Heterogeneity of asthma with nasal polyposis phenotypes: A cluster analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) affects a significant number of asthmatic patients and is notably associated with a more difficult-to-control asthma and marked inflammation. We need more studies on this specific asthma phenotype and its possible subphenotypes, in order to better individualize treatments. AIM: The aim of this study is to identify and characterize subphenotypes of asthma patients with CRSwNP using clinical, physiological and inflammatory variables. METHODS: K-means cluster analysis was performed on 17 clinical, physiological, and inflammatory variables from 1263 patients of all asthma severity and on a subpopulation of patients with asthma and CRSwNP. Study was registered on ClinicalTrials.gov (NCT03694847). RESULTS: On the overall population, three groups were identified. Cluster T1 (n = 708) are young, have a short asthma duration and a low prevalence of CRSwNP. Cluster T2 (n = 263) have the longest asthma duration and Cluster T3 (n = 292) are older with the shortest asthma duration. Patients in Clusters T2 and T3 have similar prevalences of CRSwNP. On the subpopulation of asthma with CRSwNP, three clusters were also identified. Cluster S1 (n = 83) have mild-to-moderate asthma with normal lung function. Clusters S2 (N = 53) and S3 (N = 42) include patients with severe asthma and decreased lung function, but those in Cluster S2 have a longer asthma duration, whereas those Cluster S3 have late-onset asthma. CONCLUSIONS: Despite coexistence of asthma and CRSwNP, not all patients have the same evolution of their asthma. Different phenotypes of asthma with CRSwNP can be identified and exploration of the characteristics of these subgroups could lead to a better individualized, targeted management.

Asthma with Irreversible Airway Obstruction in Smokers and Nonsmokers: Links between Airway Inflammation and Structural Changes.

BACKGROUND: The development of irreversible airway obstruction (IRAO) in asthma is related to lung/airway inflammatory and structural changes whose characteristics are likely influenced by exposure to tobacco smoke. OBJECTIVE: To investigate the interplay between airway and lung structural changes, airway inflammation, and smoking exposure in asthmatics with IRAO. METHODS: We studied asthmatics with IRAO who were further classified according to their smoking history, those with ≥20 pack-years of tobacco exposure (asthmatics with smoking-related IRAO [AwS-IRAO]) and those with <5 pack-years of tobacco exposure (asthmatics with nonsmoking-related IRAO [AwNS-IRAO]). In addition to recording baseline clinical and lung function features, all patients had a chest computed tomography (CT) from which airway wall thickness was measured and quantitative and qualitative assessment of emphysema was performed. The airway inflammatory profile was documented from differential inflammatory cell counts on induced sputum. RESULTS: Ninety patients were recruited (57 AwS-IRAO and 33 AwNS-IRAO). There were no statistically significant differences in the extent of emphysema and gas trapping between groups on quantitative chest CT analysis, although Pi10, a marker of airway wall thickness, was significantly higher in AwS-IRAO (p = 0.0242). Visual analysis showed a higher prevalence of emphysema (p = 0.0001) and higher emphysema score (p < 0.0001) in AwS-IRAO compared to AwNS-IRAO and distribution of emphysema was different between groups. Correlations between radiological features and lung function were stronger in AwS-IRAO. In a subgroup analysis, we found a correlation between airway neutrophilia and emphysematous features in AwS-IRAO and between eosinophilia and both airway wall thickness and emphysematous changes in AwNS-IRAO. CONCLUSIONS: Although bronchial structural changes were relatively similar in smoking and nonsmoking patients with asthma and IRAO, emphysematous changes were more predominant in smokers. However, neutrophils in AwS-IRAO and eosinophils in AwNS-IRAO were associated with lung and airway structural changes.

Use of a vibrating mesh nebulizer for allergen challenge.

