The mild bronchial asthma

Bronchial asthma is a heterogeneous, multifactorial disease characterized by chronic airway inflammation and bronchial hyperresponsiveness. Not only the symptomatology, but also the airway obstruction is variable in time course and intensity. The symptoms of exacerbations can be mild or severe and, without adequate treatment, can lead to death.

Bronchial asthma is a heterogeneous, multifactorial disease characterized by chronic airway inflammation and bronchial hyperresponsiveness. Typical is an attack-like and variable symptomatology. Not only the symptomatology, but also the airway obstruction is variable in time course and intensity. It is possible that periods of symptom freedom may exist with or without treatment and/or episodes of acute exacerbation may occur. Exacerbations are defined as periods of progressive increase in asthma symptoms and/or decrease in lung function that exceed the patient’s usual level of variability and require modification or intensification of therapy over several days. The symptoms of exacerbations can be mild or severe and, without adequate treatment, can lead to death.

Different forms of bronchial asthma are described, grouping certain phenotypes and/or typical disease courses into clusters. According to the severity, mild bronchial asthma is distinguished from moderate and severe asthma. The evaluation is retrospective under adequate therapy and is based on the intensity of treatment leading to control of asthma:

• Mild asthma: therapy control under level 1 or level 2 therapy.
• Moderate asthma: therapy control under level 3 therapy
• Severe asthma: therapy control under level 4 or level 5 therapy.

In German-speaking countries, there are various guidelines or recommendations that are used for the treatment of bronchial asthma:

• Diagnosis and Management of Asthma – The Swiss Guidelines Respiration 2018; 95: 364-380.
• S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma (2017) and S2k-Leitlinie Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma (2017) Addendum 2020, AWMF-Register-No. 020-009
• National Health Care Guideline Asthma Long Version 4th Edition, 2020 Version 1, AWMF-Register-No.: nvl-002
• 2021 GINA Report, Global Strategy for Asthma Management and Prevention. www.ginaasthma.org.

There is new evidence on the therapy of mild bronchial asthma, which has already led to a change in the therapy recommendation of mild asthma in the current report of the Global Initiative for Asthma (GINA). So far, this has been presented differently in national guidelines for various reasons such as the timeliness of the guideline or approval status of the drug therapy.

Epidemiology

Bronchial asthma is a common disease occurring worldwide, with different frequencies observed in different countries [1]. The prevalence of asthma in adults is 7% in Switzerland. In Germany, the prevalence in the adult population is reported to be about 5%. Mild asthma is more common than moderate or severe asthma, with about one in two asthma patients having mild asthma [2,3].

Mild asthma is not harmless

The rate of exacerbations increases with the severity of bronchial asthma. It should be noted, however, that even patients with mild-grade bronchial asthma have an annual exacerbation rate of 0.139-0.143 (US, stages 1 and 2) and 0.56 and 0.70 (UK, stages 1 and 2), respectively. In comparison, annual exacerbation rates of 0.186 (U.S.) and 0.126 have been described in patients receiving Level 4 therapy [4]. It was also shown that 3.6% of patients with mild asthma were hospitalized in the past 12 months and that 20% had visited an emergency department due to bronchial asthma in the past 12 months [5].

Medical history

The essential pillars for the diagnosis of bronchial asthma are history and evidence of typically reversible airway obstruction.

The typical symptoms are coughing, wheezing, shortness of breath and chest tightness. Symptoms may worsen during the night or early morning hours. Symptoms may vary in time and intensity and may be episodic. A variety of contributing factors and/or triggers of asthma are known and should be identified by a careful history (review 1). This also includes an allergy history including family history for atopic diseases, symptomatology of other allergological manifestations and an occupational history.

Typical findings on physical examination include dry accessory sounds such as gurgling, whistling, and humming on auscultation and prolonged expiration. In severe obstruction, the breath sound may be quiet or absent. During the inspection, pay attention to the breathing pattern or the use of auxiliary breathing muscles. Physical examination findings may also be unremarkable.

