Undernutrition as a risk factor for tuberculosis disease

Abstract

Background: Tuberculosis (TB) is a leading cause of mortality due to an infectious disease, with an estimated 1.6 million deaths due to TB in 2022. Approximately 25% of the global population has TB infection, giving rise to 10.6 million episodes of TB disease in 2022. Undernutrition is a key risk factor for TB and was linked to an estimated 2.2 million TB episodes in 2022, as outlined in the World Health Organization (WHO) Global Tuberculosis Report.

Objectives: To determine the prognostic value of undernutrition in the general population of adults, adolescents, and children for predicting tuberculosis disease over any time period.

Search methods: We searched the literature databases MEDLINE (via PubMed) and WHO Global Index Medicus, as well as the WHO International Clinical Trials Registry Platform (ICTRP) on 3 May 2023 (date of last search for all databases). We placed no restrictions on the language of publication.

Selection criteria: We included retrospective and prospective cohort studies, irrespective of publication status or language. The target population comprised adults, adolescents, and children from diverse settings, encompassing outpatient and inpatient cohorts, with varying comorbidities and risk of exposure to tuberculosis.

Data collection and analysis: We used standard Cochrane methodology and the Quality In Prognosis Studies (QUIPS) tool to assess the risk of bias of the studies. Prognostic factors included undernutrition, defined as wasting, stunting, and underweight, with specific measures such as body mass index (BMI) less than two standard deviations below the median for children and adolescents and low BMI scores (< 18.5) for adults and adolescents. Prognostication occurred at enrolment/baseline. The primary outcome was the incidence of TB disease. The secondary outcome was recurrent TB disease. We performed a random-effects meta-analysis for the adjusted hazard ratios (HR), risk ratios (RR), or odds ratios (OR), employing the restricted maximum likelihood estimation. We rated the certainty of the evidence using the GRADE approach.

Main results: We included 51 cohort studies with over 27 million participants from the six WHO regions. Sixteen large population-based studies were conducted in China, Singapore, South Korea, and the USA, and 25 studies focused on people living with HIV, which were mainly conducted in the African region. Most studies were in adults, four in children, and three in children and adults. Undernutrition as an exposure was usually defined according to standard criteria; however, the diagnosis of TB did not include a confirmatory culture or molecular diagnosis using a WHO-approved rapid diagnostic test in eight studies. The median follow-up time was 3.5 years, and the studies primarily reported an adjusted hazard ratio from a multivariable Cox-proportional hazard model. Hazard ratios (HR) The HR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. We present 95% confidence intervals (CI) and prediction intervals, which present between-study heterogeneity represented in a measurement of the variability of effect sizes (i.e. the interval within which the effect size of a new study would fall considering the same population of studies included in the meta-analysis). Undernutrition may increase the risk of TB disease (HR 2.23, 95% CI 1.83 to 2.72; prediction interval 0.98 to 5.05; 23 studies; 2,883,266 participants). The certainty of the evidence is low due to a moderate risk of bias across studies and inconsistency. When stratified by follow-up time, the results are more consistent across < 10 years follow-up (HR 2.02, 95% CI 1.74 to 2.34; prediction interval 1.20 to 3.39; 22 studies; 2,869,077 participants). This results in a moderate certainty of evidence due to a moderate risk of bias across studies. However, at 10 or more years of follow-up, we found only one study with a wider CI and higher HR (HR 12.43, 95% CI 5.74 to 26.91; 14,189 participants). The certainty of the evidence is low due to the moderate risk of bias and indirectness. Odds ratio (OR) Undernutrition may increase the odds of TB disease, but the results are uncertain (OR 1.56, 95% CI 1.13 to 2.17; prediction interval 0.61 to 3.99; 8 studies; 173,497 participants). Stratification by follow-up was not possible as all studies had a follow-up of < 10 years. The certainty of the evidence is very low due to the high risk of bias and inconsistency. Contour-enhanced funnel plots were not reported due to the few studies included. Risk ratio (RR) Undernutrition may increase the risk of TB disease (RR 1.96, 95% CI 1.73 to 2.21; prediction interval 1.50 to 2.56; 4 studies; 1,475,867 participants). Stratification by follow-up was not possible as all studies had a follow-up of < 10 years. The certainty of the evidence is low due to the high risk of bias. Contour-enhanced funnel plots were not reported due to the few studies included.

Authors' conclusions: Undernutrition probably increases the risk of TB two-fold in the short term (< 10 years) and may also increase the risk in the long term (> 10 years). Policies targeted towards the reduction of the burden of undernutrition are not only needed to alleviate human suffering due to undernutrition and its many adverse consequences, but are also an important part of the critical measures for ending the TB epidemic by 2030. Large population-based cohorts, including those derived from high-quality national registries of exposures (undernutrition) and outcomes (TB disease), are needed to provide high-certainty estimates of this risk across different settings and populations, including low and middle-income countries from different WHO regions. Moreover, studies including children and adolescents and state-of-the-art methods for diagnosing TB would provide more up-to-date information relevant to practice and policy.

Funding: World Health Organization (203256442).

Registration: PROSPERO registration: CRD42023408807 Protocol: https://doi.org/10.1002/14651858.CD015890.