BACKGROUND: Allergen inhalation tests are a valuable research tool. The allergen dose producing an early asthmatic response (EAR) can be predicted from methacholine responsiveness and allergen skin test endpoint (STE). The Wright® jet nebulizer, which is both inefficient and increasingly difficult to obtain, has been used historically. We assessed the Solo® vibrating mesh nebulizer as an alternative for allergen and methacholine challenges. METHODS: Eighteen mild atopic asthmatics completed the study. Doubling concentration allergen prick skin tests were performed to determine the STE in allergen units/mL. The Wright® protocol was used to measure the methacholine provocation dose causing a 20% forced expired volume in one second (FEV1) fall (PD20) (µg) and the allergen PD20 (units). The Solo® protocol (0.5 mL nebulized to completion, tidal breathing inhalation) was used to determine both methacholine PD20 and allergen PD20. The nebulizer order was randomized and separated by ≥ 2 weeks. RESULTS: All data were log transformed. The allergen PD20, predicted from the methacholine PD20 and the STE, was within 2 doubling doses of the PD20 measured with the Wright® and 2.64 doubling doses of that measured with Solo®. The Wright® allergen PD20 correlated with the Wright® methacholine PD20 (r = 0.74) and the STE (r = 0.78) and more strongly with the product of the two (Wright® methacholine PD20 × STE, r = 0.91, p < 0.00001). The Solo® allergen PD20 showed similar relationships with the Solo® methacholine PD20 (r = 0.61), the STE (r = 0.75) and the product of the two (Solo® methacholine PD20 × STE, r = 0.83, p < 0.00002). The Wright® and the Solo® methacholine geometric mean PD20s were not significantly different (49.3 and 54.5 µg respectively, p = 0.62). The Wright® allergen PD20 was slightly but significantly lower than the Solo® allergen PD20 (geometric means 6.7 and 10.5 units respectively, p = 0.003). CONCLUSION: The Solo® allergen PD20 showed the same relationship with methacholine responsiveness and STE as did the Wright®. The Solo® allergen PD20 was slightly but significantly higher than the Wright® allergen PD20. The Solo® vibrating mesh nebulizer was well tolerated and is an acceptable alternative for allergen challenge.Trial registration clinicaltrials.gov: NCT03491358.

Longitudinal comparison of outcomes in patients with smoking-related asthma-COPD overlap and in non-smoking asthmatics with incomplete reversibility of airway obstruction.

BACKGROUND: There is a need to characterize the impact of the smoking status on the clinical course of asthmatics with incomplete reversibility of airway obstruction (IRAO). OBJECTIVE: To compare longitudinal health care use, symptom control, and medication needs between smoking and non-smoking asthmatics with IRAO. MATERIALS AND METHODS: This was a 12-month follow-up of a cross-sectional study comparing asthmatics with IRAO according to their tobacco exposure. One group had a tobacco exposure ≥20 pack-years and was considered to have asthma-COPD overlap (ACO) and the second with a past tobacco exposure <5 pack-years was considered as non-smokers with IRAO (NS-IRAO). Study participants were contacted by telephone every 3 months to document exacerbation events and symptom control. RESULTS: A total of 111 patients completed all follow-up telephone calls: 71 ACO and 40 NS-IRAO. The number of exacerbations per patient over the 12-month follow-up was similar in both groups. However, ACO reported worse symptom control throughout the follow-up as compared to NS-IRAO, although no significant variations within a group were observed over the study period. CONCLUSION: Although asthma control scores were poorer in ACO patients over 1 year compared to NS-IRAO, exacerbation rate was similar and low in both groups of asthmatics. These observations suggest that poorer asthma control in ACO was not driven by the number of exacerbations but may reflect the influence of chronic airway changes related to the COPD component.

Asthma-COPD Overlap Phenotypes and Smoking :Comparative features of asthma in smoking or non-smoking patients with an incomplete reversibility of airway obstruction.

