Does adding azithromycin to standard therapy for asthma patients with acute exacerbations improve symptom resolution?

Background:

 Asthma is presented as a chronic long term disease that causes inflammation, narrowing and mucus production in the lungs airways resulting in difficulty breathing. It is assumed to be initiated by genetics or environmental influences. Physical activities and other contributing factors can exacerbate asthmatic symptoms that include coughing, wheezing, shortness of breath, and chest tighten. Most patient symptoms occur at a rapid onset and requires immediate treatment. Asthma is not curable but symptoms can be controlled with appropriate therapy. Patients with asthma are given treatment based on the severity and frequency of symptoms. Therapy options include SABA, LABA, corticosteroids or leukotrienes and adjustments are made as needed. However, many patients still experience uncontrolled symptoms that effect their daily activities.

Macrolide antibiotics such as azithromycin have been recently studied as adjunct therapy for asthmatics, due to their anti-inflammatory and antimicrobial properties. Researchers are geared to believe that untreated bacterial infections within the lungs are the underlying influences of asthma related problems. Despite these findings, the issue is still being investigated as patients on traditional standard therapy are still experiencing unwanted symptoms.

Literature Search

A literature search was conducted utilizing the MEDLINE database of Pubmed using MESH terms “asthma” and “azithromycin” and MESH subheading “therapy.” The terms were combined using AND which returned 37 articles. The application of additional limitations of 5 years, randomize controlled trials and humans were applied which reduced the search total amount to 17 articles. Although 17 articles were retrieved during the search, each article was evaluated based on their relevancy and criteria, the above article was selected because it addressed the question at hand.

Results

AZIthromycin in Severe ASThma (AZISAST) was a randomized double-blinded placebo control trial conducted to determine if adding azithromycin to asthmatic patients as standard therapy would be statistically and clinically beneficial.  The trial was conducted from September 2011 to April 2014, as a United Kingdom multicenter study. The study consisted of individuals ages 18-75 that had been diagnosed with persistent asthma. Inclusion criteria consisted of patients whose current therapy included high doses of inhaled corticosteroids, inhaled long acting beta agonist LABA  for six months prior to the study, two severe asthma exacerbations required systemic steroid therapy, or if they experienced a lower respiratory tract infection that required antibiotic treatment within a twelve month period2. Subjects were excluded if they had prolong QT interval, severe bronchiectasis, currently receiving macrolide treatment in past three months, laboratory abnormalities, pregnant or breastfeeding and concomitant anti-IgE treatments2. Participants were randomly selected to receive to 250mg capsules of azithromycin (n=55) and a placebo (n=54) in combination with inhaled corticosteroids and LABAs for six months2. Subjects in both treatment groups were matched in respect to the baseline characteristics.

The intervention instructed patients to take one capsule daily for five days and continue with one capsule three times a week with a total treatment period of twenty-six weeks. The primary outcome measured severe asthmatic episodes during the treatment phase in both groups, which was defined as hospitalization, emergency department visits, and the utilization of systemic corticosteroids for three days2. Secondary outcomes measured lung function (FEV1), peak expiratory flow (PEF) quality of life (QOL) and asthma control score2. Analyzing the secondary outcomes, the azithromycin group reported a number of thirty exacerbations occurred in comparison to twenty-seven form the placebo group. (p=1.000)2. Additionally, azithromycin and placebo group experience two hospitalization admission due to exacerbations (p=1.000)2. Other efficacy outcomes showed there was no significant improvement in the Asthma Quality of Life Questionnaire score between both groups.

The treatment period lasted for six months and demonstrated no significant difference between the azithromycin group and the placebo group in relation to asthma exacerbations. The estimated primary endpoints without adjustments resulted in 0.71 (95% CI 0.52 to 0.97) in the azithromycin group and 0.80 (95% CI 0.59 to 1.07) in the placebo group with a p-value of 0.600². With the addition of sensitivity analyses restricted to asthma exacerbations results were 0.55 (95% CI 0.38 to 0.78) in the azithromycin group and 0.52 (95% CI 0.36 to 0.75) in the placebo group with a p-value of 0.847². Based on the aforementioned data, add-on therapy of azithromycin is statistically and clinically insignificant, as well as did not reduce the rate of asthma exacerbation in adults.

Recommendations

• Although, the clinical trial failed to demonstrate that azithromycin was clinically /statistically significant in patients with asthma. This should not be a definite factor to rule out the therapeutic benefits azithromycin can have on patients with respiratory infections that contributes to asthma exacerbations.
• Developing an accurate interpretation from the study can be difficult considering the study focused on a small population and the duration of treatment was only twelve weeks.
• I would not recommend azithromycin as add-on therapy for patients with asthma due to it showed no improvement in comparison to patients receiving a placebo, as well as long-term use of a macrolide might lead to resistance.

References

1. Brusselle GG, VanderStichele C, Jordens P, et al. 2013. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicenter randomized double-blind placebo-controlled trial Thorax 2013;68:322-329. 10.1136/thoraxjnl-2012-202698mm