Sickle Cell Disease Clinical Trial
Official title:
A Pilot Study of Azithromycin Prophylaxis for Acute Chest Syndrome in Sickle Cell Disease
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. 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. Macrolides are a group of antibiotics that exert immunomodulatory and anti-inflammatory actions both in vitro and in vivo. In addition, macrolides reduce bacterial burden in the airway of atypical organisms, all of which play an important role in the pathophysiology of ACS. 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. 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 specific aim to examine the feasibility, safety and tolerability of azithromycin prophylaxis administration in participants with SCD , and to examine whether azithromycin prophylaxis has the potential to improve lung outcome. In addition, this study will determine whether azithromycin prophylaxis reduces inflammation in participants with SCD with a history of ACS.
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).
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