Bronchial asthma (overview) J45.9

Variable, intermittent, fully or partially reversible airway obstruction due to airway inflammation and hyperresponsiveness. Clinically, bronchial asthma is characterised by attacks of dyspnoea due to bronchoconstriction. Status asthmaticus is defined as a severe asthma attack refractory to therapy for at least 24 hours.

Note: Asthma is a clinical diagnosis that can only be made by reviewing all the findings. The careful taking of anamnesis is the most important pillar of asthma diagnostics.

Pathogenetically, bronchial asthma is divided into 2 forms, which have different prognostic and therapeutic significance.

Exogenous-allergic ast hma (extrinsic asthma or allergic bronchial asthma with a clear allergic connection - early onset asthma).

Non-allergic ast hma (intrinsic or - adult/late onset asthma).

• In non-allergic bronchial asthma, a distinction is made between:
• Infection-induced asthma (in infants and young children, there is often an infection-induced, possibly recurrent, obstructive ventilation disorder, which may subside during the first years of life).
• Drug-induced (e.g., analgesic-induced asthma = analgesic-asthma syndrome.
• Toxin- or chemical-induced (irritant) asthma
• Exercise-induced asthma
• Late-onset asthma (first manifestation in adults, women preferentially affected)
• Asthma with obesity

Remark: Mixed forms are possible, e.g. in an initially allergic asthma the intrinsic, non-allergic component may dominate the clinical symptoms in the course of the disease.

The classical classification of bronchial asthma has been extended in recent years to include a third phenotype:

Eosinophilic asthma (German Medical Association 2020).

Together with allergic asthma, it belongs to the group of type 2- (T2) high- asthma (Bundesärztekammer 2020).

In type- 2- high- asthma, Th- 2- lymphocytes are found associated with certain cytokines such as IL- 4, IL- 5, IL- 13 (Renner 2021).

The differentiation between allergic and eosinophilic asthma is of particular therapeutic importance, as eosinophilic asthma often results in an inadequate response to inhaled glucocorticoids and long-acting beta-2- agonists (LABAs) and monoclonal antibodies are indicated instead (Girndt 2022). For more details see below " Internal therapy".

As therapeutic interventions in asthma have recently expanded, a broader differentiation of the individual forms of asthma has become necessary. Currently, a distinction is made between:

1. type 2- high- asthma

These include eosinophilic asthma and allergic asthma (Renner 2021). Type- 2- (T2) high- asthma is defined according to UKSAR (UK Severe Asthma Registry) as:

- FeNO ≥ 25 ppb

plus

- Eosinophils in blood ≥ 150 / µl (Lommatzsch 2021).

2. type 2- low- asthma

This includes, for example, asthma with increased neutrophilic inflammation and asthma in obesity (Renner 2021.

Type- 2- low- asthma is defined by UKSAR as:

- FeNO < 25 ppb

plus

- Eosinophils in the blood < 150 / µl (Lommatzsch 2021).

Prevalence: 5% of adults. Up to 10% of children. The prevalence has increased significantly in recent decades, but seems to have reached a plateau. In Germany the lifetime prevalence of asthma is 8.6% (Langen U et al. 2013); m:w=2:1

In childhood, bronchial asthma is the most common chronic disease of all.

Asthma is also a common cause of chronic breathing problems in older patients. About 15% of the population suffer from unspecific bronchial hypersensitivity.

> 80% of all patients with allergic asthma also suffer from allergic rhinitis.

Pathogenesis: The cause of the non-specific hypersensitivity of the airways, which is present in all forms of extrinsic as well as intrinsic asthma, is largely unexplained. The sometimes very different triggers cause a release of inflammatory mediators from mast cells with a typical cytokine pattern, with basophilic and eosinophilic leukocytes and macrophages. These induce epithelial damage of the mucosa, contraction of the bronchial muscles, mucous membrane edema and a secretion of tough mucus.

