Diabetes and Tuberculosis

BLANCA I. RESTREPO1
1
UTHealth Houston, School of Public Health at Brownsville, Brownsville, TX 78520

ABSTRACT The increase in type 2 diabetes mellitus (DM) middle-income countries where TB is also endemic (9).
patients in countries where tuberculosis (TB) is also endemic Consequently, the World Health Organization has iden-
has led to the reemerging importance of DM as a risk factor
tified DM as a neglected, important, and reemerging risk
for TB. DM causes a 3-fold increase in TB risk and a 2-fold
increase in adverse TB treatment outcomes. Given the sheer
factor for TB (1). In this chapter, “DM” refers mostly
numbers of DM patients worldwide, there are now more to type 2 DM since it is the most prevalent form, but type
TB patients with TB-DM comorbidity than TB-HIV coinfection. 1 DM in children has also been associated with TB (9,
There is an urgent need to implement strategies for TB 10). This chapter describes the epidemiology of TB-DM,
prevention and control among the millions of DM patients the impact of DM on the clinical presentation and out-
exposed to Mycobacterium tuberculosis. This chapter comes of TB, the underlying biology that favors the co-
summarizes the current epidemiological, clinical, occurrence of the two diseases, and the public health
and immunological knowledge on TB and DM and their
implications for TB control and DM management.
clinical and public health implications. These include the
underlying mechanisms for TB risk in DM patients and their
clinical and sociodemographic characteristics that distinguish
them from TB patients without DM. TB-DM comorbidity is EPIDEMIOLOGY OF TB-DM
posing a new challenge for integrating the short-term care DM As a Risk Factor for TB

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for TB with the long-term care for DM, particularly in DM prevalence has increased worldwide as a result
low- and middle-income countries.
of population aging, urbanization, changes in diet, and
reduced physical activity patterns resulting in increasing
obesity (11). About 80% of the 415 million estimated
INTRODUCTION
DM cases globally are from low- and middle-income
The global increase in type 2 diabetes mellitus (DM) is a countries, and DM prevalence is projected to rise
recognized reemerging risk and challenge to tuberculosis most steeply in regions with high TB incidence over the
(TB) control (1). Individuals with DM have three times next 30 years (9). A systematic review of 13 observa-
the risk of developing TB, and there are now more in- tional studies found that DM increases the risk of TB
dividuals with TB-DM comorbidity than TB-HIV co- 3-fold (relative risk [RR], 3.11; 95% confidence inter-
infection (2, 3). The association between DM and TB val [CI], 2.27 to 4.26) (3). Even though this is the best-
was first described centuries ago by Avincenna, a Persian characterized aspect of the association between TB and
philosopher, and the comorbidity was a frequent topic DM, these findings present wide variation between
in the medical literature in the first half of the 20th studies, with risk ratios ranging between 0.99 and 7.83.
century (4–7). But this literature dwindled as the asso-
ciation became less evident with the introduction of Received: 25 October 2016, Accepted: 1 November 2016,
insulin for DM patients and antibiotics for TB. In the Published: 23 December 2016
1980s, publications on joint TB-DM began to reemerge Editor: David Schlossberg, Philadelphia Health Department,
Philadelphia, PA
in parallel with the DM “pandemic”: the global preva- Citation: Restrepo BI. 2016. Diabetes and tuberculosis. Microbiol
lence of DM among adults has increased by 20% in less Spectrum 4(6):TNMI7-0023-2016. doi:10.1128/microbiolspec
than 30 years (8), and the number of individuals with .TNMI7-0023-2016.
Correspondence: Blanca I. Restrepo, blanca.i.restrepo@uth.tmc.edu
DM is predicted to reach 642 million worldwide by
© 2016 American Society for Microbiology. All rights reserved.
2040, with most (80%) of the patients living in low- and

