Iron Status Predicts Treatment Failure and Mortality in Tuberculosis Patients: A Prospective Cohort Study from Dar es Salaam, Tanzania

Tanzania. PLoS ONE 7(5): e37350. doi:10.1371/journal.pone.0037350 Iron Status Predicts Treatment Failure and Mortality in Tuberculosis Patients: A Prospective Cohort Study from Dar es Salaam, Tanzania Sheila Isanaka 0 Said Aboud 0 Ferdinand Mugusi 0 Ronald J. Bosch 0 Walter C. Willett 0 Donna Spiegelman 0 Christopher Duggan 0 Wafaie W. Fawzi 0 Srikanth Prasad Tripathy, National AIDS Research Institute, India 0 1 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, 2 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America, 3 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America, 4 Departments of Global Health and Population, Harvard School of Public Health, Boston, Massachusetts, United States of America, 5 Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, 6 Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, 7 Channing Laboratory, Department of Medicine, Harvard Medical School , Boston , Massachusetts, United States of America, 8 Division of Gastroenterology and Nutrition, Children's Hospital Boston , Boston, Massachusetts , United States of America Background: Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death. Methodology/Principal Findings: We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIVuninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin,30 mg/L) and high (plasma ferritin.150 mg/L for women and.200 mg/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of Creactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). Conclusions/Significance: Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality. - Funding: This work was supported by the National Institutes of Health [grant numbers U01AI045441, 1K24HD058795 to CD] and the Harvard University Committee on African Studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. With the expansion of high-quality directly observed treatment short course programs over the last 15 years, important progress has been made in reducing the global burden of tuberculosis (TB). TB disease, however, still carries an appreciable mortality, representing the worlds second leading cause of death from a single infectious agent [1]. Variability in disease progression, with approximately 10% of TB-infected individuals developing clinical disease in the absence of immunosuppression [2], suggests that individual factors may play a role in the response to infection. Micronutrient status, an important contributor to immune function and cytokine kinetics, has been increasingly suggested to play a role in the individual response to TB. The potential role of iron in TB was first reported in 1872 when a French physician noted a greater risk of relapse among recovering TB patients given iron-rich supplements [3]. Considerable experimental evidence has since accumulated demonstrating the contribution of iron availability to mycobacterial growth in serum, cells and mice [4,5,6,7]. Nevertheless, there are few reports on host iron status at the time of TB diagnosis, and limited epidemiological research has been conducted on the potential effects of iron status on the progression of TB disease. A small number of studies have shown elevated iron levels to be associated with an increased risk of TB infection and death from TB [8,9,10]. Iron deficiency has been associated with impaired immune function in in vitro and in vivo models [11,12], but evidence on the role of iron deficiency in the context of human TB disease is limited. To better understand the role of iron status in the progression of TB, we used data collected from a micronutrient supplementation trial conducted among adult TB patients in Dar es Salaam, Tanzania to assess the association of iron status with clinical outcomes in TB. We used plasma levels of ferritin, an iron storage protein that circulates in quantities proportional to the amount of iron storage, as an indicator of iron status and related high and low plasma ferritin at baseline with the risk of treatment failure, TB recurrence and mortality. Study population Between April 2000 and April 2005, 887 adults with pulmonary TB (471 HIV-infected and 416 HIV-uninfected) were enrolled in a randomized, placebo-controlled trial to examine the effect of micronutrient supplementation on sputum conversion (defined as the finding of an acid-fast bacilli [AFB] negative sputum culture) at one month, TB recurrence, and mortality. Details of the trial have been published elsewhere (ClinicalTrials.gov identifier NCT00197704) [13]. Patients were randomized, stratified by HIV status, to receive a daily oral dose of multiple micronutrients (not including iron) or placebo; all patients received an eightSocio-demographic characteristics Median age, y (IQR) Highest educational attainment Secondary or higher Median household sizec (IQR) Median number of household assets (IQR) Median amount spent on food (IQR)d Hemoglobin ,11 g/dL C-reactive protein .10 mg/L History of tuberculosis disease Number of colonies in AFB culture Karnofsky score ,70% Median BMI (kg/m2, IQR) Median CD4 T cell count (cells/uL, IQR) WHO HIV clinical stagee HIV RNA.50,000 copies/mLe Baseline iron statusa Values are n (%), unless otherwise stated. Totals may be less than 705 due to missing values. Abbreviations used: IQR, inter-quartile range, AFB, acid-fast bacilli, BMI, body mass index, WHO, World Health Organization. aB (...truncated)