Purpose of Review
Understanding the molecular mechanisms and heterogeneity of asthma has allowed the discovery of two distinct endotypes based on the mechanisms driving the underlying airway inflammation: eosinophilic asthma, a subtype of T2-high asthma, and neutrophilic asthma, a subtype of non-T2 asthma or T2-low asthma. In this review, we highlight the current knowledge about the immunopathology of these distinct subtypes and their clinical and therapeutic implications.
The intricate interplay of immune pathways has been recently evaluated in both eosinophilic and neutrophilic asthma. The delineation of signaling molecules and cytokines in the eosinophilic pathway has led to the identification of biomarkers that can guide in diagnosing and prognosticating patients and the advent of several targeted biologic therapies. However, the mechanisms of neutrophilic asthma are still not well understood and constitute an unmet need and a therapeutic challenge especially that patients with this type of asthma are often characterized by severe and refractory disease.
The understanding of the heterogeneity of asthma profiles and the fundamental inflammatory pathways driving airway inflammation helped in stratifying the disease into distinct endotypes and phenotypes. Recognizing the diverseness of the disease helped in understanding the varying response to treatment options and accounting for the shift in treatment paradigms from a “one size fits all” approach to targeted personalized medicine mostly in eosinophilic asthma. Knowledge gaps exist in the understanding of the pathophysiology of neutrophilic asthma with further studies needed to elucidate its pathogenesis and to develop more effective therapy to target this subgroup of patients with more resistant disease.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
• Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J. 2016. https://doi.org/10.1183/13993003.01359-2015An important paper describing the importance of the concept of personalized medicine and the emergence of endotypes and phenotypes in asthma.
Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, 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. https://doi.org/10.1164/ajrccm.160.3.9812110.
Assaf SM, Hanania NA. Biological treatments for severe asthma. Curr Opin Allergy Clin Immunol. 2019. https://doi.org/10.1097/ACI.0000000000000549.
Camelo A, Rosignoli G, Ohne Y, Stewart RA, Overed-Sayer C, Sleeman MA, et al. IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells. Blood Adv. 2017. https://doi.org/10.1182/bloodadvances.2016002352.
Borish L. The immunology of asthma: asthma phenotypes and their implications for personalized treatment. Ann Allergy Asthma Immunol. 2016. https://doi.org/10.1016/j.anai.2016.04.022.
Paul WE. What determines Th2 differentiation, in vitro and in vivo? Immunol Cell Biol. 2010. https://doi.org/10.1038/icb.2010.2.
Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010. https://doi.org/10.1016/j.jaci.2009.11.017.
Persson C. Lysis of primed eosinophils in severe asthma. J Allergy Clin Immunol. 2013. https://doi.org/10.1016/j.jaci.2013.09.036.
Balzar S, Fajt ML, Comhair SAA, et al. Mast cell phenotype, location, and activation in severe asthma. Am J Respir Crit Care Med. 2011. https://doi.org/10.1164/rccm.201002-0295oc.
Fajt ML, Gelhaus SL, Freeman B, Uvalle CE, Trudeau JB, Holguin F, et al. Prostaglandin D2 pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol. 2013. https://doi.org/10.1016/j.jaci.2013.01.035.
Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004. https://doi.org/10.1016/j.jaci.2003.10.041.
Peters MC, Kerr S, Dunican EM, et al. Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol. 2019. https://doi.org/10.1016/j.jaci.2017.12.1009.
Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016. https://doi.org/10.1016/j.jaci.2015.12.1324.
Liu T, Kanaoka Y, Barrett NA, et al. Aspirin-exacerbated respiratory disease involves a cysteinyl leukotriene–driven IL-33–mediated mast cell activation pathway. J Immunol. 2015. https://doi.org/10.4049/jimmunol.1500905.
Buchheit KM, Cahill KN, Katz HR, et al. Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2016. https://doi.org/10.1016/j.jaci.2015.10.020.
Walsh CJ, Zaihra T, Benedetti A, Fugère C, Olivenstein R, Lemière C, et al. Exacerbation risk in severe asthma is stratified by inflammatory phenotype using longitudinal measures of sputum eosinophils. Clin Exp Allergy. 2016. https://doi.org/10.1111/cea.12762.
•• Westerhof GA, Korevaar DA, Amelink M, De Nijs SB, De Groot JC, Wang J, et al. Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes. Eur Respir J. 2015. https://doi.org/10.1183/09031936.00012415An important paper investigating the accuracy of surrogate biomarkers of sputum eosinophilia.
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012. https://doi.org/10.1016/S0140-6736(12)60988-X.
Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013. https://doi.org/10.1056/NEJMoa1304048.
Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011. https://doi.org/10.1164/rccm.9120-11ST.
Hanania NA, Massanari M, Jain N. Measurement of fractional exhaled nitric oxide in real-world clinical practice alters asthma treatment decisions. Ann Allergy Asthma Immunol. 2018. https://doi.org/10.1016/j.anai.2018.01.031.
Schleich F, Demarche S, Louis R. Biomarkers in the management of difficult asthma. Curr Top Med Chem. 2016. https://doi.org/10.2174/1568026616666151015093406.
Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014. https://doi.org/10.1002/14651858.CD003559.pub4.
