Definition, Diagnosis and Treatment
Background: A minority of patients with asthma have uncontrolled or partially controlled asthma despite intensive treatment. These patients present a special challenge because of the extensive diagnostic evaluation that they need, insufficient evidence regarding personalized treatments, and their high consumption of health-care resources.
Methods: The definition, diagnosis, and treatment of severe asthma are presented on the basis of a selective literature review and the authors’ clinical experience.
Results: Severe asthma is present, by definition, when adequate control of asthma cannot be achieved by high-dose treatment with inhaled corticosteroids and additional controllers (long-acting inhaled beta 2 agonists, montelukast, and/or theophylline) or by oral corticosteroid treatment (for at least six months per year), or is lost when the treatment is reduced. Before any further treatments are evaluated, differential diagnoses of asthma should be ruled out, comorbidities should be treated, persistent triggers should be eliminated, and patient adherence should be optimized. Moreover, pulmonary rehabilitation is recommended in order to stabilize asthma over the long term and reduce absences from school or work. The additional drugs that can be used include tiotropium, omalizumab (for IgE-mediated asthma), and azithromycin (for non-eosinophilic asthma). Antibodies against interleukin-5 or its receptor will probably be approved soon for the treatment of severe eosinophilic asthma.
Conclusion: The diagnosis and treatment of severe asthma is time consuming and requires special experience. There is a need for competent treatment centers, continuing medical education, and research on the prevalence of severe asthma.
The prevalence of asthma increased significantly in the 20th century and is currently estimated to be 5 to 10% in Europe (1). In the 20th century, the pertinent medical concepts were dominated by the classification of asthma as “allergic asthma” (evidence of allergic sensitization) or “intrinsic asthma” (no evidence of allergic sensitization); this classification was proposed by Francis M. Rackemann in 1918 (2, 3). In the 21st century, this is slowly being replaced by biomarker-based phenotyping of asthma, for targeted treatment of particular subtypes. The concept of asthma severity has also changed: classification by lung function is giving way to classification by degree of asthma control. This concept has been adopted in German (www.versorgungsleitlinien.de) and international (www.ginasthma.com) recommendations.
In clinical practice, asthma control is assessed using questionnaires such as the Asthma Control Test (ACT) (Table 1) and the Asthma Control Questionnaire (ACQ) (4). The majority of patients can be successfully treated with modern standard therapy. As a result, emergency room consultations and hospitalizations of asthma patients have decreased (5). However, the asthma of a minority remains only partially controlled, or even uncontrolled, despite intensive treatment. This asthma, termed severe asthma, is also important in terms of health economics, as this minority of patients accounts for the majority of medical resource use (6, 7).
There is no universally accepted definition of the features that constitute severe asthma. In 2010, the World Health Organization (WHO) recommended that severe asthma be divided into three groups (6) (Table 2). The advantage of the WHO classification is its realistic assessment of patients with severe asthma: in most cases severe asthma is not therapy resistant but falls into one of the following three categories (8):
- Untreated asthma
- Incorrectly treated asthma
- Difficult-to-treat asthma (as a result of non-adherence, persistent triggers, or comorbidities)
In the current definition (2014) of severe asthma established by a task force of the European Respiratory Society (ERS) and the American Thoracic Society (ATS), untreated patients (who need not necessarily have genuinely severe asthma) are omitted. This definition specifies the criteria for severe asthma (7) (Box 1). It also defines the term “high-dose inhaled corticosteroid (ICS)” (7) (Table 3). In a few cases (e.g. ciclesonide: maximum authorized daily dose 160 μg in Germany), the recommended doses in high-dose ICS therapy can be higher than the highest daily dose established in specific countries. It is important not to forget that the lung function-based criterion (Box 1) (forced expiratory volume in one second [FEV1] <80%) applies only if the Tiffeneau index (FEV1/FVC [forced vital capacity]: a parameter of airway obstruction) is low; this proviso is important, because restrictive lung diseases, which do not automatically make asthma more severe, are also associated with low FEV1.
Basic diagnostic procedures (9) includes the following:
- Clinical history (Box 2)
- Clinical examination
- Lung function testing (spirometry or whole-body plethysmography) followed by reversibility testing (in case of airway obstruction) or hyperreactivity testing (if there is no airway obstruction).
Allergy testing should also always be performed (clinical history, skin prick tests, blood tests). Other tests, such as the measurement of exhaled nitric oxide levels (FeNO, in ppb [parts per billion]), are optional (9). Typically, patients with severe asthma have already had a basic assessment of their disease. In the following, we describe how to proceed if a patient presents for therapy optimization.
