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Reducing the Numbers of Severe Exacerbations of Asthma With Biologics and Pharmacologic Treatments: PARTICS, MANDALA, SMART and More

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The Centers for Disease Control reported that over 25 million people in the U.S. have current asthma as of 2020, or 7.8% of the population. The prevalence of current asthma in children and adolescents <18 years of age is 5.8%, whereas in adults, it is 8.4%. The presence of asthma varies considerably among us, in descending order: American Indian/Alaska natives, 11%; Black non-Hispanic, 10.3%; White non-Hispanic, 8.1%; Hispanic, 6.7% (with Mexican at 5.2%); to Asian non-Hispanic 3.5%. The prevalence of current asthma is highest in people who are identified as <100% of the poverty threshold (for a family of four people, $27,750 in 2022). Despite the many advances that have occurred regarding pathophysiology, phenotypes (such as absolute eosinophil count >300/uL), endotypes (such as aspirin or non-steroidal anti-inflammatory drug exacerbated respiratory disease and allergic bronchopulmonary aspergillosis), concomitant comorbidities (such as GERD, chronic rhinosinusitis, allergic rhinitis, and depression), and options for treatment of asthma over the years, the CDC reported that 41% of people with asthma had experienced at least a single asthma attack in the past year. I attended the February 2023 American Academy of Allergy Asthma and Immunology meeting, where many aspects of asthma and its complexities were reported and discussed. In particular, can we help our patients likely to experience severe exacerbations, defined as when there is treatment with oral corticosteroids for at least three days, an urgent care or emergency department visit, hospitalization or death from asthma? There have been persuasive clinical trial data that has led to FDA approval of biologics with labeled indications for reducing asthma exacerbations with omalizumab, reslizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab. For some patients, there are data showing that extended administration of these biologics appears to have disease-modifying activity, meaning reduced numbers of asthma exacerbations annually. This finding requires additional study, but it is exciting to reduce the instances of severe exacerbations of asthma and reduce the aggressiveness and impact of this burdensome condition.

From the pharmacologic perspective, recent studies describe the combination of patient-activated, reliever-triggered treatment with an inhaled corticosteroid and short-acting beta-2 adrenergic agonist, albuterol, in patients with exacerbations of moderate to severe asthma. In one study, participants started an inhaler with beclomethasone dipropionate 80 ug/actuation with one actuation for each actuation of a quick-reliever inhaler or five actuation of beclomethasone dipropionate for each quick-reliever nebulizer treatment. This treatment, designated Patient-Activated, Reliever-Triggered Inhaled glucoCorticoid Strategy (PARTICS), is now added to usual care. The participants were Black or Latinx patients, often the people underrepresented in many pharmacologic asthma studies. The Asthma Control Test (ACT) scores were reduced to a baseline 14.6 (20-25 means well-controlled asthma; 16-19 means not well-controlled asthma; and 5-15 means very poorly controlled asthma). The PARTICS approach led to a 16% reduction in severe asthma exacerbations with an annualized rate of 0.69 compared with 0.82 in the usual-care group. The severe exacerbations continued to decrease throughout the 15 months of study, and the ACT scores increased by 3.4 in the PARTICS treatment arm compared with 2.5 in the usual-care wing. The second recent study, MANDALA, used a fixed-dose combination of an albuterol inhaler with budesonide. There was a 26% reduction of severe asthma exacerbations with an annualized rate of 0.43 with albuterol 180ug and budesonide 160ug (maximum of six doses/day) compared with 0.58 in the albuterol group. A supportive, secondary endpoint in this trial was the annualized dose of systemic glucocorticoid (in equivalents of prednisone) 84 mg in the fixed-dose combination inhaler wing compared with 130 mg in the albuterol-alone arm. In January 2023, the FDA approved a combination albuterol/budesonide inhalation aerosol for the “as-needed treatment or prevention of bronchoconstriction and to reduce the risk of asthma attacks in patients with asthma 18 years of age and older.” There were insufficient supporting data for FDA approval for administration in children (age four years and older) and adolescents. It is worth noting that at the onset of an exacerbation of asthma, the early treatment with a quick onset bronchodilator (albuterol as the short-acting, rapid onset-of-action bronchodilator or formoterol as a long-acting but rapid onset of action bronchodilator) combined with an inhaled corticosteroid is described by the acronym, SMART, for single maintenance and reliever inhaler therapy.

In addition to treating with biologics and or the pharmacologic approaches discussed, keep in mind that patients who are prone to severe exacerbations of asthma may have attributable causes such as the cat or dog at home, fungi at home or in the workplace, dust mites in the bedroom or unappreciated and under-treated comorbidities. It remains my conviction that the allergist-immunologist has the professional expertise to sort out these remedial triggers of allergic inflammation to assist in reducing exacerbations, helping patients gain confidence in management, and improving their quality of life.

Dr. Greenberger has no conflicts of interest to report.

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