Convergence of a diabetes mellitus, protein energy malnutrition, and TB epidemic: the neglected elderly population

("ageing"[MeSH Terms] OR "ageing"[All Fields]) AND ("tuberculosis"[MeSH Terms] OR "tuberculosis"[All Fields]) yields 523 results

Activated mononuclear phagocytes stimulate granuloma formation in response to infection. As humans age, the macrophage capacity for phagocytosis diminishes, which is why the oxidative burst is compromised in elderly persons [30]. In a study involving TB patients, alveolar macrophages were less activated and had lower hydrogen peroxide production in those with DM comorbidity [31].

Additionally, in aged individuals the up-regulation of the major histocompatibility complex (MHC) class I and II expression as well as the antigen presentation capacity are reduced in dendritic cells, [32] which as a corollary diminishes interleukin 2 production and reduces T-cell proliferation. DM has been shown to hamper receptor-bound material, [33] which further limits the role of antigen-presenting cells in lymphocyte activation by preventing the phagocytes from binding and internalizing the antigen, for processing and presentation via their Fc receptors.

It is well known that in elderly humans NK cells show diminished cytotoxic capacity on a 'per cell' basis [34]. Other aspects of NK cell function, such as the secretion of IFN-γ in response to IL-2 and IL 12 are also compromised in the aging population [35]. The decrease in IFN-γ produced by NK cells is further emphasized in individuals with concomitant DM.

As humans age, the thymus naturally atrophies and the ability of stem cells to undergo clonal proliferation declines. This further emphasizes the reduced secretion of IL IFN gamma by the macrophages and NK in ageing individuals with DM. The inability to produce adequate numbers of mature T lymphocytes compromises the ability of elderly individuals to respond effectively to infections.

As T cells age, they also lose their capacity to produce and respond to IL-2 and IL 12 as major inducers of Th1 type responses, resulting in increased susceptibility to bacterial and viral infections and neoplasias among elderly persons, compared to young adults [36]. An additional synergistic factor is the impaired host resistance in individuals with DM. Namely, lymphocyte proliferation in response to phytohaemagglutinin has been found to be weak in patients with poorly controlled DM [37].

Resistance to mycobacterial infections is mediated largely by T helper type 1 (Th1) cells and their cytokines, whilst Th2 cells and their cytokines correlate with disease susceptibility and pathology in TB [38]. Whilst Th1 cytokines induces Th1 activity and block Th2 activity, [39, 40] Th2 cytokines promote Th2 activity while inhibiting Th1 activity [41]. The decrease in Th1:Th2 ratio may be of great importance in age-related immune changes, since Th1 mainly induces maturation and activation of the cytotoxic T lymphocytes which decrease with ageing, [42] while Th2 induces increased B lymphocyte immunoglobulin production which increases with ageing [43]. A recent study showed that diabetic TB patients had lower Th1:Th2 cytokine ratios and a higher Th2 bias. Also, the concentration of IL-4 alone was significantly higher in diabetic TB patients compared to non-diabetic TB patients and healthy subjects. As higher concentration of IL-4 is also found in aged individuals due to dysregulation between Th1 and Th2, [44] this synergistic elevation in IL-4 secretion may contribute to increased pathogenesis in diabetic TB patients because IL-4 impairs anti-microbial activity of infected cells and increases availability of iron to intracellular M. tuberculosis.

Elderly DM patients also show an altered T cytokine production pattern. In aged individuals, lymphocytes produce less IFN-γ, the main T-helper-1 (Th1) cytokine and the main mediator of protective immunity against TB. DM in aged individuals might further adversely affect T-cell production of interferon γ, especially in high-glucose conditions. Consequently, T cell growth, function and proliferation is affected, further compromising effective mononuclear phagocytes and NK cell mediated response to tuberculosis.

Studies show that when the glycated hemoglobin (HbA1c) is <8.0 %, the proliferative function of CD4 T lymphocytes and their response to antigens remains unimpaired [14]. This was also illustrated in a study of 4690 elderly diabetic patients in Hong Kong: those with haemoglobin A1c > 7 % had a three times higher risk of active tuberculosis compared with those with haemoglobin A1c < 7 % (HR 3 · 11; 95 % CI 1 · 63–5 · 92) [45].

In Taiwan, a prospective study of 17 715 Taiwanese persons selected from the general population suggested that the participants’ risk of tuberculosis increased as the number of complications of DM increased (P = 0.0016), with >3-fold risk among those with ≥2 diabetes-related complications (odds ratio, 3.45; 95 % CI, 1.59–7.50) [46].

