Practical Considerations in Management of Non-eosinophilic Asthma

Abstract

School-aged children with asthma who remain with persistent poor control, or frequent exacerbations, despite being prescribed maximal therapy, have Problematic severe asthma. Maximal therapy for children is defined in the ATS/ERS guidelines for the management of severe asthma as at least 800 mcg/day budesonide (or equivalent) plus a longacting beta2 agonist and current or previous failed trial of leukotriene receptor antagonist and/or oral theophylline.1 Importantly, patients with seemingly severe asthma may have other, modifiable causes of poor asthma control. It is therefore essential to undertake a step-wise approach to diagnosis and management2 of Problematic severe asthma to ensure poor control is not because of a wrong diagnosis, and that a potentially easily remediable factor is not wrongly treated with expensive biologics. It is important that children on maximal maintenance treatment and poor control are not automatically labeled as having severe asthma, there is a sub-group with Difficult to treat Asthma (DA), in whom underlying modifiable factors explain persistent symptoms and poor control. After modifiable factors have been optimized and addressed, there remains a small group of children with good adherence and persistent poor control, these are patients with true severe therapy resistant asthma (STRA). Confirming an asthma diagnosis History and examination: Asthma is characterized by symptoms including wheeze, cough, breathlessness and chest tightness3, all of which may fluctuate over time. An essential component is to obtain objective confirmation of symptoms either as documented doctorobserved symptoms, or by administration of an objective questionnaire. A key issue that often leads to misdiagnosis in children is the mistaken assumption that all noisy breathing equates to wheeze and therefore asthma. Therefore, an accurate record of documented wheeze and symptoms consistent with asthma is critical to prevent inappropriate diagnosis, but equally importantly, inappropriate treatment. Incorporating objective tests to make a diagnosis of asthma: is this necessary? The importance of a correct diagnosis for the individual is obvious; however, equally important is the impact on cost to the health service of avoiding inappropriate prescription of asthma treatments. Application of a secondary screening program, incorporating objective assessments of lung function and airway hyperresponsiveness to a population who had a physician diagnosis of asthma, identified 28% of patients with a misdiagnosis4 of whom 71% were on asthma medication. Factors contributing to the misdiagnosis of asthma include failure to confirm reversible airflow obstruction, the relatively poor sensitivity of spirometry alone to absolutely confirm asthma (especially in children), the day-to-day variability of symptoms and the numerous phenotypes of disease. Given the availability of objective tests that can help to confirm the diagnosis and the potential unwanted effects of inappropriate or wrong diagnosis, many diagnostic algorithms now incorporate the need for objective tests in the diagnosis of asthma. Although there is no gold standard single test to make a diagnosis of asthma, there are several objective tests that can be used to help support the diagnosis. These include physiological measures such as demonstration of obstructive spirometry associated with reversibility following bronchodilator, and evidence of airway hyperresponsiveness. In addition, Noninvasive tests of airway inflammation including measurement of fractional exhaled nitric oxide (FeNO), or peripheral blood or sputum eosinophils can also be used to support the diagnosis. An important change in the approach to diagnosis has recently been introduced in England, where the National Institute for Health and Care Excellence (NICE), whose purpose is to generate evidence-based and cost-effective guidelines, has recently been published [https://www.nice.org.uk/guidance/ng80]. It was claimed by NICE that up to 1.2 million of the approximately 4 million people suffering from asthma in the UK were misdiagnosed and therefore being prescribed wrong or inappropriate medication.5 For the first time in England, it has now been recommended that both spirometry and exhaled nitric oxide tests should be used in all patients older than 5 years to help in the confirmation of the diagnosis. How to identify Difficult to treat asthma The multi-disciplinary team assessment: Numerous and often complex factors may need to be untangled to get a true picture of disease control. Common modifiable factors contributing to “difficult” disease include poor inhaler technique, inappropriate device for the age of child, poor adherence to maintenance therapy and lack of family asthma education. However, often multiple complex factors contribute to asthma being difficult to treat and these can only be identified following multi-disciplinary team input(9).6 The key components that render asthma difficult to treat and how they might be addressed are discussed below. Assessments of adherence to medication: The most common modifiable factor underlying DA is poor adherence to maintenance therapy, encompassing at least 45%-55% of all patients (adults and children).7 Good adherence is defined as the administration of > 80% of prescribed doses of ICS. The British Thoracic Society (BTS) Guidelines state all patients with asthma must have an annual adherence assessment, and the proposed gold standard method is using an electronic monitoring device, however other options include checking prescription pick up/refill. For children with problematic severe asthma, an objective assessment of adherence is an absolute requirement before consideration of therapy escalation. An observational prospective cohort study assessed spirometry with bronchodilator reversibility, FeNO, asthma control test (ACT) scores and quality of life scores before and a median of 92 days after an electronic monitoring device was given to children (median age 12.4 years). Suboptimal adherence ( < 80%) was demonstrated in 58%. Children with good adherence were split into those with improved control (need encouragement to maintain adherence), or those with persistent poor control (STRA). Among children with poor adherence, there was a sub-group whose control improved (likely over-treated), and a second sub-group with persistent poor control. The latter are of particular concern as they are at high risk of asthma death and require an adherence intervention such as directly observed therapy in school, or this may be a group for whom biologics administered in hospital may be the only safe option, even though, in truth, their disease is not necessarily treatment refractory. The prevalence of true STRA was only 18% of the entire cohort and the majority had DA7 emphasizing the importance of the time and resources spent in identifying modifiable factors before therapy escalation. Minimizing exacerbating environmental exposures: Environmental exposures that may result in persistent poor control include exposure to aero-allergens to which the child is sensitized (house dust mite, pet dander, moulds), ambient air pollution and tobacco smoke. Objective confirmation of smoke exposure by measuring urinary or salivary cotinine levels helps ensure the family seek cessation advice. Minimizing aero-allergen exposure in sensitized children is essential as there is a known relationship between exposure and increased disease severity. There is little the individual can do to reduce exposure to air pollution, although advice includes remaining indoors, closing windows and avoiding physical activity outside when pollution levels are high. However, the impact of these measures in improving asthma control is difficult to quantify and government policy to reduce emissions is likely to be more effective as has been seen with legislation to reduce exposure to environmental tobacco smoke. Identification of co-morbidities: Breathing pattern disorders including vocal cord dysfunction and hyperventilation may contribute to DA and are often present with anxiety and psychosocial exacerbators. Ideally, all children with Problematic severe asthma should have a physiotherapy assessment to allow detection and management of dysfunctional breathing8, and clinical psychology assessment.9 The complex interplay of factors contributing to DA means the multi-disciplinary team evaluation may need to be undertaken during an in-patient stay. This approach showed improvement in asthma control from 18% to 69% in children with DA.10 Moreover, immediate and sustained improvement in objective measures including spirometry, exhaled nitric oxide and exacerbations was demonstrated in 24/26 children following a 2-week in-patient assessment.9 Alarming features prompting in-patient assessment include excess use of short acting bronchodilator, discrepancy between symptom reporting and objective markers of disease severity, and safeguarding concerns9. Summary: A step-wise approach to diagnosis and management of school-aged children with Problematic severe asthma, undertaken in specialist centers, is essential To identify those with DA. Before therapy escalation, detailed MDT assessments that allow identification and correction of reversible factors contributing to poor asthma control are needed.6 Recent studies suggest only 20%-30% of all children with Problematic severe asthma have true STRA while the majority have DA, highlighting the importance of the MDT in management. The most common reversible factor is poor adherence to maintenance inhaled corticosteroids and objective adherence monitoring must be undertaken as part of the assessment.