In recent years, researchers have discovered that asthma is more than just one disease, and treatment is not one size fits all.
Tremendous progress has been made in understanding the causes and physiological effects of different types of asthma and the diverse approaches needed to treat them. Asthma is now considered a syndrome with different characteristics, or phenotypes.
A phenotype is a set of observable properties of an organism produced by the interaction between a person’s genetics and environment. The most exciting aspect of the growing knowledge regarding phenotypes is that knowing what causes asthma in one person as opposed to another provides the opportunity for more personalized, targeted treatment, including biologic therapy.
Biologic treatments used for asthma are made from antibodies, a protein that occurs naturally in our bodies. Biologics are designed to target and block parts of the immune system involved in asthma symptoms. Right now, biologics are available in Canada that target asthma with type 2 inflammation; allergic asthma and eosinophilic asthma.
Many multi-centred studies have worked to define the most common phenotypes, which are usually classified according to allergy status, age of onset and association with patient characteristics, such as obesity or occupational exacerbations. Some studies grouped patients into clusters to identify phenotypes based on clinical indicators such as steroid bursts, response to treatment and emergency room visits. More recent studies are looking at the molecular level to see what biological mechanisms are at play to help define phenotypes.
Fifty to 70 per cent of people with asthma have type 2 inflammation, an overactive immune response that is also involved in diseases like allergic rhinitis and eczema. Phenotypes can be classified by type 2 and non-type 2.
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Early-onset allergic asthma
This type of asthma begins in childhood and can be mild to severe. With this type of asthma, there is usually a strong family history and probable genetic component and it is often associated with other allergic disease, such as eczema. In allergic asthma, allergens such as pets, dust mites and pollen trigger asthma symptoms. This happens because the immune system thinks the allergens are harmful and responds by releasing immunoglobulin E (or IgE). When IgE binds to an IgE receptor, it causes the release of histamine from the cell. Histamine can trigger symptoms like sneezing and watery eyes. It can also cause swelling of the airways, leading to an asthma attack.
Mild early-onset allergic asthma responds well to treatment with inhaled corticosteroids and long-acting beta agonists. In a clinical cluster study, 70% of people with mild early-onset allergic asthma did not report ER visits or hospitalizations in the previous year but, 30 to 40% reported daily symptoms and rescue bronchodilator use.
In severe early-onset allergic asthma, people have lower lung function and need more medications and high-dose inhaled corticosteroids. In one study, nearly 40% of people reported ICU admission for asthma in their lifetime. In the same study, 70% of people in this group reported daily symptoms and poor quality of life.
Patients with severe allergic asthma may benefit from the biologic treatment, omalizumab, which binds to IgE, preventing it from binding to its receptor. By inhibiting this binding, omalizumab prevents the release of histamine.
Later-onset eosinophilic asthma
Eosinophils are a type of white blood cell. Some people produce a higher than usual amount of eosinophils, which causes inflammation of the airways, leading to asthma symptoms. This form of asthma is often associated with sinusitis or nasal polyps. This phenotype is often severe from onset. Eosinophils usually respond to corticosteroids, but in severe asthma, heightened levels of eosinophils persist despite inhaled and oral corticosteroid treatment. This type of asthma is associated with the IL‐5 protein, which plays a major role in the production of eosinophils, as well as the overactive signaling of the IL-4 and IL-13 proteins.
Biologic treatments for people with severe eosinophilic asthma, such as mepolizumab and reslizumab, work by binding to the interfering with IL-5’s binding to the IL‐5 receptor, blocking IL-5 from making more eosinophils. Benralizumab works by binding to the IL-5Rα receptor, disrupting IL-5 interactions, resulting in a decrease of eosinophils. Dupilumab inhibits the overactive signaling of the IL-4 and IL-13 proteins.
Aspirin exacerbated respiratory disease (AERD)
A subphenotype of late-onset eosinophilic asthma, AERD is a type of adult-onset, highly eosinophilic asthma, which is associated with severe sinusitis, nasal polyps and life-threatening responses to aspirin.
In this type of asthma, symptoms are primarily experienced after exercise. This type of asthma is often mild but causes narrowing of the airways in response to sustained exercise, most often and severe in cold, dry conditions.
Many people who have mild to moderate adult-onset asthma and no history of childhood allergic features are likely to have asthma that is not related to type 2 inflammation.
It has been suggested that obesity plays a substantial role in the development, control and severity of asthma. But there is debate as to whether obesity is a driver of asthma development or a comorbidity. This type of asthma is most often associated with women at an average age of 50. It is less likely to be allergic.
Very late onset asthma
The age for the diagnosis of very late-onset asthma is not consistent but has been defined as over 50 years of age in some studies and over 65 in other studies.
The mechanisms underlying smoking-related asthma are unclear but smoking heightens the risk of sensitization to allergens and increases total IgE. The recently coined “asthma-COPD overlap syndrome (ACOS)” describes patients with a long smoking history causing airflow obstruction who also have features of asthma. The criteria for ACOS includes persistent airflow limitation in individuals over 40 years old with at least 10 years of smoking, and onset of asthma before age 40. Other criteria include a tendency toward allergic diseases, improvement with bronchodilator medication and increased eosinophils.
Environmental factors, such as infection, smoking, hormones and occupation, can influence asthma. These are sometimes considered separate phenotypes or they may play a role in altering existing disease. These are as follows:
- History of smoking or second-hand smoke exposure worsens existing asthma but smoking-associated asthma may also be a separate phenotype.
- Asthma can be associated with times of hormonal changes (such as menarche, pregnancy or menopause)
- Viruses and bacteria can increase the likelihood of developing type 2-related asthma in children prone to allergic disease or may exacerbate existing asthma. Viruses or bacteria may prompt adult-onset asthma in people who are susceptible.
- Workplace-sensitized asthma occurs only in the workplace due to certain irritants, while work-place exacerbated asthma describes when existing asthma worsens in the workplace.
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To determine the phenotype of asthma, clinicians can use tests including spirometry, flow volume loop, IgE testing, blood tests for eosinophils, skin prick testing and chest xray.
While there is further study needed to define and refine asthma phenotypes, what has been found so far demonstrates that asthma is not one specific disease and its mechanisms differ from person to person. Determining phenotypes of asthma holds much promise in enabling more targeted therapies that will help people with asthma control their disease and improve their quality of life.
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