Key messages
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Having undernutrition doubles the risk of getting tuberculosis.
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These results apply to the general adult population; the risk for other groups, such as adolescents and children, is uncertain.
What is tuberculosis?
Tuberculosis (TB) is an infection caused by a bacteria (Mycobacterium tuberculosis). It primarily affects the lungs but can also affect other sites in the body. TB spreads through the air when an infected person coughs or sneezes. Some people do not develop symptoms after infection, while others progress with the disease and develop symptoms, such as persistent cough, which may be bloody, weight loss, fever, and night sweats. After a TB diagnosis, this is called TB disease.
The diagnosis of TB disease usually involves a molecular test or culture that detects the bacteria in a bodily secretion (such as sputum) after consultation with a doctor.
TB is a major health concern globally; over 10 million people develop TB, and over 1.5 million die from the disease every year.
What is undernutition?
Undernutrition is a condition where the body does not get enough essential nutrients, affecting a person's health. Body mass index (BMI) is a measure that takes into account both weight and height. It helps identify if someone is underweight, which is one of the definitions of undernutrition. For children, we use "weight-for-height" to assess growth. It compares a child's weight to what is typical for their height, helping to gauge if they are thriving or facing nutritional challenges.
What did we want to find out?
We wanted to estimate the risk of getting TB disease for people with undernutrition compared to those without undernutrition.
What did we do?
We looked at studies that included people with and without undernutrition over time and compared how frequently each group developed tuberculosis.
What did we find?
We included 51 studies with over 27 million participants from the six World Health Organization (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 combined. On average, the studies followed people for 3.5 years.
We found that having undernutrition doubled the risk of getting sick due to tuberculosis compared to those who had not.
What are the limitations of the evidence?
Many of the studies had some limitations. One problem was that many of them used sputum microscopy to diagnose TB in people with symptoms, which might have missed some diagnoses. More accurate methods, such as culture or rapid diagnostic tests, currently exist and would miss less TB.
How up-to-date is this review?
This evidence is up-to-date as of 3 May 2023.
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.
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.
To determine the prognostic value of undernutrition in the general population of adults, adolescents, and children for predicting tuberculosis disease over any time period.
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.
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.
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.
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 1.95, 95% CI 1.72 to 2.20; prediction interval 1.49 to 2.55; 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.
World Health Organization (203256442).
PROSPERO registration: CRD42023408807