The Treatment of Mild and Moderate Asthma in Adults
Background: Asthma is a chronic inflammatory airway disease that usually causes variable airway obstruction. It affects 5–10% of the German population.
Methods: This review is based on relevant publications retrieved by a selective search, as well as on national and international guidelines on the treatment of mild and moderate asthma in adults.
Results: The goal of treatment is to attain optimal asthma control with a minimal risk of exacerbations and mortality, loss of pulmonary function, and drug side effects. This can be achieved with a combination of pharmacotherapy and non-drug treatment including patient education, exercise, smoking cessation, and rehabilitation. Pharmacohterapy is based on inhaled corticosteroids (ICS) and bronchodilators. It is recommended that mild asthma should be treated only when needed, either with a fixed combination of ICS and formoterol or with short-acting bronchodilators. For moderate asthma, maintenance treatment is recommended, with an inhaled fixed combinations of ICS and long-acting beta-mimetics, possibly supplemented with long-acting anticholinergic agents. Allergen immunotherapy, i.e., desensitization treatment, should be considered if the allergic component of asthma is well documented and the patient is not suffering from uncontrolled asthma. Asthma control should be monitored at regular intervals, and the treatment should be adapted accordingly.
Conclusion: The treatment of asthma in adults should be individually tailored, with anti-inflammatory treatment as its main component.
Asthma is a heterogeneous disease characterized by chronic inflammation of the airways and in most cases variable degrees of airway obstruction; it affects around 5% of the world’s population (1, 2). The prevalence of asthma increased markedly during the 20th century and now appears to have leveled off (3). In Germany, the lifetime prevalence of asthma is 8.6% (4). In patients with asthma, periods with no symptoms can alternate with symptomatic periods of variable severity. Clinically, the picture is dominated by recurrent episodes of chest tightness, shortness of breath, and characteristic stridor and/or coughing, especially at night and in the early morning. The symptoms of asthma usually regress either spontaneously or after appropriate treatment. Acute worsening of the disease in the form of asthma attacks or exacerbations can occur at any moment without warning and can be life-threatening (5). The information contained in this article is based on analysis of the evidence, recommendations in current national (6, 7) and international guidelines (5), and a selective literature search of PubMed, and applies to adult patients with asthma.
After studying this article, the reader should:
- Be familiar with current concepts in the diagnosis and treatment of asthma;
- Be able to list the pharmacological and nonpharmacological treatment options for asthma;
- Understand how to carry out and manage inhalation therapy in patients with asthma.
The international recommendations for the treatment of asthma are updated every year by the Global Initiative for Asthma (GINA) and are freely available on the internet (www.ginasthma.com) (5). The clinical guideline issued by the German-language medical societies was last updated in 2017 (7) and the National Disease Management Guideline for Asthma (Nationale Versorgungsleitlinie [NVL] Asthma) was updated in 2020 (7).
Types of asthma and biomarkers
In adults, two common types of asthma are distinguished. The first is allergic asthma, where there is a clear relationship with allergy. Onset is often during childhood or adolescence and often accompanied by allergic rhinitis and/or atopic dermatitis; this form is known as “early-onset asthma.” The second is an intrinsic (eosinophilic) type, usually with onset in adulthood and usually without evidence of any relevant allergies; this form is referred to as “adult-onset” or “late-onset asthma”) (8). In both types of asthma, an increased level of typical cytokines and eosinophil granulocytes is found, together with dysfunction of structural cells (including bronchial epithelial cells, which release increased amounts of nitric oxide [NO]) (9)—characteristics referred to collectively under the name “type 2 asthma” (10). The inflammation can be measured through biomarkers (Box 1). Routine diagnostic procedures covered by statutory health insurance carriers in Germany include blood eosinophil count and allergy markers; fractional exhaled NO (FeNO) measurement is available as a self-pay option. It should be noted that these biomarkers can be “falsified”: for example, eosinophil counts can be greatly reduced by inhaled or oral steroids (11) and FeNO levels by tobacco smoke (12).
The diagnosis of asthma rests on four pillars (Box 2), of which careful history taking is the most important. Since 39.25% of asthma patients in Europe are smokers (1), to rule out chronic obstructive pulmonary disease (COPD) it is particularly helpful to ask questions about variability of symptoms over time (in COPD there is little variability), nighttime symptoms (usually absent in COPD), and whether symptoms respond well to steroids (in COPD this is rarely the case). Asthma is a clinical diagnosis that can only be made by considering all the findings together.