Triggering (or co-triggering) factors that may induce asthmatic reactions:

• Allergens: pollen, house dust, animal epithelia, nutritive allergens
• Drug-induced: NSAR (aspirin) triggered (so-called pseudoallergic) intrinsic asthma
• Chemical stimuli: Smoke and dust; Chemicals
• Situational factors: whereabouts, activities (e.g. workplace, hobbies);
• Physical stress (exercise induced asthma)
• Infections: Viral, bacterial and mycotic infections can induce an asthma attack in both extrinsic and intrinsic asthma.

Other factors: Temperature influences such as cold, psychological stress.

Genetic factors:

• People with polymorphisms in the ORMDL3 gene have a 70% increased risk of developing bronchial asthma.
• Allergic disposition: positive family history (if both parents have bronchial asthma, children have a 60-80% risk of developing it). In the presence of other IgE-mediated atopic diseases (e.g. allergic rhinitis) an increased disposition to develop allergic asthma is present.

The pathophysiology of bronchial asthma is heterogeneous and far from being fully understood (Nelson 2020).

In eosinophilic asthma, in addition to an increase in eosinophils, abnormal production and release of T- cells such as T- helper type 2 lymphocytes (Th2) and innate lymphoid type 2 cells such as IL- 5 are found (Bakakas 2019 / Gonzalez 2019).

Eosinophil activation, differentiation, and survival are regulated by cytokine IL- 5. IL- 5 sits on the surface of eosinophils and basophils and binds to the IL- 5 receptor (IL- 5R). IL- 5 plays a critical role in the pathogenesis of severe asthma. (Gonzalez 2019).

Allergic asthma predominantly begins in childhood. The average age of first manifestation of non-allergic asthma is > 40 years.

The diagnosis "asthma" is a clinical diagnosis. It is based on characteristic complaints and symptoms and evidence of airway obstruction and/or bronchial hyperreactivity. Phases of complete freedom from symptoms may alternate with phases of varying degrees of severity. Characteristic is the repeated occurrence of seizure-like, often nocturnal shortness of breath and/or chest tightness and/or coughing with or without sputum. Such attacks can occur at any time without prior notice and can be life-threatening.

Medical history: The symptoms may be continuous or intermittent, e.g. localised, e.g. at the workplace, or event-related, e.g. animal contact, or seasonal, e.g. pollen count.

Auscultatory: Dry background noises (wheezing, whistling, humming) during auscultation, possibly to be provoked by forced expiration; prolonged expiration. In case of severe obstruction with pulmonary hyperinflation or pronounced emphysema often very quiet breathing sounds (silent lung). During the seizure, the patient sits upright and breathes with the aid of the respiratory muscles

In case of severe respiratory distress (especially in children): thoracic retractions (especially jugulum, intercostal, epigastric). If the patient becomes exhausted, possibly respiratory alternans (alternation between thoracic and abdominal breathing)

Proof of the signs of airway obstruction may be missing in the symptom-free interval.

Chronic cough without asthma (as asthma equivalent) may be an indication of bronchial asthma.

Tachycardia: possible pulsus paradoxus (inspiratory blood pressure drop >10mmHg)

Staging of the airway obstruction

• Stage I (mild): Low dyspnoea, diffuse gushing
• Stage II (moderate): dyspnea at rest, use of accessory respiratory muscles, loud gushing, normal or restricted gausal exchange
• Stage III (severe): severe dyspnoea, cyanosis, use of accessory respiratory muscles, gulling or absence of breathing sounds (silent lung), pulsus paradoxus (with the over-inflation of the lungs, at a capacity of <1.25 l per second, a drop in systolic blood pressure during inspiration runs parallel; RR expiratory 10 mm Hg higher than inspiratory). Gaussian exchange significantly restricted.
• Stage IV (acutely life-threatening): severe dyspnoea, cyanosis, lethargy, confusion, pulsus paradoxus (drop in systolic blood pressure during inspiration >30-50mm Hg).