The development of COPD features, such as an incomplete reversibility of airway obstruction (IRAO), in smoking or non-smoking asthmatic patients, a condition often named Asthma-COPD Overlap (ACO), has been recognized for decades. However, there is a need to know more about the sub-phenotypes of this condition according to smoking. This study aimed at comparing the clinical, physiological and inflammatory features of smoking and non-smoking asthmatic patients exhibiting IRAO. In this cross-sectional study, patients with an IRAO with (ACO, ≥20 pack-years) or without (NS-IRAO, <5 pack-years) significant smoking history completed questionnaires about asthma control (ACQ, score 0-6, 6 = better score) and quality of life (AQLQ, score 1-7, 1 = better score) and performed expiratory flows, lung volume and carbon monoxide diffusion capacity measurements. Blood sampling and induced sputum were obtained for systemic and lower airway inflammation assessment. A total of 115 asthmatic patients were included (75 ACO: age 61 ± 10 years, 60% women and 40 NS-IRAO: age 64 ± 9 years, 38% women). ACO patients had worse asthma control scores (1.8 ± 0.9 vs 1.4 ± 0.9, P = 0.02) and poorer asthma quality of life (5.3 ± 1.0 vs 5.9 ± 1.0, P = 0.003). In addition, ACO had higher residual volume (145 ± 45 vs 121 ± 29% predicted, P = 0.008) and a lower carbon monoxide diffusing capacity corrected for alveolar volume (90 ± 22 vs 108 ± 20% predicted, P = 0.0008). No significant differences were observed in systemic or lower airway inflammation. In conclusion, in smokers and non-smokers, the presence of IRAO in asthmatics is associated with different phenotypes that reflect the addition of smoking-induced changes to asthma physiopathology.

Comparative prevalence of co-morbidities in smoking and non-smoking asthma patients with incomplete reversibility of airway obstruction, non-smoking asthma patients with complete reversibility of airway obstruction and COPD patients.

BACKGROUND: Asthma with incomplete reversibility of airway obstruction (IRAO) may often be associated to smoking-induced changes. Nevertheless, a high proportion of patients showing IRAO have never smoked. These patients with IRAO often share features of patients with chronic obstructive pulmonary disease (COPD). Although IRAO is still a poorly defined condition, it has been associated with a higher morbidity and mortality than asthma with complete reversibility of airway obstruction (CRAO) or even COPD alone. A high prevalence of comorbidities could contribute to the reported poorer clinical outcome in IRAO, in comparison to CRAO or COPD alone. AIM: To determine the prevalence of past and current comorbidities in IRAO patients compared to patients with CRAO or COPD. METHODS: This was a retrospective, cross-sectional study. Demographic data, clinical characteristics and 36 predetermined comorbidities documented from self-report and chart review, were recorded from smoking-associated IRAO (S-IRAO), non-smoking IRAO (NS-IRAO), CRAO and COPD patients. RESULTS: A total of 199 patients were included in the final analysis (111F/88M, mean (±SD) age of 63 ± 10 years). The CRAO group had more comorbidities than the three other groups, but this difference was significant only with the NS-IRAO group (P = 0.04). For most comorbidities, the prevalence of comorbidities in both IRAO sub-groups was intermediate between CRAO and COPD, with significant differences between S-IRAO and NS-IRAO only for hypertension (P = 0.03), nasal polyps (P = 0.002) and pneumonia (P = 0.04). Typical asthma-associated comorbidities tended to be more prevalent in NS-IRAO patients and COPD-associated comorbidities in S-IRAO patients. CONCLUSION: In this study, the prevalence of comorbidities was not superior in patients with IRAO, compared to those with CRAO or COPD alone. The prevalence of comorbidities in the two main types of IRAO patients reflects exposure to cigarette smoke and asthma-related mechanisms.

Acute effects of nicotine-free and flavour-free electronic cigarette use on lung functions in healthy and asthmatic individuals.

We designed a crossover and placebo-controlled trial to investigate the impact of a 1-h acute vaping session of nicotine-free and flavour-free e-liquid on the pulmonary functions and respiratory mechanics of healthy and asthmatic individuals. This study shows that a 1-h vaping session of a high-grade and contaminant-free mixture of propylene glycol and glycerol using a commercially available electronic cigarette performed in a controlled environment does not significantly impact pulmonary functions, respiratory mechanics or symptoms in healthy or asthmatic subjects.

CysLT1-R expression following allergen provocation in asthma and allergic rhinitis.

Cysteinyl leukotrienes (CysLTs) contribute to allergic and inflammatory diseases through CysLT(1)-R. We aimed to assess CysLT(1)-R mRNA expression in induced sputum of rhinitics with or without asthma before and following allergen challenges. Both groups underwent nasal and "low dose" lung allergen challenges. Asthmatics also underwent "standard" lung challenge. Sputum was obtained before and at different time-points following the challenges for CysLT(1)-R, 5-lipoxygenase (5-LO), and eotaxin mRNA assessments. At baseline, there was no difference in mediator levels between groups. An increase in CysLT(1)-R mRNA (p=0.04) and a trend towards an increase in 5-LO and eotaxin (p=0.06 for both) at 24 h post-nasal challenge were observed. Following "low dose" lung allergen challenge, there was a trend towards an increase in CysLT(1)-R (p=0.07). In conclusion, CysLT(1)-R gene expression changes can be detected in sputum following allergen challenges. No difference was observed between groups, suggesting that changes in CysLT(1)-R expression occur whether or not the subject has concurrent asthma.

