Pathogenesis (development of disease)
Asthma is mainly a disease of the bronchi – the airways that connect the trachea to the lungs. The bronchi are surrounded by smooth muscle tissue. Furthermore, the bronchial walls contain mucus-producing glands and cells of the immune system such as mast cells, lymphocytes and eosinophilic granulocytes. When these are activated, they produce inflammatory mediators – chemical “facilitators” – such as histamine and leukotrienes, which bind to receptors within the bronchi. During an asthma attack, a sequence of events occurs that results in the production of histamine and leukotrienes. Leukotrienes are produced from arachidonic acid. These inflammatory mediators cause changes in the bronchial tissues: a dramatic increase in mucus production and a simultaneous narrowing of the airways (bronchoobstruction/bronchial obstruction) results. In the following hours, “inflammatory cells” such as mast cells and eosinophilic granulocytes migrate into the affected area, small blood vessels become permeable to fluid, and tissue is directly damaged. This perpetuates the inflammatory process and mucosal edema (swelling of the mucosa due to fluid retention). The following respiratory system changes occur in bronchial asthma:
- Subacute inflammation maintained primarily by mast cells, eosinophilic granulocytes; these lead to a
- Bronchoconstriction (bronchoconstriction).
- Vascular dilatation (vasodilatation)
- Mucosal edema
- Impaired mucociliary clearance (ciliated epithelium no longer moves enough mucus toward the mouth and throat)
- Hypertrophic mucous glands (→ mucus).
All these changes lead to chronic airway inflammation associated with hyperresponsiveness (exaggerated airway responsiveness to an exogenous stimulus (e.g., cold air, inhalation toxins)) and seizure-like bronchial obstruction (“airway constriction”). The patient wheezes and coughs. Air is “trapped” in the small alveoli or the smaller bronchial branches. This allows less oxygen to be exchanged and possibly causes blood levels of carbon dioxide (pCO2) to rise and levels of oxygen (pO2) to fall. Oxygen consumption also increases due to the increased muscle work required to maintain adequate air exchange. The cause of bronchial hyperreactivity (an exaggerated readiness of the airways to react to an exogenous stimulus (e.g., cold air, inhalation toxins), which leads to a pathological narrowing of the airways (bronchoobstruction)) in asthmatics has not yet been fully scientifically clarified. However, the so-called T cells of the immune system seem to play a central role. In addition to genetics and epigenetics, the intestinal microbiome (gut flora) certainly plays a major role in the development of bronchial asthma. The two main phenotypes are allergic (extrinsic) and non-allergic (intrinsic) bronchial asthma. It has been demonstrated that allergic asthma is triggered by the hyperfunction of a protein – interleukin-33 (IL-33).When allergens such as mites, pollen or molds enter the airways, they release proteases (enzymes that can hydrolytically break down (digest) other enzymes, proteins and polypeptides). Upon contact with the proteases, IL 33 breaks down into overactive fragments that trigger chain reactions, which in turn are responsible for allergic symptoms. Other phenotyping forms refer to the patient’s dominant complaint: e.g. occupational asthma, analgesic, exercise-induced asthma, nocturnal, cough-induced asthma, cold-induced asthma, late-onset asthma, reflux-induced asthma. Allergic asthma versus non-allergic asthma.
| Allergic asthma (extrinsic asthma) | Non-allergic asthma (intrinsic asthma) | |
| Onset of disease | Childhood: maximum 8-12 years of age. | Middle age (> 40 years) |
| Frequency | 50-70 % | 30-50 % |
| Trigger | Allergens
|
Nonspecific triggers (trigger factors).
|
| Pathogenesis | Sensitization → IgE-mediated inflammatory responses. | No sensitization; IgE independent, i.e., nonspecific inflammatory responses |
Note: The distinction between allergic and nonallergic (intrinsic) asthma is of therapeutic importance because specific therapeutic options may arise in allergic asthma, such as specific immunotherapy (SIT), allergen restriction, or treatment with biologics.
Etiology (causes)
Biographic causes
- Genetic burden – In allergic bronchial asthma, there is a genetically determined propensity to produce IgE antibodies to common environmental allergens; there is undoubted familial clustering. One parent with allergic asthma bronchiale implies a risk of about 40% for the offspring. If both parents have the disease, the risk for the children is about 60-80 %. The risk is also increased if allergic rhinitis (hay fever) or allergic exanthema (skin rash) has already occurred in the family.
- Genetic risk dependent on gene polymorphisms:
- Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
- Genes: GSDMB, GSTP1
- SNP: rs7216389 in the gene GSDMB
- Allele constellation: TT (1.5-fold).
