Biomarkers of airways inflammation in patients with severe asthma in a real clinical practice

Severe asthma is a heterogeneous disease consisting of several endotypes and phenotypes diagnosed due to different biomarkers. Frequency of different endotypes and phenotypes in real clinical practice needs further investigation.

The aim of this study was to assess biomarkers of T2-inflammation in patients with severe asthma in a single secondary care center.

Methods. We examined 96 adult outpatients (34% male) with severe asthma. Data collected included demographics, smoking history, asthma exacerbations during previous 12 months, medication use, comorbidities. Lung function tests were assessed by using the Spirograph 2120 (Vitalograph, Great Britain). Blood eosinophils (Eos) were measured by automatic haemoanalyser. Atopic status was determined by positive skin prick-test (> 3 mm) and/or serum specific IgE to common inhalant allergens. Serum total IgE levels were assessed by immunofluorescence assay. FeNO was measured by a chemiluminescence analyzer (Model LR4000; Logan Research, Rochester, UK). Presence of allergy, need for regular oral steroid use, blood Eos ≥ 150 cell/μl and FeNO ≥ 20 ppb were considered as markers of T2-driven inflammation. Asthma control and quality of life were assessed by using Russian versions of ACQ-5 and St. George's Respiratory Questionnaire (SGRQ). Statistical analyses were performed with Statistica Ver. 10.0 (StatSoft, Inc., USA).

Results. The majority of patients with severe asthma (93%) have at least one or more elevated markers (presence of allergy, need for regular oral steroid use, Eos ≥ 150 cell/μl or FeNO ≥ 20 ppb) of T2-inflammation. Biomarkers levels did not differ in non-steroid-dependent and steroid-dependent patients. The most frequent markers were allergy and blood Eos ≥ 150 cell/μl. Two or more elevated biomarkers were revealed in 72% of patients.

Conclusion. The majority of patients with severe asthma in real clinical practice have signs of T2-inflammation. It seems that many severe asthmatics have indications for prescription of biological and can be treated by more than one of monoclonal antibodies against major cytokines of T2-inflammation.

1. Global Initiative for Asthma. Updated 2020. Available at: www.ginasthma.org [Accessed: June 20, 2020].

2. Chung K.F., Wenzel S.E., Brozek J.L. et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 2014; 43 (2): 343–373. DOI: 10.1183/09031936.00202013.

3. de Carvalho-Pinto R.M., Cukier A., Angelini L. et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respir. Med. 2012; 106 (1): 47–56. DOI: 10.1016/j.rmed.2011.08.013.

4. Russian Respiratory Society. Federal clinical guidelines for the diagnosis and treatment of bronchial asthma. Updated 2019. Available at: https://spulmo.ru [Accessed: June 20, 2020] (in Russian).

5. Fedoseev G.B., Uspenskaya E.P., Korovina O.V. [Clinical and etiopathogenetic variants of bronchial asthma: diagnosis and treatment]. Problemy pul'monologii. 1980; 8: 275 (in Russian).

6. Haldar P., Pavord I.D., Shaw D.E. et al. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 2008; 178 (3): 218–224. DOI: 10.1164/rccm.200711-1754OC.

7. Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin. Exp. Allergy. 2012; 42 (5): 650–658. DOI: 10.1111/j.1365-2222.2011.03929.x.

8. Schleich F., Brusselle G., Louis R. et al. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir. Med. 2014; 108 (12): 1723–1732. DOI: 10.1016/j.rmed.2014.10.007.

9. Nenasheva N., Belevsky A., Kravchenko N. et al. Pre - liminary analysis of the data of patients with severe bron - chial asthma included in the Russian National Register of Severe Asthma (RSAR). Eur. Respir. J. 2019; 54 (Suppl. 63): PA4261. DOI: 10.1183/13993003.congress-2019.PA4261.