GINA defines the goals of treatment for asthma as follows (5):
- Achieving the best possible asthma control;
- Minimizing the risk of exacerbations and death, loss of lung function, and adverse medication effects.
In addition, the patient’s individual treatment goals should be taken into account. To achieve these goals, the use of nonpharmacological strategies and the most effective pharmacological interventions with fewest adverse effects is recommended.
Asthma control and severity of asthma
The key goal of treatment is good asthma control, and for this reason considerable importance attaches to measuring asthma control in the everyday clinical setting. Asthma control is classified into three grades:
- Controlled asthma
- Partly controlled asthma
- Uncontrolled asthma.
The level of asthma control should be monitored at regular intervals (e.g., every 3 months) in order to determine whether treatment needs to be stepped up (13). According to GINA (5) and the National Disease Management Guidelines (7), four questions suffice to determine the level of asthma control; in addition, restriction of lung function and the number of exacerbations should be taken into account (Figure 1). Alternatively, the Asthma Control Test (ACT, which contains five questions) can be used to measure asthma control (13). The asthma severity level is defined according to the response to treatment (Box 3) (6, 14).
Principles of asthma treatment
Asthma is a disease that is primarily managed in the outpatient setting; inpatient treatment is rarely needed. Both nonpharmacological strategies (Box 4) and pharmacological treatment are available for the management of asthma, mostly with a strong evidence base (7). According to a metaanalysis by Bateman et al. (64 RCTs, 42 527 patients), however, only drug regimens containing inhaled steroids (ICS) improve patients’ quality of life (15). During a patient’s consultation with the physician, the treatment goal is defined taking account of the patient’s individual life circumstances and preferences. Recommendations for treatment need to take into account the variable severity as well as the intra-individual variability of the disease over time, with treatment being adjusted on the basis of the level of asthma control. Often, treatment plans are a compromise between the physician’s recommendations for treatment and the patient’s willingness to adhere to the treatment. Using the step approach, treatment can be stepped up and down:
- When asthma is either uncontrolled or only partly controlled, treatment should be stepped up until good control is achieved.
- When asthma has been well controlled for at least 3 months, treatment can be stepped down. In patients with only seasonal symptoms, treatment may be governed by allergen exposure at the time, so that a step down may be possible even after quite a short treatment period. It is recommended that, after each step up or down, asthma control should be checked again after 3 months.
- The goal is maintenance of good asthma control with the least possible number of drugs at the lowest possible dosage.
Theophylline preparations no longer play a role in long-term treatment, because of their narrow therapeutic range, their potential adverse effects, and the existence of more effective alternatives (16). Antitussives and mucoregulators are not indicated; the cough symptoms typical of asthma can usually be controlled by anti-inflammatory agents and bronchodilators (7).
Paradigm shift in the treatment of mild asthma
Hitherto, for treatment at step 1 (symptoms at most twice a week), purely “as-needed” relief treatment with short-acting inhaled β2-agonists (SABAs) was recommended. At stage 2 (SABAs needed more than twice a week, but not daily), a long-term low-dose ICS plus a SABA as needed was recommended. Both these recommendations were controversial, because:
- β2-Agonist monotherapy in asthma increases bronchial hyperresponsiveness and mortality (and is therefore contraindicated for long-term treatment) (17).
- Patients often use maintenance ICS treatment irregularly or in an on/off manner (18).
Fixed-dose ICS+LABA combinations offer many advantages (Box 5). Because of their rapid bronchodilatory effect (similar to that achieved with salbutamol), ICS+LABA fixed-dose combinations containing formoterol can also be used for rapid relief. To date, fixed-dose ICS+formoterol combinations are only approved in Europe as an as-needed inhaled add-on to ICS+formoterol long-term treatment (19).
