**4. Treatment, management and prevention**

As we mentioned before, asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation, requiring ongoing and comprehensive treatment with the goal to reduce symptoms and minimize the risk of developments of exacerbations, and treatment side effects. The pathophysiology of the disease is complex and heterogeneous for which treatment is based on a stepwise approach and the management is control-based. This involves interactive cycle assessment where symptoms and risk factors are evaluated, adjustment of treatment and review of response in which patient preferences should also be taken into account. Anti-inflammatory treatment has been the mainstay of asthma management to reduce airway inflammation and help prevent symptoms; among these are the inhaled corticosteroids. For rapid relief of symptoms short-acting beta agonists (SABA) are the ones used to reduce airway bronchoconstriction causing relaxation of airway smooth muscles. The National and International guidelines have recommended SABA as the first line treatment for patients with mild asthma, since the Global Initiative for Asthma guideline (GINA) was first published in 1995, adopting

the approach to control symptoms rather than the underlying condition. GINA was established by the WHO and NHLBI in 1993 to increase awareness about asthma and to improve asthma prevention and management through a coordinated worldwide effort. The SABA approach was initially thought to be due believing that asthma symptoms were related to bronchoconstriction rather than presence of a concomitant condition caused by airway inflammation.

GINA 2019 guideline review introduced substantial changes, adjusting asthma treatment for individual patients and adopting the concept of anti-inflammatory reliever in all degrees of severity as a crucial component in the management of the disease and efficacy of the treatment. The use of reliever medication (SABA) was placed as an addendum in the recommendations to be used in case the real treatment (the controller) failed to maintain disease control. As we know, SABA can effectively induce rapid symptom relief but are ineffective on the underlying inflammatory process. To achieve control, the intensity of the controller therapy was related to the disease severity with preferred controlled choice varying from low-dose inhaled corticosteroids (ICS)/long-acting bronchodilator (LABA), medium-dose ICS/LABA, up to high-dose ICS/LABA and with a SABA as the rescue medication. As a result of this patients with mild disease or mild symptoms were left without any anti-inflammatory treatment such as ICS and relying only on SABA rescue treatment. An important point to mention is one of the major limitations for control of asthma, which is poor adherence to therapy. A lot of patients seem to be administering inhaled medication only when asthma symptoms occur. In the absence of symptoms, patients perceive therapy unnecessary and avoid taking controlled medication. Therefore, when symptoms worsen, patients prefer to use reliever therapy which could result in overuse of SABA. An as seen in previous studies, there is evidence that suggest that overuse of beta-agonist alone is associated with risk of death from asthma, and at the same time with each exacerbation the risk of death also increases. Regular use of SABA, even for 1–2 weeks, is associated in increased airway hyper-responsiveness (AHR), reduced bronchodilator effect, increased allergic response and eosinophils [39].

Based on this evidence, in latest GINA 2022 guidelines treatment options are recommended in 5 Steps and divided in two tracks, to clarify how to step treatment up and down with the same reliever. First track which is the preferred strategy, is with the use of low-dose ICS/LABA (formoterol) as a reliever, introducing the single maintenance and reliever treatment (SMART). This strategy is the preferred due to evidence suggesting reduced risk of exacerbations compared with use of SABA only as a reliever, with similar symptoms control and lung function [40]. The SMART strategy containing the rapid-acting formoterol was recommended throughout GINA Steps based on solid evidence [41]. This recommendation continues since GINA 2019, where SABA as a reliever alone in STEP 1 was no longer recommended based on key studies SYGMA 1, SYGMA 2, Novel START and PRACTICAL [42, 43].

The second track, which is an alternative non-preferred strategy, is with the use of SABA as the reliever. This strategy is less effective in reducing exacerbations, however, continues to be used in case that therapy with low-dose ICS/LABA (Formoterol) is not possible. Also, it can be considered if patient has good adherence with their controller and has had no exacerbation in the last year. For patients who have asthma that remains uncontrolled after step 4 treatment should be referred for phenotypic assessment with or without add-on therapy. As mentioned before asthma is a complex and heterogeneous disease for which therapy should be individualized based on the underlying condition, presence or absence of allergy, and other coexisting conditions. In severe asthma or difficult-to-treat asthma, poor control can be linked to poor


#### **Figure 8.**

*Relevant questions to identify environmental factors contributing to difficult to treat asthma.*

adherence to medication, incorrect inhaler technique, and coexisting conditions, including exposure to allergens and irritants. Based on this the National Asthma Education Prevention Program (NAEPP) they recommended multicomponent allergen mitigation in sensitized individuals who have exposure to indoor allergen for pets. It was recommended to do integrated pest management alone, or as part of multi-core component intervention, and for dust mites that recommended using impermeable covers only as part of multicomponent intervention. Immunotherapy is recommended in mild to moderate allergic asthma but recommended using sub cutaneous immunotherapy. Also, important component of this therapy is to avoid any allergens or irritants that may trigger disease including smoke, dust mite, cockroach, animals, etc. Irritant or allergen sensitivity can also be determined by patient exposure and symptoms history, confirmed with skin or blood test. Leukotriene modifiers who have been used widely are mostly used especially in aspirin exacerbated respiratory disease and exercise-induced bronchial constriction who have been shown to have greater response.

When we are dealing with environmental and occupation factors, we need to categorize the patient and start the adequate therapy. The most important step is to make the diagnosis which can be made with peak flow changes in different environments of interest or investigated exposures. Changes in symptoms with changes in expiratory flow are classic in environmental exposures causing symptoms. Most of the patients will have recognized symptoms when exposed to the irritant or allergen. In patients that exposure is not clear, several algorithms of identification can be used with specific questions of daily life activities. Relevant questions to identify environmental factors (**Figure 8**).
