Severe exacerbations in moderate-to-severe asthmatics are associated with increased pro-inflammatory and type 1 mediators in sputum and serum

Abstract

Background Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. Methods We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. Results The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1β, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). Conclusions Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children. Electronic supplementary material The online version of this article (10.1186/s12890-019-0906-7) contains supplementary material, which is available to authorized users.

Immune maturation and modulation in childhood allergies : Aspects of epigenetic, mucosal and systemic immune mediators in allergy development and prevention

“…recurrent episodes of exacerbations including wheeze, chest tightness as well as breathing difficulties. 318 In previous studies by us 113 and others [114][115][116][117][118][119] , elevated levels of the Th1-associated chemokines have been associated with development of wheeze and asthma. In Paper I, we could corroborate these results for CXCL10, as increased circulating concentrations at ages 1 and 8 years associated with later development of asthma ( Figure 11A, Paper I: Figure 2A-B, Figure S2A) However, unlike the findings for CXCL10, decreased CXCL11 levels at birth associated with asthma development at age 16 years, and elevated neonatal levels seemed protective on the outcome ( Figure 11B, Paper I: Figure S2B, OR=0.4, 95% CI 0.2-0.8, p=0.012).…”

“…Chemokines are important regulators of immune cell recruitment 36 , and a number of chemokines have been related to the development of allergic diseases, such as CCL17, CCL18, CCL22, CXCL10 and CXCL11. [113][114][115][116][117][118][119][120]124,125 The study of these chemokines in the natural course of allergy development has, however, not been previously performed in a larger population of children. Hence, the circulating levels of the above-mentioned allergy-related chemokines were measured in blood samples from children included in an observational birth cohort.…”

“…A summarising outline of the production and effects of allergy-related cytokines and chemokines. lavage fluid 115,116 , serum 117 , bronchial epithelial cells 118,119 , sputum 117 and bronchoalveolar lavage. 120 In relation to sensitisation, however, the Th1-associated chemokines show a more complicated mechanism of action.…”

Chitinase-like protein YKL-40 regulates human bronchial epithelial cells proliferation, apoptosis, and migration through TGF-β1/Smads pathway

“…It was found that the release of many proinflammatory cytokines (such as IL-4, IL-8, IL-6) increased in asthmatic patients. 22 Several studies showed inhibition pro-inflammatory cytokines production could control allergic asthma and ameliorate airway condition in an allergic asthma model, which mechanism is associated with TGF-b1/ Smads pathway. 13 Interestingly, in this study, YKL-40 treatment increased the secretion of IL-4, IL-8, and IL-6 in BEAS-2B cells.…”

Circulating Chemokine Levels and the Development of Allergic Phenotypes from Infancy to Adolescence: A Population-Based Birth Cohort Study

“…23,24,25 Previously believed to be mainly involved in autoimmunity 26 , the Th1-associated chemokines are nowadays also known to counteract Th2 responses driving allergic in ammation. 9 Increased levels of CXCL10 and/or CXCL11 in viral-induced 27,28 , moderate to severe [29][30][31] and allergen challenged asthma 32 , emphasise this complex regulation. In line with previous ndings, children developing recurrent wheezing present with higher circulating levels of CXCL10, with a similar tendency for CXCL11 at two years of age.…”