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Green indicates low risk of bias; yellow indicates moderate risk of bias; red indicates high risk of bias.

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Hazard ratio of the risk of incident TB disease due to undernutrition. The blue squares represent the hazard ratios of the individual studies. The red diamond represents the meta‐analysis for each subgroup, the green diamond represents the overall meta‐analysis, and their width represents the confidence interval. The green horizontal line emanating from the diamond represents the prediction interval (which can be found reported in the main text). ROB1: Study Participation; ROB2: Study Attrition; ROB3: Prognostic Factor Measurement; ROB4: Outcome Measurement; ROB5: Study Confounding; ROB6: Statistical Analysis and Reporting. The green, yellow, and red circles in each ROB column represent low, moderate, and high risk of bias, respectively.

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Contour‐enhanced funnel plot for the overall hazard ratio for the risk of incident TB disease due to undernutrition. The Y axis represents the standard error, and the X axis represents the log scale of the hazard ratios. The grey areas indicate the regions in which the different P values of the included studies map—Begg's test for asymmetry P value = 0.07.

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Odds ratio estimations for incident TB disease due to undernutrition. The blue squares represent the odds ratios of the individual studies. The green diamond represents the meta‐analysis, and its width represents the confidence interval. The green horizontal line emanating from the diamond represents the prediction interval (which can be found reported in the main text). ROB1: Study Participation; ROB2: Study Attrition; ROB3: Prognostic Factor Measurement; ROB4: Outcome Measurement; ROB5: Study Confounding; ROB6: Statistical Analysis and Reporting. The green, yellow, and red circles in each ROB column represent low, moderate, and high risk of bias, respectively.

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Risk ratios for the risk of incident TB disease due to undernutrition. The blue squares represent the risk ratios of the individual studies. The green diamond represents the meta‐analysis, and its width represents the confidence interval. The green horizontal line emanating from the diamond represents the prediction interval (which can be found reported in the main text). ROB1: Study Participation; ROB2: Study Attrition; ROB3: Prognostic Factor Measurement; ROB4: Outcome Measurement; ROB5: Study Confounding; ROB6: Statistical Analysis and Reporting. The green, yellow, and red circles in each ROB column represent low, moderate, and high risk of bias, respectively.

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Subgroup analysis by age groups for the risk of incident TB disease due to undernutrition. The blue squares represent the hazard ratios of the individual studies. The red diamond represents the meta‐analysis for each subgroup, the green diamond represents the overall meta‐analysis, and their width represents the confidence interval.

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These are the subgroups according to age reported in each individual study for the risk of incident TB disease due to undernutrition. As the studies had different definitions for age groups, these subgroups could not be pooled and were reported separately. Only one study indicated subgroup differences across the three age categories (Park 2022). The blue squares represent the hazard ratios of the individual studies. The red diamond represents the meta‐analysis for each subgroup, and their width represents the confidence interval.

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Subgroup analysis by sex for the risk of incident TB disease due to undernutrition. The blue squares represent the hazard ratios of the individual studies. The red diamond represents the meta‐analysis for each subgroup, and their width represents the confidence interval.

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Subgroup analysis for the recurrence of TB. Figure from Youn 2022 (Creative Commons Attribution Licence). The round dot represents the point estimate and the horizontal lines the confidence intervals. The dotted vertical line, the line of no effect (RR = 1).

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Subgroup analysis by HIV status for the risk of incident TB disease due to undernutrition. The blue squares represent the hazard ratios of the individual studies. The red diamond represents the meta‐analysis for each subgroup, the green diamond represents the overall meta‐analysis, and their width represents the confidence interval.

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Subgroup analysis by degree of undernutrition for the risk of incident TB disease due to undernutrition. Severe malnutrition was defined in the studies as BMI < 16 (Chang 2015), < 17 (Liu 2015), or weight‐for‐height < ‐3 SD (Beshir 2019; Li 2013). The blue squares represent the hazard ratios of the individual studies, the red diamond represents the meta‐analysis for each subgroup, and their width represents the confidence interval.

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Subgroup analysis for the risk of incident TB disease due to undernutrition based on comparison/reference group: Studies comparing underweight vs no undernutrition as a reference group (usually BMI > 18.5 kg/m², including overweight and obesity) and studies comparing underweight with a normal weight range as a reference group (usually BMI 18.5 to 25 kg/m²). The blue squares represent the hazard ratios of the individual studies, the red diamond represents the meta‐analysis for each subgroup, the green diamond represents the overall meta‐analysis, and their width represents the confidence interval.

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Subgroup analysis stratified by different time point categories for the risk of incident TB disease due to undernutrition: < 2 years, 2 to 5 years, 5 to 10 years, and 10 or more years. The blue squares represent the hazard ratios of the individual studies, the red diamond represents the meta‐analysis for each subgroup, the green diamond represents the overall meta‐analysis, and their width represents the confidence interval.

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Risk of recurrent TB disease due to undernutrition (HR: hazard ratio; RR: risk ratio). The blue squares represent the ratios of the individual studies, the red diamond represents the meta‐analysis for each subgroup, and their width represents the confidence interval.