Bronchial asthma is the most common chronic respiratory disease of childhood. Cough is one of its defining symptoms. This study investigated the associations between selected inflammatory biomarkers and cough reflex sensitivity after capsaicin inhalation in children with mild and moderate well-controlled type 2 endotype asthma compared with non-asthmatic probands. Sensitivity to the cough reflex was measured by recording the cough response after capsaicin inhalation. The sandwich ELISA method was used to measure serum concentrations of the investigated potential inflammatory biomarkers (interleukin 13, interleukin 1beta, eosinophil-derived neurotoxin). The acquired data were statistically evaluated according to descriptive analyses for summarization and comparison between cough reflex sensitivity parameters and individual biomarker values in the observed and control groups modeled by a simple linear regression model. Statistical significance was defined as p<0.05. We showed a statistically significant association (p-value 0.03) between cough reflex sensitivity - C2 value (capsaicin concentration required for two cough responses) and interleukin 1beta serum concentrations in the asthma group compared with the control group of non-asthmatic children. Our results support the possibility of interleukin 1beta as a potential additive inflammatory biomarker used in clinical practice in children with asthma because of its correlation with the activity of the afferent nerve endings in the airways.

Clinic of Pediatric Respiratory Diseases and Tuberculosis Comenius University in Bratislava Jessenius Faculty of Medicine in Martin National Institute of Pediatric Tuberculosis and Respiratory Diseases Dolny Smokovec Slovak Republic Department of Pathological Physiology Comenius University in Bratislava Jessenius Faculty of Medicine in Martin Slovak Republic

Zobrazit více v PubMed

Jesenak M, Zelieskova M, Babusikova E. Oxidative stress and bronchial asthma in children-causes or consequences? Front Pediatr. 2017;5:162. doi: 10.3389/fped.2017.00162. PubMed DOI PMC

Licari A, Castagnoli R, Brambilla I, Marseglia A, Tosca MA, Marseglia GL, Ciprandi G. Asthma endotyping and biomarkers in childhood asthma. Pediatr Allergy Immunol Pulmonol. 2018;31:44–55. doi: 10.1089/ped.2018.0886. PubMed DOI PMC

Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Domingo Ribas C, Hilton Boon M, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55:1901136. doi: 10.1183/13993003.01136-2019. PubMed DOI PMC

Chung KF. Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome. J Thorac Dis. 2014;6(Suppl 7):S699–S707. doi: 10.3978/j.issn.2072-1439.2014.08.41. PubMed DOI PMC

Kunc P, Fabry J, Lucanska M, Zatko T, Grendar M, Pecova R. Cough reflex sensitivity in asthmatic children. Physiol Res. 2020;69(Suppl 1):S147–S150. doi: 10.33549/physiolres.934399. PubMed DOI PMC

Ish P, Malhotra N, Gupta N. GINA 2020: what’s new and why? J Asthma. 2021;58:1273–1277. doi: 10.1080/02770903.2020.1788076. PubMed DOI

Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–338. doi: 10.1183/09031936.05.00034805. PubMed DOI

Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV, Kastelik JA, et al. ERS guidelines on the assessment of cough. Eur Respir J. 2007;29:1256–1276. doi: 10.1183/09031936.00101006. PubMed DOI

Varechova S, Plevkova J, Hanacek J, Tatar M. Role of gender and pubertal stage on cough sensitivity in childhood and adolescence. J Physiol Pharmacol. 2008;59(Suppl 6):719–726. PubMed

Donovan C, Liu G, Shen S, Marshall JE, Kim RY, Alemao CA, Budden KF, et al. The role of the microbiome and the NLRP3 inflammasome in the gut and lung. J Leukoc Biol. 2020;108:925–935. doi: 10.1002/JLB.3MR0720-472RR. PubMed DOI

Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, Mayall JR, et al. Role for NLRP3 Inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma. Am J Respir Crit Care Med. 2017;196:283–297. doi: 10.1164/rccm.201609-1830OC. PubMed DOI

Wei W, Huang J, Ma Y, Ma X, Fang L, Fang W, Hao C. IL-1 signaling pathway molecules as key markers in childhood asthma. Pediatr Allergy Immunol. 2021;32:305–313. doi: 10.1111/pai.13388. PubMed DOI

Eljaszewicz A, Ruchti F, Radzikowska U, Globinska A, Boonpiyathad T, Gschwend A, Morita H, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021;147:1865–1877. doi: 10.1016/j.jaci.2020.08.042. PubMed DOI

Aron JL, Akbari O. Regulatory T cells and type 2 innate lymphoid cell-dependent asthma. Allergy. 2017;72:1148–1155. doi: 10.1111/all.13139. PubMed DOI

Agache I, Strasser DS, Klenk A, Agache C, Farine H, Ciobanu C, Groenen PMA, Akdis CA. Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics. Allergy. 2016;71:1192–1202. doi: 10.1111/all.12906. PubMed DOI