Typically, eosinophilic asthma is found to have:

- ≥ 300 eosinophils / µl blood (Herold 2022).

- Eosinophils in sputum > 2 % (Bakakas 2019 / Renner 2021))

- Th2- cytokines IL- 4, IL 5 and IL 13 increased (Stockert 2020).

Pulmonary function:

In eosinophilic asthma, fraction expiratory nitric oxide (FeNO) levels are typically > 50 ppb (Bakakas 2019)

Detailed medical history (Smoker history - 39.2% of patients with asthma in Europe smoke)

Proof of variable and/or stress-induced airway obstruction by a pulmonary function test (Lufu)

Increased exhalation of nitrogen monoxide: increased fraction of exhaled NO, FeNO, measured in parts per billion (>/- 20ppb)

Lufu: FEV1, FEV1/VC, PEF decreased, increased airway resistance, improved after inhalation of a beta-sympathomimetic (broncholysis test). Methacholine test to detect bronchial hyperreactivity.

Allergological stepwise diagnosis (prick test, specific IgE in serum, eosinophilic granulocytes and ECP in blood and sputum increased, see below). Asthma extrinsic.

ECG: Signs of right heart strain

Lab. Blood count (eosinophilic granulocytes in blood and sputum elevated), BSG (CRP). Sputum analysis

Atypical pneumonia (protracted course)

Pulmonary artery embolism

Heart failure/cardiovascular diseases (lung congestion)/coronary heart disease

Aspiration, e.g. foreign bodies

Neuromuscular diseases (respiratory pump disorders)

Postinfectious disorders (e.g. pertussis, bronchiolitis obliterans)

Bronchiectasis

Psychosomatic respiratory disorders (psychogenic hyperventilation,

vocal cord dysfunction)

Chronic persistent cough of other etiology

Spontaneous pneumothorax

Chronic obstructive bronchitis with/without emphysema (COPD)

Trachobronchomalacia

Diffuse parenchymatous lung diseases (including exogenous allergic alveolitis, sarcoidosis) Tuberculosis

gastroesophageal reflux

Cystic fibrosis (cystic fibrosis)

Therapy goals of asthma management:

The goal of any asthma therapy is "asthma control", which means maximum freedom from symptoms. The aim is to achieve or maintain the status of controlled asthma. By assessing the degree of control, the respective therapy goal is defined at the same time.

Note: Every patient should receive a written therapy plan (with emergency plan and the necessary emergency medication) as well as asthma training.

The following therapy goals should be aimed for depending on the patient's age and concomitant diseases (GINA):

• Normalization or achievement of the best possible lung function and reduction of bronchial hyperresponsiveness;
• Improvement of health- and asthma-related quality of life;
• Reduction of asthma-related lethality.

For better comparability, 3 degrees of asthma control are distinguished. This therapeutic state should be controlled 3-monthly (O'Byne PM et al. 2010):

• Controlled asthma
• Partially controlled asthma
• Uncontrolled asthma

To assess asthma control, 4 questions are sufficient. In the last 4 weeks, did the patient have:

• Grades of asthma control
  • >2x/week daytime symptoms
  • Nighttime awakenings due to asthma
  • Use of on-demand medication for symptoms >2x/week.
  • Activity limitation due to asthma
• Additional criteria (risk of future worsening).
  • Lung function limitation (airway obstruction)
  • Occurrence of exacerbations

(Assessment: Well controlled =no criterion met, partially controlled =1-2criteria met, uncotrolled =3-4criteria met).

Treatment of eosinophilic asthma is according to the guideline of 5-step therapy for adults. However, since 2016, additional monoclonal antibodies are available (Buhl 2017).

If the trigger mechanism of the asthma attack can be blocked by medication, drug therapy is indicated. The most important antiasthmatics are available for inhaled administration.

Note: If several dosage forms of an agent are available, inhaled administration should be preferred.

