Immunomodulation with Recombinant Interferon-��1b in Pulmonary Tuberculosis

BackgroundCurrent treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-��1b (rIFN-��b) 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-��1b 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-1��, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-��1b group from baseline to week 16. Both rIFN-��1b 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-��1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-��1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-��1b versus DOTS alone.ConclusionRecombinant interferon-��1b 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背景 目前肺结核的治疗方案至少需要6个月的疗程。采用重组干扰素-γ1b（recombinant interferon-γ1b，rIFN-γ1b）开展免疫辅助治疗，可通过促进痰液更早转阴，减轻肺部炎症并缩短传染期。方法与主要结果 我们针对89例空洞型肺结核患者开展了一项随机对照临床试验，对比单纯直接观察治疗（directly observed therapy, DOTS）与在DOTS基础上联合雾化或皮下注射rIFN-γ1b的治疗方案，疗程均为4个月。分别于治疗第0天和第4个月采集支气管肺泡灌洗液（bronchoalveolar lavage, BAL）与血液样本。仅雾化吸入rIFN-γ1b组的24小时支气管肺泡灌洗液上清液中，炎性细胞因子IL-1β、IL-6、IL-8及IL-10水平自基线至第16周出现显著下降。两个rIFN-γ1b给药组在第4周时，其CD4+淋巴细胞对结核菌素纯蛋白衍生物（PPD）的应答水平均出现显著的3倍升高。相较于单纯DOTS组或皮下注射rIFN-γ1b联合DOTS组，雾化吸入rIFN-γ1b辅助治疗组在第4周时的痰涂片结核分枝杆菌（Mycobacterium tuberculosis, Mtb）转阴率存在显著差异（p=0.03）。此外，相较于单纯DOTS组，接受rIFN-γ1b治疗的患者在第4周时的发热、喘息与盗汗患病率均出现显著降低。结论 针对空洞型肺结核患者，重组干扰素-γ1b辅助治疗联合DOTS可降低病灶局部的炎性细胞因子水平，提升痰液中结核分枝杆菌的清除率，并改善全身症状。试验注册 ClinicalTrials.gov 编号NCT00201123