However, studies have shown that purely as-needed treatment with ICS+formoterol is not inferior to existing treatment options at steps 1 and 2 (SABA as needed; low-dose ICS maintenance treatment plus SABA) in terms of the course over time of lung function, and in terms of reduction of severe exacerbations it is even superior (20, 21, 22). Table 1 shows the results of the Novel-START study, a randomized study carried out under everyday clinical conditions (21). Moreover, with purely as-needed ICS+formoterol therapy, ICS exposure is 50 to 83% lower than with ICS maintenance therapy (20, 21, 22). Thus, for mild asthma, purely as-needed ICS+formoterol therapy is the safest strategy, with the fewest adverse effects. GINA therefore recommends low-dose as-needed ICS+formoterol therapy as the preferred option at step 1 and as an equivalent alternative to ICS maintenance therapy at step 2 (18).
As of April 2020, the use of ICS+formoterol on a solely as-needed basis for asthma has not been formally approved in Europe, but the reality is that this purely as-needed regimen is already in use by many patients.
Stepwise approach to asthma treatment in adults
Current national and international asthma guidelines recommend a five-step approach to treatment (7). Treatment is based on regular patient education, checking the patient’s inhaler technique, reducing asthma triggers (e.g., allergen exposure or smoking), and treatment of comorbidities (Figure 2) (7). Potential workplace-related asthma triggers should be identified and eliminated; in some cases a change of workplace or occupation may be unavoidable (23).
Subcutaneous or sublingual allergen immunotherapy (AIT, previously known as hyposensitization or specific immunotherapy) (24) may be considered at any treatment step in patients with allergic asthma, provided the allergic components of the asthmatic symptoms are well documented (proven specific sensitization and clear clinical symptoms after allergen exposure) and the criteria specified in the summary of product characteristics are fulfilled (Figure 2) (recommendation grade A, strong positive recommendation) (7). Uncontrolled asthma is a contraindication to AIT. AIT is not a substitute for adequate inhalation therapy, which must be continued during AIT. Within the provisions of the German therapy allergens ordinance (Therapieallergene-Verordnung), the efficacy of AIT preparations must be proven in placebo-controlled studies. A regularly updated list of preparations with evidence of their efficacy is available on the website of the German Society of Allergology and Clinical Immunology (Deutsche Gesellschaft für Allergologie und klinische Immunologie) (25). Decisions regarding indications, selection of allergens, modes of administration, and the carrying out and management of AIT require specialist expertise and should therefore if possible be carried out by qualified allergists.
In previously untreated patients who meet the criteria for partly controlled asthma, long-term therapy should start at step 2; in those whose asthma is uncontrolled it should start at step 3 at the lowest (recommendation grade B, weak positive recommendation) (6, 7).
Steps 1 and 2
At step 1, either ICS+formoterol as needed or SABA as needed is recommended (5, 21, 22, 23) (Figure 2). From step 2 at the latest, treatment with an ICS is recommended as these medications reduce the inflammation and hyperresponsiveness of the airways, result in improved asthma control and quality of life, and reduce the risk of exacerbations and life-threatening asthma attacks (26). At step 2, either low-dose long-term ICS or purely as-needed ICS+formoterol may be used. A less effective alternative is the leukotriene receptor antagonist montelukast (27), which can be used in patients who refuse ICS treatment or are unable to tolerate it, e.g., because of local adverse effects. If symptoms occur only on physical exercise (“exercise-induced asthma”), inhaling a SABA before physical effort is still recommended (28). Patients with asthma often avoid physical activity for fear of inducing symptoms. However, physical activity has many positive effects on the disease itself and on potential concomitant conditions, so regular physical activity (combined with medication) should be expressly recommended (recommendation grade A, strong positive recommendation) (5, 29). Pregnant women with asthma often reduce their inhalation therapy for fear of adverse effects on the fetus (30). However, all guidelines make strong recommendations for consistently adhering to ICS or ICS+LABA therapy during pregnancy, since the risks associated with loss of asthma control or exacerbations far outweigh the potential risk of medication adverse effects (for which no evidence exists at present) (5, 6, 7).
From step 3 onwards, regular long-term maintenance treatment is recommended (Figure 2), either
- With a fixed-dose combination of a low-dose ICS with a long-acting β2-agonist (LABA) with additional use of a SABA as needed for quick relief, or else
- With a fixed-dose combination of a low-dose ICS with formoterol (ICS+formoterol) used for both maintenance and as-needed relief (“single-inhaler maintenance and reliever therapy” [SMART]) (19).