- SNP: rs1695 in the gene GSTP1
- Allele constellation: AG (increased risk of allergic asthma).
- Allele constellation: GG (greatly increased risk of allergic asthma; 3.5-fold increased risk of developing an allergic form compared with the nonallergic form)
- Mutations in chromosome 17q21 – in children in such cases, the risk of developing asthma within the first four years of life is significantly increased; the risk of disease is even much greater if such children grow up in a household with smokers.
- Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
- Genetic risk dependent on gene polymorphisms:
- Mother: higher maternal intake of free sugars during pregnancy may increase the risk of atopy and atopic asthma in offspring.
- Delivery by caesarean section (cesarean section; 23% increase in risk).
- Low birth weight (< 2,500 g).
- Hormonal factors – early menarche (first appearance of menstruation).
- Occupations – occupations with high exposure to dust, fumes or solvents, as well as thermal stress (occupational asthma) [should be considered, as far as possible, already in the choice of occupation].
- Bakery, confectionery (flour dust).
- Gardener (pollen)
- Woodworking: carpenters, joiners (wood dust).
- Beekeeping, weaving (insect dust)
- Agriculture (animal hair)
- Painting, varnishing
- Pharmaceutical industry (drug dust)
- Hot processing of plastics (isocyonates).
- Detergent industry (enzymes)
- U . v. m.
- Socioeconomic factors – low household income and lack of education.
Behavioral causes
- Nutrition
- High intake of fat, sugar, and salt; high prevalence (disease incidence) of severe bronchial asthma
- Micronutrient deficiency (vital substances) – see prevention with micronutrients.
- Consumption of stimulants
- Tobacco (smoking)
- A link between smoking and asthma can be demonstrated in more than 70 percent of asthma patients! Children of smoking parents also have a greatly increased risk of asthma.
- Maternal smoking (at least 5 cigarettes per day) throughout pregnancy is associated with an increased risk of early and persistent wheezing (OR 1.24) and bronchial asthma (OR 1.65) for the child.
- Tobacco (smoking)
- Physical activity
- Physical exertion – If an asthma attack occurs approximately five minutes after the completion of physical exertion or during exercise, the condition is referred to as exercise-induced asthma (“EIA”; DD exertion-induced bronchoconstriction).
- Psycho-social situation
- Stress – it is undisputed that emotional factors significantly influence the course of the disease.
- Overweight (BMI ≥ 25; obesity).
- Overweight individuals have a threefold higher risk of developing bronchial asthma. Obesity can activate a gene in the lungs that can control inflammation in the lungs.
- Children with consistently high BMI into school age were most often diagnosed with bronchial asthma:
- Age and sex adjusted odds ratio (aOR): 2.9.
- Allergic asthma aOR: 4.7
- Obesity increased the risk of asthma by 26% (RR 1.26; 1.18-1.34). Obese children developed bronchial asthma confirmed by spirometry (lung function testing) in 29% (RR: 1.29; 1.16-1.42).
Disease-related causes
- Respiratory infections Infection-related bronchial asthma (infectious asthma) first occurs after a bronchopulmonary infection. Both viral (e.g., rhinoviruses) and bacterial respiratory infections are considered possible triggers.
- Febrile seizures in children
- Gastroesophageal reflux disease (synonyms: GERD, gastroesophageal reflux disease; gastroesophageal reflux disease (GERD); gastroesophageal reflux disease (reflux disease); gastroesophageal reflux; reflux esophagitis; reflux disease; Reflux esophagitis; peptic esophagitis) – inflammatory disease of the esophagus (esophagitis) caused by the pathological reflux (reflux) of acid gastric juice and other gastric contents.
Medication
- Antidepressants – the use of older antidepressants in pregnancy was associated with an increased risk of asthma
- Asthma can also be triggered by the use of analgesics (painkillers) – analgesic-induced bronchial asthma (analgesic asthma). These include, for example. Acetylsalicylic acid (ASA; aspirin-intolerant asthma (“aspirin-exacerbated airway disease: AERD”); prevalence (disease frequency): 5.5-12.4% of asthma patients) and non-steroidal anti-inflammatory drugs (NSAID; NSAID-exacerbated respiratory disease (NERD)), which interfere with prostaglandin metabolism. This is a genetically determined pseudoallergic reaction.
- Paracetamol
- Regarding paracetamol exposure, the Norwegian Mother and Child Cohort Study demonstrated that in:
- Paracetamol intake before pregnancy, there was no association with the risk of asthma in the child.
- Prenatal exposure, the adjusted asthma rate was 13% higher in three-year-olds and 27% higher in seven-year-olds than in unexposed children.
