ABSTRACT

The converging epidemics of non-communicable disease like DM (DM) and an infectious disease like tuberculosis (TB) is a double burden. DM is increasing in the same population that is at high risk for developing TB. There is a two-to-four-fold higher risk of active TB in individuals with DM and up to 30% of individuals with TB are likely to have DM. Immune deficiency either in absolute or relative quantities are sufficient for re-activation of latent TB. From a 10% risk of reactivation over the whole lifetime of an immunocompetent individual, the risk of reactivation increases to 10% every year in immune-deficient individuals. DM impairs cell mediated immunity and poor glycemic control affects cytokine response and alters the defenses in the alveolar macrophages. Fever, hemoptysis, extensive parenchymal lesions, and lung cavities are more common in those with DM particularly heavier and older males. DM increases the risk of treatment failure, death, and relapse. Evidence collected from meta-analysis conclude that DM can increase the odds of developing Multi Drug resistant TB (MDR-TB). The synergism between DM and TB necessitates bi-directional screening. Sputum examination for Ziehl-Neelsen staining is both a sensitive and specific screening test. Rapid molecular diagnostic tests like cartridge based nucleic acid amplification tests (CB-NAAT) are useful in cases where there is a high-index of suspicion and difficulty in arriving at a definitive diagnosis exists. Random plasma glucose and HbA1c (glycosylated Hemoglobin) measurements are convenient tests for DM screening that can be done in non-fasting individuals. Screening for DM more than once during the course of illness is sensible so that transient DM and new-onset DM can be identified. Anti-TB drugs affect glycemic control as they interact with anti-diabetic drugs by either stimulating or inhibiting the metabolizing enzymes. They may also aggravate metabolic, ocular, and neuropathic complications of DM. Insulin is the preferred drug in most instances. The presence of renal and hepatic dysfunction affects TB and hyperglycemic management. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Tuberculosis (TB) and diabetes mellitus (DM) are two diverse conditions of immense public health importance existing for centuries. TB was traditionally identified with poverty while DM was considered as an entity associated with prosperity. TB is today one of the commonest and widespread communicable infectious diseases largely but not necessarily confined to low-economic groups. DM on the other hand spearheads the group of chronic non-communicable diseases affecting people across all socio-economic strata. Contrary to previous beliefs, a larger number of people with DM are living in middle- and low-income countries. Unfortunately, these are the countries where DM is expected to increase in the near future (1). Both DM and TB have been associated with significant morbidity and mortality from time immemorial. Advancements in modern medical science over the years has definitely improved the outcome in both these conditions. But the magnitude of these two diseases has not waned and both are collaborative in worsening each other. In fact, the increase in the population affected with DM is sustaining the TB epidemic.

TB is associated with the endocrine system in different ways. The effects of TB on the endocrine system are discussed in detail in another Endotext chapter (2). The interaction of TB and DM is discussed in this chapter.

TUBERCULOSIS

TB is a global health threat, particularly to the poor and the susceptible. It is estimated that on average approximately 9 to 10 million people are affected by TB and around 1 to 2 million succumb to it annually (3). In 2019, 1.3 million people died due to TB. In developed countries, TB has slipped down in ranking among the global list of top 10 diseases causing mortality. However, in the underdeveloped regions it still remains among the top 10 diseases with high mortality (up to 30%). When in concurrence with retroviral infections, the risk of active TB is 12 to 20 times higher and the mortality is higher even in developed countries (4). Multi drug resistant TB is another rising problem which requires expensive second line drugs and a longer duration of treatment. A large proportion of the global population is at risk and the true prevalence and the annual incidence also depends on access to health care facilities and the laboratory-based testing capacity of the regions. Individuals who are in close contact with affected individuals, people living in crowded places, immigration to a country or area with a high prevalence of TB, and children less than 5 years of age are considered vulnerable to getting infected by the TB bacilli (Table 1). Bacillary load in the sputum of the infectious individual and close proximity to the infectious persons are two important external determinants for infection in any individual after exposure.

DIABETES MELLITUS

The prevalence of DM is rapidly increasing to justify it to be termed as an epidemic disease. According to WHO, the global prevalence of DM has doubled from 4.7% in 1980 to 8.5% in 2014 (8). From an estimated prevalence of 463 million in 2019, it is estimated to increase to 578 million in 2030, and 700 million in 2045. For every diagnosed individual with DM there is another undiagnosed person with DM (9). The differences in the prevalence of DM between high and middle-income countries and similarly between rural and urban population are decreasing.