Alternatively, at step 3 ICS monotherapy at an intermediate dose can be started: a fixed-dose combination of low-dose ICS and LABA is, however, preferable because it is better tolerated and is more effective (26). In cases where LABA is contraindicated or the patient suffers adverse effects to LABA therapy (Box 6), a combination of low-dose ICS and a long-acting anticholinergic (long-acting antimuscarinic receptor antagonist, LAMA), or a combination of low-dose ICS and montelukast can be used. LAMAs (such as tiotropium) are not approved for use for this indication, so the rationale for its use needs to be demonstrated (31, 32). Neither LABA or LAMA should be given as monotherapy in asthma, and neither should a combination consisting exclusively of LABA+LAMA (7).
Steps 4 and 5
From step 4 onwards, the preferred option is an ICS+LABA fixed-dose combination with the ICS at an intermediate or high dose, and from step 5 on the ICS should be at the highest dose (Figure 2). The National Disease Management Guideline for Asthma defines four ICS dose levels (Table 2) (7). The risk–benefit ratio is most favorable in the low-dose range (26). Raising the ICS dose to high or highest can result in better asthma control in patients with severe forms of asthma, but increases the risk of local (Box 6) and systemic adverse effects (e.g., osteoporosis, diabetes, cataract, suppression of adrenal function) (26). A highest dose of ICS can equate to a dose of 2 to 5 mg prednisolone-equivalent per day (33). For this reason, regular follow-up (e.g., every 3 months) is required to check whether highest-dose ICS therapy continues to be necessary. From step 4 onward, to improve asthma control and lung function and reduce the exacerbation rate and ICS requirement, a LAMA can be added, either as a separate inhaler (to date only tiotropium under the name Respimat is approved for this use) or as triple therapy in a single inhaler (ICS+LABA+LAMA; not currently approved as a treatment for asthma) (34). Two phase-III studies have shown an increase in lung function by 57 to 73 mL and reduction in exacerbations by 12–15% with triple therapy (ICS+LABA+LAMA) compared to ICS+LABA therapy (34). According to the National Disease Management Guideline, at step 5, before further therapy options are investigated, highest-dose ICS therapy in combination with a LABA or LAMA should be tried for at least 3 months (Figure 2). If it is not possible to achieve good asthma control under this regimen, or exacerbations continue to occur, the use of highly potent biologics (Table 3) should be considered (9). To avoid severe adverse effects, long-term therapy with systemic glucocorticoids should be given only in carefully selected individual cases (7).
Inhaler technique and inhaler systems
The great majority of patients with asthma can achieve good asthma control solely through the use of highly effective inhalants (5). This requires, however, that the right type of inhaler is chosen for each individual patient and the patient carefully instructed in the technique for using it. More than 20% of patients make critical errors in their inhaler technique and thus remain to all intents and purposes untreated (35). In choosing an inhaler system, patients’ individual abilities and preferences need to be taken into account. Metered-dose aerosol inhalers and Respimat require the patient to be able to coordinate release of the drug with inspiration; dry powder inhalers, on the other hand, require sufficient sucking strength to release the drug from the inhaler (36). Adding a spacer can improve bronchial deposition of metered-dose aerosols, so the use of a spacer should be especially considered in patients with severe asthma or those experiencing local adverse effects. As a matter of principle, every patient should be prescribed only one inhalation system, since it is too confusing for patients to have to cope with different techniques for different inhalers (36), and when the physician has trained a patient on one inhaler, the pharmacy should not be permitted to change it. To support patient training in inhaler technique, 2- to 3-min instruction videos on the use of every inhaler are available free on the website of the German Airways League (Deutsche Atemwegsliga; www.atemwegsliga.de).
Prevalence of asthma
In Germany, the lifetime prevalence of asthma is 8.6%.
Forms of asthma
Allergic asthma often starts during childhood or adolescence, whereas intrinsic asthma (asthma without evidence of allergy) usually starts during adulthood.
Types of asthma and biomarkers
In adults, two common types of asthma are distinguished: allergic asthma, where there is a clear relationship to allergy, and intrinsic or eosinophilic asthma, which usually starts in adulthood without evidence of any relevant allergies.
Asthma is a clinical diagnosis that can only be made by considering all the findings together. A careful history is the most important part of asthma diagnosis.