- Exclusive exposure during the first six months of life, the adjusted asthma rate was 29% higher in three-year-olds and 24% higher in seven-year-olds.
- A British-Swedish research team considers the association between the use of certain analgesics during pregnancy and a predisposition of the child to asthma as proven, but not causal. According to these authors, the association can probably be attributed to maternal influences such as anxiety, stress or chronic pain.
- Paracetamol (acetaminophen): children who received paracetamol in the first years of life are more likely to develop bronchial asthma and allergic rhinitis later.
- The AVICA (Acetaminophen versus Ibuprofen in Children with Asthma) study examined the effects of therapy in children aged 1 to 5 years with mild persistent asthma in terms of the number of asthma exacerbations (marked worsening of the clinical picture). Results: acetaminophen group averaged 0.81 and ibuprofen group 0.87 exacerbations (no significant difference).
- A mutation in the GSTP1 gene was now associated with an increased risk of asthma disease (odds ratio 1.77; 1.09-2.85) and asthma-like symptoms (odds ratio 1.74; 1.14-2.64). The gene contains information for the enzyme glutathione S-transferase (GST), which forms the antioxidant glutathione in the liver. Glutathione is consumed during the degradation of paracetamol.Thus, a lack of paracetamol leads to increased toxicity.
- Regarding paracetamol exposure, the Norwegian Mother and Child Cohort Study demonstrated that in:
- Beta blockers can also trigger asthma attacks!
- H2 receptor antagonists/proton pump inhibitors (proton pump inhibitors, PPI; acid blockers) – taken during pregnancy for heartburn increases children’s risk by 40% (H2 receptor antagonists) or 30% (proton pump inhibitors) of developing bronchial asthma in the first years of life. Note: Pantoprazole and rabeprazole are contraindicated in pregnancy, and omeprazole should be used only after careful risk-benefit consideration, according to the guidelines.
Environmental exposure – intoxications (poisonings).
- Allergens in allergic bronchial asthma (allergic asthma). These include:
- Inhalant allergens:
- Plant dust (pollen)
- Animal allergens (house dust mite droppings, animal hair, feathers): most common causes of perennial (“year-round”) allergic asthma are house dust mite allergy and animal hair allergy
- Mold spores
- Food Allergens
- Occupational allergens (see below)
- Inhalant allergens:
- Occupational exposure (occupational allergens): in some occupational groups, asthma occurs more frequently due to frequent contact with allergenic, irritant or toxic (poisonous) substances. These are e.g. metal salts – platinum, chromium, nickel -, wood and plant dusts, industrial chemicals. Also known is the so-called baker’s asthma, fungal asthma and also people who work with isocyanates often suffer from asthma.
- Air pollutants: staying in an air and polluted environment (exhaust fumes, particulate matter, nitrous gases, smog, ozone, tobacco smoke).
- Hazard ratio of 1.05 (1.03 to 1.07) for each 5 µg/m3 increase in particulate matter (PM2.5) concentration and of 1.04 (1.03 to 1.04) for a corresponding increase in PM10 concentration
- Damp walls (mold; during the first year of life).
- Thunderstorm asthma (Melbourne thunderstorms) – interaction of meteorological and genetic conditions and high concentrations of allergens in the air we breathe; most common late in spring and summer when high concentrations of airborne pollen occur
- Phthalates (mainly as plasticizers for soft PVC) – could lead to permanent epigenetic changes in the genome of the child, which later promote the development of allergic asthma.Note: Phthalates belong to the endocrine disruptors (synonym: xenohormones), which even in the smallest amounts can damage health by altering the hormonal system.
- Cold air and fog
- Repeated exposure to the triggering allergens (e.g., chlorinated water in swimming pools) – e.g., baby swimming Chlorinated water in swimming pools increases the risk of allergic rhinitis (hay fever) and, if predisposed, may increase the frequency of attacks of bronchial asthma. The reason for this is probably that chlorine compounds damage the barrier of the lung epithelium, making it easier for allergens to penetrate. Since 1980, the water in swimming pools may contain a maximum of 0.3 to 0.6 mg / l free and 0.2 mg / l combined chlorine at a pH between 6.5 and 7.6 according to DIN standards.
- Household sprays – clear dose-response relationship: in individuals who used household sprays at least once a week, the risk of asthma was half that of participants who refrained from doing so; four times a week use of household sprays already led to a doubling of the risk of asthma!
- Cleaning products in the first years of life, especially if they contained fragrances: more often asthma-like respiratory symptoms (“wheezing”) and more often was diagnosed with asthma disease (versus households with a sparing use).
