A Pilot Study of Azithromycin Prophylaxis for Acute Chest Syndrome in Sickle Cell Disease

Specific Aims:

Acute chest syndrome (ACS), a lung complication in sickle cell disease (SCD), is the second
most common cause of hospitalization and leading cause of death in SCD. Recurrent ACS has
been associated with poor lung function outcome that is comparable to cystic fibrosis. ACS is
associated with airway inflammation, and a major cause is pulmonary infection from atypical
organisms. To date, there are no drugs available to reduce inflammation and risk of recurrent
ACS. Thus newer therapies are urgently needed to address this important issue associated with
increased morbidity from debilitating chronic lung disease and mortality in SCD. Macrolides
are a group of antibiotics that exert immunomodulatory and anti-inflammatory actions both in
vitro and in vivo. It has been shown to inhibit neutrophil activation and mobilization,
modulate oxidant production by neutrophils and of proinflammatory cytokine synthesis and
release by leukocytes, reduce systemic markers of inflammation, inhibit intercellular
adhesion molecules on epithelial cell surfaces, and block the activation of certain nuclear
transcription factors. In addition, macrolides reduce bacterial burden in the airway of
atypical organisms, all of which play an important role in the pathophysiology of ACS.
Indeed, numerous studies have evaluated macrolide prophylaxis in conditions associated with
lung inflammation, such as cystic fibrosis, asthma, bronchiectasis etc., and high quality
evidence have found macrolides to be beneficial as a disease modifying agent that leads to
improvement in airway inflammation, reduced pulmonary exacerbations and improved lung
function. However, azithromycin has never been studied before in SCD. The investigators
hypothesize that azithromycin prophylaxis is well tolerated and has the potential to reduce
inflammation and improve lung outcome in children with SCD with a history of ACS.

A prospective, single arm, open label feasibility study of azithromycin prophylaxis will be
performed in children with SCD with a history ACS with the following specific aims:

Specific Aim 1: Examine the feasibility, safety and tolerability of azithromycin prophylaxis
administration in children with SCD. A cohort of 15 participants with sickle cell disease 6
to 16 years old will be placed on azithromycin prophylaxis, and followed closely to evaluate
medication adherence and for any adverse effects from taking the medication.

Specific Aim 2: Examine whether azithromycin prophylaxis has the potential to improve lung
outcome in participants with SCD with a history of ACS. In the same cohort of 15 patients,
baseline pulmonary function testing will be performed evaluating Forced expiratory volume 1
sec (FEV1) and Forced vital capacity (FVC) measurements prior to starting azithromycin
prophylaxis, and then again at study end period after 1 year to evaluate for any change.

Specific Aim 3: Determine whether azithromycin prophylaxis reduces inflammation in
participants with SCD with a history of ACS. In the same cohort of 15 participants, baseline
markers of inflammation will be performed, specifically C-reactive protein (CRP), Tumor
necrosis factor Alpha (TNF-α), interleukin IL-1, IL-1β, IL-4, IL-6, and IL-8, and then
repeated at specific time intervals of 16 weeks, 32 weeks and 48 weeks (study end).

Inclusion Criteria:

- Established diagnosis of SCD (Hemoglobin SS, hemoglobin Sβ0 thalassemia)

- History of acute chest syndrome - the history of acute chest syndrome will be
confirmed by a retrospective medical chart review that meets the standard definition
as mentioned in the Background section.

- Age ≥ 6 years to 16 years old

Exclusion Criteria:

- Hemoglobin Sβ+thalassemia and hemoglobin SC subject will be excluded as this group of
patients do not typically have severe SCD that places them at risk of developing
recurrent acute chest syndrome

- No history of acute chest syndrome

- Significant neurologic impairment as judged by health care provider.

- Inability to take/swallow a tablet

- History of poor adherence to clinic visits.

- History of renal or hepatic dysfunction

- Chronic red blood cell transfusion

- History of allergy to azithromycin or macrolide antibiotic

- History of cardiac arrhythmia

- History of prolonged QT