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This illustrates the complexity of studying DM as a risk TB-DM increased by at least 2.8% among TB patients
factor for TB given the heterogeneity in DM popula- diagnosed between 2006 and 2013, and this was not
tions worldwide with respect to age, access to health explained by higher glucose testing implemented at TB
care, level of glucose control, and type and number of clinics in Mexico (20) (Fig. 2). A more remarkable in-
DM complications and medications. Furthermore, co- crease, 83%, was reported for all Mexican states be-
occurrence of DM with other host characteristics can tween 2000 and 2012 (21).
further synergize TB risk among DM patients, as sug-
gested for DM plus smoking, micro- and macrovascular Contribution of DM to TB Control
complications of DM, and even social environment (12– At the population level, the contribution of DM to TB
14). This emphasizes the need for studies reporting a is generally between 10 and 20%, but it can vary sub-
thorough characterization of DM and other host factors stantially even within a country. For example, in the
with multivariable analysis in order to reach reliable United Kingdom the general population attributable
conclusions. risk is 10%, but the risk rises to 20% in Asian males
The prevalence of TB-DM is higher in low- and (22). In countries where TB and DM are endemic, such
middle-income countries where TB and DM are most as India and Mexico, the population attributable risk
prevalent. Of the 10 countries with the highest num- reaches at least 20% (23, 24). At the Texas-Mexico
ber of DM patients worldwide, 6 are classified as “high border, our findings are even more striking, with data
burden” for TB by the World Health Organization, suggesting that DM is the underlying attributable risk
meaning that they contribute to 80% of the TB cases for nearly one-third (28%) of the adult TB cases and
worldwide (Fig. 1). As studies on the epidemiology 51% among TB patients who are 35 to 60 years old.
of TB-DM increase worldwide, certain regions display In this region, HIV contributes to only 3 to 6% of the
particularly high rates of prevalence of DM among TB adult TB cases (18). Therefore, even though DM confers
patients, including South India (54%), the Pacific Islands a significantly lower risk of TB at the individual level
(40%), and northeastern Mexico (36%) (15–18). How- (3-fold) than does HIV (>20-fold), in communities like
ever, developed countries are not exempt and can have these where the sheer number of DM patients is high,
subpopulations with similar hot spots, as in the case of the contribution of DM to TB can be higher than that
U.S. communities adjacent to Mexico, where the DM of HIV (25). A study using dynamic TB transmission
prevalence among TB patients is nearly 40% (18). The models to analyze the potential effects of DM on TB
co-occurrence of TB-DM is not likely to diminish any- epidemiology in 13 countries with a high burden of TB

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time soon. Longitudinal analysis of 163 countries re- concluded that stopping the rise of DM would avoid
ported increased TB incidence in settings where DM 6 million (95% CI, 5.1, 6.9) incident cases and 1.1 mil-
prevalence increased over time (19). In the Mexican state lion (1.0, 1.3) TB deaths in these countries in 20 years
of Tamaulipas, across the border with the United States, (26). Thus, every community worldwide needs to eval-
uate the prevalence of DM and its contribution to TB.
This information is variable between regions and critical
as guidance for the most efficient use of limited resources
FIGURE 1 Convergence of countries with highest burden
of TB and DM worldwide. Among the 10 countries with the
for TB control programs.
highest number of DM patients worldwide, 6 are also among
the 22 high-burden countries that contribute 80% of the TB Profile of the TB-DM Patient
cases worldwide (40). The profile of TB-DM patients is strikingly different
from that of patients with TB only, with TB-DM patients
being older, obese, and more likely to be females, who
are not as likely to present factors classically associated
with TB, such as alcohol abuse, consumption of illicit
drugs, incarceration, or HIV-AIDS. Thus, physicians
need to be trained in contemporary times to “think TB”
when examining patients with pulmonary infections
and a “nonclassical” sociodemographic profile for TB,
in order to avoid delays in TB diagnosis. TB-DM pa-
tients (versus patients with TB only) are also more likely
to have lower education and higher unemployment,

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 Diabetes and Tuberculosis

DM patients who have presumably been in contact for

years with their health care providers. However, TB-DM
patients should be distinguished from TB patients with
transient hyperglycemia secondary to the inflamma-
tion induced during TB (30). Thus, a new DM diagnosis
can be established only once the TB patient is no longer
febrile.

Impact of Association between TB and

DM on Early DM Diagnosis and Management
Given that an estimated 50% of DM patients in devel-
oping countries are not aware of their DM diagnosis,
TB clinics are becoming hubs for new diagnoses of
DM worldwide. Some studies show that newly diag-
nosed DM patients with TB (versus patients with pre-
viously diagnosed DM) have a different profile: they are
more likely to be males and younger and to have lower
HbA1cs (15, 18, 20). This highlights the importance of
TB clinics to reach males, who are not as likely to be in
contact with the health care system as are females, or to
identify patients who are at an earlier stage of their DM
before the presentation of additional and irreversible
micro- and macrovascular complications of DM. Thus,
FIGURE 2 Increase in the prevalence of TB-DM among a growing public health challenge for low- and middle-
TB cases over an 8-year period. Longitudinal analysis of the income countries where the two diseases are most likely
prevalence of TB-DM among newly diagnosed TB patients
to converge is to coordinate the long-term care required
reported to the state of Tamaulipas in northeastern Mexico
revealed an increase of 2.8% between 2006 and 2014 that is for DM with the immediate short-term care required for
not attributable to an increase in blood glucose testing for DM TB control.
diagnosis at TB clinics. Adapted from reference 20 with per-