Confirmation of the diagnosis
If severe asthma is suspected, differential diagnoses that may mimic asthma (Box 3) should first be ruled out. This requires a detailed clinical history (Box 2). Because up to 40% of asthma patients in Europe smoke (10), subacute reversibility testing using systemic steroid therapy (e.g. prednisolone 50 mg for 7 to 14 days) should be performed in addition to acute reversibility testing (using a short-acting bronchodilator) to rule out chronic obstructive pulmonary disease (COPD). If prednisolone therapy largely or completely restores lung function, COPD is unlikely.
Computed tomography (CT) of the chest may also be useful, as it can rule out many differential diagnoses (including malformations, dysplasias, tumors, bronchiolitis, bronchiectasis, pulmonary embolism, alveolitis, and various interstitial lung diseases). The consensus paper of the ERS/ATS task force (7) therefore gives a conditional recommendation for a chest CT in case of atypical presentation of severe asthma. The following procedures may also be useful:
- Bronchoscopy to rule out endobronchial changes, for biopsy, or for diagnostic bronchoalveolar lavage
- Echocardiography to rule out heart failure or structural heart disease
- 24-hour pH measurement to rule out gastroesophageal reflux.
Ruling out diseases associated with asthma
Aspirin-exacerbated respiratory disease (AERD), also known as ASA (acetylsalicylic acid) intolerance, is an intolerance of cyclooxygenase (COX) 1 inhibitors. It is associated with hypersensitivity to ASA, nasal polyps, chronic sinusitis, and asthma (often severe). The exact prevalence of AERD is uncertain and is reported as between 4 and 21% of asthma patients (37). Diagnosis can be confirmed only using ASA provocation as there is no valid skin or laboratory test for AERD (9).
Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in the following cases:
- Very high total IgE levels (usually well over 1000 kU/L)
- Specific IgG and IgE antibodies to Aspergillus fumigatus (particularly IgE antibodies to recombinant Aspergillus antigens rAsp F4 and rAsp f6)
- Fleeting pulmonary opacities
- Central bronchiectasis.
Churg–Strauss syndrome (CSS) should be suspected in the following cases:
- Blood eosinophils >10%
- Migrating pulmonary opacities
Wherever possible, suspected cases of CSS should be further clarified by biopsy (evidence of extravascular eosinophilic infiltrations).
Adherence, triggers, and comorbidities
Common causes of severe asthma are poor treatment adherence and/or persistent triggers (WHO class II: Table 2 (8). Because of this, adherence and triggers should always be systematically investigated (Box 4) before additional medication is prescribed. In addition, comorbidities that affect asthma severity, such as chronic rhinosinusitis, gastroesophageal reflux, sleep-related breathing disorders, or heart disease, must be sought. Obesity can not only adversely affect asthma control but can also be the cause of an asthma misdiagnosis, as both its symptoms and its lung function findings can mimic asthma (7). This requires examination by a respiratory physician.
How often COPD and asthma co-occur is currently being discussed using the term “asthma–COPD overlap syndrome” (ACOS) (www.ginasthma.com). In most unclear cases, however, the clinical history and course of disease indicate either COPD or asthma relatively clearly. Evidence of a psychiatric disorder—depression or an anxiety disorder is present in up to 50% of patients—should be clarified by a specialized physician (11, 12).
Allergy testing (skin prick test and/or measurement of allergen-specific IgE antibodies) are part of standard assessment. Total serum IgE level is required to evaluate omalizumab therapy (9). A differential blood count is needed to identify the eosinophilic phenotype (this is essential for specific treatment decisions (e.g. anti-interleukin-5 therapy or macrolide therapy) (13). Total eosinophil count in peripheral blood is the key parameter in this regard: cut-off values between 0.15 × 109/L (13, 14) and 0.3 × 109/L (15) are currently being discussed. Systemic corticosteroid therapy makes it impossible to ascertain patients' “genuine” eosinophil status; a steroid-free interval can be considered in such cases. The ERS/ATS consensus paper gives a conditional recommendation against asthma management using FeNO measurement (7). Persistently high FeNO levels (above 50 ppb) during high-dose ICS therapy, however, may indicate poor adherence, persistent exposure to allergens, or strong intrinsic disease activity (16).