Aside from clinically manifested diabetes, a study on infected guinea pigs showed that non-diabetic hyperglycaemia has the potential to significantly worsen active TB, [47] suggesting that inflammation-associated insulin resistance during TB infection may be an additional factor contributing to hyperglycaemia.

The lower disease-fighting capacity of the elderly, especially diabetics, which is partly attributable to the deregulation of the immune system and the greater secretion of macrophage pro-inflammatory cytokines in response to antigenic challenge, also leads to greater or longer-lasting body metabolic changes in this population group [48].

Whilst no change was found in T cell function in very healthy elderly individuals without nutritional deficit,[48] micronutrient deficiency has been shown to further lower immunity by affecting all parameters of CMI, well beyond the effect attributable to the ageing process alone, resulting in increased susceptibility to infectious diseases [49]. The decrease in immune functions strongly correlates with the level of nutritional deficiency, [50] with severely immuno-deficient aged individuals suffering from severe PEM, a condition marked by insufficient protein and calorie intake. Whilst PEM significantly affects innate immunity in the elderly, [51] it chiefly impairs CMI. The resultant atrophy of the thymus [52] reduces the number of circulating T cells, thereby decreasing the effectiveness of the memory response to antigens. PEM is also associated with significantly reduced vaccine antibody responses in the elderly population [53].

The link between body weight and TB has been increasingly reported in scientific literature. A systematic review from 2009 found a strong and consistent log-linear relationship between TB incidence and BMI across a variety of settings, with different levels of TB burden [54]. In populations where protein insufficiency is common, it may contribute substantially to TB incidence [55]. Namely, a recent large prospective study showed that the population-estimated hazard of developing TB for persons with low BMI (<18.5 kg/m²) was HR 12.4 (95 % CI: 5.7, 26.9) greater compared to persons with normal BMI, after controlling for socio-economic factors, excess alcohol consumption, smoking and diabetes mellitus [28].

Also, a cohort study in Taiwan involving patients with a mean age of 64.6 years found that insufficient body weight was associated with higher risks of TB-specific and non-TB-specific mortality during TB treatment, particularly in male patients, after adjusting for age, sex, clinical findings, and comorbidities [56].

Insulin is a strongly anabolic hormone for protein, [57] fat, [58] and glycogen [59] accrual, and deficiency or resistance to insulin may also promote PEM. In addition, comorbidities that diabetic patients are more prone to, such as catabolic events including myocardial infarctions, strokes, infection, ischemic atrophy, [60, 61] cutaneous ulcers and gangrene [62] in the extremities increase the likelihood of PEW/ PEM. Studies have demonstrated a higher frequency of protein-wasting in diabetic patients compared to nondiabetic end-stage renal disease patients on maintenance dialysis therapy [63‐65].

It is noteworthy that ageing is also associated with decreased capacities to cope with metabolic changes resulting from underfeeding and/or nutritional responses to disease [66]. A personal communication by Nyadzayo-Rossi (who carried out a not yet published cohort study in moderately undernourished adults in Zimbabwe) found that moderately undernourished adult TB patients appear to be at a higher risk of not responding to nutritional treatment compared to those not affected by TB. This finding highlights the need for preventing undernutrition in aged individuals in order to improve TB control, while considering the impact on glycaemic control.

PEM in turn contributes to increased frailty due to depletion of protein body reserves and consequent susceptibility to recurrent TB episodes or other infections in these individuals, already suffering from a lower protection against free radicals. Consequently, PEM is compounded in aged individuals, who suffer from reduced immune responses [49]. Moreover, there is also a possibility of increased TB drug malabsorption in elderly patients [67]. This may be accentuated by PEM, which in turn impairs drug absorption, [68] thereby adding a new dimension to the growing problem of MDR TB. In 2011, a meta-analysis estimated that DM patients have a risk ratio (RR) for the combined outcome of failure and death of 1.69 (95 % CI, 1.36 to 2.12) and an increased risk of relapse (RR, 3.89; 95 % CI, 2.43 to 6.23) after TB treatment [69]. Several studies have reported a high prevalence of DM among patients with MDR-TB, [70‐72] including an association between DM and MDR-TB after adjusting for confounding factors [73]. However, 4 studies in disparate settings showed no significant increased risk [74‐76].

According to WHO estimates, less than 50 % of all cases worldwide are currently diagnosed and treated [77]. Furthermore, due to compromised immunity, such as HIV infection, atypical clinical and radiological features in elderly individuals with DM and PEM as well as false negative tuberculin reactions may be very frequent [78]. A recent study underscored how untimely and difficult diagnosis, along with a higher risk of poor outcomes even after treatment completion emphasizes the need to devise specific strategies for this vulnerable group [79].