Pulmonary function diagnostics

The goal is to detect variable, reversible airway obstruction using pulmonary function diagnostics, typically spirometry. Obstruction should be detected at least once, i.e. the FEV1 to vital capacity ratio is lower than the lower limit of normal in one measurement.

Documentation of the variability of airway obstruction can be accomplished through a variety of approaches:

• Evidence of a positive reversibility test with an increase in FEV1 >12% or >200 ml after inhalation of a rapid-acting beta-2 mimetic (SABA).
• Evidence of positive reversibility test with an increase in FEV1>12% or >200 ml after 4 weeks of anti-inflammatory therapy with an inhaled steroid, in combination with other antiasthmatics if necessary.
• Evidence of increased peak flow variability with PEF variability >10%.
• Evidence of a positive provocation test by means of indirect provocation such as physical exertion.
• Evidence of a positive provocation test using direct provocation such as methacholine, histamine, hyperventilation, hypertonic saline, or mannitol

Here, the diagnosis of bronchial asthma is considered confirmed if the reversibility test shows complete reversibility when bronchial obstruction is demonstrated. In case of incomplete reversibility and/or pathological provocation test, the diagnosis of bronchial asthma is considered probable.

Provocation test

A bronchial provocation test is used to determine whether a direct or indirect stimulus can induce airway obstruction [6,7]. Methacholine is often used as a direct stimulus, and physical stress as an indirect stimulus. Direct bronchial provocation tests are considered sensitive for the detection of bronchial hyperresponsiveness, but they are less specific for asthma. More specific for bronchial asthma, although less sensitive, are indirect provocation tests such as exercise-induced or allergen-specific provocation. Provocation testing requires careful consideration of indication and contraindications, as well as adequate patient preparation, staff training, and availability of emergency treatment. The time resource for a provocation test is relatively high.

Exercise-induced bronchoconstriction [7]: The stimulus in exercise-induced bronchoconstriction (EIB) is increased ventilation. The examination is usually performed on a treadmill or ergometer. Here, it is considered methodologically crucial that a rapid increase in ventilation is achieved. The protocol should be directed to achieve the target heart rate (>85% of maximum intended heart rate; maximum heart rate 220-age in years) or target ventilation (60% of maximum voluntary ventilation (MMV); MMV = FEV1 × 40) within 2-3 minutes, after which the level should be maintained for 6 minutes. Spirometry should be measured before and up to 30 minutes after exercise to detect EIB. Often, the lowest FEV1 is measured 5-10 minutes after the end of exercise. A drop in FEV1 of at least 10% or >200 ml from baseline is considered pathologic.

Methacholine test [6]: Methacholine is a muscarinic receptor agonist. In patients with bronchial hyperresponsiveness, inhalation with methacholine at lower doses causes bronchoconstriction than in individuals with healthy airways. Methacholine is applied in increasing concentration as an aerosol via a nebulizer according to a standardized protocol. Spirometry is measured after each inhalation step. Finally, spirometry is performed after the administration of a SABA. The test is considered positive when FEV1 drops by 200 ml or by 20% or airway resistance doubles. The test result is the cumulative provocation dose that resulted in a 20% decrease in FEV1.

An interesting more recent study on reversibility testing and provocation testing in the context of diagnosis of V.a. bronchial asthma was published by Louis and colleagues [8]. In this retrospective study, the results of the reversibility test and the provocation test using methacholine were analyzed in symptomatic patients without continuous therapy who presented with the question of the presence of bronchial asthma. FEV1 averaged 94%, FEV1/VC 77%. Bronchial asthma was diagnosed in 91% of cases. Here, only 3% had a positive reversibility test, 17% showed a positive reversibility and provocation test, while the methacholine test alone was positive in 71%.

In the workup of asthma, other tests may be used for diagnosis and/or characterization. These include differential blood count/eosinophilia, fractionated exhaled nitric oxide (FeNO), chest x-ray, and a stepwise allergology diagnostic test.

