Abstract
BackgroundCurrent treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-γ1b (rIFN-γb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance.Methodology/Principal FindingsWe performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-γ1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1β, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-γ1b group from baseline to week 16. Both rIFN-γ1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-γ1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-γ1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-γ1b versus DOTS alone.ConclusionRecombinant interferon-γ1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms.Trial RegistrationClinicalTrials.gov NCT00201123
Highlights
Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population, resulting in 9.2 million active cases per year [1]
Demographics There were 96 patients who were randomized and 89 who were eligible for the study. 10 patients did not complete the trial including 4 patients who were lost to follow-up, 2 who withdrew consent, and 4 who were withdrawn due to serious adverse events (SAE’s): 2 hepatitis, 1 community acquired pneumonia, 1 hypoxia
1 died from massive hemoptysis, and 1 died in a domestic accident
Summary
Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population, resulting in 9.2 million active cases per year [1]. Sputum culture positive at two months, cavitation on chest radiography, being underweight, and bilateral pulmonary involvement increases the risk of treatment failure and/or relapse [7]. Responses of whole blood PBMC to PPD and other mycobacterial antigens are reduced in active tuberculosis probably due to suppressor T cells (Tregs ) or cytokines, e.g. IL-10 or TGF-b [8,9]. Bronchoalveolar lavage (BAL) of patients with pulmonary tuberculosis has shown increases in inflammatory cytokines and percent CD4+ cells compared to uninfected controls, and in advanced, cavitary tuberculosis markers of effective immunity are reduced. We evaluated BAL cytokines,, mycobacterial and clinical response, immunological outcomes, and postulate mechanisms that rIFN-c1b augmented to achieve an improved outcome. Immune adjuvant therapy with recombinant interferon-c1b (rIFN-cb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance
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