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Brittle Asthma Current Respiratory Medicine Reviews, 2007, 3, 7-13 7 Brittle Asthma Raana Haqqee and Syed Hasan Arshad* Department of Respiratory Medicine, University Hospital of North Staffordshire, City General Hospital, Newcastle Road, Stoke-on-Trent, ST4 6QG, UK Abstract: About 5% of asthmatics do not behave like ‘classical’ asthmatics and may not respond adequately to conven- tional therapy. The terms used to describe such non-responders include severe, refractory, near fatal, difficult and difficult to control asthma. Within the umbrella term of severe or refectory asthma, there are distinct sub-phenotypes including brittle asthma. Brittle asthma is rare and may occur in 0.05% of all asthmatics. Currently the diagnosis of brittle asthma is made on clinical grounds based on the variability of peak flow and uncertainty and unpredictability of sudden onset of disabling and severe symptoms despite maximal medical therapy with high dose inhaled corticosteroids, inhaled and nebulised bronchodilators and either maintenance or repeated courses of systemic corticosteroids. The role of genetics, environmental exposure and infection is the focus of ongoing research in the development of severe asthma. Atopy, female sex and psychosocial factors are recognised to be associated with brittle asthma. Other factors, in- vestigated as possible initiating or contributing factors in brittle asthma include nutrient deficiency, reduced antioxidants activity and immunodeficiency with low IgG subclass levels. This review will highlight the related phenotypes, risk factors, mortality and morbidity, pathogenesis and management of patients with brittle asthma. Keywords: Brittle asthma, refractory asthma, related phenotypes, severe asthma, pathogenesis, risk factors, management. INTRODUCTION control to a level of mild-moderate persistent asthma. The seven minor criteria were related to aspects of lung function, Asthma is a chronic inflammatory disorder of the airways exacerbation, disease stability, and the amount of additional with airflow obstruction and bronchial hyperresponsiveness medications. This definition would be applicable to patients as its characteristic features. The airflow obstruction is vari- in whom other conditions have been excluded, exacerbating able and usually responds to standard management with factors have been optimally treated and patients have been bronchodilators and anti-inflammatory agents such as corti- found to be compliant with their asthma treatment [1]. costeroids. However, it is also recognised that some patients Clinically, these patients may suffer from one or more of the with severe disease are not controlled on the standard ther- following features; a) severe and chronic airflow limitation, apy and hence suffer from higher morbidity, requiring more b) progressive loss of lung function, c) inadequate response extensive use of medications and health care resources. Over to corticosteroids and, d) rapid onset of a life threatening a period of time, various names and labels have been used to asthma episode. describe this severe variety of bronchial asthma which may occur in approximately 5% of asthmatics. These terms in- In 1977, Turner Warick used the term ‘brittle asthma’ for clude chronic severe asthma, difficult asthma, life threaten- the first time when describing a sub-group of patients with ing asthma, irreversible asthma, difficult or difficult to con- severe asthma who manifested wide variation in their peak trol asthma, rapid onset asthma, and fatal and near fatal expiratory flow rates despite high doses of inhaled steroids asthma. In 2000, ATS Workshop Report [1] gave the term, [2]. After 21 years, in 1998, Jon Ayres [3] further classified ‘Refractory Asthma’ to include all patients who have been brittle asthma into two types. Type I was characterised by a regarded as having severe asthma. This includes sub-phe- chaotic, unpredictable and wide peak expiratory flow (PEF) notypes with specific characteristics, such as brittle asthma. variability (> 40% diurnal variation for >50% of the time over a period of at least 150 days despite considerable medi- cal therapy including a dose of inhaled steroids of at least In order to have defined criteria for recognition of these 1500 μg of beclomethasone or equivalent). The condition is variable presentations associated with the diagnosis of re- more commonly seen in females (male: female ratio of 1: 3) fractory asthma, the working party agreed on a definition between the ages of 15 and 55 years. Over 90% of patients based on one of two major and two of seven minor criteria. are atopic. Type II brittle asthma was characterised by sud- The major criteria were defined as a need to treat with con- den acute attacks occurring in less than three hours without