Therapy

In principle, the non-drug therapeutic measures are available to all asthma patients regardless of their severity. These include patient education, physical training, respiratory physiotherapy, tobacco cessation, psychosocial aspects, and body weight control. In addition, hyposensitization may be offered for allergic bronchial asthma.

Previous guideline-compliant therapy for mild bronchial asthma stage 1: For stage 1 therapy, demand therapy with SABA is/was recommended as the first preference; a low-dose inhaled steroid (ICS) as long-term therapy (Table 1) plus demand therapy with SABA is an alternative treatment option. Demand therapy with SABA alone should be used only in patients who rarely present with short-lasting daytime symptoms (less frequently than twice monthly), do not describe nocturnal symptoms, and demonstrate normal pulmonary function.

Previous guideline-compliant treatment of mild bronchial asthma stage 2: The first choice in stage 2 is or was treatment with a low-dose ICS as long-term therapy in combination with on-demand therapy with SABA. This usually involves patients who typically require as-needed inhalation more than twice a week. As an alternative, long-term therapy with a leukotriene receptor antagonist (LTRA) plus on-demand therapy with SABA may be considered. LTRAs are considered in adults primarily for patients who refuse or cannot tolerate ICS.

New insights into the drug treatment of mild asthma

For safety reasons, GINA no longer recommends that adult patients with bronchial asthma be treated with SABA alone, without inhaled steroids. This recommendation is based on the fact that treatment with SABA alone does not optimally protect patients from severe exacerbations. Five directional clinical studies are available for this purpose.

START reloaded: inhaled steroid as continuous therapy for rare symptomatology [9]: START was a randomized, multicenter trial that tested inhaled therapy with budesonide (400 µg, 1 daily) versus placebo in patients with persistent asthma. START reloaded conducted a post-hoc analysis at a later time point that examined treatment effects as a function of baseline symptomatology: patients with symptoms on 0-1 day/week, patients with symptoms on 1-2 days/week versus patients with symptoms on more than 2 days/week. It was shown that in all three study groups, continuous inhaled therapy with budesonide was beneficial compared with placebo: the time to the first severe event was longer, the risk of exacerbations was reduced, lung function was better, and symptoms were less severe. From the results of the study, it was concluded that inhaled steroid therapy should also be considered for patients with mild bronchial asthma with little symptomatology.

SYGMA 1: Combined inhaled demand therapy with budesonide and formoterol for mild asthma [10]: The prospective double-blind multicenter study evaluated three treatment arms over a 52-week study period in 3849 patients with mild asthma: twice-daily placebo + terbutaline as needed versus twice-daily placebo + budesonide/formoterol (Bud/Form) as needed versus twice-daily budesonide + terbutaline as needed. The primary endpoint of this study was asthma control. Adherence was supported by twice-daily reminders and was comparatively high at 79%. With respect to the primary endpoint of asthma control (percent weeks with controlled asthma), Bud/Form demand therapy was superior to demand therapy with terbutaline but inferior to continuous therapy with budesonide. The annual rate of severe exacerbations was significantly lower in the Bud/Form study group than in the terbutaline demand therapy study group and comparable to the budesonide continuous therapy study group. The change in FEV1 was greater with budesonide continuous therapy than with Bud/Form demand therapy, which in turn was greater than with terbutaline as demand therapy.

SYGMA 2: Combined inhaled demand therapy with budesonide and formoterol for mild asthma [11]: The results of SYGMA 2 appeared in the same issue of the New England Journal of Medicine as SYGMA 1. SYGMA 2 was also a prospective, double-blind, multicenter, 52-week study in which 4215 patients with mild bronchial asthma were randomized 1:1 to treatment with twice-daily placebo + budesonide/formoterol as demand therapy versus twice-daily budesonide + terbutaline as demand therapy. As with SYGMA 1, the Turbohaler was used as the device. Here it had no memory of regular inhalation. The primary endpoint was the annual rate of severe exacerbations, for which superiority was initially to be shown, and non-inferiority later in the study, for demand therapy with budesonide/formoterol. Therapy with budesonide/formoterol as demand therapy (annual exacerbation rate 0.11) was noninferior to continuous therapy with budesonide + terbutaline demand therapy (annual exacerbation rate 0.12) with respect to the primary end point. Regarding the symptomatology, which was examined by means of the Asthma Control Questionnaire (ACQ test), there was a statistically significant, but clinically not relevant difference (ACQ difference <0.5 points). FEV1, on the other hand, improved more significantly with continuous budesonide therapy (difference 32.6 ml). Adherence to therapy was lower than in SYGMA 1, with 64% of placebo doses in the budesonide/formoterol requirement group and 63% in the budesonide continuous therapy group.

