DEFINING ASTHMA

The Global Initiative for Asthma (GINA, 2021) provides a clinical definition of asthma, describing it as a heterogeneous disease (a condition that has several etiologies) usually characterized by chronic airway inflammation. Asthma is defined by the history of such respiratory symptoms as:

Wheezing
Shortness of breath
A feeling of tightness in the chest
Cough that varies over time and in intensity
Variable expiratory airflow limitation

These symptoms and airflow limitations may resolve by themselves or in response to medication, and may be absent sometimes for weeks or months at a time. For other individuals, however, episodic flare-ups of asthma may be life threatening.

Asthma Phenotypes and Endotypes

A disease phenotype describes clinically observable characteristics of a disease without direct relationship to an underlying pathophysiology. Endotypes, however, describe subtypes of a disease defined by an intrinsically distinct pathogenetic mechanism; they refer to specific cells or molecules in blood or sputum.

ALLERGIC (EXTRINSIC) ASTHMA

Allergic (extrinsic) asthma is the result of antigen/antibody reaction in the respiratory tract, causing release of inflammatory mediators from mast cells which elicits the clinical response associated with an asthma attack. This is the most recognizable phenotype. It most often begins in childhood and is associated with a past and/or a family history of allergic diseases (e.g., eczema). Common allergies may include, but are not limited to:

Tobacco smoke
Animal dander (cats, birds, dogs)
Dust mites
Cockroaches
Molds
Pollens
(GINA, 2021)

NONALLERGIC (INTRINSIC) ASTHMA

Nonallergic (intrinsic) asthma is the result of neurological imbalances in the autonomic nervous system in which alpha and beta adrenergic as well as cholinergic sites of the system are not properly coordinated. The autonomic nervous system plays an important role in asthma, primarily through the parasympathetic pathway, promoting bronchoconstriction. The airways of people with nonallergic asthma respond to such factors as:

Cold or dry air
Heat and humidity
Fragrances
Stress
Anxiety
Strenuous exercise
Hormonal changes

In addition, any factor that diminishes oxygen availability can also play a part in intrinsic asthma. These may include:

Anemia
Dehydration
Tissue alkalosis
Neuromuscular disease (thoracic cage, diaphragm, and accessory muscles)

Patients with nonallergic asthma often demonstrate less short-term responses to inhaled corticosteroids (GINA, 2021).

Occupational Asthma

Occupational asthma is a type of intrinsic asthma caused by exposure to inhaled irritants in the workplace. It is often a reversible condition, meaning that symptoms may disappear when the irritants that caused the asthma are avoided. However, permanent damage can result if the person experiences prolonged exposure. Examples of workplace irritants include:

Animal substances, such as proteins found in dander, hair, scales, fur, saliva, and body wastes
Chemicals used to make paints, varnishes, adhesives, laminates, soldering resin, insulation, packaging materials, foam mattresses, and upholstery
Enzymes used in detergents and flour conditioners
Metals, particularly platinum, chromium, and nickel sulfate
Plant substances, including proteins found in natural rubber latex, flour, cereals, cotton, flax, hemp, rye, wheat, and papain (digestive enzyme derived from papaya)
Respiratory irritants, such as chlorine gas, sulfur dioxide, and smoke

Specific symptoms of occupational asthma include airway irritation, obstruction, and inflammation, worsening after arriving at work and improving on weekends or during extended periods away from work (Johns Hopkins Medicine, 2021; Mayo Clinic, 2020a).

Eosinophilic Asthma

Eosinophilic asthma, a nonallergic intrinsic endotype of the disease, is characterized by an increase in the number of eosinophils in the blood, lung tissue, and mucus in the respiratory tract. The entire respiratory tract is involved in airflow obstruction, from the sinuses to the small or distal airways.

Eosinophils release a number of different mediators with the capacity to cause airway hyperresponsiveness and are major effectors of lung tissue damage in asthma, contributing to airway remodeling. Early eosinophilia is an early feature of asthma exacerbations (also referred to as asthma attacks).