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mission. LCI and UCI, lower and upper confidence intervals,
respectively. CLINICAL PRESENTATION OF
TB IN TB-DM PATIENTS AND
which complicates TB and DM management given PUBLIC HEALTH IMPLICATIONS
that these sociodemographic factors are associated with Many studies suggest that DM is associated with the
less access to health care and poorer glucose control clinical presentation of TB. Namely, TB-DM patients
(20). (versus TB patients without DM) are more likely to
present with pulmonary (versus extrapulmonary), cavi-
Directionality of the Association tary (versus noncavitary), and sputum smear-positive
Most studies on TB-DM are observational, with few TB at diagnosis. During the course of TB treatment, TB-
cohorts (all retrospective based on medical records), DM patients take longer to convert from sputum smear
so strict inference of directionality in the association is positive to negative. Some studies also find that DM
not possible. However, most data provide support for patients are more likely to present with drug-resistant
DM preceding TB. All cohorts to date indicate that and multidrug-resistant (MDR) TB, although this rela-
DM develops before TB, and those with further char- tionship is not seen in all studies (Fig. 3). I expand on
acterization of the DM patients suggest that it is not DM each of these below.
itself but poorly controlled DM that increases TB risk
(14, 27, 28). Cross-sectional studies also support the Pulmonary versus Extrapulmonary TB
concept of DM preceding TB, with chronic DM patients Pulmonary TB accounts for 70 to 80% of TB cases,
(median, 7 years) presenting other DM complications and it is generally accepted that immune compromise
prior to TB development (18, 20, 29). This highlights facilitates hematogenous dissemination of Mycobacte-
the missed opportunities for preventing TB among rium tuberculosis, predisposing to extrapulmonary TB.

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FIGURE 3 Impact of DM on the natural history of TB: association with dysfunctional

immunity and clinical characteristics. Exposure of M. tuberculosis-naïve individuals to a
pulmonary TB patient generally results in no infection (70%) or LTBI or primary TB (30%).
Among those infected, the lifetime risk of reactivation TB is 10%. If the host has DM (most
likely chronic and poorly controlled DM), the TB risk will increase 3-fold, although
the contribution of DM to LTBI, primary TB, or reactivation TB has not been quantified.

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Once TB develops, possible treatment outcomes include cure, treatment failure, or death.
DM increases the last two outcomes. TB relapses can occur among presumably cured
individuals. A history of TB does not confer immunity against all strains, and exposure to
another M. tuberculosis strain can lead to reinfection. DM can also increase reinfection
risks. Bold arrows and “DM” indicate stages of TB in which DM appears to have an impact.
As the natural history of TB evolves in the DM host, so does the immune response with
characteristics that contrast with those in the non-DM host. The TB-DM host is more likely
to present with clinical characteristics associated with enhanced TB transmission, but the
impact of disease spread in the community has not been systematically studied (bottom
text box; “DM?”). The dysfunctional immune response of the DM host to M. tuberculosis
antigens is likely to influence the development, clinical presentation, and outcomes of
TB, but the mechanisms involved are poorly understood (88). PTB, pulmonary TB; EPTB,
extrapulmonary TB; LTBI, latent TB infection; Mtb, M. tuberculosis.

Such is the case of TB patients with HIV-AIDS (31) or Cavitary and Smear-Positive TB
those taking tumor necrosis factor blockers (32). This M. tuberculosis induces a strong cell-mediated immu-
contrasts with TB-DM patients, who are less likely to nity leading to the formation of pulmonary granu-
present with extrapulmonary TB (17, 28, 33, 34). This lomas (tubercles), which are thought to be a double-
may be due to a hyperreactive cell-mediated immune edged sword for the host (38). Granulomas initially limit
response to M. tuberculosis in DM patients that may M. tuberculosis growth, but in hosts in whom the or-
be suboptimal for containing M. tuberculosis growth ganism continues to replicate, these structures undergo
within the lungs but effective for preventing its dissem- central caseation, with rupturing and spilling of thou-
ination and reactivation elsewhere (35–37). sands of viable bacilli into the airways. This cavitary TB

