Treatment-resistant Severe Asthma Research Articles

Severe asthma: Comparison of different classifications of severity and control.

Criteria of asthma severity and control lack standardization. to compare classifications of asthma severity and control, applied to patients from a severe asthma clinic. Cross-sectional study of 473 patients followed up for ≥6 months, reclassified using three criteria: 1) the World Health Organization (WHO) 2010, 2) the American Thoracic Society (ATS) 2000, and 3) the European Respiratory Society (ERS)/ATS 2014. In order to evaluate disease control, the 2012 and 2014 Global Initiative for Asthma (GINA) classifications were compared. According to the definition of WHO 2010, 429 had Difficult-to-treat severe asthma and only 12 presented Treatment-resistant severe asthma. 114 patients had Refractory asthma by ATS 2000 and 88 had Severe asthma by ERS/ATS 2014. Considering the definitions of WHO 2010, only 9 out of 12 with Treatment-resistant and 64 out of 429 with Difficult-to-treat severe asthma met the criteria of ATS 2000 and ERS/ATS 2014. As for GINA classification of control, 208 (44%) of the 473 subjects were classified as having asthma controlled by the 2014 criteria, whereas only 45 (10%) patients had controlled asthma by the GINA 2012 criteria. The Kappa statistic indicates the highest agreement of the severity classification occurred between the criteria of ATS 2000 and ERS/ATS 2014 (0.64). Good agreement was found between Refractory asthma ATS 2000 and Severe asthma ERS/ATS 2014 classifications. However, poor agreement was observed between the severity rating proposed by the WHO and other classifications. The GINA control classifications of 2012 and 2014 also agreed poorly.

Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma.

Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy.

Airway Surfactant Protein D Deficiency inAdults With Severe Asthma.

Surfactant protein D (SP-D) is an essential component of the innate immune defense against pathogens within the airways. SP-D also regulates allergic inflammation and promotes the removal of apoptotic cells. SP-D dysregulation is evident in several pulmonary diseases. Our aim was to investigate whether airway and serum levels of SP-D are altered in treatment-resistant severe asthma. SP-D concentrations were measured in matched serum and BAL samples collected from 10 healthy control subjects (HC) and 50 patients with asthma (22 with mild asthma [MA] and 28 with severe asthma [SA]). These samples were also evaluated by using Western blot analysis to investigate variations in SP-D size. SP-D levels in BAL samples were significantly lower in SA compared with HC and MA (P< .001) and inversely correlated with BAL eosinophil cationic protein concentrations in SA (P< .01). Serum SP-D was significantly increased in SA compared with HC and MA (P< .001), and BAL/serum ratios were significantly lower in SA compared with HC and MA(P< .001). Reduced SP-D levels in BAL samples, with concomitant increases in serum in SA, were associated with degraded fragments of SP-D in the serum and increased BAL neutrophil counts and lipopolysaccharide levels. These findings suggest defective innate immunity within the airways in SA, as reflected by low BAL SP-D concentrations and altered bacterial presence with airway neutrophilia. Furthermore, BAL SP-D leakage into the serum in patients with SA may provide a peripheral blood biomarker, reflecting increased epithelial damage and/or epithelial permeability within the peripheral airways.

Phenotypes of severe asthma among children and adolescents in Brazil: a prospective study

BackgroundThe morbidity associated with severe uncontrolled asthma is disproportionately higher in low- and middle-income countries than in high-income countries. The aim of this study was to describe the phenotypic characteristics of difficult-to-treat severe asthma and treatment-resistant severe asthma in a sample of children and adolescents in Brazil.MethodsThis was a prospective study, conducted between 2010 and 2014, following 61 patients (6–18 years of age) who had been diagnosed with severe uncontrolled asthma. The patients were classified and managed in accordance with the World Health Organization asthma follow-up protocol, which calls for re-evaluations of the diagnosis, level of control (functional and clinical), comorbidities, inhaler technique, and environmental factors, together with adjustment of the treatment to achieve a target level of control. We assessed pulmonary function, measured fractional exhaled nitric oxide, and performed sputum cytology. After the target rate of ≥ 80% adherence to inhaled corticosteroid treatment had been reached and all of the re-evaluations had been performed, the patients incorrectly diagnosed with severe uncontrolled asthma were excluded and the remaining patients were classified as having treatment-resistant or difficult-to-treat severe asthma.ResultsWe found that, of the 61 patients evaluated, 10 had been misdiagnosed (i.e., they did not have asthma), 15 had moderate asthma, and 36 had severe uncontrolled asthma. Among those 36 patients, the asthma was classified as treatment-resistant in 20 (55.6%) and as difficult-to-treat in 16 (44.4%). In comparison with the patients with difficult-to-treat severe asthma, those with treatment-resistant severe asthma showed a higher median level of fractional exhaled nitric oxide (40 ppb vs. 12 ppb; P < 0.037) and a lower median forced expiratory volume in one second (61% vs. 87%; P < 0.001).ConclusionsAlthough patients with treatment-resistant severe asthma cannot always be distinguished from those with difficult-to-treat severe asthma on the basis of baseline clinical characteristics, reduced airflow and elevated fractional exhaled nitric oxide are factors that could distinguish the two groups. Patients diagnosed with severe uncontrolled asthma should be re-evaluated on a regular basis, in order to exclude other diagnoses, to reduce exacerbations, and to identify patients with persistent airflow limitation.