Eosinophilic asthma is rare and usually begins in adults ages 35–50. The symptoms are often severe and can be persistent. The medications used in the treatment of asthma do not have much effect on eosinophilic asthma, even at high doses (APFED, 2020).

Obesity-Associated Asthma

Obesity-associated asthma, a type of intrinsic asthma, occurs in both children and adults. Both asthma and obesity have a considerable hereditary component, and potential underlying mechanisms include a shared genetic complement, dietary and nutritional factors, alterations in the gut microbiome, systemic inflammation, metabolic abnormalities, and changes in lung anatomy and function.

Maternal obesity and weight gain during pregnancy are independently associated with an increased risk of asthma in their children. Excessive weight gain in infancy has also been linked to recurrent wheezing and asthma (Peters et al., 2018).

Aspirin-Exacerbated Respiratory Disease (AERD)

AERD is a distinct intrinsic eosinophilic phenotype of severe asthma consisting of three key features: asthma, nasal polyps, and severe respiratory symptoms that are exacerbated by aspirin, other nonsteroidal anti-inflammatory drugs, and beta blockers. This asthma phenotype is characterized by the initial symptoms of rhinosinusitis and then progresses to severe asthma symptoms.

AERD usually begins in young adulthood, although children can be affected, and may not include any other allergies (Comhair et al., 2018)

Cough-Variant Asthma

Asthma may present as an apparently nonspecific cough. When cough is the only asthma symptom, it is known as cough-variant asthma. In this type of asthma, the cough may come and go with the seasons, appear after an upper respiratory infection, or become worse when the person is exposed to cold air or certain chemicals or fragrances. Cough-variant asthma may cause coughing during the day or night, sometimes disrupting sleep.

Specific symptoms include a chronic, nonproductive cough with a sensitive cough reflex. In some children, chronic cough can be the most prominent presenting symptom of asthma. The cough is typically dry, and there is an absence of wheezing, exertional dyspnea, or atopy (genetic predisposition for allergies). It is possible for this form of asthma to progress to asthma with all of its other symptoms.

Most studies have indicated that asthma is an uncommon cause of cough in children, as some children show no benefit from treatment with beta agonists and steroids (Mayo Clinic, 2019; Marchant & Chang, 2020).

NOCTURNAL ASTHMA

Nocturnal asthma can be either intrinsic or extrinsic and is a characteristic feature of asthma that is not well-controlled in a patient with daytime asthma symptoms. Nocturnal asthma is associated with circadian patterns in which the best lung function occurs at around 4 p.m. and worst at around 4 a.m. It is also associated with more severe disease and increased mortality, with over 50% of asthma deaths occurring at night.

Nocturnal asthma is caused by:

Neurohormonal change
Lung function and bronchial hyperresponsiveness
Distal airway inflammation
Inhibition of the anti-inflammatory effect of glucocorticoids
Increased pulmonary capillary blood volume
Reduced beta-2 adrenoceptor function and gene function
Gastroesophageal reflux with aspiration
(Martin, 2021)

EXERCISE-INDUCED BRONCHOCONSTRICTION

Exercise-induced bronchoconstriction (EIB) was formerly referred to as exercise-induced asthma, wrongly suggesting that exercise causes asthma. EIB is a narrowing of the airways in the lungs triggered by strenuous exercise. EIB occurs in up to 90% of people with asthma and up to 20% of those without asthma. Elite athletes have an increased prevalence of up to 70%.

EIB is caused by an acute large increase in the amount of air entering the airways that requires heating and humidifying. This can result in inflammatory, neuronal, and vascular changes, ultimately leading to bronchoconstriction and symptoms of asthma.

EIB symptoms usually begin during exercise and become worse 5 to 10 minutes after stopping exercise. Symptoms most often resolve in another 20 to 30 minutes and can range from mild to severe. Occasionally, some individuals will experience a second wave or late phase of symptoms 4 to 12 hours after stopping exercise. These symptoms are frequently less severe and can take up to 24 hours to resolve (Physiopedia, 2021a).