The drugs are divided into:

• as-needed therapeutics for rapid symptomatic therapy
• and
• Long-term therapeutics

Demand therapeutics for rapid symptomatic therapy:

• SABA=Short acting beta-2-agonist: rapid acting beta-2 sympathomimetics. These include: fenoterol, salbutamol, terbutaline, and the protracted-acting formoterol.
• Inhaled short-acting beta-2 sympathomimetic (SABA) plus anticholinergic as a fixed combination: fenoterol plus ipratropium.
• Theophylline (drops or solution = rapid release preparations).

Long-term therapeutics

• Inhaled corticosteroids (ICS= inhaled corticosteroid): Beclometasone, budesonide, fluticasone, etc.
• LABA = long acting beta-2 agonist: inhaled long acting beta-2 sympathomimetics. These include: formoterol, salmeterol.
• Leukotriene receptor antagonist (LTRA): Montelukast
• Combination ICS/LABA: formoterol/beclometasone, formoterol/budesonide, salmeterol/fluticasone. In long-term studies in a larger group of patients (n=4176), combination therapy was shown to significantly reduce the amount of inhaled glucocorticosteroids (Bateman 2018).

Other drugs (to be used only in justified cases): Systemic glucocorticosteroids.

Theophylline (sustained-release preparations).

Omalizumab: Anti-IgE treatment with the monoclonal antibody: omalizumab is an option in adults and children 6 years and older with severe persistent (IgE-mediated) allergic asthma.

Dupilumab: Therapy with the fully humanized anti-interleukin 4/13 receptor monoclonal antibody ar highly successful in a large RCT with significantly lower exacerbation rates and decreased glucocorticoid use (Castro et al. 2018).

SCIT: Strict indication, as its efficacy in asthma is uncertain based on current studies. SCIT is contraindicated in uncontrolled or severe asthma with FEV1 ≤ 70% of set point (in adults). SCIT can be considered in stable allergic asthma (FEV1 > 70 % in adults) as a therapeutic option besides allergen abstinence and pharmacotherapy.

Note: In principle, immunotherapy is not a substitute for effective antiasthmatic pharmacotherapy.

Note: Avoidance or elimination of a recognized etiologic noxious agent precedes any drug treatment.

Eosinophilic asthma

Corticosteroids

• Inhaled corticosteroids are used to treat asthma. However, severe eosinophilic asthma is characterized by corticosteroid resistance (Sada 2021).

Bronchodilators

Considered in this context are:

• - Beta- 2 sympathomimetics (short-acting = SABA or long-acting = LABA).
• SABA include e.g. salbutamol, fenoterol, LABA e.g. salmeterol, formoterol.

SABA and LABA:

- stimulate bronchial muscle relaxation via beta- 2 receptors

- suppress by release of mediator substances

- Increase mucociliary clearance in the bronchial system (Braun 2018).

For more details, see beta- 2 sympathomimetics.

Leukotriene receptor antagonists

These are biologically active metabolites of arachidonic acid that have bronchodilator and anti-inflammatory effects, among others (Krogel 1997). For more details see Leukotriene receptor antagonists.

Monoclonal antibodies

Monoclonal antibodies are a targeted therapy for severe eosinophilic asthma. The latter should have occurred by at least 2 times detection of > 300 eosinophils per µl blood in the past 2 years and outside of exacerbations (Bundesärztekammer 2020). It should be taken into account that systemic therapy with glucocorticoids has an influence on the number of eosinophil granulocytes (Buhl 2017). If the above-mentioned treatment with an inhaled corticosteroid, leukotriene receptor antagonist, short- or long-acting beta- 2 mimetic has proven to be refractory to therapy - which is not uncommon in eosinophilic asthma (Girndt 2022) - there is an indication for the administration of monoclonal antibodies such as mepolizumab or reslizumab (Herold 2022) or benralizumab (Bundesärztekammer 2020).