PRACTICAL: Combined inhaled demand therapy with budesonide and formoterol for mild to moderate asthma, open-label study design [12]: PRACTICAL is an open-label, prospective randomized, multicenter study from New Zealand that, similar to SYGMA 2, compared demand therapy with budesonide/formoterol to budesonide continuous therapy + terbutaline demand therapy in 890 patients with mild to moderate asthma. The primary endpoint was the rate of severe exacerbations. Adherence was relatively high at 76%. In this study, the rate of annual severe exacerbations was significantly lower in the Bud/Form demand therapy study group than in the budesonide continuous therapy study group. ACQ-5 and FEV1 were comparable.

NOVEL START: Combined inhaled demand therapy with budesonide and formoterol for mild to moderate asthma, open-label study design [13]: NOVEL-START is also an open-label, prospective randomized, multicenter study that enrolled 668 patients with mild to moderate asthma in New Zealand, the United Kingdom of England, Italy, and Australia. Tested similar to SYGMA 1 was treatment with SABA as-needed therapy with albuterol versus bud/form as-needed therapy and budesonide as continuous therapy + albuterol as needed. The primary endpoint was the rate of exacerbations. Adherence was low at 56%. The annual rate of exacerbations was significantly lower with Form/Bud demand therapy than with SABA demand therapy and comparable with budesonide continuous therapy. The number of severe exacerbations was even lower with form/bud as-needed therapy than with budesonide continuous therapy. The ACQ-5 scores also showed statistically significant but not clinically relevant difference here. FEV1 differences before and after therapy were not different between study arms in this study.

In the 4 clinical trials described for demand therapy with budesonide/formoterol, comparative dosages were used: in budesonide continuous therapy, budesonide 400 µg/day was used; for budesonide/formoterol demand therapy, the dosage 200/6 µg was used when needed. The device chosen for ICS-containing therapy was the turbohaler.

New therapy options for stage 1 and stage 2

The GINA recommendations already incorporate the new evidence and no longer see a treatment option for exclusive SABA requirement therapy (Table 2). Two so-called tracks are now described, with track 1 being characterized by the fact that it does not provide for demand therapy with SABA: for both track 1 and track 2, demand therapy of the fixed combination with ICS/LABA is recommended. Track 2 provides for an as-needed therapy with SABA for stage 1; if there is a need, an ICS should also be taken. Stage 2 includes recommendation of long-term therapy with a low-dose ICS in combination + SABA demand therapy.

When prescribing, however, it should be noted that the fixed combination ICS/LABA as an as-needed therapy as well as the as-needed therapy with an inhaled steroid are not approved in this indication and thus an off-label use exists. There is an urgent need for clarification here, both for the patient and for the prescriber. It remains to be seen whether and how the planned guideline of the European Respiratory Society (ERS; “ERS Guideline on ICS/formoterol on demand”) will comment on this.

Evaluation of bronchial asthma

It should be checked at regular intervals, usually after 3 months, whether asthma control is present and/or whether therapy adjustment (intensification or de-escalation) is required. For this purpose, it is recommended to assess the risk of exacerbation in addition to the analysis of the symptomatology (Tab. 3). The medical history can be supported by standardized questionnaires such as the Asthma Control Test (ACT) or Asthma Control Questionnaire (ACQ-5). At the same time, it is recommended to evaluate comorbidities as well as relevant treatment aspects.