10. van Bragt J.J.M.N., Adcock I.M., Bel E.H. et al. Cha - racteristics and treatment regimens across ERS SHARP severe asthma registries. Eur. Respir. J. 2020; 55 (1): 1901163. DOI: 10.1183/13993003.01163-2019.

11. Wang E., Wechsler M.E., Tran T.N. et al. Characterization of severe asthma worldwide. Data from the International Severe Asthma Registry. Chest. 2020; 157 (4): 790–804. DOI: 10.1016/j.chest.2019.10.053.

12. Woodruff P.G., Modrek B., Choy D.F. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 2009; 180 (5): 388– 395. DOI: 10.1164/rccm.200903-0392OC.

13. Pavord I.D., Afzalnia S., Menzies-Gow A., Heaney L.G. The current and future role of biomarkers in type 2 cytokinemediated asthma management. Clin. Exp. Allergy. 2017; 47 (2): 148–160. DOI: 10.1111/cea.12881.

14. Dweik R.A., Boggs P.B., Erzurum S.C. 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; 184 (5): 602–615. DOI: 10.1164/rccm.9120-11ST.

15. Malinovschi A., Janson C., Borres M., Alving K. Simult - aneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity. J .Allergy Clin. Immunol. 2016; 138 (5): 1301–1308.e2. DOI: 10.1016/j.jaci.2016.01.044.

16. Holguin F., Cardet J.C., Chung K.F. et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2020; 55 (1): 1900588. DOI: 10.1183/13993003.00588-2019.

17. Busby J., Holweg C.T.J., Chai A. et al. Change in type-2 biomarkers and related cytokines with prednisolone in uncontrolled severe oral corticosteroid dependent asthmatics: an interventional open-label study. Thorax. 2019; 74 (8): 806–809. DOI: 10.1136/thoraxjnl-2018-212709.

18. Mesnil C., Raulier S., Paulissen G. et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J. Clin. Invest. 2016; 126 (9): 3279–3295. DOI: 10.1172/JCI85664.

19. Januskevicius A., Jurkeviciute E., Janulaityte I. et al. Blood eosinophils subtypes and their survivability in asthma pati - ents. Cells. 2020; 9 (5): 1248. DOI: 10.3390/cells9051248.

20. Peters M.C., Kerr Sh., Dunican E.M. 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. DOI: 10.1016/j.jaci.2017.12.1009.

21. Sergeeva G.R., Emel'yanov A.V. Korovina O.V. et al. [Severe asthma: characteristics of patients in clinical practice]. Terapevticheskiy arkhiv. 2015; (12): 26–31. DOI: 10.17116/terarkh2015871226-31 (in Russian).

22. Albers F.C., Müllerová H., Gunsoy N.B. et al. Biologic treatment eligibility for real-world patients with severe asthma: the IDEAL study. J. Asthma. 2018; 55 (2): 152–160. DOI: 10.1080/02770903.2017.1322611.

23. Wynn T.A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 2015; 15 (5): 271–282. DOI: 10.1038/nri3831.

24. Agache I., Cojanu C., Laculiceanu A., Rogozea L. Critical points on the use of biologicals in allergic diseases and asthma. Allergy Asthma Immunol. Res. 2020; 12 (1): 24–41. DOI: 10.4168/aair.2020.12.1.24.

25. Tran T.N., Zeiger R.S, Peters S.P. et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann. Allergy Asthma Immu - nol. 2016; 116 (1): 37–42. DOI: 10.1016/j.anai.2015.10.027.

26. Chapman K.R., Albers F.C., Chipps B. et al. The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma. Allergy. 2019; 74 (9): 1716–1726. DOI: 10.1111/all.13850.

27. Pérez de Llano L.A.P., Cosío B.G., Domingo C. et al. Efficacy and safety of reslizumab in patients with severe asthma with inadequate response to omalizumab: a multicenter, open-label pilot study. J. Allergy Clin. Immunol. Pract. 2019; 7 (7): 2277–2283.e2. DOI: 10.1016/j.jaip.2019.01.017.