Comparative clinical and airway inflammatory features of asthmatics with or without polyps.

BACKGROUND: Nasal polyposis (NP) is associated with a more severe and steroid-resistant asthma. OBJECTIVE: To compare clinical and airway inflammatory features of asthmatics with or without NP. METHODS: Two groups of asthmatic patients were studied: group 1; n=39, with NP; group 2; n=40, without NP. Asthma control was assessed according to the Asthma Control Scoring System (ACSS). Expiratory flows, induced sputum, and blood eosinophils were also measured. RESULTS: ACSS score was lower (poorer control) in group 1 (meanA+-SEM = 73A+-3%) compared with group 2 (82A+-2%, p=0.01). FEV1 (mean of predicted value A+- SEM) was 81A+-3 for group 1 and 96A+-3 for group 2 (p=0.001), and the FEV1/FVC ratio was lower in group 1 (70A+-2%) compared with group 2 (76A+-1%, p=0.01). Blood and induced sputum eosinophils, as well as fibronectin and eosinophil cationic protein levels, were higher in group 1. CONCLUSION: Asthmatic subjects with NP have increased airway obstruction, increased inflammatory cells and reduced asthma control compared to those without NP. This may suggest a contribution of nasal polyps to the severity of asthma or a common susceptibility to develop upper and lower airways mucosal inflammation.

Effects of protease inhibitors on mediator preservation in the supernatant of induced sputum.

Addition of protease inhibitors in induced sputum samples may help improve the recovery of mediators. The effect of protease inhibitors, in induced sputum, on the measurement of fibronectin, VEGF, IL-5, IL-6, and IL-8 was assessed. Protease inhibitors were added to sputum supernatant of atopic asthmatic subjects. Mediators were measured by ELISA or EIA. No differences were found in VEGF, IL-5, and IL-8 levels between protease inhibitors studied. Concentrations of IL-6 and fibronectin were higher when using, respectively, the commercial cocktail, and aprotinin. Protease inhibitors, if added, should be carefully chosen at the beginning of each study, to optimize the results.

The relationships between atopy, rhinitis and asthma: pathophysiological considerations.

PURPOSE OF REVIEW: A close relationship has been described between atopy, allergic rhinitis and asthma. The purpose of this work was to review recent data that have become available on the interactions between these conditions and the ways in which they influence one another. RECENT FINDINGS: Recent findings support previous observations suggesting that atopic dermatitis and rhinitis often accompany or precede the development of asthma. Further data support the notion that early-life exposure to domestic animals, a farming environment, passive smoking, and being raised in a large family, may be protective against the development of atopy and/or allergic diseases, although this seems modulated by genetic factors. Furthermore, the appearance of house-dust-mite-specific immunoglobulin E antibodies in early childhood has been identified as a major risk factor for the development of asthma in children with atopic dermatitis; and the association between sensitization to specific allergens and airway hyperresponsiveness was reported to be the strongest for indoor allergens such as house-dust-mite and cat. Allergen exposure can increase airway responsiveness in non-asthmatic subjects with allergic rhinitis and is associated with an increase in markers of lower airway inflammation, particularly with indoor allergens. Furthermore, nasal allergen provocation can induce bronchial inflammation and vice versa, suggesting close interrelations between upper and lower airways. SUMMARY: In summary, the recent observations on the relationships between atopy, rhinitis and asthma support the hypothesis of a unique systemic condition with variable manifestations, which may develop following an imbalance between T helper cell types 1 and 2 lymphocyte populations. The latter may be influenced by environmental exposure in early life. Upper- and lower-airway inflammatory events influence each other, supporting the concept of 'united airways'. Further studies should look at the relationships between these conditions to identify individuals at high-risk of developing them and develop strategies to possibly prevent their onset.