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 Diabetes and Tuberculosis

is associated with sputum smear positivity (39). TB-DM during treatment), which is also more likely in TB-DM
patients are more likely than TB patients without DM to patients than in TB patients without DM (51, 53, 54).
present with cavitary TB that is accompanied by higher
bacillary burdens in sputa (34, 40). Death
Together, the higher frequency of pulmonary versus Death was a hallmark of the comorbidity in the 1950s,
extrapulmonary TB, cavitary TB, and smear-positive with studies reporting that patients with DM were likely
TB at diagnosis and extending during treatment would to die from a diabetic coma or TB (4–7). In a systematic
predict that TB-DM patients are more infectious than review and meta-analysis of contemporary literature,
TB patients without DM (41). Studies investigating this Baker et al. concluded that the risk of death from TB
have never been conducted, but if confirmed, this would or any other cause in 23 unadjusted studies was nearly
mark another public health implication for the TB-DM 2-fold (RR, 1.89; 95% CI, 1.52 to 2.36), and this in-
comorbidity. creased to 4.95 (95% CI, 2.69 to 9.10) in 4 studies that
adjusted for age and potential confounders (51).
Drug-Resistant and MDR TB
The relationship between drug-resistant or MDR TB Relapse and Reinfection
and DM is unclear, as there are conflicting findings on TB-DM patients also appear to have a higher risk of
the association between higher rates of drug resistant relapse. The review by Baker et al. reported a nearly
or MDR TB in TB patients with DM when compared 4-fold risk of relapse in TB-DM patients versus that in
to those without DM (20, 42–50). In a meta-analysis of TB patients without DM (RR, 3.89; 95% CI, 2.43
publications up to 2010, the prevalence of drug-resistant to 6.23) (51). A prospective study in southern Mexico
or MDR TB among recurrent TB cases was not signifi- with 1,262 TB patients characterized for M. tuberculosis
cantly higher in TB-DM patients (odds ratio [OR], 1.24; genotypes further distinguished between relapses and
95% CI, 0.72, 2.16) (51). However, these findings were reinfections and found higher adjusted odds of both
based on only four studies. Hence, there is a need for outcomes in DM patients than in patients without DM
more studies that systematically evaluate the relation- (OR = 1.8 for both recurrence and relapse) (53).
ship between MDR TB and DM comorbidity, with
appropriate testing for MDR TB among the entire pop- Should TB-DM Patients Be Managed
ulation at the time of TB diagnosis (not just those with Differently from TB Patients Without DM?
treatment failures), multivariable analysis to sort out the The clinical findings and higher risk of adverse outcomes

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independent contribution of DM versus those of other in TB-DM patients indicate the need for prospective
confounders, and characteristics of the study population cohort studies aimed at confirming these observations
and protocols of the local TB control programs in order and identifying the underlying factors leading to treat-
to understand the circumstances under which MDR TB ment failures in DM. Two underlying factors are prime
and DM may synergize. suspects. The first is poor glucose control. Chronic hy-
perglycemia is associated with the dysfunctional immu-
nity to M. tuberculosis in DM patients (Fig. 3) and hence
TB TREATMENT OUTCOMES is likely to reduce the efficiency of antimycobacterial
IN TB-DM PATIENTS treatment. Hyperglycemia may also compromise M. tu-
There is growing evidence from observational studies berculosis killing by affecting the microvasculature and
that TB-DM is associated with an increase in adverse TB reducing lung tissue perfusion for optimal immune sur-
treatment outcomes, specifically for delays in mycobac- veillance. However, the need for intervention studies
terial clearance, treatment failures, death, relapse, and to assess the effect of glucose control on TB treatment
reinfection (Fig. 3) (27, 52, 53). outcomes is questionable (55), and the WHO considers
the available data to be sufficient to recommend opti-
Delays in Sputum Smear Clearance mized glucose control as part of the management of
and Treatment Failure TB-DM patients for improved TB outcomes (56). The
TB-DM patients are more likely than TB patients with- second suspect is possible suboptimal levels of anti-
out DM to remain sputum smear positive after com- mycobacterial antibiotics in the plasma of DM versus
pletion of the intensive phase of treatment, and this non-DM patients (57–59). While these studies have con-
outcome is an early predictor of treatment failure (spu- flicting results, further assessment of suboptimal drug
tum smear or culture positivity at 5 months or later levels and their relationship to treatment failure among