These antibodies lead to a reduction in exacerbations and improvement in lung function (Bakakas 2019).

- Mepolizumab:

Trade name: Nucala

It is a humanized monoclonal IgG1- Kappa- antibody that reduces eosinophils in the blood (Aktoris 2022). It blocks interleukin- 4 and interleukin- 13 (Bakakas 2019), thereby inducing apoptosis of granulocytes (Aktoris 2022).

- Dosage recommendation: 100 mg s. c. 1 x monthly (Vogelmeier 2022).

- Reslizumab:

Trade name: Cinqaero (Schwabe 2018).

This is a monoclonal anti- IL- 5- IgG4- antibody that binds to the alpha subunit of the cytokine IL- 5 (Bakakas 2019). It leads to a reduction in eosinophils and inflammation (Aktoris 2022).

- Dosage recommendation: 3 mg / kg bw as i. v. infusion 1 x monthly (Buhl 2017).

- Benralizumab:

Trade name: Fasenra (Aktoris 2022).

This is a chimeric monoclonal IgG1- kappa antibody (Aktoris 2022). It targets the IL- 5Alpha- receptor and results in almost complete depletion of eosinophils in the blood (Bakakas 2019).

- Dosage recommendation: 30 mg s.c. every 4 weeks, after 3 times administration extend the injection interval to 8 weeks with the same dose (Vogelmeier 2022).

Therapy with monoclonal antibodies should be given for at least 4 months (Bundesärztekammer 2020).

Parallel to the treatment with monoclonal antibodies, the previous inhaled or oral asthma treatment should be maintained for at least 4 weeks (Buhl 2017). The dose of corticosteroids can usually always be reduced during therapy with monoclonal antibodies (Schulte Strathaus 2018).

Strategies to control symptoms and avoid risk factors (see also bronchial asthma and prevention)

• Patient training for all patients (especially children and adolescents and their families) with learning strategies for symptom control and risk reduction. The aim is to enable good clinical asthma control by monitoring the symptoms (peak flow measurements), by learning physiotherapeutic measures, and by learning adequately adapted treatment modalities (therapy plan, learning inhalation techniques).

• The majority of patients with asthma can achieve good asthma control by the use of highly effective inhalants alone. This requires the selection of a suitable inhaler and careful training in inhalation techniques. More than 20% of patients make critical inhalation errors and must therefore be considered "untreated". Metered dose inhalers or the Respimat require the patient to be able to coordinate the release of the drug with breathing. Powder inhalations, on the other hand, require sufficient suction power to release the drug from the inhaler. In metered dose inhalers, the additional use of spacers can improve bronchial deposition, so that their use should be considered for severe forms of the disease.

• Creation of an individual asthma action plan

• Rehabilitation measures

• In case of allergic asthma: avoidance strategies by avoiding allergens as far as possible.

• Important: elimination of a humid indoor climate and mould
• Physical exercise: Physical exercise can help to reduce asthma symptoms, improve exercise capacity and improve quality of life/reduce morbidity (e.g. school sports, participation in lung sports groups).
• Respiratory physiotherapy: learning of techniques of physiotherapeutic respiratory therapy. The aim is to reduce shortness of breath, coughing and anxiety and to improve self-management and quality of life.
• Tobacco cessation: It is undisputed that smoking makes asthma worse. This also affects passive smoking patients. Abstinence from tobacco is strongly recommended.
• Psychosocial aspects: Psychosocial impairments due to disease-related disabilities in private and professional life are common among asthma patients. Thus, the elimination of disturbing factors can positively influence the acceptance of the diagnosis and the acceptance of the necessary therapeutic measures.
• Body weight control: Weight reduction should be recommended for obese asthma patients.

SIT is recommended as a therapy for mild bronchial allergic asthma (grade 1-2).

Further details see below:

• Bronchial asthma and prevention
• Bronchial asthma and pregnancy
• Bronchial asthma and comorbidities

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