Ohne Y, Silver JS, Thompson-Snipes L, Collet MA, Blanck JP, Cantarel BL, Copenhaver AM, Humbles AA, Liu Y-J. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat Immunol. 2016;17:646–655. doi: 10.1038/ni.3447. PubMed DOI

Schuler CF, 4th, Malinczak CA, Best SKK, Morris SB, Rasky AJ, Ptaschinski C, Lukacs NW, Fonseca W. Inhibition of uric acid or IL-1β ameliorates respiratory syncytial virus immunopathology and development of asthma. Allergy. 2020;75:2279–2293. doi: 10.1111/all.14310. PubMed DOI PMC

Owczarczyk AB, Schaller MA, Reed M, Rasky AJ, Lombard DB, Lukacs NW. Sirtuin 1 regulates dendritic cell activation and autophagy during respiratory syncytial virus-induced immune responses. J Immunol. 2015;195:1637–1646. doi: 10.4049/jimmunol.1500326. PubMed DOI PMC

Mahmutovic Persson I, Menzel M, Ramu S, Cerps S, Akbarshahi H, Uller L. IL-1β mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation. Respir Res. 2018;19:16. doi: 10.1186/s12931-018-0725-z. PubMed DOI PMC

Liao Z, Xiao H-T, Zhang Y, Tong R-S, Zhang L-J, Bian Y, He X. IL-1β: a key modulator in asthmatic airway smooth muscle hyper-reactivity. Expert Rev Respir Med. 2015;9:429–436. doi: 10.1586/17476348.2015.1063422. PubMed DOI

Sobkowiak P, Wojsyk-Banaszak I, Kowalewska M, Wasilewska E, Langwiński W, Kycler Z, Skibińska M, et al. Interleukin 1β polymorphism and serum level are associated with pediatric asthma. Pediatr Pulmonol. 2017;52:1565–1571. doi: 10.1002/ppul.23893. PubMed DOI

He Y, Peng S, Xiong W, Xu Y, Liu J. Association between polymorphism of interleukin-1beta and interleukin-1 receptor antagonist gene and asthma risk: a meta-analysis. ScientificWorldJournal. 2015;2015:685684. doi: 10.1155/2015/685684. PubMed DOI PMC

Sarnowski C, Sugier PE, Granell R, Jarvis D, Dizier M-H, Ege M, Imboden M, et al. Identification of a new locus at 16q12 associated with time to asthma onset. J Allergy Clin Immunol. 2016;138:1071–1080. doi: 10.1016/j.jaci.2016.03.018. PubMed DOI

Abushouk A, Alkhalaf H, Aldamegh M, Shigair SB, Mahabbat N, Hakami M, Abu-Jaffal AS, Nasr A. IL-35 and IL-37 are negatively correlated with high IgE production among children with asthma in Saudi Arabia. J Asthma. 2022;59:655–662. doi: 10.1080/02770903.2021.1878533. PubMed DOI

Chawes BL, Wolsk HM, Carlsson CJ, Rasmussen MA, Følsgaard N, Stokholm J, Bønnelykke K, et al. Neonatal airway immune profiles and asthma and allergy endpoints in childhood. Allergy. 2021;76:3713–3722. doi: 10.1111/all.14862. PubMed DOI

Kunc P, Fabry J, Zatko T, Grendar M, Tatar M, Pecova R. Cough reflex sensitivity and fractional exhaled nitric oxide in children with asthma. Physiol Res. 2020;69(Suppl 3):S455–S461. doi: 10.33549/physiolres.934601. PubMed DOI PMC

Driessen AK, McGovern AE, Narula M, Yang S-K, Keller JA, Farrell MJ, Mazzone SB. Central mechanisms of airway sensation and cough hypersensitivity. Pulm Pharmacol Ther. 2017;47:9–15. doi: 10.1016/j.pupt.2017.01.010. PubMed DOI

Mazzone SB, Chung KF, McGarvey L. The heterogeneity of chronic cough: a case for endotypes of cough hypersensitivity. Lancet Respir Med. 2018;6:636–646. doi: 10.1016/S2213-2600(18)30150-4. PubMed DOI

Liu L, Yue D, Hu L, Wang F, Huang Y, Liao Y. Relationship between interleukin-13 rs20541 single nucleotide polymorphisms and therapeutic efficacy in children with asthma. J Int Med Res. 2020;48:0300060520929179. doi: 10.1177/0300060520929179. PubMed DOI PMC

An J, Lee JH, Sim JH, Song W-J, Kwon H-S, Cho YS, Moon H-B, Kim C-K, Kim T-B. Serum eosinophil-derived neurotoxin better reflect asthma control status than blood eosinophil counts. J Allergy Clin Immunol Pract. 2020;8:2681–2688.e1. doi: 10.1016/j.jaip.2020.03.035. PubMed DOI