According to WHO, non-communicable diseases constitute 7 out of the top 10 leading causes of death and DM is prominent among them. In 2019 the estimated number of deaths to have occurred due to DM globally is approximately 4 million (10). DM is associated with significant morbidity due to its microvascular and macrovascular complications and high cardiovascular mortality. DM is a major cause of cardiac ischemia, stroke, renal failure, blindness, and amputations.

THE DIABETES-TUBERCULOSIS EPIDEMIOLOGY: THE BIDIRECTIONAL LINK

The high prevalence of DM and TB being in epidemic proportions has rightly earned them the names ‘the converging epidemics’ and ‘double burden’ (11,12). Due to rapid changes in lifestyle, urbanization, and epidemiological changes, DM is increasingly seen in low- and medium-income groups, and in younger individuals more frequently than before. The prevalence of DM is increasing faster where TB is endemic already. Unfortunately, these are the regions in the world where health care facilities are less common. According to International Diabetes Federation, the 50-55% increase in the prevalence of DM over the next 2 decades will occur predominantly in the continent of Africa (10). A longitudinal, multi-national study involving low-income countries concluded that an odds ratio of 4.7 for prevalence and 8.1 for incidence of TB is highly likely in those counties where DM has increased over the last decade (13). The WHO states that younger age group individuals are three times more likely to get infected with TB (14). There is a two-to four-fold higher risk of active TB in individuals with DM compared to non-diabetic individuals (15). According to a meta-analysis by Wilkinson et al, around 4% of people with type 2 DM develop TB (16). Since the number of individuals with undiagnosed DM in the world is expected to be more than 50%, the proportion of TB in DM also should be much higher. Analytical models that try to project the future burden of TB in DM predict that the increase in DM counteracts the decreasing incidence of TB by at least 3% over the next 15 years (17).

Increased chances of finding undetected and uncontrolled hyperglycemia in close household contacts of subjects with TB have been mentioned in studies from Asian counties. In fact, a systemic analysis of a group of heterogenous studies on bi-directional screening i.e., screening for TB in DM affected individuals and vice versa has shown some evidence to support active screening for both DM and TB in the affected individuals and family members (18). Up to 35% of TB patients may have DM and the quoted figures are variable in literature (19). Jean Jacques Noubiap et al in their systematic review and meta-analysis of data from 2.3 million people with TB world-wide estimated that the prevalence of DM in patients with TB is around 15% and was twice that of the general population (20). These data clearly give epidemiological evidence for the co-existence of DM and TB as a syndemic. A potentially lethal combination of a communicable disease and a non-communicable disease having a synergistic effect is a challenge on the public health system.

Epidemiology of Diabetes Among Patients with Active Tuberculosis

The WHO collaborative framework recommends for a joint plan for DM and TB related activities which have to be reflected in the national plans on non-communicable diseases and TB respectively (21). As per the WHO approximately15% of TB cases in the world are associated with DM. Of these 15%, India accounts for more than 40% of the cases (19). Estimates of the burden of DM and TB co-existence has primarily come from studies looking at prevalence of DM and glucose intolerance among newly diagnosed patients with TB diagnosed in TB clinics. The community prevalence of these two disorders co-existing are not clear. Many of these studies have been done in hospitals where sicker patients with TB are treated which would probably account for a higher percentage of patients having glucose intolerance and DM. In a study from five randomly selected TB care clinics in the southern state of Tamil Nadu, around 25% of patients with TB had coexisting DM. Around 10% of these patients had newly diagnosed DM. Risk factors for having DM in this group of patients included older age, higher basal metabolic index (BMI), family history of DM among first degree relatives, and following a sedentary lifestyle (22). Close to Tamil Nadu in the southern state of Kerala, the prevalence of DM in patients with TB was nearly double that observed in the previous study. Among the patients with TB in Kerala, 44% had DM. Among them about half (21%) had newly diagnosed DM (23). The risk of DM was higher among those with sputum positive TB in both of these studies. In a study from Odisha on the Eastern part of India, 13.9% of tribal patients with TB had DM suggestive of a significant burden of disease even among poorer regions of the country (24). In a retrospective study, among 1000 patients with TB from the northern state of Punjab, 11.6% had DM and TB coexistence (25). In the same state the authors found 30% of patients with TB diagnosed in a tertiary referral hospital had DM (26).

