Journal of Tropical Pediatrics, 2016, 62, 29–37 doi: 10.1093/tropej/fmv073 Advance Access Publication Date: 22 October 2015 Original Paper
Active Tuberculosis in HIV-Exposed Tanzanian Children up to 2 years of Age: Early-Life Nutrition, Multivitamin Supplementation and Other Potential Risk Factors
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Harvard T.H. Chan School of Public Health, Boston, MA 02115, U.S.A. Muhimbili University of Health and Allied Sciences, United Nations Rd, Dar es Salaam, Tanzania. 3 Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, U.S.A. Correspondence: Ibironke O. Olofin, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Tel: 617-432-1232. Fax: 617-432-6733. E-mail . 2
ABSTRACT Background: Over half a million children worldwide develop active tuberculosis (TB) each year. Early-life nutritional exposures have rarely been examined in relation to pediatric TB among HIVexposed children. We therefore investigated independent associations of early-life nutritional exposures with active TB among HIV-exposed children up to 2 years of age. Methods: Participants were children from a randomized controlled multivitamin supplementation trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008, who received daily multivitamin supplements or placebo for 24 months. Results: Lower mean corpuscular volumes [relative risks (RR): 0.48, 95% confidence interval (CI): 0.27, 0.87] and higher birth weights (RR: 0.61, 95% CI: 0.37, 0.99) were protective against active TB, whereas multivitamin supplementation was not associated with TB risk (RR: 0.87, 95% CI: 0.65, 1.16). Conclusions: Knowledge of nutrition-related risk and protective factors for TB in HIV-exposed children could enhance preventive and case-finding activities in this population, contributing to efforts to reduce the global TB burden. K E Y W O R D S : pediatric tuberculosis, nutrition-related factors
INTRODUCTION Tuberculosis (TB) is the second most important single infectious cause of mortality worldwide [1]. According to the World Health Organization (WHO), over half a million children develop active TB each year [1], though the estimate may be closer
to 1 million [2] because TB infection may be underdiagnosed [3], especially in children [4]. Some risk factors for TB have been identified by different studies; however, few studies have examined early-life nutritional factors as risk factors for symptomatic TB disease, particularly in young HIV-exposed children.
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by Ibironke O. Olofin,1 Enju Liu,1 Karim P. Manji,2 Goodarz Danaei,1 Christopher Duggan,1,3 Said Aboud,2 Donna Spiegelman,1 and Wafaie W. Fawzi1
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Nutrition-associated factors and Pediatric Tuberculosis
MATERIALS AND METHODS The study involved children who participated in a randomized controlled trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008. In the trial (described elsewhere [7]), 2387 HIVexposed infants were randomly assigned at age 6 weeks to receive daily oral placebo or multivitamin supplements (vitamin C, vitamin E, thiamine, riboflavin, niacin, vitamin B-6, folate and vitamin B-12) for 24 months. At monthly study visits, nursing staff recorded infant feeding information, took medical history, performed symptoms checks and assessed compliance with assigned regimens. Children also received routine immunizations and growth monitoring. Study physicians diagnosed and treated illnesses whenever they occurred, in addition to providing routine examinations every 3 months to all study children. All children received standard care according to Tanzanian Ministry of Health guidelines. At enrollment and every 6 months thereafter, children provided blood samples for complete blood count estimation and T-lymphocyte subset counts. Children were tested for HIV infection at 6 weeks and 18 months of age using an HIV-1 DNA polymerase chain reaction test, and infected children were treated according to national guidelines. Starting in July 2005, the standard first-line antiretroviral (ARV) regimen administered to eligible adults comprised stavudine, lamivudine and nevirapine,
while children received zidovudine, lamivudine and nevirapine. Before this, standard care consisted of nevirapine prophylaxis for preventing mother-tochild transmission of HIV—mothers received one nevirapine dose at the start of labor, while the newborn received one dose within 72 h of birth.
Statistical analysis We defined incident active TB as a new presumptive diagnosis of active TB made by study physicians, possible active TB identified using clinical criteria modified from the Edwards TB score [8] (Supplementary Table S1) or both. We evaluated the performance of the case definition among 130 HIV-infected study children who were seen by the Management and Development for Health program, Dar es Salaam, no more than 18 months after identification as a TB case and within 18 months of the last study visit for non-cases. Of these children, 19 had pulmonary TB, which was diagnosed by physicians based on clinical and chest X-ray findings (prevalence 14.6%), and the case definition had a specificity of 77.5%, sensitivity of 47.4%, positive predictive value (PPV) of 26.5% and negative predictive value (NPV) of 89.6% among these HIV-infected children. One infant with possible active TB at baseline was excluded from analyses. To identify independent risk factors for active TB in this population, we examined independent associations of maternal and family factors with active TB in children: family size, daily amount spent on food for each family member, mother’s years of education and time-varying factors: mother’s age, CD4 T-cell count, antiretroviral therapy (ART) initiation status, mean corpuscular volume (MCV) and hemoglobin concentration. Multivariate models included the listed variables, as well as the year of study enrollment. Next, we examined the independent associations of child-specific factors with active pediatric TB, including risk factors related to nutritional status, such as birth weight, whether colostrum was given after birth, baseline length-for-age, number of months of breastfeeding and time-varying MCV as a surrogate for iron status. Other child factors were sex, Bacille-Calmette-Guerin (BCG) vaccination status, whether the child was born at term, size for
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We therefore sought first to examine if risk factors suggested by previous studies were important in HIV-exposed children. We also aimed to examine relationships of early-life nutritional factors, such as birth weight, height/length-for-age and iron status, with active TB in HIV-exposed children up to 2 years old, after accounting for previously identified risk factors. Third, multivitamin supplementation led to increased hemoglobin concentrations of the HIVexposed children in our study [5], and given the potential of the Mycobacterium tuberculosis organisms to use the heme component of hemoglobin as an iron source for their growth [6], we aimed to understand the effect of multivitamin supplementation on the incidence of active TB among HIV-exposed children.
Nutrition-associated factors and Pediatric Tuberculosis
RESULTS Of the 2387 infants enrolled in the randomized trial, 2358 qualified for the current study (Fig. 1). Most children had mothers with at least 7 years of schooling, received BCG vaccination at birth and were being breastfed at study enrollment; 11% were HIVinfected at baseline (over 60% of HIV-infected infants had started ART at baseline). Baseline characteristics were similar for children in the multivitamin and placebo groups (Table 1). The incidence rate of active TB among children was 5.5 per 100 child years, with a median time to first diagnosis of 6.6 months (interquartile range 2.811.5 months) for the 183 TB cases. Maternal and family risk factors for active TB in children are presented in Table 2. After adjusting for other risk factors, having a mother with >7 years of schooling significantly lowered a child’s risk of TB by 40% [95% confidence interval (CI): 5–61% lower, p ¼ 0.03]. Table 3 shows univariate and multivariate estimates of the associations of child-specific factors with active TB. After adjusting for family, maternal and the other child-specific factors, boys were significantly more likely than girls to develop active TB (RR: 1.44, 95% CI: 1.03, 2.02). HIV-infected
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children had a TB risk 4.8 times (95% CI: 3.2–7.1 times) greater than the risk of HIV-uninfected children. Also associated with a higher risk of active TB were having CD4 T-cell percentages