Asthma control is the basis of short-term (relief) and long-term (maintenance) treatment.
The goal is to achieve and maintain asthma control by suppressing the asthmatic inflammation with a minimum of drugs at the lowest possible dose.
Principles of treatment
Asthma is treated by both pharmacological and nonpharmacological means.
Long-term treatment with an anti-inflammatory drug is recommended as soon as an as-needed reliever drug is in use >2×/week.
Asthma and the workplace
Potential asthma triggers associated with the workplace should be identified and eliminated. In some cases, a change of workplace or occupation may be unavoidable.
Because of their narrow therapeutic spectrum, their potential adverse effects, and the existence of more effective alternatives, theophylline preparations no longer have a place in the long-term treatment of asthma.
Allergen immunotherapy may be considered in any patient with mild to moderate allergic asthma in whom there is a clear relationship between respiratory symptoms and allergen exposure.
Contraindication to allergen immunotherapy
Uncontrolled asthma is a contraindication to allergen immunotherapy.
At step 1, either ICS+formoterol as needed or a SABA as needed is recommended. At step 2, either ICS+formoterol as needed or a long-term low-dose ICS is recommended.
From step 3 onward, long-term treatment with fixed-dose combinations of ICS and a long-acting β2-agonist (LABA) is recommended.
To improve asthma control and lung function and reduce the exacerbation rate and ICS requirement, long-acting anticholinergics (LAMAs) may be added to ICS+LABA treatment.
Increasing ICS to high-dose or highest-dose
Increasing the ICS dose to high or highest can result in greatly improved asthma control in patients with severe forms of asthma, but the risk of local and systemic adverse effects also increases.
To ensure correct adjustment of treatment, asthma control should be checked every 3 months.
For inhalation therapy for asthma to be effective, the right choice of inhaler must be made together with the patient and the patient carefully instructed in the technique for using it.
Conflict of interest statement
Professor Lommatzsch has received lecture and consultancy fees from ALK, Allergopharma, Astra Zeneca, Bencard, Berlin-Chemie, Boehringer-Ingelheim, Bosch, Chiesi, Circassia, GSK, HAL Allergy, Janssen-Cilag, MSD, Mundipharma, Novartis, Nycomed/Takeda, Sanofi, TEVA, and UCB. He has received reimbursement of attendance fees for conferences and educational events, and of travel and accommodation costs from Novartis and AstraZeneca. He has received research support from DFG, GSK, and AstraZeneca. He has received funding for performing clinical studies from AstraZeneca and Sanofi.
Dr. Korn has received lecture and consultancy fees from AstraZeneca, Boehringer-Ingelheim, Bosch, Chiesi, GlaxoSmithKline, Novartis, Sanofi, TEVA, and UCB. She has received reimbursement of attendance fees for conferences and educational events, and of travel and accommodation costs from Novartis and AstraZeneca. She has received research support and funding for performing clinical studies from DFG, Astra Zeneca, Bosch, GlaxoSmithKline, Novartis, Roche, and Sanofi. She has received funding for performing clinical studies from Astra Zeneca, Boehringer Ingelheim, GSK, Novartis, Roche, and Sanofi.
Professor Buhl has received lecture and consultancy fees from AstraZeneca, Berlin Chemie, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi. He has received reimbursement of attendance fees for conferences and educational events, and of travel and accommodation costs from AstraZeneca, Berlin Chemie, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi, as well as research support at the University of Mainz as part of personally initiated projects and clinical studies from DFG, AstraZeneca, Boehringer-Ingelheim, Bosch, GlaxoSmithKline, Novartis, Roche, and Sanofi.
Translated from the original German by Kersti Wagstaff.
Manuscript received on 30 April 2019, revised version accepted on 14 April 2020
PD. Dr. med. Stephanie Korn
III. Medizinische Klinik
55131 Mainz, Germany
Cite this as:
Lommatzsch M, Buhl R, Korn S:
The treatment of mild and moderate asthma in adults. Dtsch Arztebl Int 2020; 117: 434–44. DOI: 10.3238/arztebl.2020.0434
Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center, Johannes Gutenberg University Mainz: PD Dr. med. Stephanie Korn, Prof. Dr. med. Roland Buhl
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