Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3–like protein 1

BackgroundDisease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood.ObjectiveWe aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients.MethodsOne hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis.ResultsSevere asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels.ConclusionIn 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma

Recognising the risk of aspirin-sensitive respiratory disease in a patient with asthma who has previously tolerated aspirin

Asthma is a common chronic condition composed of numerous different phenotypes. One clinically relevant phenotype is that of aspirin-sensitive respiratory disease (ASRD) which is more frequently seen in patients with difficult asthma. Reliance on a history of previous reaction to non-steroidal anti-inflammatory drugs (NSAIDs) in order to diagnose ASRD may give false reassurance. We describe the case of a 58-year old man with late onset asthma who was suspected to have ASRD on the basis of associated clinical features despite having taken aspirin safely in the past. The diagnosis of ASRD was subsequently confirmed by an inadvertent aspirin challenge which led to a serious adverse asthma outcome

The effect of bariatric surgery in the difficult asthma-obesity phenotype: a case report

INTRODUCTIONObesity and asthma have become increasingly prevalent conditions in recent years; they often coexist and place a significant burden on the National Health Service. Asthma in the obese is more difficult to treat than in those with a normal body mass index (BMI) and is associated with resistance to traditional asthma therapies and increased use of healthcare resources. Weight loss can improve asthma control in such patients. The degree of weight loss achieved through dietary strategies, however, is often only modestly successful in this group. Bariatric surgery is increasingly used to achieve sustained significant weight loss in morbid obesity. It may offer under-recognized benefit in the difficult asthma-obesity phenotype.CASE STUDY We describe the case of a 32-year-old female with difficult asthma who had a BMI of 45 kg/m(2) at the time of referral to our clinic. Her asthma was uncontrolled despite maximal inhaled therapy, oral therapy with Zafirlukast, and daily high-dose (25 mg) oral prednisolone. Additional therapies (subcutaneous Terbutaline and the steroid-sparing agent Methotrexate) had little impact on asthma control and she remained morbidly obese. She underwent gastric bypass surgery and, over the following 18 months, her BMI dropped to 27.7 kg/m(2), her corticosteroid dose was reduced to 7.5 mg (adrenal insufficiency proven), and maintenance inhaled therapy and oral medications were stopped as she maintained good asthma control.CONCLUSIONThis case demonstrates the dramatic improvement that bariatric surgery can have on asthma symptoms and medication use in morbidly obese patients with very difficult to control asthma

Definitions are important and not all wheeze is asthma

We read with great interest the paper by Moncayo et al 1 showing a predominance of non-atopic compared with atopic wheeze in children in rural Ecuador. Undoubtedly their study adds to the literature regarding the influence of environmental factors, particularly chronic helminth infections, on wheezing phenotypes. However, we feel that the interpretation and presentation of findings in this paper is open to question. This concern stems from the authors' lack of distinction between wheeze and asthma. While the analysis focused predominantly on current wheeze, subsequent … <br/

Does environment mediate earlier onset of the persistent childhood asthma phenotype?

Objective. We investigated the role of environmental and hereditary factors in determining whether persistent childhood wheezing phenotypes had an early or late onset.Methods. In a whole population birth cohort (n = 1456), children were seen at birth and at 1, 2, 4, and 10 years. At each visit, information was collected prospectively regarding wheeze prevalence and used to classify subjects into wheezing phenotypes. Information on genetic and environmental risk factors in early life was also obtained prospectively, and skin-prick testing to common allergens was performed at 4 years.Results. Early-onset persistent wheezers (n = 125) had wheeze onset in the first 4 years, still present at age 10, whereas late-onset persistent wheezers (n = 81) had wheeze onset after age 4 years that was still present at 10 years. Multivariate logistic regression analysis identified independent significance only for inherited factors (parental asthma, family history of rhinitis, eczema at 4 years, and atopic status at 4 years) in the development of late-onset persistent wheeze. However, low social class at birth, recurrent chest infections at 2 years, and parental smoking at 2 years plus inherited factors (eczema at 2 years; food allergy at 4 years; maternal asthma, sibling asthma, maternal urticaria, and atopic status at 4 years) demonstrated independent significance for early-onset persistent wheeze.Conclusion. Inheritance seems to be of prime significance in the cause of persistent childhood wheeze. Environmental exposure in early life may combine with this tendency to produce an early onset of persistent wheeze. Absence of these environmental factors might delay but not prevent the onset of wheeze in children with atopic heredity.</p

The natural history of fatal childhood asthma: a case from the Isle of Wight birth cohort

Subjects with severe and unstable asthma are at high risk of fatal asthma attack. We describe a case of fatal childhood asthma in an 11-year old girl whose asthma was apparently stable with supranormal lung function and identify additional characteristics that should be considered as increasing the risk for fatal asthma. This opportunity was provided by this girl's participation in the Isle of Wight Whole Population Birth Cohort Study. Prospectively collected data identified her as an early-onset persistent wheezer with significant allergic comorbidity. She was highly atopic with multiple allergen sensitization and a total IgE exceeding 5000 Ku/L (normal range: 0-180 ku/l) at 10 years. Additionally at that age, whilst possessing normal lung function (FEV(1) 2.15 Litres; 110% predicted), she was found to have marked bronchial hyper-responsiveness (PC(20) Methacholine 1.71 mg/ml). At the age of 11 years, despite apparent clinical stability and use of regular controller asthma therapy, she suffered a fatal acute asthma attack that may have been related to acute allergen exposure. This report provides further insight into factors associated with fatal childhood asthma. We propose that highly atopic children with early onset persistent asthma are at a higher risk of fatal asthma even if their asthma is apparently stable and lung function is normal. Marked bronchial hyper-responsiveness provides a clue and should be assessed if there is concern