Macrolide Therapy to Improve Forced Expiratory Volume in 1 Second in Adults With Sickle Cell Disease

Sickle cell anemia (SCA) is a life-threatening, monogenic disorder associated with early death when compared to individuals without SCA. Pulmonary complications, namely acute chest syndrome, obstructive lung disease and pulmonary hypertension, are the most common causes of death in patients with SCA. Recent studies suggest that lung specific inflammation is a hallmark of SCA and underlies pulmonary pathology. To date, no therapy has been shown to improve the pulmonary complications of SCA. Macrolides have pleomorphic effects in the lung with improvement in pulmonary function, symptoms and inflammatory markers demonstrated in several inflammatory pulmonary conditions such as cystic fibrosis, asthma, COPD and post-transplant bronchiolitis obliterans. Investigators hypothesize that low dose macrolide therapy is well tolerated and can improve pulmonary function and symptoms in patients with SCA. The objective of this project is to assess the feasibility of macrolides to attenuate or reverse the decrease in %predicted FEV1 in adults with SCA in a single-site, randomized, placebo-controlled feasibility trial.

Specific aim 1: To determine acceptability of a clinical trial in which participants are randomly allocated to either a placebo or azithromycin 500 mg 3 days a week for 6 months for adults with SCD who have FEV1\<80%.

To assess acceptability of this intervention, investigators will measurement recruitment rate, retention and adherence to the study medication. Recruitment will be assessed by proportion of eligible participants that agree to be randomized. Retention will be measured as proportion randomly allocated who complete the trial. Dropout due to toxicity will be categorized using a questionnaire. Medication adherence will be assessed using the previously validated 8 item modified Morisky medication adherence scale (MMAS-8), where responses are categorized: high adherence (8 points), average adherence (6-7 points), and poor adherence (0-5 points). If recruitment rate is \< 60%, the retention rate \< 80%, or average adherence rate is ≤5 points, the original protocol will be examined and alternative strategies to enhance recruitment, retention, and adherence will be considered.

Specific aim 2: To evaluate the effect of 6 months of low dose azithromycin therapy on FEV1 and respiratory symptoms in patients with SCA. Baseline FEV1 testing with a portable, in-office spirometer will be completed at study enrollment and at the end of the study period (6 months). The previously validated American Thoracic Society (ATS-DLD-78 for adults) questionnaire will also be used to evaluate respiratory symptoms at baseline and end of the study. Under a separate protocol, investigators will calculate the coefficient of variation for FEV1% predicted in adults with sickle cell disease in order to define the within-subject variability for tests of respiratory function in this specific population, which has not been previously described within the medical literature. Calculation of the coefficient of variation for FEV1 % predicted will be essential for the interpretation of clinically and statistically meaningful changes in spirometry for participants who are treated with azithromycin to improve their baseline pulmonary function when compared to controls.

Eligibility Criteria:
Inclusion criteria:

1. Established diagnosis of sickle cell disease (HbSS, HbSC, HbS/β+, HbS/β0)
2. Age between 18-50 years
3. FEV1 \< 80% predicted
4. Willingness to make return visits and availability by telephone for the duration of the study.

Exclusion criteria:

1. Acute respiratory symptoms
2. FEV1\>80%
3. Inability to swallow pills
4. Hypersensitivity to macrolides.
5. History of cardiac arrhythmias
6. Prolonged QTc interval (\>500 ms) at on baseline EKG
7. Baseline impairment of hearing by pure tone audiometry defined as patients with age-adjusted hearing thresholds \>95th percentile at any one frequency of 500, 1000, 2000 and 4000 Hz.
8. The presence of a diagnosis other than SCD that results in the patient being medically unstable, or having a predicted life expectancy less than 1 year.
9. Special patient groups: prisoners, pregnant women, institutionalized patients
10. Women who are at risk of becoming pregnant during the study, and who refuse to use an acceptable means of birth control (hormonal based oral, intrauterine device or barrier contraception) for the duration of the study.
11. Patients taking tacrolimus, pimozide, disopyramide, cyclosporine, nelfinavir, bromocriptine, or hexobarbital.
12. Patients taking any medications that prolong QTc interval.