Key messages
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Having diabetes probably increases the risk of developing tuberculosis disease to about double the population risk (1.5 to 2.4 times increased risk).
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These results apply to the general adult population; the risk for other groups, such as adolescents and children, is unclear.
What is tuberculosis?
Tuberculosis (TB) is an infection caused by the bacterium Mycobacterium tuberculosis. It primarily affects the lungs but can also affect other sites in the body. TB spreads through the air when a person with TB disease coughs or sneezes. Some people do not develop symptoms after infection, while others develop the disease and symptoms, such as persistent cough, weight loss, fever and night sweats. This is called TB disease.
The diagnosis of TB disease usually involves the administration of a molecular test or culture that detects the bacteria in a bodily secretion (such as sputum (mucus and saliva)) after consultation with a doctor.
TB is a major health concern globally; over 10 million people develop TB disease, and approximately 1.3 million die from the disease every year.
What is diabetes?
Diabetes is a chronic condition characterised by abnormally high blood glucose (sugar) due to inadequate insulin production by the pancreas or the body's inability to properly utilise the insulin it produces, or a combination of both. There are many different types of diabetes; the most frequent is called 'type 2 diabetes mellitus'. Insulin is a hormone that regulates blood sugar. This leads to symptoms such as thirst, frequent urination, tiredness, and slow healing of wounds. Without proper management, diabetes can lead to complications such as heart disease, kidney damage, nerve problems, and eye issues. Managing diabetes involves healthy eating, staying active, taking medicine, and monitoring health parameters to prevent complications.
What did we want to find out?
We wanted to estimate the risk of developing TB disease for people with diabetes compared to those without diabetes.
What did we do?
We looked at studies that included people with and without diabetes over time and compared how frequently each group developed tuberculosis.
What did we find?
We included 48 studies with over 61 million participants from the six WHO regions. However, the representation was variable as we found eight whole-population studies from South Korea, 19 from China, and only one from the African region (Ethiopia). Most studies were in adults, four in children and three in children and adults. On average, the studies followed people for five years.
We found that people with diabetes were at 1.5 to 2.4 times higher risk of developing tuberculosis compared to those without diabetes.
What are the limitations of the evidence?
Many of the studies had 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 fewer cases of TB. Moreover, well-defined diagnostic criteria for diabetes, including the type of diabetes and how well-controlled the glucose levels are, are needed to estimate the risk associated with the condition accurately.
How up-to-date is this review?
This evidence is up-to-date as of 3 May 2023.
Diabetes probably increases the risk of developing TB disease in the short term (< 10 years) and may also increase the risk in the long term (≥ 10 years). As glycaemic control and access to care may be potential effect modifiers of the association between diabetes and the risk of TB disease, the overall estimates should be interpreted with caution when applied locally. Policies targeted at reducing the burden of diabetes are needed to contribute to the aims of ending TB. Large population-based cohorts, including those derived from high-quality national registries of exposures (diabetes) and outcomes (TB disease), are needed to provide estimates with a high certainty of evidence 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 currently recommended methods for diagnosing TB would provide more up-to-date information relevant to practice and policy.
Tuberculosis (TB) is amongst the leading causes of death from an infectious disease, with an estimated 1.3 million deaths from TB in 2022. Approximately 25% of the global population is estimated to be infected with the TB bacterium, giving rise to 10.6 million episodes of TB disease in 2022. The prevalence of diabetes influences TB incidence and TB mortality. It is associated not only with an increased risk of TB disease but also death during TB treatment, TB relapse after treatment completion and multidrug-resistant TB. Since 2011, the World Health Organization (WHO) has recommended collaborative TB and diabetes activities as outlined in the Collaborative Framework for Care and Control of TB and Diabetes.
To determine the prognostic value of diabetes mellitus (DM) in the general population of adults, adolescents and children for predicting tuberculosis disease.
We searched the literature databases MEDLINE (via PubMed) and WHO Global Index Medicus, and 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. Prognostic factors assessed at enrolment/baseline included diabetes, as defined by the individual studies, encompassing patient-reported status, abstracted from medical records or claims data, or diagnosed by plasma glucose/glycosylated haemoglobin. The primary outcome was the incidence of tuberculosis disease. The secondary outcome was recurrent TB disease. We performed a random-effects meta-analysis for the adjusted hazard ratios, risk ratios, or odds ratios, employing the restricted maximum likelihood estimation. We rated the certainty of the evidence using the GRADE approach.
We included 48 cohort studies with over 61 million participants from the six WHO regions. However, the representation was variable as eight population-based studies were from South Korea and 19 from China, with overlapping study periods, and only one from the African region (Ethiopia). All studies included adults, and nine studies also included children and adolescents. Most studies diagnosed DM based on clinical records, including fasting blood glucose levels or glucose-lowering treatments. The studies did not distinguish between type 1 and type 2 DM; only one study focused on type 1 DM. Diagnosis and exclusion of TB were performed using culture or molecular WHO-recommended rapid diagnostic tests (mWRD) in only 12 studies, which could have biassed the effect estimate. The median follow-up time was five years (interquartile range 1.5 to 10, range 1 to 16.9), 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 show between-study heterogeneity represented in measuring 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).
DM may increase the risk of tuberculosis disease (HR 1.90, 95% CI 1.51 to 2.40; prediction interval 0.83 to 4.39; 10 studies; 11,713,023 participants). The certainty of the evidence is low, due to a moderate risk of bias across studies and inconsistency. Considering a risk without diabetes of 129 cases per 100,000 population, this represents 102 more (59 to 153 more) cases per 100,000.
When stratified by follow-up time, the results are more consistent across < 10 years follow-up (HR 1.52, 95% CI 1.47 to 1.57; prediction interval 1.45 to 1.59; 7 studies; 10,380,872 participants). This results in a moderate certainty of the evidence due to a moderate risk of bias across studies.
However, at 10 or more years of follow-up, the estimates yield a wider CI and a higher HR (HR 2.44, 95% CI 1.22 to 4.88; prediction interval 0.09 to 69.12; 3 studies; 1,332,151 participants). The certainty of the evidence is low due to the moderate risk of bias and inconsistency.
Odds Ratio (OR)
DM may increase the odds of tuberculosis disease (OR 1.61, 95% CI 1.27 to 2.04; prediction interval 0.96 to 2.70; 4 studies; 167,564 participants). Stratification by follow-up time was not possible as all studies had a follow-up < 10 years. The certainty of the evidence is low due to a moderate risk of bias and inconsistency.
Risk Ratio (RR)
The RR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. DM probably increases the risk of tuberculosis disease (RR 1.60, 95% CI 1.42 to 1.80; prediction interval 1.38 to 1.85; 6 studies; 44,058,675 participants). Stratification by follow-up time was not possible as all studies had a follow-up < 10 years. The certainty of the evidence is moderate due to a moderate risk of bias.
World Health Organization (203256442)
PROSPERO registration: CRD42023408807