Divekar R, Hagan J, Rank M, Park M, Volcheck G, O’Brien E, et al. Diagnostic utility of urinary LTE4 in asthma, allergic rhinitis, chronic rhinosinusitis, nasal polyps, and aspirin sensitivity. J Allergy Clin Immunol Pract. 2016. https://doi.org/10.1016/j.jaip.2016.03.004.
Izuhara K, Conway SJ, Moore BB, Matsumoto H, Holweg CTJ, Matthews JG, et al. Roles of periostin in respiratory disorders. Am J Respir Crit Care Med. 2016. https://doi.org/10.1164/rccm.201510-2032PP.
Jia X, Li S, Xu TT, Ji N, Huang M. Diagnostic accuracy of periostin in predicting asthma: a systematic review and meta-analysis. J Asthma. 2019. https://doi.org/10.1080/02770903.2019.1684518.
Kuo CHS, Pavlidis S, Loza M, et al. A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED. Am J Respir Crit Care Med. 2017. https://doi.org/10.1164/rccm.201512-2452OC.
•• Chang HS, Lee TH, Jun JA, Baek AR, Park JS, Koo SM, et al. Neutrophilic inflammation in asthma: mechanisms and therapeutic considerations. Expert Rev Respir Med. 2017. https://doi.org/10.1080/17476348.2017.1268919A review discussing the pathomechanisms and clinical implications of neutrophilic asthma.
Al-Ramli W, Préfontaine D, Chouiali F, Martin JG, Olivenstein R, Lemière C, et al. T H 17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009. https://doi.org/10.1016/j.jaci.2009.02.024.
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest. 2012. https://doi.org/10.1378/chest.11-1838.
Raundhal M, Morse C, Khare A, et al. High IFN-γ and low SLPI mark severe asthma in mice and humans. J Clin Invest. 2015. https://doi.org/10.1172/JCI80911.
Maniscalco M, Paris D, Melck DJ, D’Amato M, Zedda A, Sofia M, et al. Coexistence of obesity and asthma determines a distinct respiratory metabolic phenotype. J Allergy Clin Immunol. 2017. https://doi.org/10.1016/j.jaci.2016.08.038.
Sutherland ER, Goleva E, King TS, Lehman E, Stevens AD, Jackson LP, et al. Cluster analysis of obesity and asthma phenotypes. PLoS One. 2012. https://doi.org/10.1371/journal.pone.0036631.
Peters U, Dixon AE, Forno E. Obesity and asthma. J Allergy Clin Immunol. 2018. https://doi.org/10.1016/j.jaci.2018.02.004.
Peters MC, McGrath KW, Hawkins GA, et al. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. 2016. https://doi.org/10.1016/S2213-2600(16)30048-0.
Takahashi K, Pavlidis S, Ng Kee Kwong F, et al. Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis. Eur Respir J. 2018. https://doi.org/10.1183/13993003.02173-2017.
Hanania NA, King MJ, Braman SS, et al. Asthma in the elderly: current understanding and future research needs - a report of a National Institute on Aging (NIA) workshop. J Allergy Clin Immunol. 2011. https://doi.org/10.1016/j.jaci.2011.06.048.
Dunn RM, Busse PJ, Wechsler ME. Asthma in the elderly and late-onset adult asthma. Allergy Eur J Allergy Clin Immunol. 2018. https://doi.org/10.1111/all.13258.
Mathur SK. Allergy and asthma in the elderly. Semin Respir Crit Care Med. 2010. https://doi.org/10.1055/s-0030-1265899.
Baptist AP, Busse PJ. Asthma over the age of 65: all’s well that ends well. J Allergy Clin Immunol Pract. 2018. https://doi.org/10.1016/j.jaip.2018.02.007.
Maes T, Cobos FA, Schleich F, et al. Asthma inflammatory phenotypes show differential microRNA expression in sputum. J Allergy Clin Immunol. 2016. https://doi.org/10.1016/j.jaci.2016.02.018.
Nair P, Aziz-Ur-rehman A, Radford K (2015) Therapeutic implications of “neutrophilic asthma.” Curr Opin Pulm Med https://doi.org/10.1097/MCP.0000000000000120.
Cavaleiro Rufo J, Madureira J, Oliveira Fernandes E, Moreira A. Volatile organic compounds in asthma diagnosis: a systematic review and meta-analysis. Allergy Eur J Allergy Clin Immunol. 2016. https://doi.org/10.1111/all.12793.
Schleich FN, Zanella D, Stefanuto PH, et al. Exhaled volatile organic compounds are able to discriminate between neutrophilic and eosinophilic asthma. Am J Respir Crit Care Med. 2019. https://doi.org/10.1164/rccm.201811-2210OC.
Murillo JC, Dimov V, Gonzalez-Estrada A. An evaluation of fevipiprant for the treatment of asthma: a promising new therapy? Expert Opin Pharmacother. 2018. https://doi.org/10.1080/14656566.2018.1540589.
Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017. https://doi.org/10.1016/S0140-6736(17)31281-3.
Brusselle GG, VanderStichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013. https://doi.org/10.1136/thoraxjnl-2012-202698.
Conflict of Interest
Sara M. Assaf and Nicola A. Hanania declare no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Lung Transplant
About this article
Cite this article
Assaf, S.M., Hanania, N.A. Eosinophilic vs. Neutrophilic Asthma. Curr Pulmonol Rep (2020). https://doi.org/10.1007/s13665-020-00244-0
- Eosinophilic asthma
- Neutrophilic asthma
- Targeted therapies