;388(10056):2115–2127.
125.  Fitzgerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti–interleukin–5 receptor monoclonal antibody, as add–on treatment for patients with severe asthma, uncontrolled eosinophilic asthma (CALIMA):a randomized, double–blind, placebo–controlled phase 3 trial. Lancet. 2016;6736(16):2128–2141.
126. Ziegler SF, Artis D. Sensing the outside world:TSLP regulates barrier immunity. Nat Immunol. 2010;11(4):289–293.
127. Ying S, O’Connor B, Ratoff J, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th–2 attracting cytokines and disease severity. J Immunol. 2005;174(12):8183–8190.
128. Lindén  A. Role of interleukin–17 and the neutrophil in asthma. Int Arch Allergy Immunol. 2001;126(3):179–184.
129. Kolls J, Lindén A. Interleukin–17A family members and inflammation. Immunity. 2004;21(4):467–476.
130. Lindén A, Laun M, Anderson GK. Neutrophils, interleukin–17A and lung disease. Eur Respir J. 2005;25(1):159–172.
131. Brusselle GG, Provoost S, Bracke RR, et al.  Inflammasomes in respiratory disease:from bench to bedside. Chest. 2014;145:1121–1133.
132. Guilleminaut L, Ouksel H, Belleguic C, et al. Personalized medicine in asthma:from curative to preventive medicine. Eur Respir J. 2017;2017;26(143):160010.
133. Canonica GW, Ferrando M, Baiardini I, et al. Asthma:personalized and precision medicine. Curr Opin Allergy Clin Immunol. 2018;18(1):51–58.