Difficult/therapy‐resistant asthmaThe need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies

Chung, Kian Fan; Godard, P.; Ädelroth, E; Ayres, Jon G.; Barnes, Neil; Barnes, Peter J.; Bel, Elisabeth H.; Burney, Peter; Chanez, Pascal; Connett, Gary; Corrigan, Christopher; Blic, J. de; Fabbri, Leonardo M.; Holgate, S. T.; Ind, P W; Joos, Guy; Kerstjens, Huib A. M.; Leuenberger, P; Löfdahl, Claes Gor̈an; McKenzie, S A; Magnussen, H; Postma, D.S.; Saetta, Marina; Salmeron, S.; Sterk, PJ

doi:10.1034/j.1399-3003.1999.13e43.x

Cited by 130 publications

(2 citation statements)

References 77 publications

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“…Severe asthma is more strongly associated with Th1/Th17 responses and neutrophilic airway inflammation [ 1 , 2 , 3 , 4 , 5 , 6 ]. Approximately 5–20% of asthma patients respond poorly to corticosteroids even at high doses, and no effective treatments are currently available for severe, steroid-resistant asthma [ 3 , 7 , 8 ]. Recent studies have reported that NLRP3-dependent IL-1β is associated with severe neutrophilic asthmatic progression and pathological exacerbation, and the levels of IL-1β in sputum were elevated with the severity of the disease [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation

2021

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The stimulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and IL-1β synthesis are associated with chronic respiratory diseases such as neutrophil-dominant severe asthma. Leukotriene B4 (LTB4) is a principal chemoattractant molecule for neutrophil recruitment, and its receptors BLT1 and BLT2 have been suggested to contribute to neutrophil-dominant asthmatic airway inflammation. However, the relationship between BLT1/2 and NLRP3 in neutrophil-dominant asthmatic airway inflammation has not been previously studied. In the present study, we investigated whether BLT1/2 play any roles in stimulating the NLRP3 inflammasome and IL-1βsynthesis. The blockade of BLT1 or BLT2 clearly suppressed the stimulation of the NLRP3 inflammasome and IL-1β synthesis in house dust mite (HDM)/lipopolysaccharide (LPS)-induced neutrophilic airway inflammation. The enzymes 5-lipoxygenase and 12-lipoxygenase, which catalyze the synthesis of BLT1/2 ligands [LTB4, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), and 12-hydroxyheptadecatreinoic acid (12-HHT)], were also critically associated with the stimulation of NLRP3 and IL-1β synthesis. Together, our results suggest that the 5-/12-LOX-BLT1/2-linked cascade are necessary for the simulation of the NLRP3 inflammasome and IL-1β synthesis, thus contributing to HDM/LPS-induced neutrophil-dominant airway inflammation.

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Section: Introductionmentioning

confidence: 99%

Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation

2021

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“…To better understand and treat the extensive heterogeneity of asthma, many expert groups have proposed distinctive classifications of SA (7)(8)(9)(10)(11), with the goal of advancing research and treatment paradigms toward precision medicine. In recent years, much research has led to the identification of SA phenotypes wherein specific biological pathways and mechanisms (endotypes) are being identified to explain the observable properties of the phenotypes, and improving the future prospects for these difficult-to-treat patients (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Severe asthma and eligibility for biologics in a Brazilian cohort

et al. 2020

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Objective: This study aims to describe the eligibility for biologic therapies for severe asthma (SA) in a cohort of patients attending the Program for Control of Asthma (ProAR) in Bahia, Brazil. Methods: Data from SA patients (!18 years old) attending the ProAR, that were included in a case-control study conducted from 2013 to 2015, were used to reassess patients according to a modified ERS/ATS 2014 SA criteria. Patients were then classified according to the eligibility for SA biological therapy based on current prescription labels. Results: From 544 patients in the cohort, 531 (97.6%) were included and 172 (32.4%) were identified as SA patients according to the ERS/ATS 2014 modified criteria. Of these 172 patients, 69 (40.1%) were ineligible for any of the biologicals approved for asthma (omalizumab, mepolizumab, reslizumab and benralizumab), 60 (34.9%) patients were eligible for one of the biological therapies, and 10 (5.8%) patients were eligible for all biological therapies. Conclusions: More than half of patients with SA were eligible for biologic therapy in our study, but none of them received this form of treatment. Almost half of them were not eligible to any of the approved biologics, however. The variability and overlap in patients' eligibility highlight the importance of evaluating each patient individually for a more personalized treatment approach. While there is a need to increase access for some of those eligible that may really need a biologic treatment, continuous efforts are required to develop alternatives to those who are not eligible.

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Sputum induction in children with difficult asthma: Safety, feasibility, and inflammatory cell pattern

Lex

Payne

Zacharasiewicz

et al. 2005

Pediatric Pulmonology

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Difficult childhood asthma is defined by persistent symptoms despite maximal conventional therapy. We aimed to establish a safe method of sputum induction for these children and to study cytology and the relationship to exhaled nitric oxide (eNO). Sputum induction was performed in 38/40 children (aged 6-16 years) with difficult asthma, using 3.5% saline for four 5-min periods after bronchodilator pretreatment. Two children were excluded from sputum induction because postbronchodilator forced expired volume in 1 sec (FEV(1)) was <65% predicted. Seven of 38 children had symptoms (dyspnea and wheezing) during induction; of these, 3 experienced a fall in FEV(1) of >20% from postbronchodilator FEV(1), readily reversed with salbutamol. Sputum induction was successful in 28/38 children, with a higher success rate in children >/= 12 years than in younger children (87% vs. 50%, P = 0.02). Only 9/28 had abnormal sputum cytology; of these, 6 had predominant sputum eosinophilia (>2.5% eosinophils, 54% neutrophils). Of 23 children with elevated eNO values, only 6 had sputum eosinophilia. In conclusion, sputum induction can be used to assess airway inflammation in children with difficult asthma, but abnormal sputum cytology is only present in a minority. Raised nitric oxide is only poorly predictive of sputum eosinophilia in these children.

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Difficult/therapy‐resistant asthmaThe need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies

Cited by 130 publications

References 77 publications

Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation

Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation

Severe asthma and eligibility for biologics in a Brazilian cohort

Sputum induction in children with difficult asthma: Safety, feasibility, and inflammatory cell pattern

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