Diabetes negatively affects TB drug treatment, especially in patients with poor glycaemic control, which may be attributed to altered drug pharmacokinetics in DM. DM affects protein, lipid and carbohydrate metabolism as well as various aspects of pharmacokinetics. These include changes in absorption for several drugs administered via the subcutaneous and intramuscular route, as well as the oral route due to disordered gastric emptying (generally abnormally slow in 30–50 % DM patients, also slower during hyperglycaemia and accelerated during hypoglycaemia) [80]. Furthermore, the impact of DM on enzymes/transporters involved in drug biotransformation, as well as the reduction of plasma protein binding and displacement of drugs from their protein binding sites (due to higher circulating amount of free fatty acids in DM) [76] also affects drug pharmacokinetics. A recent study on TB showed that disease progression in guinea pigs with impaired glucose tolerance was similar to that of non-diabetic controls in the early stages of infection but got more severe by day 90 [81]. Drug toxicity risk may be higher due to excessive drug accumulation in the body, as a result of diabetic nephropathy.

A study involving 17 Indonesian patients with TB-DM comorbidity found 53 % lower plasma concentrations of rifampicin in these patients, compared to patients with TB only. These pharmacokinetic changes have been associated with clinical failure and acquired drug resistance [82]. These observations are congruent with those of a study from Mexico published in 2013 which reported that the proportion of TB patients on first line TB therapy who converted sputum cultures to negative ≥60 days of treatment was significantly greater in patients with DM (45.9 %) compared to those without DM (37.2 %) [83].

The influence of DM on MDR-TB patient outcomes is understudied [84]. Findings from a study on MDR-TB in 2012 involving diabetic patients from five countries, reported a lower non-significant univariate rate ratio (HR 0.76, 95 % CI 0.54–1.06) of sputum culture conversion among patients with DM [85]. These findings are congruent with those of a recent cohort study of adult pulmonary MDR-TB patients from Georgia, according to which, after adjusting for important confounding factors, the rate of sputum culture conversion and the risk of poor treatment outcome was similar in MDR-TB patients with and without DM, adjusted HR estimate (0.95, 95 % CI 0.71–1.28).

A bi-directional relationship has also been observed, as ethionamide or protionamide have been shown to make DM management in patients undergoing treatment with the above drugs more difficult [66].

Randomized clinical trials exploring the optimal methods of monitoring for PEM as well as prevention and treatment of these disorders in diabetic elderly patients are clearly needed.

At a biological level, there is a need of a better understanding of diabetes-related immunopathogenic mechanisms reinforcing immunosenescence, and mechanisms by which DM may lead to MDR TB.

Although a large prospective study found that persons with low BMI (<18.5 kg/m²) are at higher risk of developing active TB compared to those with normal BMI, after controlling for socio-economic factors, excess alcohol consumption, smoking, and diabetes mellitus, it may also be useful to adjust for micronutrient deficiencies. Also, this area of research would benefit from a case control study, wherein active TB elderly patients are compared to non active TB patients in terms of BMI, using the WHO BMI categorization [87]: <16 = severe malnutrition, 16–16.99 = moderate malnutrition, 17–18.49 = mild malnutrition; 18.5-24.99 = normal weight, 25–29.99 = overweight; ≥30 = obese.

Furthermore, it may also be necessary to explore more thoroughly whether TB patients have more difficulties in recovering from malnutrition compared to non-TB patients, a recommendation which is also stipulated in the WHO nutritional guidelines for TB [88].

Reducing the duration of infectiousness will require establishment of an appropriate clinical diagnostic algorithm and adaptation of clinical guidelines to address elderly patients with DM. Clinical research is warranted to establish a clinical diagnostic algorithm as well as clinical management guidelines targeting this population.

Twenty randomized trials involving treatment of latent TB infection (LTBI) to prevent active TB in more than a dozen countries demonstrated that isoniazid (INH) administered for at least 6 months in persons with LTBI reduced subsequent TB incidence by 25 to 92 % [89]; the differences were mainly attributed to variation in treatment completion. In the elderly population with DM and PEM, the effectiveness of an INH regimen still needs to be determined, along with exploring its high potential for hepatotoxicity and the pharmaco-epidemiology of INH interaction with other drugs.

Studies have shown that TB can even cause DM in those not previously known to be diabetic, with TB patients showing higher rates of glucose intolerance than community controls [33, 90, 91]. This may not only lead to a global explosion of TB cases, but also DM cases. Furthermore, determining the bi-directionality of TB and DM and the potential of DM to fuel not only a TB, but potentially a MDR TB epidemic will need to be investigated.