Introduction
Asthma is a heterogeneous disease with different causes presenting with wheezing, dyspnea (shortness of breath), chest tightness, and chest pain associated with variable respiratory obstruction. About 300 million individuals are affected each year of all age groups and races. Studies reveal an inadequate asthma treatment of asthma as only five to six percent of asthmatics are given inhaled corticosteroids (ICS). Uncontrolled asthma patients are labeled severe asthmatics, and these represent a financial burden to healthcare providers as they do not get relief despite adequate therapy.
Recent research into asthma has improved the understanding with the recognition that the condition is not a single entity and that it has many clinical phenotypes driven by various molecular mechanisms. Subsequently, it has led to novel therapies directed at various targets of the disease mechanism involving severe asthma.
What Is Severe Asthma?
Before a consensus on severe asthma definition, clinicians have used many terminologies to characterize these patients. They used “brittle” asthma, corticosteroid-resistant asthma, difficult-to-treat asthma, and life-threatening asthma. The World Health Organization (WHO) groups such patients into three groups.
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Untreated Severe Asthma: This group represents patients who are unable to receive treatment for asthma as they cannot afford or are inaccessible to such treatments.
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Difficult-To-Treat Severe Asthma: This comprises patients managed for their asthma but non-responsive to the same for various reasons, including non-compliance or not receiving accurate treatment.
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Treatment-Resistant Severe Asthma: It represents the patients in which adequate control is not attained despite the best treatment. It also denotes the group of asthmatics for which control maintenance can only be with the recommended treatment.
What Are the Various Clinical Severe Asthma Phenotypes?
A phenotype emerges from a genetic code expression and environmental factors influence. Severe asthma phenotyping has been started due to a severe eosinophilic asthma phenotype. It comprises recurrent asthma exacerbations despite a high dose of ICS, oral corticosteroids, high eosinophil (an inflammatory cell raised in allergies such as asthma) count, and increased nitric oxide levels in exhaled breath. Clinicians describe severe asthma phenotypes as:
Early Childhood Onset Severe Allergic Asthma: In this condition, children develop wheezing between ages three and six. Wheezing is strongly associated with increased nitric oxide levels on exhalation due to sensitization to inhaled allergens. Also, there is severe and irreversible lung function reduction that requires mandatory asthma medication.
Late Adult-Onset Eosinophilic Asthma: Adult-onset eosinophilic asthma is a severe and difficult-to-treat asthma subtype. It is associated with persistent airflow limitation and severe exacerbation risk. Still, the symptoms are mild and atypical. As a result, it is extremely crucial to identify this rare asthma subtype at an early phase. However, at the onset of asthma, these patients are older than classical asthmatics. Therefore, they can be misdiagnosed as chronic obstructive pulmonary disease (COPD, an obstructive lung disease) patients, which requires specific management that differs from eosinophilic asthma.
Obesity-Associated Asthma: Obese subjects have increased asthma risk. Further, obese asthmatics have more symptoms and recurrent and severe exacerbations. They also have reduced response to medications and impaired quality of life (QoL).
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Obese children have increased asthma severity, poor disease control, and lower QoL. Many obese asthmatic children show heightened responses to inflammatory stimuli, insulin resistance, and lipid metabolism changes. Furthermore, among hospitalized asthmatic children, obesity is linked to a longer stay and a higher possibility of mechanical ventilation. Also, these children are more susceptible to exposure to indoor pollutants.
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Obese adults have more severe asthma with about six times higher risk of hospitalization as compared to lean adults with asthma. Approximately 60 percent of adults worldwide with severe asthma are obese. Further, obese adults have worse asthma control and lower QoL.
Aspirin-Associated Asthma: Aspirin (a painkiller) can induce an asthmatic attack within an hour of ingestion in some individuals. Aspirin-induced asthma (AIA) consists of asthma, chronic rhinosinusitis (nose and sinuses inflammation) with nasal polyps (nasal mucosa growths), and asthma attacks in response to aspirin. The syndrome prevalence in the adult asthmatic population is approximately ten percent. Studies suggest that respiratory disease may be serious and refractory to treatment in these patients.
Smoking-Associated Asthma: Tobacco smoke irritates the respiratory passage leading to swelling, narrowing, and mucus production in the airways. One must note that similar events occur during an asthma flare-up. Smoking-associated asthma might be more severe and difficult to control.
The Severe Asthma Research Program (SARP) reports five phenotypic groups of severe asthma, including three groups in adults and two in children. These are categorized by the age of onset, sensitization to allergens, lung function, drugs, healthcare utilization, and underlying medical conditions.
What Is the Current Treatment Approach for Severe Asthma?
After the phenotyping of a patient with severe asthma, an adequate therapeutic approach is the final aim.
Controller Treatment: A combination of long-acting beta-agonist (LABA, inhaled asthma medications) with ICS in a medium or high dose is given. Furthermore, an effective addition is leukotriene antagonists (drugs that work against leukotriene, a molecule increased in asthma) and long-acting muscarinic antagonists (LAMA, a medication with a similar function as LABA).
Biologic Therapy:
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Omalizumab: Omalizumab is the first authorized biologic (a biological, medical product) for asthma. It is an artificially created monoclonal antibody (mAb, an immune protein) that binds to immunoglobulin E (IgE, raised in asthma). As a result, it prevents the further release of inflammatory mediators. A study of severe allergic asthma patients showed that Omalizumab resulted in a 25 percent reduction in exacerbations. Further, the study revealed that it improved the QoL of patients and asthma symptoms. However, treatment response must be assessed at four months, including parameters such as QoL, frequency of exacerbations, and healthcare use.
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Mepolizumab, Reslizumab, and Benralizumab: These mAbs block the pathway required for eosinophil maturation, survival, and transport into blood. They are approved for severe eosinophilic asthma patients that have a raised blood eosinophil count and encounter frequent exacerbations. Mepolizumab, Reslizumab, and Benralizumab also decrease the risk of exacerbations by about 50 percent, with favorable effects on lung function.
Bronchial Thermoplasty: Bronchial thermoplasty is a procedure in which heat is applied to the airway passages to remove the smooth muscle, cells, and nerves. In severe asthmatics, it shows a modest effect in alleviating asthma-related QoL.
Long-term Macrolide Treatment: An abnormal microorganism community is linked to severe asthma phenotypes. Antibiotics in severe asthma treatment can decrease the neutrophil (cells raised in acute inflammation) count and bacterial load. Azithromycin (a macrolide antibiotic) reduces airway bacterial load and improves asthma symptoms. However, studies suggest an emergence of antimicrobial resistance against the antibiotic. Hence, it is unclear whether long-term macrolide treatment is effective in severe uncontrolled asthma.
Conclusion
Physicians have recognized severe and persistent asthma from varied conditions with shared symptoms. Recently, studies have recognized severe asthma phenotypes. The delineation of distinct phenotypes has led to novel asthma treatments targeting specific immune mechanisms. Emerging therapies can enable physicians to deliver personalized care to patients with severe asthma. However, further research needs to determine the appropriate time to administer these treatments for severe asthma.