Fixed airways obstruction among patients with severe asthma: findings from the Singapore General Hospital-Severe Asthma Phenotype Study.

BackgroundA subset of severe asthma patients has fixed airways obstruction, which is characterized by incomplete reversibility to bronchodilator challenge. We aimed to elucidate the factors associated with fixed airways obstruction in a cohort of patients with severe asthma in Singapore.Methods245 patients from the Singapore General Hospital-Severe Asthma Phenotype Study (SGH-SAPS) were screened. These patients fulfilled World Health Organization criteria for "treatment-resistant severe asthma" and were all on combination of high-dose inhaled corticosteroids and long-acting beta2 agonists. 76 patients had pre- and postbronchodilator lung function tests and were selected for analysis. They were divided into two groups based on postbronchodilator (Post BD) forced expiratory volume in one second, PostBDFEV1 % predicted: ≥70% (Non-Fixed Obs) and < 70% (Fixed Obs). We compared clinical and demographic parameters between the two groups.ResultsPatients in the Fixed Obs group were more frequently past or current smokers and had a higher pack-year smoking history. Overall, pack-year smoking history had a modest negative correlation with PostBDFEV1 % predicted. Atopy, allergen sensitization (type and numbers), comorbidities, symptoms, health care utilization and medication use did not differ between the two groups. The prebronchodilator FEV1 % predicted, FEV1/FVC and FVC % predicted were significantly lower in the Fixed Obs group. In addition, prebronchodilator FVC % predicted accounted for more variability than FEV1/FVC in predicting PostBDFEV1% predicted.ConclusionSmoking is associated with fixed airways obstruction in patients with treatment-resistant severe asthma in Singapore. Furthermore, our results suggest that both small and large airways obstruction contribute independently to fixed airways obstruction in severe asthma.

Significant Increase of IL-8 Sputum Levels in Treatment Resistant Severe Asthma Compared with Difficult to Treat Severe Asthma Patients

The spectrum of severe asthma includes different groupings and phenotypes. World Health Organization proposes to differentiate two categories: difficult-to-treat-severe asthma (DTTSA) and treatment-resistant-severe asthma (TRSA). DTTSA includes controllable severe asthma and TRSA includes patient’s not achieving adequate levels of control and persisting indicators of severity despite receiving and using maximum levels of inhaled medications. We hypothesized that granulocyte counts from sputum samples could differentiate pathogenic differences between both groups. We analyzed the number of sputum neutrophils and eosinophils in both categories of severe asthma patients admitted for an asthma exacerbation in a respiratory-based hospital. We also compared our results with mild to moderate asthma patients (MMA) and healthy controls (HC). We measured cytokines levels relevant to neutrophil recruitment (IL-8 and IL17-A) and inflammatory cytokines. We found a significant increase in neutrophil numbers in TRSA compared to DDTSA, MMA and HC; moreover, we detected a significant increase of IL-8 levels in sputum samples of TRSA patients. However we found no differences in exhaled FeNO and IL17-A levels among groups. This study shows that the sputum neutrophilic profile predominates in patients with TRSA, could be useful in distinguishing from DTTSA, and may provide insight into the pathogenic differences between both groups.

Airway Hyperresponsiveness: New Insights into the Pathogenesis

Airway hyperresponsiveness (AHR) is the most characteristic clinical feature of asthma. The pathogenesis of AHR in asthma is characterized by a variety of epithelial, microbial, and inflammatory triggers on one hand and abnormalities of effector structures in the airways such as smooth muscle cells, blood vessels, and nerves on the other hand. Obesity is increasingly recognized as an important additional factor in the diagnosis and the pathogenesis of AHR in asthma. It is important to note that structural changes in the asthmatic airway can persist in the absence of inflammation. This may be one reason for the observation that potent new antiinflammatory drugs for the treatment of asthma have only little impact on AHR. New therapeutic strategies are, therefore, needed to modulate structural and functional changes in the airways, especially in patients with treatment-resistant severe asthma.

WHO universal definition of severe asthma

In 2009, an expert panel met to propose a WHO definition of asthma severity and control, and criteria for describing exacerbations and their severity, which would be globally applicable. This review addresses their findings in the context of recent literature, and assesses the usefulness of these definitions in children in particular. Severe asthma was defined by the level of current clinical control and risks as: 'Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)'. Severe asthma includes three groups, with different public health messages and challenges: untreated severe asthma, due to undiagnosed asthma or unavailability of therapy, difficult-to-treat severe asthma (due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or co-morbidity), and treatment-resistant severe asthma, including asthma for which control is not achieved despite the highest level of recommended treatment or asthma which is controlled only with the highest level of recommended treatment. These definitions will enable more precise measurement of the burden of severe childhood asthma globally. International collaborations in epidemiological and mechanistic studies, and randomized controlled trials of treatment, will be facilitated. However, both pathophysiology and severity are influenced by a number of factors with wide global variation; international comparisons should be interpreted with caution.

Uniform definition of asthma severity, control, and exacerbations: Document presented for the World Health Organization Consultation on Severe Asthma

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.