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Restrepo

TB-DM patients is required, particularly in the contin- TB-naive host with DM, we found that monocytes from
uation phase of treatment (60). This not only may lead healthy individuals with DM (versus individuals with-
to treatment failure but also can favor the development out DM) have a significantly reduced association (bind-
of MDR TB as discussed above. With the available in- ing and phagocytosis) with M. tuberculosis. This defect
formation, a joint group of expert clinicians have pro- appears to be attributable to alterations in the diabetic
vided recent guidelines for treatment of drug-susceptible monocyte itself as well as in serum opsonins for M. tu-
TB with specific recommendations for DM patients. berculosis, particularly the C3 component of comple-
First, depending on the resources and epidemiology of ment, which mediates M. tuberculosis phagocytosis (65,
the community, screening for DM should be performed 66) (Fig. 4). These in vitro findings in humans are con-
on all new TB patients with an age of >45 years, body sistent with in vivo observations in mice with chronic
mass index of >25, first-degree relative with DM, and DM, in which there is also a reduced uptake of M. tu-
race/ethnicity of African American, Asian, Hispanic, berculosis by alveolar macrophages within 2 weeks of
American Indian/Alaska Native, or Hawaiian Native/ infection (67). Furthermore, this model of chronic DM
Pacific Islander. Second, pyridoxine (vitamin B6) should in mice is associated with delayed innate immunity to
be given with isoniazid to DM patients, given their M. tuberculosis due to late delivery of M. tuberculosis-
higher risk of neuropathy. Third, given that DM patients bearing antigen-presenting cells to the lung draining
are more likely to present with cavitations and smear lymph nodes (68). Efficient phagocytosis and priming of
positivity at diagnosis and/or remain culture positive at 2 the adaptive immune responses are necessary to activate
months of treatment, a continuation phase of 7 months the cell-mediated immune response that restricts initial
duration is recommended, for a total of 9 months of M. tuberculosis growth (68), and these delays likely
therapy. Fourth, consideration should be given to mea- contribute to the higher risk in DM patients of M. tu-
suring their drug concentrations in serum (therapeutic berculosis infection and persistence (Fig. 3).
drug monitoring) to gain insights into the adequacy of
drug dosing and need for tailored adjustments. If the Adaptive Immune Responses to
DM patient has end-stage renal disease, then therapeutic M. tuberculosis in DM Hosts with LTBI and TB
drug monitoring may be necessary to adjust drug levels Studies with individuals with LTBI and DM
in the context of dialysis, assess interactions with other The scanty literature regarding individuals with latent
medications for the comorbid condition, and monitor TB infection (LTBI) and DM (LTBI-DM) versus LTBI
toxicity (61). without DM shows decreased frequencies of LTBI (69,

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70). It is possible that lower levels of proinflammatory
cytokines in DM can favor progression from LTBI to TB
BIOLOGICAL BASIS FOR THE ASSOCIATION in DM, but further studies are required to understand
BETWEEN TB AND DM the impact of lower anti-inflammatory cytokines as well.
Immunological impairment has played a major role in
TB susceptibility throughout history, and with the DM Studies with individuals with TB and DM
pandemic, DM is now among the most common causes In contrast to the case with LTBI, there are a number
of compromised immunity that favor TB development of immunological studies with TB-DM patients that in-
in contemporary times, along with HIV/AIDS, mal- dicate a hyperinflammatory response to M. tuberculosis
nutrition, aging, and smoking (62, 63). But DM differs antigens compared to that of TB patients without DM.
from these other underlying conditions in that the im- Most studies indicate that the ex vivo (whole blood) and
munity against M. tuberculosis is not necessarily “com- in vitro stimulation of peripheral white blood cells with
promised” but rather “dysfunctional,” with excessive mycobacterial antigens results in higher Th1 and Th17
and/or delayed responses against M. tuberculosis (64). responses, including higher levels of secretion of gamma
A summary of the key innate and adaptive components interferon (IFN-γ) (Fig. 5) and interleukin 17 (IL-17)
of the immune response that affect TB outcomes is (35–37). Levels of other cytokines promoting immu-
provided elsewhere. nity, such as IL-2 and granulocyte-macrophage colony-
stimulating factor, have also been reported to be higher
Innate Immunity to M. tuberculosis in TB-DM patients than in TB patients without DM
in the TB-Naive DM Host (35, 37). TB-DM cases also have a higher frequency
In studies to simulate the first encounter between of single- and double-cytokine-producing CD4+ Th1
M. tuberculosis and the innate immune response of a cells in response to M. tuberculosis antigens (for IFN-γ,

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 Diabetes and Tuberculosis

FIGURE 4 Lower phagocytosis of M. tuberculosis by monocytes from patients with DM.

