A Randomized, Placebo-Controlled, Double-Blinded, 250-Subject Clinical Trial of Vitamin D Replacement in Patients With Pulmonary Tuberculosis

Tuberculosis Tuberculosis (TB) is a global emergency. In 2004, there were an estimated 8.9 million new cases and 1.7 million deaths due to the disease1. In Pakistan, pulmonary tuberculosis (TB) is a major public health problem. The population of Pakistan is 160,943,000 with an estimated prevalence of all cases of tuberculosis at 263/100,000, an incidence of smear positive pulmonary TB of 181/100,000, and a mortality of 34/100,0002.

The management of TB remains a complicated issue even with the availability of effective anti-tuberculous drugs. One important aspect of this issue has been the difficulty clinicians' face in measuring clinical response in these patients, especially in smear-negative pulmonary and extra-pulmonary disease. Christian et al 3. have recently developed and validated a simple clinical score for the evaluation of TB patients. The score is based on eleven clinical variables, which were obtained from the WHO clinical manual for TB. These included self-reported parameters (e.g., cough, hemoptysis, dyspnoea, chest pain and night sweats), and signs comprising of anemic conjunctivae, tachycardia, positive findings at lung auscultation, axillary temperature >37.0˚C, body mass index (BMI) and middle upper arm circumference (MUAC). Each variable contributes 1 point, except for BMI and MUAC which contribute 2 points each, giving a maximum score of 13. Using this, score patients can be divided into 3 severity classes, providing an easy tool for clinical follow up and prognosis.

Vitamin D Vitamin D is normally synthesized in the skin under the influence of sunlight or ingested, It is readily metabo-lized in the liver to form 25-hydroxyvitamin D (25(OH)D), the accepted measure of vitamin D status. 25(OH)D is then further metabolized by the 1 hydroxylase enzyme to its biologically active metabolite, 1 , 25 dihy-droxyvitamin D (1 ,25[OH]2D) 4,5 . Activated vitamin D circulates with a binding protein and enters the target cell to interact with its nuclear receptor. This complex then combines with the retinoic acid X receptor to form a heterodimer, which in turn interacts with the Vitamin D response element on the target gene. By increasing in-testinal calcium and phosphate absorption6, increasing renal calcium reabsorption, and enhancing PTH-mediated bone resorption (via its effect on RANKL), vitamin D has the net effect of increasing the serum cal-cium and phosphate concentrations. Additionally, the vitamin D receptor element is present on multiple genes, the vitamin D receptor in many organs, and 1-alpha hydroxylase activity occurs in extrarenal tissues7. These local tissue effects are responsible for the non-mineral-related effects of vitamin D; such as cell differentiation and proliferation and immune regulation8.

Vitamin D deficiency The two most common causes of vitamin D deficiency remains decreased intake of vitamin D containing food and reduced sun exposure. The major source of vitamin D is exposure to sunlight, anything that diminishes the transmission or penetration of solar UVB into the skin will affect the cutaneous synthesis of vitamin D3. Vita-min D deficiency can therefore occur in people who live without sun exposure (including those whose skin is constantly protected from the sun by protective clothing, indoor life styles and sunscreen use.). In addition, very few foods naturally contain vitamin D and foods that are fortified with with vitamin D are often inadequate to satisfy the vitamin D requirements. Serum levels of less than 20 ng/mL (50 nmol/L) of 25-OH vitamin D are a commonly accepted cutoff for vitamin D deficiency , whereas levels between 20 and 30 ng/mL (50 to 75 nmol/L), are considered insufficiency9,10.

Asymptomatic or minimally symptomatic vitamin D deficiency is increasingly being recognized around the world. In Pakistan, a number of small studies have identified a high prevalence of vitamin D deficiency in pa-tient populations that include those presenting with hip fractures, obstetric cases and those attending ambulatory care clinics. Risk factors include a history of poor nutrition, lack of exposure to sunlight, and a low socioeco-nomic status. Zuberi LM et al11 reported that 92% of outpatients presenting to the AKUH, were vitamin D defi-cient; 62% had severe, 24% moderate and 8% had mild deficiency. Almost half of all these patients (including those with severe deficiency) were asymptomatic. Two separate studies from our center involving healthy, as-ymptomatic volunteers have identified a high prevalence of vitamin D deficiency (unpublished data). Baig MA et al12, in a study on outpatients from two public hospitals in Karachi, identified that 92% patients were vitamin D deficient and that the most severe form of D deficiency was seen in patients with tuberculosis.