To better understand the prevalence of DM among newly diagnosed patients with TB a large multicentric study involving five centers is in progress (GIANT Study - Glucose Intolerance Among New patients with TB - Clinical Trial Registry India - CTRI/2019/05/019396). This study incorporates simultaneous OGTT and HbA1c determinations at three different time points to ascertain if HbA1c can replace the standard oral glucose tolerance test (OGTT) in this population and avoid the inconvenience of performing an OGTT.

A recent systemic review and meta-analysis ascertained the worldwide prevalence of DM among active cases of TB. This meta-analysis involved over 200 studies that included a little under 2.3 million patients with active TB. The overall pooled prevalence was similar to the WHO estimate of 15% prevalence of DM in patients with active TB. However, this varied from 0.1% in Latvia to 45% in the Marshall Islands. The high prevalence areas as per the International Diabetes Federation included North America, Western Pacific (which includes Australia and China), South East Asia, North Africa, and Middle East Asia (27). Figure 1 summarizes the information on the prevalence of DM and active TB in 7 regions of the world.

Figure 1.

Prevalence of DM among patients with active TB in the seven International Diabetes Federation (IDF) regions of the world. The areas in red have the high burden of DM co-existing with active TB. The low burden areas are marked in blue. (adapted from ref 27)

DIABETES PREDISPOSING TO TUBERCULOSIS

Absolute or relative immune deficiency is sufficient for re-activation of latent TB. The association of increased prevalence of TB in immune deficient diseases like HIV is well established. The wider prevalence of DM makes DM a more important risk factor for developing TB than retroviral diseases. The higher incidence of multi-drug resistant TB reported to be significant in some studies (Odds Ratio of 2.1) reiterates the role of immune dysregulation in DM (28). The immune response in DM to TB is supposed to be hyper-reactive but ineffective and even deleterious as it may produce pulmonary tissue damage.

Chronic hyperglycemia impairs immunity (both innate and adaptive). DM impairs cell mediated immunity and poor glycemic control affects cytokine response and alters the defenses in the alveolar macrophages. Hyperglycemia disrupts the recruitment of neutrophils, chemotactic movement of monocytes, and phagocytic action of alveolar macrophages. Also, the antigen-specific interferon-gamma release is affected as the T-helper cell activation is ineffective. In addition, altered pulmonary microvasculature and micronutrient deficiency facilitate the invasion and establishment of TB as surveillance and nutrition is compromised. The chronic immunosuppression or ineffective immune response predisposes the individual for TB infection and with a higher bacilli load. This is summarized in Figure 2.

Figure 2.

DM is associated with increase in active TB and relapse in TB which both may be a result of the direct effect of diabetes. There is increased death in DM and TB which may be secondary to TB or due to the inherent excess mortality of DM due to cardiovascular disease

CLINICAL PRESENTATION

The manifestations of tuberculous infection in patients with DM have been documented to be different from those without diabetes. Fever and hemoptysis in diabetic population is more common compared to the general population. Radiographic differences include higher than usual parenchymal lesions and lung cavities (30). There are reports of a higher incidence of lower lobe involvement in individuals with DM in contrast to the classical upper lobe involvement in the general population. Also, a higher rate of other atypical presentations like a reduced rate of sputum conversion (low quality evidence), higher probability of treatment failure and death (moderate quality evidences) is known to occur when DM occurs with TB. A higher rate of recurrence and reactivation of latent TB infection (OR=1.83) has been documented (31). Subjects affected with TB and DM are found to be heavier and older males compared to those without diabetes. More pulmonary than extra-pulmonary involvement is seen in TB with DM (32).

BI-DIRECTIONAL SCREENING FOR DIABETES AND TUBERCULOSIS

The synergism between DM and TB in terms of epidemiology and outcome necessitates bi-directional screening for the presence of either TB or DM in the presence of the other disorder. The Collaborative Framework for Care and Control of TB and DM proposed by the World Health Organization (WHO) along with the International Union against TB and Lung is an effort towards bi-directional screening and management of both these conditions (36). Studies implementing bi-directional screening point towards its feasibility and effectiveness (18).

Radiography of the Chest

It has good sensitivity to pick up asymptomatic pulmonary cases, but there can be false positive results. Inconsistent evidence exists on the presence of atypical findings of TB in the chest x-rays of individuals with diabetes. The presence of clinical symptoms of fever, cough, hemoptysis, and weight loss with an abnormal chest-x-ray helps in the presumptive diagnosis of TB. Figure 3, 4, and 5 show different radiological presentations of pulmonary TB.

