Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia

A prospective clinical study

Anna P. Ralph, Muhammad Redzwan S. Rashid Ali, Timothy WILLIAM, Kim Piera, Uma Parameswaran, Elspeth Bird, Christopher S. Wilkes, Wai Khew Lee, Tsin Wen Yeo, Nicholas M. Anstey

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    Abstract

    Background: Vitamin 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.

    Methods: In 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.

    Results: 1,25D 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 63.9nmol/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 <25nmol/L was uncommon, occurring in only five TB patients; 1,25D was elevated in three of them.

    Conclusions: In 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.

    Original languageEnglish
    Article number312
    Pages (from-to)1-11
    Number of pages11
    JournalBMC Infectious Diseases
    Volume17
    Issue number1
    DOIs
    Publication statusPublished - 27 Apr 2017

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    Malaysia
    Vitamin D
    Tuberculosis
    Prospective Studies
    Vitamin D-Binding Protein
    Vitamin D Deficiency
    1,25-dihydroxyvitamin D
    Clinical Studies
    Weight Gain
    Albumins
    X-Rays
    Kidney
    Macrophage Activation
    25-hydroxyvitamin D
    Therapeutics
    Sputum
    Parathyroid Hormone
    Pulmonary Tuberculosis
    Observational Studies
    Healthy Volunteers

    Cite this

    Ralph, Anna P. ; Rashid Ali, Muhammad Redzwan S. ; WILLIAM, Timothy ; Piera, Kim ; Parameswaran, Uma ; Bird, Elspeth ; Wilkes, Christopher S. ; Lee, Wai Khew ; Yeo, Tsin Wen ; Anstey, Nicholas M. / Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia : A prospective clinical study. In: BMC Infectious Diseases. 2017 ; Vol. 17, No. 1. pp. 1-11.
    @article{30427bf3c3f641c7b04352e21c3f2d6a,
    title = "Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia: A prospective clinical study",
    abstract = "Background: Vitamin 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. Methods: In 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. Results: 1,25D 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 63.9nmol/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 <25nmol/L was uncommon, occurring in only five TB patients; 1,25D was elevated in three of them. Conclusions: In 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.",
    keywords = "1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, Calcitriol, Cholecalciferol, Tuberculosis",
    author = "Ralph, {Anna P.} and {Rashid Ali}, {Muhammad Redzwan S.} and Timothy WILLIAM and Kim Piera and Uma Parameswaran and Elspeth Bird and Wilkes, {Christopher S.} and Lee, {Wai Khew} and Yeo, {Tsin Wen} and Anstey, {Nicholas M.}",
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    Ralph, AP, Rashid Ali, MRS, WILLIAM, T, Piera, K, Parameswaran, U, Bird, E, Wilkes, CS, Lee, WK, Yeo, TW & Anstey, NM 2017, 'Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia: A prospective clinical study', BMC Infectious Diseases, vol. 17, no. 1, 312, pp. 1-11. https://doi.org/10.1186/s12879-017-2314-z

    Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia : A prospective clinical study. / Ralph, Anna P.; Rashid Ali, Muhammad Redzwan S.; WILLIAM, Timothy; Piera, Kim; Parameswaran, Uma; Bird, Elspeth; Wilkes, Christopher S.; Lee, Wai Khew; Yeo, Tsin Wen; Anstey, Nicholas M.

    In: BMC Infectious Diseases, Vol. 17, No. 1, 312, 27.04.2017, p. 1-11.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia

    T2 - A prospective clinical study

    AU - Ralph, Anna P.

    AU - Rashid Ali, Muhammad Redzwan S.

    AU - WILLIAM, Timothy

    AU - Piera, Kim

    AU - Parameswaran, Uma

    AU - Bird, Elspeth

    AU - Wilkes, Christopher S.

    AU - Lee, Wai Khew

    AU - Yeo, Tsin Wen

    AU - Anstey, Nicholas M.

    PY - 2017/4/27

    Y1 - 2017/4/27

    N2 - Background: Vitamin 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. Methods: In 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. Results: 1,25D 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 63.9nmol/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 <25nmol/L was uncommon, occurring in only five TB patients; 1,25D was elevated in three of them. Conclusions: In 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.

    AB - Background: Vitamin 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. Methods: In 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. Results: 1,25D 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 63.9nmol/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 <25nmol/L was uncommon, occurring in only five TB patients; 1,25D was elevated in three of them. Conclusions: In 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.

    KW - 1,25-dihydroxyvitamin D

    KW - 25-hydroxyvitamin D

    KW - Calcitriol

    KW - Cholecalciferol

    KW - Tuberculosis

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