The details of standard therapy can be found in the asthma guidelines (17) and the German National Disease Management Guideline. Basic therapy consists of an inhaled corticosteroid (ICS), to which additional controllers are added if asthma control is inadequate: an inhaled long-acting beta 2 agonist (LABA), montelukast, and/or theophylline. If this therapy does not adequately control asthma, oral corticosteroids (e.g. prednisolone) are added. Specific immunotherapy for severe asthma is only a theoretical possibility, for the following reasons (18, 19):
- Either there is no detectable allergen or there is polysensitization with no clear relationship between allergen exposure and symptoms.
- Lung function is often too poor (immunotherapy requires FEV1 >70% for safety reasons).
- There is a lack of randomized clinical trials on severe asthma.
Although patients with severe asthma are often deficient in vitamin D, current evidence does not support a universal recommendation of vitamin D therapy (20). There are specific treatment principles for the diseases associated with asthma (Table 4). Below we outline basic measures and additional treatment options following a diagnosis of severe asthma.
Optimizing inhaled therapy
Poor inhalation technique and poor adherence are common and very straightforward causes of uncontrolled asthma. Where necessary, patients must be re-educated and retrained; resources for this include freely available online videos (approximately 2 to 3 minutes per video) (www.atemwegsliga.de). Whether switching to inhalers with extrafine formulations (average particle size 1 to 3µm) can improve asthma control by means of better ICS deposition in the smaller airways is currently under discussion (21). Optimized patient–inhaler interaction is an essential key to successful inhaled therapy. Therefore, patients should be involved in inhaler selection (e.g. dry powder or metered-dose inhaler). Finally, check whether the maximum daily ICS dose stated in international recommendations has been prescribed (Table 3).
Eliminating persistent triggers
Persistent asthma triggers are a common feature of difficult-to-treat asthma (WHO class II). Identifying persistent (often perennial and/or domestic) sources of allergens can be challenging. Allergens may be uncommon, or exposure may not be obvious and the patient may not consider it worth reporting. Eliminating sources of allergens (e.g. cats) can be even more difficult, due to emotional obstacles. One underestimated challenge is the elimination of occupational allergens, the avoidance of which may threaten patients emotionally as well as economically (e.g. a baker working in a family-owned bakery).
Therapy for comorbidities
For obese patients, weight reduction can have a positive effect on asthma control (22). Chronic rhinosinusitis is an important trigger of asthma and should be investigated and properly treated by a specialized physician; there is a guideline on this subject (ARIA: Allergic Rhinitis and Its Impact on Asthma) (23). Symptomatic gastroesophageal reflux disease (GERD) also requires treatment, as does depression or an anxiety disorder (11, 12).
Additional treatment options
If the basic therapeutic measures mentioned above have been exhausted, additional treatment options that serve in particular to reduce oral and inhaled corticosteroid doses should be evaluated. In general, the evidence advocating these additional options is weak (7), as there are only a few clinical trials on severe asthma that address each one specifically. As a result, in everyday clinical practice treatment decisions can often be made only on the basis of experience and outcomes in similar circumstances. Treatment options can be divided into two groups according to whether or not they can be begun without further phenotyping (Figure 1).
For most patients, asthma requires lifelong medical care which cannot be optimally provided on an outpatient basis or in acute-care hospitals. Inpatient rehabilitation in appropriate specialized facilities is, therefore, recommended. This is particularly important in patients with severe asthma, in whom additional psychosocial or socioeconomic factors often contribute to asthma severity (24, 25). Rehabilitation aids in incorporating therapeutic needs into daily routine and provides patients with knowledge of their disease that allows them to organize their daily lives. Rehabilitation can stabilize asthma in the long term, significantly reduce resource consumption, and result in fewer hospitalizations and days off school or work (26).
The usefulness of long-acting muscarinic antagonists (LAMAs) is obvious, because it is primarily the parasympathetic nervous system that controls airway tone (27) (Figure 2). Three placebo-controlled clinical trials all showed that additional tiotropium therapy improved asthma patients’ lung function (mean FEV1 increase approximately 100 mL greater than the placebo effect) and reduced their number of exacerbations. These patients had had persistent symptoms and at least one exacerbation treated with systemic corticosteroids in the last 12 months despite high-dose ICS/LABA therapy (ICS dose ≥800 μg budesonide equivalent) (28, 29). Tiotropium was therefore approved for asthma patients in Germany, with this restriction (medium- or high-dose ICS/LABA combination therapy, at least one exacerbation treated with systemic corticosteroids in the last 12 months), in September 2014. No clinical trials of other anticholinergics (glycopyrronium, aclidinium, umeclidinium) have yet been published for the indication severe asthma.
