Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

/pdf/international-ers-ats-guidelines-on-definition-evaluation-sedelwbk4v.pdf

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma

Background: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.Purpose: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.Methods: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.Results: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge ...

/pdf/an-official-american-thoracic-society-european-respiratory-18b801porh.pdf

An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.

These guidelines have been replaced by British Guideline on the Management of Asthma. A national clinical guideline. Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma. Thorax 2008 May; 63(Suppl 4): 1–121.

/pdf/british-guideline-on-the-management-of-asthma-a-national-3q1wreyszl.pdf

British guideline on the management of asthma: A national clinical guideline

There is current evidence to demonstrate a close association between fungal sensitisation and asthma severity. Whether such an association is causal remains to be confirmed, but this is explored by means of a detailed literature review. There is evidence from two randomised controlled trials that, in the example of allergic bronchopulmonary aspergillosis (ABPA), treatment with systemic antifungal therapy can offer a therapeutic benefit to ∼60% of patients. ABPA is only diagnosed if a combination of clinical and immunological criteria is achieved. It is not known whether such cases are a discrete clinical entity or part of a spectrum of the pulmonary allergic response to fungi or fungal products. This paper describes the epidemiological evidence that associates severity of asthma with fungi and discusses possible pathogenetic mechanisms. Many airborne fungi are involved, including species of Alternaria , Aspergillus , Cladosporium and Penicillium , and exposure may be indoors, outdoors or both. The potential for a therapeutic role of antifungal agents for patients with severe asthma and fungal sensitisation is also explored. Not only are many patients with severe asthma desperately disabled by their disease, but, in the UK alone, asthma accounts for 1,500 deaths per yr. The healthcare costs of these patients are enormous and any treatment option merits close scrutiny. Within this report, the case for the consideration of a new term related to this association is put forward. The current authors propose the term “severe asthma with fungal sensitisation”. However, it is recognised that enhanced and precise definition of fungal sensitisation will require improvements in diagnostic testing.

https://erj.ersjournals.com/content/erj/27/3/615.full.pdf

The link between fungi and severe asthma: a summary of the evidence

Background: It has been suggested that asthmatic subjects with persisting symptoms despite adequate maintenance therapy should be systematically evaluated to identify factors contributing to poor control. The aims of this study were to examine the prevalence of these factors in a cohort of sequentially referred poorly controlled asthmatics, and to determine if any factor or combination of factors predicted true therapy resistant asthma (TRA).

Methods: Patients were evaluated using a systematic evaluation protocol including induced sputum analysis, psychiatric assessment, ear, nose and throat examination, pulmonary function testing, high resolution CT scan of the thorax, and 24 hour dual probe ambulatory oesophageal pH monitoring; any identified provoking factor was treated. Asthma was managed according to BTS guidelines.

Results: Of 73 subjects who completed the assessment, 39 responded to intervention and 34 had TRA. Subjects with TRA had a greater period of instability, a higher dose of inhaled steroids at referral, more rescue steroid use, and a lower best percentage forced expiratory volume in 1 second (FEV1%). Oesophageal reflux, upper airway disease, and psychiatric morbidity were common (57%, 95%, 49%, respectively) but were not more prevalent in either group. Using multivariate logistic regression analysis, inhaled steroid dose >2000 μg BDP, previous assessment by a respiratory specialist, and initial FEV1% of <70% at referral predicted a final diagnosis of TRA.

Conclusions: In poorly controlled asthmatics there is a high prevalence of co-morbidity, identified by detailed systematic assessment, but no difference in prevalence between those who respond to intervention and those with TRA. Targeted treatment of identified co-morbidities has minimal impact on asthma related quality of life in those with therapy resistant disease.

https://thorax.bmj.com/content/thoraxjnl/58/7/561.full.pdf

Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol

Objective and background:  To understand the effects of asthma and its treatment and to draw accurate conclusions with respect to different management programmes, including clinical trials. In more severe asthmatics, it is imperative that the health-related quality of life (HRQL) be measured accurately and validly. This study had a twofold objective: (i) to examine the psychometric characteristics of the Asthma Quality of Life Questionnaire (AQLQ) in patients with difficult asthma, and (ii) to explore to what extent suffering from asthma affects the HRQL in patients with difficult asthma.



Methods:  Eighty-six adult patients with difficult asthma (33 men) participated in the study.



Results:  The internal consistency reliability (α) ranged from 0.80 (environment subscale) to 0.96 (overall score), and the 2- to 4-week reproducibility (intraclass correlation coefficients) ranged from 0.82 (environment subscale) to 0.92 (overall score).The AQLQ correlated significantly with an asthma disease severity scale, the EQ-5D, and the visual analogue scale indicator of global quality of life (P < 0.0001). No relationship was found between the AQLQ score and FEV1%.



Conclusions:  The results suggest that the AQLQ may be a useful outcome measure for clinical trials in severe asthmatics. The results of this study showed that the HRQL in patients with difficult asthma is substantially impaired. The dominant feature of this group is high symptom scores, with environmental exposure scoring lowest. Mean AQLQ values for this group compared with published means from other less severe asthmatics suggest that patients with difficult asthma experience clinically significant, poorer health-related quality of life. This study presents the poorest health-related quality of life reported in patients with asthma.

Assessment of impairment in health-related quality of life in patients with difficult asthma: psychometric performance of the Asthma Quality of Life Questionnaire.

Aim

To examine the relationship between cortisol suppression and asthma symptoms in patients with difficult asthma.



Methods

Patients, referred to a specialist difficult asthma service and who fulfilled the criteria for difficult asthma, were recruited to the study in a sequential, unselected manner. At each clinic visit, all patients completed a validated asthma control questionnaire. For measuring cortisol suppression, early morning urinary cortisol [corrected for creatinine to give urinary cortisol creatinine ratio (UCC ratio)] was used. The urine samples were collected and stored at − 70 °C until ready for analysis. Urinary cortisol was extracted (solid-phase extraction) and analysed using high-performance liquid chromatography. The Pearson correlation coefficient was used for correlation analysis while t-tests were used for between-group differences for normally distributed data. If the data were not normally distributed, nonparametric statistics were used. A P-value < 0.05 was considered statistically significant.



Results

During the study period all the patients who attended the difficult asthma clinic and fulfilled the criteria for difficult asthma (n = 66) agreed to take part in the study. There were moderate to strong and significant associations between several measures of asthma control and UCC ratio. The correlation coefficient with five indicators of asthma control ranged between 0.3 and 0.5 (P < 0.05).



Conclusions

We have demonstrated a relationship between cortisol suppression and asthma control in difficult asthmatics on high-dose steroid therapy. We have proposed a model based on the relationship between symptom control and cortisol suppression, whereby both adherence and therapeutic adjustments could potentially be made. A properly controlled prospective clinical trial should examine the utility of this approach in clinical practice.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.2006.02745.x

A cross-sectional study evaluating the relationship between cortisol suppression and asthma control in patients with difficult asthma.

The impact of non-adherence to inhaled long-acting β2-agonist / steroid combination therapy on healthcare costs in difficult to control asthma

Relationship between adherence to prescribed regimens and asthma control in patients with difficult asthma

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