Cancer Council of Western Australia and the Sir Charles Gairdner Research Advisory Group.

BackgroundVitamin D deficiency (low plasma 25-hydroxyvitamin D [25D] concentration) is often reported in tuberculosis. Adjunctive vitamin D has been tested for its potential to improve treatment outcomes, but has proven largely ineffective. To better understand vitamin D in tuberculosis, we investigated determinants of 25D and its immunologically active form, 1,25-dihydroxyvitamin D (1,25D), their inter-relationship in tuberculosis, longitudinal changes and association with outcome.MethodsIn a prospective observational study of adults with smear-positive pulmonary tuberculosis in Sabah, Malaysia, we measured serial 25D, 1,25D, vitamin D-binding protein (VDBP), albumin, calcium, parathyroid hormone, chest x-ray, week 8 sputum smear/culture and end-of-treatment outcome. Healthy control subjects were enrolled for comparison.Results1,25D was elevated in 172 adults with tuberculosis (mean 229.0 pmol/L, 95% confidence interval: 215.4 - 242.6) compared with 95 controls (153.9, 138.4-169.4, p < 0.001), directly proportional to radiological severity (p < 0.001), and fell rapidly within one week of treatment commencement. Tuberculosis patients with higher baseline 1,25D achieved significantly higher percentage weight gain over time, including when controlling for baseline weight, however persistently elevated 1,25D was associated with worse residual x-ray changes and lower end-of-treatment BMI. 1,25D was inversely associated with PTH (p < 0.001), consistent with the extra-renal origin of the 1,25D. 25D did not differ between tuberculosis patients (mean 63.9 nmol/L, 95% CI: 60.6 - 67.3) and controls (61.3, 57.2- 65.3, p = 0.24), and was unassociated with outcomes. Among tuberculosis patients in multivariable analyses, sex, age and VDBP were associated with 25D, and age and albumin with 1,25D. 1,25-dihydroxyvitamin was not significantly asscociated with 25D. Vitamin D deficiency <25 nmol/L was uncommon, occurring in only five TB patients; 1,25D was elevated in three of them.ConclusionsIn an equatorial setting, high extra-renal production of 1,25D was seen in tuberculosis, including in individuals with 25D in the deficient range; however, severe 25D deficiency was uncommon. Baseline elevation of 1,25D, a marker of macrophage activation, was associated with better weight gain but persistent elevation of 1,25D was associated with worse radiological and BMI outcomes. 1,25D warrants testing in larger datasets including TB patients less responsive to treatment, such as multi-drug resistant TB, to test its utility as a marker of tuberculosis severity and treatment response.

IntroductionMalignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation.Methods and analysisA multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0–1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate.Ethics and disseminationThe Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberACTRN12615000963527; Pre-results.