vitamin-d-2 and Tuberculosis--Pulmonary

Current tuberculosis treatments leave patients with clinically significant lung injury and increased all-cause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis.. In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0·5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2·5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV. Between Nov 18, 2016, and Sept 27, 2018, 200 patients were screened and randomly assigned to different treatment groups (n=40 per group, apart from n=39 in the everolimus group after one patient withdrew consent). 11 treatment-emergent serious adverse events occurred either during treatment or within 30 days after treatment discontinuation, of which three were attributable to a host-directed treatment. Life-threatening thrombocytopenia occurred in an auranofin recipient; apparent intra-abdominal sepsis leading to death occurred in another auranofin recipient and was classified as a suspected unexpected serious adverse reaction. Tuberculous spondylitis occurred as an apparent paradoxical reaction in a patient receiving ergocalciferol. Two patients in the control group had life-threatening, treatment-attributable liver injury. No treatment-emergent, treatment-attributable serious adverse events occurred in patients receiving CC-11050 or everolimus. Mean FEV. CC-11050 and everolimus were safe and reasonably well tolerated as adjunctive therapies for tuberculosis, and analysis of preliminary efficacy suggests they might also enhance the recovery of FEV. The Bill & Melinda Gates Foundation and the South African Medical Research Council.

Topics: Adult; Antitubercular Agents; Auranofin; Double-Blind Method; Drug Therapy, Combination; Ergocalciferols; Everolimus; Female; Forced Expiratory Volume; Humans; Indoles; Male; Middle Aged; Mycobacterium tuberculosis; Phosphodiesterase 4 Inhibitors; Prospective Studies; South Africa; Sputum; Sulfones; Tuberculosis, Pulmonary

We report the first prospective controlled study designed to determine the effect of vitamin D ingestion on serum calcium concentration in patients with tuberculosis. Every patient admitted to the tuberculosis ward over a 6 month period, who was free of any condition which might influence serum calcium concentration, was randomly assigned to one of two groups. The diet of the first group was substituted with ergocalciferol 5000 units daily. The diet of the second group was not supplemented. In addition, the second group was randomly subdivided into two subgroups. The first subgroup received a diet unrestricted in vitamin D. The second subgroup received a diet containing less than 50 units of vitamin D. Serum calcium was determined at weekly intervals. In contradistinction to the results of a previously reported retrospective study, there was no significant difference between the group receiving supplemental vitamin D and the control group at any time during the entire period of study. Furthermore, there was no significant difference between the subgroup of patients receiving normal dietary vitamin D and the subgroup maintained on the diet restricted in vitamin D.

Topics: Adult; Aged; Calcium; Ergocalciferols; Female; Humans; Male; Middle Aged; Prospective Studies; Random Allocation; Tuberculosis, Pulmonary

Available evidence indicates that hypercalcemia in pulmonary tuberculosis results from increases in circulating 1 alpha, 25-dihydroxyvitamin D [1 alpha, 25(OH)2D]. To further characterize vitamin D metabolism in this disorder, the effects of vitamin D, 100,000 units a day for 4 days, were compared in 25 normal subjects and 11 patients with active pulmonary tuberculosis who were normocalcemic and had not had hypercalcemia. Serum calcium, phosphorus, 25-hydroxyvitamin D (25-OHD) and 1 alpha, 25(OH)2D were measured. Whereas vitamin D increased mean serum 25-OHD from 20 +/- 2 (+/- SE) to 40 +/- 5 ng/ml (P less than 0.001) and did not change mean serum 1 alpha, 25(OH)2D in the normals (33 +/- 2 vs. 31 +/- 2 pg/ml), it increased mean serum 25-OHD from 21 +/- 4 to 55 +/- 13 ng/ml (P less than 0.05) and mean serum 1 alpha, 25(OH)2D from 28 +/- 2 to 35 +/- 3 pg/ml (P less than 0.05) in the patients. Serum calcium was normal and remained within the normal range in all subjects and patients. The findings indicate that there is a modest but significant abnormality in the regulation of circulating 1 alpha, 25(OH)2D in normocalcemic patients with pulmonary tuberculosis. The results are similar to those previously reported by us in normocalcemic patients with sarcoidosis.

Topics: Adult; Aged; Calcifediol; Calcitriol; Calcium; Creatinine; Ergocalciferols; Female; Humans; Male; Middle Aged; Phosphorus; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Insulin; Male; Radiography; Tuberculin; Tuberculosis, Pulmonary

Topics: Adolescent; Aminosalicylic Acids; Blood Sedimentation; Bronchography; Bronchoscopy; Child; Child, Preschool; Ergocalciferols; Female; Follow-Up Studies; Gastric Lavage; Humans; Infant; Isoniazid; Male; Pneumonectomy; Prognosis; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Abscess; Adrenal Insufficiency; Adult; Calcium; Chloramphenicol; Citrates; Citric Acid Cycle; Empyema; Empyema, Tuberculous; Ergocalciferols; Female; Furunculosis; Humans; Hypercalcemia; Hypocalcemia; Intestinal Absorption; Isoniazid; Klebsiella Infections; Lung Abscess; Lupus Vulgaris; Lymphadenitis; Male; Middle Aged; Paronychia; Penicillins; Pleurisy; Prednisone; Streptomycin; Suppuration; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Ergocalciferols; Humans; Middle Aged; Radiography; Tuberculosis, Pulmonary

Topics: Abscess; Cholestanes; Cold Temperature; Ergocalciferols; Humans; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D; Vitamins

Topics: Cholestanes; Ergocalciferols; Humans; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D; Vitamins

Topics: Aminosalicylic Acid; Ergocalciferols; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D; Vitamins

Topics: Anti-Bacterial Agents; Ergocalciferols; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D; Vitamins

Topics: Anti-Bacterial Agents; Cholestanes; Ergocalciferols; Humans; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D; Vitamins

Topics: Anti-Bacterial Agents; Cholestanes; Ergocalciferols; Humans; Thiosemicarbazones; Tuberculosis; Tuberculosis, Pulmonary; Vitamin D; Vitamins

Topics: Ergocalciferols; Humans; Tuberculosis, Pulmonary

Topics: Ergocalciferols; Tuberculosis; Tuberculosis, Pulmonary