The goal of asthma therapy is to maintain asthma control with the lowest possible number of antiasthmatics at the lowest possible dose. Therapy goals are:

• Avoidance of exacerbations
• Avoidance of disease-related impairment of physical and social activities in everyday life
• Avoidance of complications and consequential damage
• Avoidance of undesirable side effects of the therapy
• Normalization of lung function and reduction of bronchial hyperresponsiveness.
• Improvement of health- and asthma-related quality of life
• Reduction of asthma-related lethality

Early detection of asthma

In the case of early detection, a diagnosis brought forward in time should make it possible to identify forms of the disease that are treatable with a greater chance of success. To this end, it is implicitly assumed that without treatment, the disease would evolve over time into forms with a worse prognosis [14]. Studies on a possible approach, the optimal test selection and the therapeutic as well as economic effect of early detection of asthma are limited so far. A study in Denmark tested the combination of a questionnaire in the first stage and a medical history in combination with spirometry and, if necessary, a provocation test in the second stage in 10 877 study participants. There were 493 study participants identified with bronchial asthma, with a new diagnosis in 249 study participants. This represents 2.3% of the original 10,877 people contacted. 47% of participants with newly diagnosed asthma had mild asthma, and 53% had moderate to severe asthma [15].

A Canadian study asked 12,117 people about respiratory symptoms in the first step after random selection using a standardized question. For individuals with complaints, a medical history was obtained by telephone interview. After exclusion of individuals with known lung disease and other defined comorbidities, the remaining 1706 participants were screened by asthma screening questionnaire and spirometry. Bronchial asthma was diagnosed in 73 participants, or 0.6% of those initially contacted. 35 participants or 48% had mild asthma [16].

For children, there is a position paper from the American Thoracic Society that screening cannot currently be recommended. While early detection in the adult general population does not seem to be effective either, screening of risk groups to be defined may be beneficial.

Bronchial asthma and chronic rhinosinusitis with nasal polyps

Patients with chronic rhinosinusitis represent a clinically relevant risk group for bronchial asthma. Chronic rhinosinusitis (CRS) can be distinguished between a form without (CRSsNP) or with nasal polyps (CRSwNP) [17]. CRSwNP affects approximately 1 in 5 patients with CRS, and the prevalence in the European population ranges from 2.1-4.4% [18]. CRSwNP is the variant that appears to have the greater significance in the context of bronchial asthma, as they are related pathophysiologically through the inflammatory profile of TH2 inflammation and clinically. A prospective multicenter case-control study from the United Kingdom assessed the incidence of bronchial asthma using a standardized questionnaire in patients undergoing treatment for rhinosinusitis: this was the case in 21% of patients with CRSsNP compared with 47% of patients with CRSwNP [19]. Comparable results are provided by a prospective American study that assessed patients with CRS using a standardized asthma questionnaire and pulmonary function test. Here, the prevalence of bronchial asthma was found to be 16% in CRSsNP and 48% in CRSwNP, respectively [20]. Systematic screening of patients with CRS, especially with nasal polyps, for the frequently accompanying bronchial asthma gives patients the chance for the earliest possible detection of bronchial asthma and optimal therapy of both diseases.

Take-Home Messages

• Mild asthma is not harmless.
• Clinical assessment and accurate pulmonary function diagnosis, including direct and/or indirect provocation testing when appropriate, are critical to the diagnosis of mild bronchial asthma.
• Short-acting beta-2 mimetics as demand therapy as sole therapy is inferior to demand therapy with budesonide+fomoterol (200 µg/6 µg) or continuous therapy with budesonide (400 µg/day) in preventing exacerbations.
• GINA no longer recommends a sole SABA requirement therapy. Demand therapy with budesonide + formoterol is preferred as a new treatment option for mild bronchial asthma for stage 1 and 2. Alternatively, if SABA is chosen as an as-needed therapy, it is recommended that an inhaled steroid be taken when SABA is used (Level 1) or continuous therapy with an inhaled steroid (Level 2). However, budesonide + formoterol as needed and an inhaled steroid as needed have not yet been approved in Europe.

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HAUSARZT PRAXIS 2022; 17(1): 10-15

Stefanie Keymel, MD