Figure 3.

Chest Radiographs suggesting fibrocavitatory lesions. Post primary infections and reactivation of pulmonary TB are more likely to cavitate. They are most common in the posterior segments of the upper lobes (85%) as seen in Picture A.Red arrow pointing to the cavity. The other common site is the superior segment of the lower lobe (Picture B) Yellow arrow pointing to the cavity (Picture courtesy- Prof Mary John, Christian Medical College and Hospital, Ludhiana)

Figure 4.

Chest Radiographs suggesting lobar consolidation.(Picture courtesy- Prof Mary John& Dr Neeru Mittal, Christian Medical College and Hospital, Ludhiana)

Figure 5.

Chest Radiographs suggesting miliary TB. It represents hematogenous dissemination of an uncontrolled tuberculous infection. Although implants are seen throughout the body, the lungs are usually the easiest location to image. Miliary deposits appear as 1-3 mm diameter nodules uniformly distributed in the lung parenchyma. (Picture courtesy- Prof Mary John & Dr Neeru Mittal, Christian Medical College and Hospital, Ludhiana)

Rapid Molecular Diagnostic Tests

Tests like cartridge based nucleic acid amplification test (CB-NAAT) (Figure 6) or rapid automated molecular test Expert MTB/ RIF assay using polymerase chain reaction have a quick turnaround time of two hours and additional advantage of using a single sputum sample. They also detect the presence of rifampicin resistance. Being expensive it cannot be used for screening all patients with DM even though it has high sensitivity and specificity. But they are useful in cases with high-index of suspicion and difficulty in arriving at a definitive diagnosis.

Figure 6.

All district hospitals in India have been provided with Cartridge Based-Nucleic Acid Amplification Testing equipment under the RNTPC program. Picture of the equipment at Civil Hospital, Ludhiana (Picture courtesy- Dr Ashish Chawla, Civil Hospital, Ludhiana)

MANAGEMENT OF DIABETES AND TUBERCULOSIS

ANTI-DIABETES THERAPY IN TUBERCULOSIS

The outcome of TB in DM is also dependent on good glycemic control. The management of hyperglycemia in TB depends on many factors like age, duration of diabetes, presence of complications of DM and co-morbidities, existing drugs, patient support and preferences, economic background and access to medical facilities.

Changes in the lifestyle pattern is once again reiterated when starting ATT. Adequate nutrition with high quality protein without affecting glycemic control is the corner stone of managing nutrition associated glycemic status in TB. In the presence of nephropathy or liver disease, the protein intake has to be modified appropriately and spurious use of protein is avoided. Vitamins particularly pyridoxine (B6), methylcobalamine (B12), vitamin A and Vitamin D should be adequately replaced. Tobacco use and alcohol consumptions have to be stopped. Moderate intensity exercise can help weight lose and improve glycemic control in overweight individuals.

Drug regimen, monitoring and follow-up should be individualized to maximize benefit with minimal discomfort and side effects like hypoglycemia, arrhythmias etc. Monitoring of capillary blood glucose at home, dose adjustment, monitoring of renal and liver functions are required during follow-up.

Anti-TB drugs can influence the metabolism of anti-diabetic medications (Table 3). Rifampicin, by cytochrome p450 enzyme induction, increases the metabolism of most oral anti-diabetic drugs, which may worsen the hyperglycemia. INH on the other hand inhibits cytochrome P450 enzymes and prolongs the effect of anti-diabetic drugs.

Aggressive therapy of DM is necessary for optimal response to TB therapy (Table 4). Insulin is the drug of choice in most illnesses including TB; insulin has the advantage of producing an anabolic effect, positive influence on appetite, and faster relief of hyperglycemic symptoms. It is the most suitable anti-hyperglycemic agent in cachexic and low BMI individuals. It is a mandatory therapeutic agent in Type 1 diabetes, pancreatic diabetes, severe DM and TB, coexisting renal or hepatic diseases, situations complicated by drug interactions and oral drug intolerance. Insulin is neutral in drug-to-drug interactions and achieves glycemic control faster than oral drugs. In the presence of fasting hyperglycemia of > 200 with ketonuria, Insulin is used to treat the hyperglycemia. It is also the preferred drug in renal impairment. The main disadvantage with insulin is that it has to be injected and more than twice a day in presence of infection/ stress. The indications for insulin use in patients with active TB and DM is summarized in Figure 7.

Figure 7.

