Evidence for 2 clusters among patients with noneosinophilic asthma.

BACKGROUND: Although asthma is often seen as an eosinophilic disease associated with atopy, patients with noneosinophilic asthma represent a substantial part of the population with asthma. OBJECTIVE: To apply an unsupervised clustering method in a cohort of 588 patients with noneosinophilic asthma (sputum eosinophils < 3%) recruited from an asthma clinic of a secondary care center. METHODS: Our cluster analysis of the whole cohort identified 2 subgroups as cluster 1 (n = 417) and cluster 2 (n = 171). RESULTS: Cluster 1 comprised a predominantly female group with late disease onset, a low proportion of atopy (24%), and a substantial smoking history (53%). In this cluster, treatment burden was low (<50% of inhaled corticosteroid users); asthma control and quality of life were poor, with median Asthma Control Test, Asthma Control Questionnaire, and Asthma Quality of Life scores of 16, 1.7, and 4.5, respectively, whereas lung function was preserved with a median postbronchodilation forced expiratory volume in 1 second of 93% predicted. Cluster 2 was a predominantly male group, almost exclusively comprising patients with atopy (99%) with early disease onset and a moderate treatment burden (median inhaled corticosteroids dose 800 µg/d equivalent beclomethasone). In cluster 2, asthma was partially controlled, with median Asthma Control Test and Asthma Control Questionnaire scores reaching 18 and 1.3, respectively, and lung function well preserved with a median postbronchodilation of 95% predicted. Although systemic and airway neutrophilic inflammation was the dominant pattern in cluster 1, cluster 2 essentially comprised paucigranulocytic asthma with moderately elevated fraction exhaled nitric oxide. CONCLUSION: Noneosinophilic asthma splits into 2 clusters distinguishing by disease onset, atopic status, smoking history, systemic and airway inflammation, and disease control and quality of life.

Super-responders to anti-IL-5/anti-IL-5R are characterised by high sputum eosinophil counts at baseline.

Several clinical trials have demonstrated that anti-IL-5(R) biologics were able to improve lung function, asthma control and chronic oral corticosteroid exposure and reduce exacerbations among eosinophilic asthmatic patients. However, a certain variability in clinical responses to anti-IL-5(R) biologics was brought to light. Our study aimed at evaluating the role of baseline sputum eosinophils in identifying super-responders to mepolizumab and benralizumab. Our study reinforces the importance to examine sputum eosinophils in patients suffering from severe asthma before starting a biologic as it is associated with the intensity of response to mepolizumab and benralizumab.

Patients With Asthma Only Sensitized to Staphylococcus aureus Enterotoxins Have More Exacerbations, Airflow Limitation, and Higher Levels of Sputum IL-5 and IgE.

BACKGROUND: Staphylococcus aureus enterotoxins (SE) may act as superantigens and induce an intense T-cell activation, causing local production of polyclonal IgE and resultant eosinophil activation. OBJECTIVE: To assess whether asthma with sensitization to SE but not to common aeroallergens (AAs) displays different inflammatory characteristics. METHODS: We conducted a prospective study on a series of 110 consecutive patients with asthma recruited from the University Asthma Clinic of Liège. We compared clinical, functional, and inflammatory characteristics of this general population of patients with asthma categorized into 4 groups according to sensitization to AAs and/or SE. We also compared sputum supernatant cytokines in patients sensitized to SE or not. RESULTS: Patients with asthma sensitized only to AAs represented 30%, while 29% were sensitized to both AAs and SE. One-fifth of the population had no specific IgE. Sensitization to SE but not to AA (21%) was associated with later onset of disease, higher rate of exacerbations, nasal polyps, and more severe airway obstruction. As for airway type 2 biomarkers, patients presenting with specific IgE against SE displayed higher fractional exhaled nitric oxide, sputum IgE, and sputum IL-5 levels but not IL-4. We confirm that the presence of specific IgE against SE is associated with elevated serum IgE to levels well above those observed in patients sensitized only to AAs. CONCLUSIONS: Our study suggests that asthma specialists should measure specific IgE against SE during the phenotyping process because it may allow the identification of a subgroup of patients with more asthma exacerbations, more nasal polyposis and chronic sinusitis, lower lung function, and more intense type 2 inflammation.

Sputum Type 2 Markers Could Predict Remission in Severe Asthma Treated With Anti-IL-5.