tinuous or near continuous (more than 50% of the year) high an obvious trigger on a background of apparent normal air- dose inhaled corticosteroids or oral corticosteroids to achieve way function or well controlled asthma. No sex difference has been identified in this group [3]. *Address correspondence to this author at the Department of Respiratory The existence of brittle asthma as a separate entity has Medicine, University Hospital of North Staffordshire, City General Hospi- been questioned in the literature. However, the more precise tal, Newcastle Road, Stoke on Trent, ST4 6QG, UK; Fax: 01782552323; definition and description of Type I brittle asthma by Ayres E-mail: [email protected] 1573-398X/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. 8 Current Respiratory Medicine Reviews, 2007, Vol. 3, No. 1 Haqqee and Arshad [3] has lent support to it being a separate variety of asthma dle aged men, who are at increased risk of life-threatening with increased morbidity and mortality. Since then, brittle episodes due to poor compliance with treatment and asthma asthma has been recognised as a sub-group of 1-10% of se- care plan. The authors carefully considered and ruled out the vere asthmatics (depending on the criteria used to define possibility that this lack of care was due to poor education or severe asthma), who are considered to be phenotypically inadequate health care provision. different from the typical variety of severe asthmatics. Ayers Near fatal asthma: Near fatal asthma [7] has been at- et al., from the West Midlands Brittle Asthma Database, tributed to poor quality of medical care in New Zealand estimated the prevalence of brittle asthma to be 0.05% of the [8-11] and some other studies [12-16]. In some cases, errors asthmatic population [3]. Both varieties of brittle asthma in self management plans may lead to serious asthma attacks have increased risk of death from asthma attacks and in- requiring hospitalisation [17, 18]. creased morbidity due to repeated hospital admissions, psy- chosocial problems and adverse effects of therapy particu- Mortality and Morbidity larly with systemic steroids and subcutaneous terbutaline infusion. Patients with Type I brittle asthma shows a chaotic pat- tern of PEF with wide diurnal variations. Studies have shown Related Phenotypes that these patients have an increased risk of dying from acute asthma [19-22]. Morbidity associated with brittle asthma is Other varieties of severe asthma have been described in also significant. There are frequent visits to accident and the literature with overlapping features to brittle asthma. emergency units following a sudden severe life threatening These include rapid onset asthma (ROA), severe life threat- attack. This occurs on a background of apparent stability in ening asthma (SLTA) and near fatal asthma (NFA). Rapid type II brittle asthma and extreme lability in PEF in type I deterioration of asthma with respiratory failure and need for brittle asthma. The severity of acute attacks in both type of mechanical ventilation is the common feature amongst these brittle asthma may necessitate invasive or non invasive ven- groups. However, other features may differ. tilation for a variable duration. Both types of brittle asthmat- Rapid onset asthma: Gustavo et al. [4] defined rapid ics often use large amount of medications in high doses. This onset asthma (ROA) as life threatening asthma episode de- can lead to distressing adverse effects of weight gain and veloping over a period of <6 hours. Plaza et al. [5] used a osteoporosis from high dose inhaled or systemic steroids, stricter definition of ROA as those with an asthma exacerba- oesophageal reflux from smooth muscle relaxation with high tion, on a background of stability, leading to seeking of dose beta 2 agonists and subcutaneous nodular lesions and medical help within two hours of onset of symptoms. In the abscess formation from continuous subcutaneous terbutaline study by Plaza et al., 20% (of 220) patients met the criteria infusions [23,24]. for ROA, whereas, 11.3% (of 403) were classified as ROA Psychosocial factors: Patients with severe asthma, in- in the study by Gustavo et al. Both studies showed a male cluding brittle asthma, have an increased psychosocial mor- preponderance, lower rates of respiratory infections causing bidity. These patients tend to have increased General Health exacerbation, higher severity indices for the asthma episode Questionnaire (GHQ60) and life event scores [25]. The but a more rapid response to treatment compared to those studies have also highlighted the inappropriate coping re- patients who had a slower onset of their asthma episode. The sponse to worsening symptoms of asthma by delay in seek- criteria used to define ROA are very similar to that
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