Statistical Cluster Analysis of the British Thoracic Society Severe Refractory Asthma Registry: Clinical Outcomes and Phenotype Stability

Abstract

BackgroundSevere refractory asthma is a heterogeneous disease. We sought to determine statistical clusters from the British Thoracic Society Severe refractory Asthma Registry and to examine cluster-specific outcomes and stability.MethodsFactor analysis and statistical cluster modelling was undertaken to determine the number of clusters and their membership (N = 349). Cluster-specific outcomes were assessed after a median follow-up of 3 years. A classifier was programmed to determine cluster stability and was validated in an independent cohort of new patients recruited to the registry (n = 245).FindingsFive clusters were identified. Cluster 1 (34%) were atopic with early onset disease, cluster 2 (21%) were obese with late onset disease, cluster 3 (15%) had the least severe disease, cluster 4 (15%) were the eosinophilic with late onset disease and cluster 5 (15%) had significant fixed airflow obstruction. At follow-up, the proportion of subjects treated with oral corticosteroids increased in all groups with an increase in body mass index. Exacerbation frequency decreased significantly in clusters 1, 2 and 4 and was associated with a significant fall in the peripheral blood eosinophil count in clusters 2 and 4. Stability of cluster membership at follow-up was 52% for the whole group with stability being best in cluster 2 (71%) and worst in cluster 4 (25%). In an independent validation cohort, the classifier identified the same 5 clusters with similar patient distribution and characteristics.InterpretationStatistical cluster analysis can identify distinct phenotypes with specific outcomes. Cluster membership can be determined using a classifier, but when treatment is optimised, cluster stability is poor.

Cluster analysis on longitudinal data of patients with adult-onset asthma

“…Some studies have involved short follow-ups (1-3 years). 6,7,9,10 In a previous prospective longitudinal analysis of severe asthma, the clusters did not show cluster-specific disease courses regarding outcome of asthma, suggesting a potential limitation in the way of performing current cluster analyses. 9 In addition to the natural disease variability, many factors such as therapy, lifestyle, and comorbidities may modify the disease course.…”

“…Furthermore, no information on the diagnostic phase has been included in the previous analyses. In addition, many previous analyses have clustered patients with severe asthma, 7,8 leaving milder forms with less attention. Some studies have involved short follow-ups (1-3 years).…”

Pilot Project «All-Russian Registry of Patients with Severe Bronchial Asthma.» The First Results in a Children’s Group of Patients (Moscow’s Observation Program)

“…Пациенты с атопией реагируют на многочислен-ные аллергены гиперпродукцией иммуноглобулинов (Ig) E и активацией Th2-пути воспаления; в патологический процесс вовлекаются верхние дыхательные пути, конъ-юнктива, кожные покровы. Клинически это проявляется аллергическим ринитом, аллергическим конъюнктиви-том, пищевой аллергией, атопическим дерматитом [3,4]. Именно поэтому был проведен тщательный анализ клинической характеристики пациентов, включенных в регистр, и особое внимание уделено сопутствующим аллергическим состояниям.…”

“…Полученные данные о частоте коморбидных аллерги-ческих заболеваний и наследственной предрасположен-ности к развитию заболевания у пациентов с БА отражают общемировую тенденцию [3][4][5][6]. Аллергический ринит -достаточно распространенное заболевание, поражает до 30% общей популяции [5].…”

“…Аллергический ринит часто предшествует БА, являясь фактором риска. Атопический дерматит поражает до 20% детской и 3% взрослой популяции в мире, и заболевае-мость продолжает расти [3,4,6]. …”