Indications of Insulin Use in patients with Type 2 DM and Active TB

Metformin has the advantage of not producing hypoglycemia when used alone. It can however reduce appetite and needs caution while being used in renal or hepatic dysfunction. It doesn’t interact much with ATT and doesn’t influence cytochrome enzyme induced metabolism. It can help to shorten the course of TB therapy. It modifies the immune response and inflammation. It acts on the mitochondrial respiratory chain and can reduce the intracellular growth by acting through AMPK pathway which has a negative impact on the inflammatory process.

Metformin increases the host cell production of reactive oxygen species and acidification of mycobacterial phagosome (60). It has been found to downregulate oxidative phosphorylation, mammalian target of rapamycin (mTOR) signaling, and type I interferon response pathways (61). Sulphonylureas can be used for quick glycemic control. The long acting sulphonylureas like glibenclamide and glimepride have a risk of prolonged hypoglycemia particularly seen in anorexic individuals. Their plasma concentration and their duration of action are modified by drugs acting on cytochrome P450 system and hence monitoring of glycemic status is essential while on these drugs. Thiazolidinediones (pioglitazone) do not produce GI symptoms and are non-hypoglycemic when used as monotherapy. Monitoring of hepatic enzymes is required particularly when TB drugs are co-administered. Alpha-glucosidase inhibitors may be helpful in mild postprandial hyperglycemias. SGLT-2 inhibitors have the risk of further weight loss, euglycemic ketoacidosis, worsening of dehydration in sick patients, and urinary tract infections. They should not be used for glycemic control in patients who are sick and cachexic. In individuals who have no contra-indications they can be continued selectively under close follow-up (62, 63).

CO-MORBIDITIES OF DIABETES

PREVENTIVE METHODS

Aggressive DM screening among the population with TB and effective management of both TB and DM can improve outcome on an individual basis. The more effective approach to have an impact at the community level is to have a preventive strategy like vaccination against TB and aggressive prevention and management of DM (29).

SUMMARY

Epidemiological evidence for an uncharacteristic alliance between non-communicable disease like DM and a communicable disease like TB as a syndemic are overwhelming. A two-to four-fold higher risk of active TB in individuals with DM and twice the prevalence of DM in patients with TB explains the double burden. Ranked among the top ten mortal diseases, the geographical spread of both these diseases is unfortunately overlapping and the co-existence is progressive. They are increasing alarmingly in those regions where health care facilities are limited. DM impacts TB both from infection to disease stage and disease stage to progression stage. Chronic hyperglycemia compromises the alveolar defenses.

Latent TB infection is a dormant subclinical disease which lasts for weeks or decades. Immune deficiency either in absolute or relative quantities are sufficient for its re-activation. The clinical and radiological presentations of active TB have been reported to be pulmonary predominantly and atypical when DM co-exists with TB. DM increases the risk of treatment failure, death and relapse. The risk ratio for combined treatment failure and death was 1.69, unadjusted and adjusted risk ratios for death were 1.89 and 4.95 respectively and risk ratio for relapse was 3.89.

Bidirectional screening is recommended to improve the outcome in both diseases. Sputum microscopic examination, rapid molecular tests, random plasma glucose and glycosylated hemoglobin are the available among the screening tests with their own merits and limitations.

Anti-TB treatment has adverse impact on glycemic control and the complications of diabetes. The metabolism of some DM drugs is modified by ATT which affects glycemic control. Modifications of medications are required in co-morbid illnesses of DM like cardio-vascular diseases, renal, and hepatic dysfunction. Insulin is the drug of choice in lean diabetes, severe hyperglycemia, ketotic states, anorexic patients, and in drug intolerance. Metformin if tolerated has an advantage as a non-hypoglycemic agent with some favorable anti-TB activity.

Lifestyle modification, antihypertensive treatment, lipid-lowering therapy, and anti-platelet therapy are the cornerstones in the management of cardiovascular disease in DM and TB. Anti-platelet drugs are withdrawn in patients with hemoptysis. Chronic kidney diseases can predispose to TB and its management is complicated by drug toxicity and dose adjustment of ATT is required along with careful monitoring of response and renal functions. In case of ATT induced hepatotoxicity, ATT is withdrawn and second line agents are substituted. Once liver enzymes normalize the first line drugs are restarted cautiously.

Effective preventive strategies like vaccination against TB and aggressive prevention and management of DM will be the approach to be adopted till time throws new light on the means to fight these dual epidemics more effectively.

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