BACKGROUND: Biotherapies targeting IL-5 allow a tangible improvement of asthma. However, all patients do not respond the same way to these treatments. Even if high blood eosinophil counts seem to be associated with a reduction in exacerbations with treatment targeting IL-5, we lack biomarkers for the prediction of remission after these very expensive treatments. RESEARCH QUESTION: Are there biomarkers of remission after therapy targeting IL-5 in the sputum of patients with severe eosinophilic asthma? STUDY DESIGN AND METHODS: This observational study included 52 patients with severe asthma initiated with anti-IL-5 therapy and recruited from the asthma clinic of the Centre Hospitalier Universitaire of Liege, Belgium. Remission was defined as patients who combined the following at 1 year after therapy: no chronic treatment with oral corticosteroids; no exacerbation; asthma control questionnaire score < 1.5, asthma control test score > 19, or both; FEV1 of ≥ 80% predicted, improvement of FEV1 of ≥ 10%, or both; and a blood eosinophil count < 300 cells/µL. Eosinophil peroxidase (EPX), IgE, IL-3, IL-4, IL-5, IL-13, IL-25, IL-33, granulocyte-macrophage colony-stimulating factor, thymic stromal lymphopoietin (TSLP), and eotaxin-1 levels were measured in the sputum of these patients before anti-IL-5 treatment. RESULTS: Among the 52 patients, 11 were classified as being in remission. These patients were characterized by higher sputum eosinophil, macrophage, and lymphocyte counts, whereas the sputum neutrophil percentage was lower than in the nonremission group. In addition, the sputum eotaxin-1, TSLP, IL-5, EPX, and IgE protein levels were higher at baseline in the remission group compared with the nonremission group. Univariate regression analysis revealed that male vs female sex, sputum neutrophil percentage, eotaxin-1, IL-5, and EPX were potential predictors of remission. INTERPRETATION: Sputum type 2 markers seemed to be potentially predictive of remission after anti-IL-5 therapy in a cohort of patients with severe eosinophilic asthma. These results need validation on a larger cohort.

Revisiting differences between atopic and non-atopic asthmatics: When age is shaping airway inflammatory profile.

Background: Atopic asthma is one of the most common asthma phenotypes and is generally opposed to the non-atopic counterpart. There have been very few large-scale studies comparing atopic and non-atopic asthmatics in terms of systemic and airway inflammation across the age spectrum. Methods: Here, we have undertaken a retrospective study investigating 1626 patients (924 atopic and 702 non-atopic asthmatics) recruited from our university asthma clinic who underwent extensive clinical investigations including induced sputum. Atopy was defined by any positive specific IgE to common aeroallergens (>0,35 kU/L). We performed direct comparisons between the groups and sought to appreciate the influence of age on the airway and systemic inflammatory components. The study was approved by the ethics committee of the University Hospital of Liege (Ref. 2016/276). Informed consents were obtained from healthy subjects. Results: Atopic asthmatics were younger (P < .001), had a higher male/female ratio (P < .001), an earlier disease onset (P < .001) and a greater proportion of treated rhinitis (P < .001) while non-atopic asthmatics had greater smoke exposure (P < .001), lower FEV1/FVC ratio (P = .01) and diffusing capacity (P < .001). There was no difference between the 2 groups regarding FEV1 (% predicted), asthma control, asthma quality of life and exacerbations in the previous 12 months. Regarding inflammation, atopic patients had higher FeNO levels (median = 28 ppb, P < .001), were more eosinophilic both in blood (median = 2.8%, P < .001) and in sputum (median = 2.2%, P < .001) while non-atopic patients displayed greater blood (median = 57%, P = .01) and sputum (median = 58.8%, P = .01) neutrophilic inflammation. However, stratifying patients by age showed that non-atopic asthmatics above 50 years old became equally eosinophilic in the sputum (P = .07), but not in the blood, as compared to atopic patients. Likewise, FeNO rose in non-atopic patients after 50 years old but remained, however, lower than in atopic patients. Conclusions: We conclude that, while sharing many features, atopic group still differentiates from non-atopic asthmatics by demographics, functional and inflammatory profiles. When atopic asthmatics showed a constant eosinophilic pattern across the age spectrum, non-atopic asthmatics were found to be neutrophilic before the age of 50 but eosinophilic above 50 years old.