Endotypes identified by cluster analysis in asthmatics and non-asthmatics and their clinical characteristics at follow-up: the case-control EGEA study

Nadif, Rachel; Febrissy, Mickaël; Andrianjafimasy, Miora; Moual, Nicole Le; Gormand, F.; Just, Jocelyne; Pin, Isabelle; Siroux, Valérie; Matran, Régis; Dumas, Orianne; Nadif, Mohamed

doi:10.1136/bmjresp-2020-000632

Cited by 17 publications

(18 citation statements)

References 33 publications

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“…A marker of oxidative stress, 8-isoprostane has also been shown to be elevated in the urine of severe asthmatics and to be worsened by smoking ( Emma et al, 2018 ). Cluster analyses of an asthma cohort have revealed subsets associated with elevated 8-isoprostane in the blood ( Nadif et al, 2020 ). Elevated hydrogen peroxide levels and 8-isoprostane can also be detected in exhaled breath condensate in asthma and are inversely correlated with lung function ( Emelyanov et al, 2001 ; Brussino et al, 2010 ).…”

Section: Nrf2 and Diseasementioning

confidence: 99%

Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

2021

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. Nrf2 is present in an inactive state in the cytoplasm of cells. Its activation by internal or external stimuli, such as infections or pollution, leads to the transcription of more than 500 elements through its binding to the antioxidant response element. The lungs are particularly susceptible to factors that generate oxidative stress such as infections, allergens and hyperoxia. Nrf2 has a crucial protective role against these ROS. Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases affecting the airways, including asthma and chronic obstructive pulmonary disease (COPD), or the pulmonary parenchyma such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Several compounds, both naturally occurring and synthetic, have been identified as Nrf2 inducers and enhance the activation of Nrf2 and expression of Nrf2-dependent genes. These inducers have proven particularly effective at reducing the severity of the oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for the management of respiratory pathologies associated with oxidative stress but there is thus far little evidence of efficacy through human trials. The purpose of this review is to summarize the involvement of Nrf2 and its inducers in ARDS, COPD, asthma and lung fibrosis in both human and in experimental models.

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Section: Nrf2 and Diseasementioning

confidence: 99%

Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

2021

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“…Five respiratory endotypes were previously identified by cluster analysis [13] and are described in Table 1: two among never asthmatics (NA) and three among current asthmatics (CA), after taking into account a total of 23 variables for never asthmatics and 28 variables for current asthmatics. Cluster analysis jointly considered personal (age, sex, smoking status and BMI), clinical/functional (age of asthma onset, respiratory symptoms, asthma treatments, dyspnoea, skin prick tests positivity for at least one of 12 aeroallergens, current rhinitis, ever eczema, asthma attacks, hospital or emergency admission, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and biological (neutrophil and eosinophil counts, total IgE and level of Fluorescent oxidation products) characteristics.…”

Section: Definition Of Respiratory Endotypesmentioning

confidence: 99%

“…[11] In the Epidemiological study on the Genetics and Environments of Asthma (EGEA), we recently identified five respiratory endotypes using cluster analysis jointly integrating asthma clinical characteristics and biomarkers related to oxidative stress and inflammation. [13] In particular, we identified among asthmatics an endotype characterized by poor lung function, respiratory symptoms, high level of fluorescent oxidation products (FlOPs, a biomarker of damages related 8 to oxidative stress), and high blood neutrophil counts. We hypothesized occupational exposure to irritants may be associated to this specific endotype.…”

Section: Introductionmentioning

confidence: 99%

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults

et al. 2021

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AimThe biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation.MethodsWe used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status.ResultsPrevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5).ConclusionOccupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms.

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“…Over the past decade it has become clear that there exist several different underlying pathophysiological mechanisms, but even so, with few exceptions, almost all patients with asthma have an inflammatory infiltrate in the airways. In a recent cluster analysis of over 400 asthmatic patients, more than 85% showed type‐2 inflammation (allergic or eosinophilic) 1 …”

Section: Introductionmentioning

confidence: 99%

“…In a recent cluster analysis of over 400 asthmatic patients, more than 85% showed type-2 inflammation (allergic or eosinophilic). 1 However, inflammation does not seem to explain the full picture of asthma, and abnormal functioning of the structural cells, such as smooth muscle and epithelial cells and fibroblasts, also forms an integral part of the underlying anomalies. The pendulum swinging from asthma, thought of in the 70-80s as a reversible bronchoconstriction, to asthma thought of as a purely inflammatory disease in the 90s 2 is now considered to rest somewhere in between these two models.…”

Section: Introductionmentioning

confidence: 99%

An independent in‐depth analysis proposing adjusted Global Initiative on Asthma Step 1–2 treatment suggestions

Larenas‐Linnemann

Navarrete-Rodríguez

Luna-Pech³

et al. 2022

Clin Experimental Allergy

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The Global Initiative on Asthma (GINA) strategy included major changes for the treatment of mild asthma in the 2020 version that are even taken to the next level in 2021, leaving a preferred track with only rescue therapy with inhaled corticosteroid and formoterol (ICS‐FORM) for steps 1–2 in 12+ years old. It has been questioned how solid the evidence behind these recommendations is. We decided to independently conduct an in‐depth analysis of published evidence based on a comprehensive evaluation of original articles and related appendices and publications, including quality of evidence and risk of bias per article. We first defined the major asthma treatment goals and proceeded to review how these were met in publications referenced in the main asthma guidelines. For patients with GINA (2021) Step 1 characteristics, the analysis supports GINA's decision to avoid SABA monotherapy and to prefer ICS‐FORM rescue with an alternative ICS rescue every time a SABA is used for ≥12 years, even though evidence is extrapolated from step 2 patients. For 6‐ to 11‐year‐olds, we propose to consider ICS‐FORM rescue as an alternative, as its use has been approved in this age group, be it not as rescue medication. For patients with GINA 2021 Step 2 characteristics, our proposal slightly differs from GINA 2021. We propose to continue avoiding the separate use of SABA, using ICS rescue whenever a fast‐acting bronchodilator is taken (even with ICS maintenance). Also, the superiority of ICS‐FORM rescue over classical step 2 treatment is not uniform and year‐long experience is lacking. Consequently, for now, both treatment options seem equal: ICS‐FORM rescue or ICS maintenance with SABA (+ICS) rescue. For 6‐ to 11‐year‐olds, ICS rescue every time a SABA is used has the advantage of lower total ICS dose; as alternative we suggest ICS‐FORM rescue. The best treatment option depends on patient characteristics and treatment goals. Recommendations should be reviewed as soon as new evidence becomes available.

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Endotypes identified by cluster analysis in asthmatics and non-asthmatics and their clinical characteristics at follow-up: the case-control EGEA study

Cited by 17 publications

References 33 publications

Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

Association between occupational exposure to irritant agents and a distinct asthma endotype in adults

An independent in‐depth analysis proposing adjusted Global Initiative on Asthma Step 1–2 treatment suggestions

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