Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids

Peters, Michael C.; Kerr, Sheena C.; Dunican, Eleanor M.; Woodruff, Prescott G.; Fajt, Merritt L.; Levy, Bruce D.; Israel, Elliot; Phillips, Brenda R.; Mauger, David T.; Comhair, Suzy; Erzurum, Serpil C.; Johansson, Mats W.; Jarjour, Nizar N.; Coverstone, Andrea M.; Castro, Mario; Hastie, Annette T.; Bleecker, Eugene R.; Wenzel, Sally E.; Fahy, John V.

doi:10.1016/j.jaci.2017.12.1009

Cited by 147 publications

(115 citation statements)

References 28 publications

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“…RNA was extracted from sputum cells with the RNeasy Qiagen kit (Qiagen), as previously described (10,11). RNA concentration and quality were measured with the Agilent 2100 bioanalyzer (Biogen, Weston, Mass), and samples with an RNA integrity number (RIN) less than 5 were considered degraded and excluded from analysis.…”

Section: Rna Extractionmentioning

confidence: 99%

COVID-19–related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

Peters

Sajuthi²,

DeFord³

et al. 2020

Am J Respir Crit Care Med

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412

403

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Background: Coronavirus disease 2019 is caused by SARS-coronavirus 2 (SARS-CoV-2). Angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among asthma patients may identify subgroups at risk for COVID19 morbidity. Methods:We analyzed gene expression for ACE2 and TMPRSS2, and for intercellular adhesion molecule 1 (ICAM-1)(rhinovirus receptor as a comparator), in sputum cells from 330 participants in the Severe Asthma Research Program-3 and 79 healthy controls.Results: Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes was similar in asthma and health. Among asthma patients, male gender, African Americans race, and history of diabetes mellitus, was associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide (TA) did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to gender, race, and use of ICS. Conclusion:Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID19 morbidity. the participant level with restricted maximum likelihood models. P-values <0.05 were considered statistically significant. RESULTS SubjectsThe demographic and clinical features of the asthma patients and healthy controls are shown in Table 1. Gene expression for SARS-Cov-2-and HRV-related genes in induced sputum cells from asthma patients and healthy controlsIn induced sputum cells collected at the baseline visit, the expression levels of ACE2 were lower than the expression levels of TMPRSS2, and some sputum samples had undetectable ACE2 ( Figure 1A). The expression of ACE2 and TMPRSS2 did not differ significantly in health and in asthma ( Figure 1A,B). In contrast to the SARS-Co-V2related genes, gene expression of ICAM1 was higher in asthma than in health ( Figure 1C). The expression of ACE2 was strongly associated with the expression of TMPRSS2 in the healthy control subgroup (Figure 2A) and the asthma subgroup ( Figure 2B), suggesting that these genes are expressed in similar cells(18). Relationship between clinical and demographic variables and expression levels of SARS-Cov-2-and HRV-related genes in asthma patientsHere we analyzed gene expression data in the induced sputum samples collected at the baseline visit 2 and the follow up visits 4 (year 1) and 6 (year 3). The total number was 556 samples from 330 asthma subjects. ACE2 and TMPRSS2 expression levels increased slightly with age, bu...

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Section: Rna Extractionmentioning

confidence: 99%

COVID-19–related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

Peters

Sajuthi²,

DeFord³

et al. 2020

Am J Respir Crit Care Med

Self Cite

412

403

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“…Another important cytokine, IL-6, has also been recently shown to cause systemic inflammation in a subgroup of asthma patients with obesity and severe disease [33]. The notable observation in this study was increased plasma IL-6 levels in the subset of obese patients with more severe asthma and not in all obese asthmatics.…”

Section: Introductionmentioning

confidence: 58%

“…The authors proposed the “type 2 gene mean” (T2GM) as a combined multigene metric of IL-4, IL-5, and IL-13 expression in sputum cells. This concept of a type 2 gene expression profile was recently corroborated in a SARP sub-cohort [33]. …”

Section: Rna Transcriptomics (Study Of Gene Expression)mentioning

confidence: 84%

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

Kuruvilla

Lee

2018

Clinic Rev Allerg Immunol

780

719

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The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.

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“…Notably, this effect of obesity was only observed in asthmatics and not in healthy controls. Indeed, in severe asthmatics with type2-high asthma who are obese, many continue to have high expression of type 2 cytokine-dependent gene expression in sputum cells, despite inhaled corticosteroid use (42). While these studies indicate that obesity does indeed reduce the response to steroids, there may be an important additional reason why obese asthmatics do not respond well to these agents: steroids target the immune processes that mediate allergic responses, but many obese subjects with severe asthma are non-atopic (43–45).…”

Section: Obesity Increases the Severity Of Asthmamentioning

confidence: 99%

Obesity and severe asthma

Tashiro

Shore

2019

Allergology International

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Obesity is an important global health issue for both children and adults. Obesity increases the prevalence and incidence of asthma and also increases the risk for severe asthma. Here we describe the features of severe asthma phenotypes for which obesity is a defining characteristic, including steroid resistance, airway inflammation, and co-morbidities. We also review current concepts regarding the mechanistic basis for the impact of obesity in severe asthma, including possible roles for vitamin D deficiency, systemic inflammation, and the microbiome. Finally, we describe data indicating a role for diet, weight loss, and exercise in the treatment of severe asthma with obesity. Better understanding of the mechanistic basis for the role of obesity in severe asthma could lead to new therapeutic options for this population.

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Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids

Abstract: Despite ICS therapy, many asthmatic patients have persistent airway type 2 inflammation (srT2-high asthma), and these patients are older and have more severe disease. Body weight and age modify the performance of blood-based biomarkers of airway type 2 inflammation.

Cited by 147 publications

References 28 publications

COVID-19–related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

COVID-19–related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

Obesity and severe asthma

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