For patients with severe allergic asthma, additional treatment with the anti-IgE antibody omalizumab leads to a reduction (by 50%) in the number of severe exacerbations, improved asthma control and quality of life (30), and reduced need for corticosteroids: the average daily dose of prednisolone falls from 15.5 mg to 5.8 mg (31). Omalizumab therapy is safe (32) but is expensive. Omalizumab is administered subcutaneously every 2 to 4 weeks and is approved for the treatment of asthma, provided the following conditions are all met:
- Persistent symptoms and recurrent exacerbations despite high-dose ICS/LABA therapy
- FEV1 <80%
- Sensitization to perennial airborne allergens
- Total serum IgE between 30 and 1500 kU/L (although the upper limit is lower for body weights above 50 kg: see summary of product characteristics).
If there is no improvement within four months of therapy, a subsequent response is unlikely (7). Omalizumab can be as effective in intrinsic asthma (patients with no evidence of allergy) as in allergic asthma (3) but is approved only for the latter. Such off-label use of omalizumab to treat intrinsic asthma should be evaluated on a case-by-case basis in an experienced asthma center.
Because of their immunomodulating effects, the use of macrolides in asthma has been discussed for years. In a clinical trial, azithromycin (3 × 250 mg per week; initially 250 mg per day for five days) reduced the risk of an exacerbation by 46% in severe noneosinophilic asthma, but not in eosinophilic asthma (33). Because this therapy has potential serious side effects (ototoxicity, QT interval prolongation, macrolide resistance), and because there is only one positive trial, the current ERS/ATS consensus paper gives a conditional recommendation against long-term macrolide therapy for severe asthma (7). As there are no specific alternative treatment options for noneosinophilic asthma, however, we believe that azithromycin therapy can be considered as a last resort if a patient with a low eosinophil count (less than 0.2 × 109/L in the absence of systemic corticosteroid therapy) suffers from frequent exacerbations.
Potential future treatment options
The phosphodiesterase 4 inhibitor roflumilast has shown clinical efficacy in asthma (34), but trials exploring the role of roflumilast as an additional treatment option for severe asthma are lacking. Despite some positive clinical studies, thermoplasty (endobronchial radiofrequency ablation through a dedicated catheter) should be performed only within clinical trials or independent registries (7). The use of antibodies targeting interleukin-5 (mepolizumab, reslizumab) or its receptor (benralizumab) is currently being investigated in phase III trials in patients with eosinophilic asthma (14, 15, 35). As yet, patients can only be treated with anti-IL5 antibodies or anti-IL5 receptor antibodies as part of clinical trials. This treatment is expected to be approved in Germany for severe eosinophilic asthma in the near future. Th2 cytokine antagonists (lebrikizumab, tralokinumab, dupilumab) are currently undergoing clinical development (35).
Requirements for treatment optimization
The treatment of patients with severe asthma requires experience, is time-consuming, and often necessitates off-label drug use. As a result, severe asthma is sometimes inadequately diagnosed and treated (36). In our view, this situation makes the following desirable:
- Inclusion of as many patients as possible in severe asthma registries such as www.german-asthma-net.de
- Better coverage of the diagnosis and treatment of severe asthma in physicians’ training
- Assessment of patients with severe asthma in specialized asthma centers, in order to give them the opportunity to participate in clinical trials.
Conflict of interest statement
Prof. Lommatzsch has received consultancy and lecture fees and reimbursement of travel and participation costs from Allergopharma, Astra Zeneca, Bencard, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, GSK, Janssen-Cilag, MSD, Mundipharma, Novartis, Nycomed/Takeda, TEVA, and UCB. He has also received fees for commissioned clinical trials from Astra Zeneca and research funding from GSK.
Prof. Virchow has received consultancy and lecture fees and reimbursement of travel and participation costs from Allergopharma, Astra Zeneca, Avontec, Bayer, Bencard, Berlin-Chemie, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Takeda, Pfizer, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, Stallergens, TEVA, UCB, and Zydus/Cadila. He has also received research funding from GSK and MSD.
Manuscript received on 30 May 2014, revised version accepted on
11 September 2014.
Translated from the original German by Caroline Devitt, M.A.
Prof. Dr. med. Marek Lommatzsch
Abteilung für Pneumologie/Interdisziplinäre Internistische Intensivstation
Medizinische Klinik I
18057 Rostock, Germany
Prof. Dr. med. Lommatzsch, Prof. Dr. med. Virchow
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