Allergy & Asthma

With asthma, the airways become inflamed and narrow, and there is overproduction of mucus, resulting in symptoms like shortness of breath, recurrent wheezing, chest tightness, and coughing. These symptoms come and go and can worsen and lead to a decline in lung function with exposure to environmental triggers like viral respiratory infections, biological allergens, cold air, and air pollution (3).

Asthma is a serious and potentially life-threatening condition, accounting for 455,000 deaths in 2019. These asthma-related deaths mostly happen in older adults and low and lower-middle-income countries struggling with under-diagnosis and under-treatment (4).

Though asthma is heterogeneous by nature, consisting of a range of diseases with distinct observable traits (phenotypes) and mechanisms (endotypes), the condition is caused mainly by allergy and atopy, the predisposition to produce excess immunoglobulin E (IgE) as an immune response to exposure to allergens and antigens, with T-helper cells type 2 (Th2) playing a central role in its pathological process (5, 6).

An increase in Th2 cells in the airways is accompanied by the release of large amounts of cytokines, including IL-4, IL-5, and IL-13, resulting in eosinophilic airway inflammation and immunoglobulin E (IgE) production. IgE then causes mediators that contract airway smooth muscle, such as histamine, tryptase, prostaglandins, and cysteinyl leukotrienes to be released (7).

However, asthma may also occur without the Th2 immune response. Less is known about the inflammatory pathways underlying this type of asthma, but it is thought to be characterized by neutrophilic inflammation (defined by an increase in neutrophil levels to above 60% or 76% in induced sputum) or paucigranulocytic inflammation (defined by sputum eosinophil levels of less than 3% and neutrophil levels of less than 76%) and resistance to corticosteroid therapy (5, 8, 9). Hence, asthma can be broadly classified into Th2-high (Type-2 inflammation) and Th2-low asthma (Non-type-2 inflammation) based on the inflammatory processes involved (10).

Th2-high asthma occurs in half of patients and is more common in children and young adults (5, 11). Patients may have Th2-high asthma in the early stage and Th2-low asthma in a later stage or the other way around. They may also have both Th2-high and Th2-low asthma at the same time (10).

Besides Th-2 cytokines, other contributors in Th2-high asthma pathogenesis include Th9 cells which produce IL-9, IL-10, and IL-21. IL-9, in particular, contributes to inflammation by activating Th2 cells and stimulating mast cells (10). On the other hand, Th2-low asthma may be mediated by Th17 cytokines, including IL-17A, IL-17F, and IL-22, and Th1 cytokines, such as IL-2, TNF-α, and IFN-γ. Th17 cytokines, for instance, contribute to neutrophilic airway inflammation by stimulating the secretion of neutrophil chemokines such as CXCL1 and CXCL8, thereby recruiting neutrophils to the lungs. IL-17A, in particular, is recognized as a significant driver of asthma as it facilitates airway smooth muscle contraction, resulting in airway narrowing and remodeling (12).

Asthma’s heterogeneity, in terms of its mechanisms, clinical presentations, severity, and treatment responsiveness, is influenced by the complex interactions of susceptibility genes and environmental risk factors. Genetic factors are responsible for 60 – 80% of the predisposition to the condition (1). So far, evidence suggests that over 100 susceptibility genes exist, each having minimal impact on disease risk (13). A 2019 genomewide association study of asthma identified 123 childhood-onset asthma-associated variants and 56 adult-onset asthma-associated variants (14). These susceptibility genes may be involved in immune system function, mucosal biology and function, lung function, and disease expression (13).

Environmental factors such as air pollution, biological allergens, exposure to tobacco smoke, obesity, viral and bacterial infections, and stress may increase the risk of developing asthma. These environmental factors may also trigger episodes of asthma attacks and worsen asthma.

Because this condition is yet to be curable, treatment focuses on controlling asthma symptoms and reducing the likelihood of asthma worsening with as few medication side effects as possible (15). However, treatment process can be complicated, and in some cases, treatment may be ineffective due to the complex nature of the disease. About 17% of asthma cases are grouped as “difficult to treat,” with 3.7% recognized as severe, despite the appropriate prescription and adherence to medicines (16). Hence, new and more effective treatments are needed to manage the disease and reduce the increasing global burden of this disease (1).

Researchers suggest the potential of effectively treating asthma with targeted therapy (6). Biological therapies targeting cell signaling pathways of asthma may be especially beneficial for treating severe and difficult-to-treat asthma in adults (17).

References

1. Komlósi ZI, van de Veen W, Kovács N, et al. Cellular and molecular mechanisms of allergic asthma. Mol Aspects Med. 2022;85:100995.

2. Sachdeva K, Do DC, Zhang Y, Hu X, Chen J, Gao P. Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence. Front Immunol. 2019;10:2787.

3. ScienceDirect https://www.sciencedirect.com/topics/immunology-and-microbiology/pathophysiology-of-asthma (Accessed June 21, 2023)

4. World Health Organization https://www.who.int/news-room/fact-sheets/detail/asthma (Accessed June 21, 2023)

5. Kuruvilla ME, Lee FE, Lee GB. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clin Rev Allergy Immunol. 2019;56(2):219-233.

6. Athari SS. Targeting cell signaling in allergic asthma. Signal Transduct Target Ther. 2019;4:45. Published 2019 Oct 18. Quirt, J., Hildebrand, K.J., Mazza, J. et al. Asthma. Allergy Asthma Clin Immunol 2018;14 (Suppl 2), 50

7. Quirt, J., Hildebrand, K.J., Mazza, J. et al. Asthma. Allergy Asthma Clin Immunol 14 (Suppl 2), 50 (2018).

8. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65.

9. Yamasaki A, Okazaki R, Harada T. Neutrophils and Asthma. Diagnostics (Basel). 2022;12(5):1175.

10. Habib N, Pasha MA, Tang DD. Current Understanding of Asthma Pathogenesis and Biomarkers. Cells. 2022;11(17):2764.

11. Maison N, Omony J, Illi S, et al. T2-high asthma phenotypes across lifespan. Eur Respir J. 2022;60(3):2102288.

12. Kudo M, Ishigatsubo Y, Aoki I. Pathology of asthma. Front Microbiol. 2013;4:263.

13. Thomsen SF. Genetics of asthma: An introduction for the clinician. Eur Clin Respir J. 2015;2:10.3402/ecrj.v2.24643.

14. Ferreira MAR, Mathur R, Vonk JM, et al. Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct. Am J Hum Genet. 2019;104(4):665-684.

15. UpToDate https://www.uptodate.com/contents/an-overview-of-asthma-management (Accessed June 21, 2023)

16. Narsimhan K. Difficult to Treat and Severe Asthma: Management Strategies. Am Fam Physician. 2021;103(5):286-290.

17. Cevhertas L, Ogulur I, Maurer DJ, et al. Advances and recent developments in asthma in 2020. Allergy. 2020;75(12):3124-3146.