Monocytes from TB-naive individuals with and without DM were cultured in RPMI medium
plus 20% fresh or heat-inactivated autologous serum. M. tuberculosis was added, and
after 2 h, the nonbound bacteria were washed. Then the associated (bound or phago-
cytosed) M. tuberculosis organisms were stained with auramine (orange), and monocyte
nuclei were stained with 4[prime],6-diamidino-2-phenylindole (DAPI) (blue) (left image).
The percent of monocytes with at least one associated M. tuberculosis organism was
quantified using fluorescence microscopy. Adherence of M. tuberculosis to monocytes is
mediated by antibodies to mycobacteria (Ab) and serum complement (C′) in fresh serum
and the corresponding Fc receptors and complement receptors on monocytes. Upon
serum heat inactivation, M. tuberculosis binding is mediated only by antibodies (65).

tumor necrosis factor alpha, or IL-2) (37). These hy- M. tuberculosis killing. There are several possible ex-
peractive responses in peripheral blood contrast with planations for the contribution of dysfunctional immu-
the results from a few studies conducted at the site of nity to these adverse treatment outcomes. (i) The higher
infection (in bronchoalveolar lavage fluid) in which TB- Th1 and Th17 response is present only in the peripheral
DM patients appear to have reduced activation of im- blood of TB-DM patients, while anti-inflammatory re-

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munity; one reported a lower proportion of activated sponses that facilitate M. tuberculosis growth occur
alveolar macrophages (71), and another reported higher only in the lungs. (ii) There is a higher production of
anti-inflammatory (IL-10) and lower proinflammatory proinflammatory cytokines like IFN-γ in the lungs of
(IFN-γ) cytokine levels (72). The impact of the host humans (as observed in mice), but it is not effective for
compartment (peripheral blood versus lung) requires downstream activation of macrophages or cytotoxic
further study. In mice with chronic DM and TB, there is T cells that ultimately kill M. tuberculosis. (iii) The
a higher pulmonary M. tuberculosis burden and more hyperreaction to M. tuberculosis antigens may be dele-
extensive inflammation with higher expression of proin- terious and contribute to lung tissue damage, with more
flammatory cytokines like IFN-γ (68, 73, 74). These severe TB and a higher frequency of death in TB-DM
findings in the lungs of mice resemble the hyperresponse patients. Understanding this complex relationship be-
to M. tuberculosis antigens in the peripheral blood of tween excessive immunity and TB-DM will help improve
TB-DM patients (versus TB patients without DM), with the clinical management of TB patients, regardless of
similar findings in the guinea pig model of TB-DM (75). their DM status. Current TB research interests include
the identification of host-directed therapies that syner-
Understanding Immune Dysfunction With gize with antibiotics for effective M. tuberculosis elimi-
Regard to M. tuberculosis in DM Patients nation. The goal of these host-directed therapies is to
Given that efficient M. tuberculosis killing by antimyco- boost immune mechanisms that diminish excess inflam-
bacterial antibiotics requires cooperation between the mation to reduce lung tissue damage and limit M. tuber-
innate and adaptive immune responses, the higher fre- culosis growth. Coincidently, the most commonly used
quency of adverse outcomes in DM patients suggests medication for type 2 DM, metformin, is one of the
that the hyperreactive immune response to mycobac- candidates for TB host-directed therapy (76). Prelimi-
terial antigens in TB-DM patients is not effective for nary findings suggest that metformin may be beneficial

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were clustered (similar genotypes, suggesting recent in-

fection) versus nonclustered (different M. tuberculosis
genotypes, suggesting reactivation of TB) did not differ
between TB-DM patients and TB patients without DM
(M. tuberculosis genotypes were clustered in 24% and
nonclustered in 76% in both study groups) (24). How-
ever, other findings suggest that DM may increase the
risk of primary TB. First, a cohort of close contacts of TB
patients in China reported that DM was a risk factor for
TB development within 5 years after the diagnosis of TB
in the index case (adjusted OR, 3.4; 95% CI, 1.0 to 11.3)
(79). Second, TB-DM patients are more likely to have
infiltrates in the lower lobe of the lung, which is where
M. tuberculosis implants upon inhalation. This is clas-
sical of primary TB, compared to upper lung infiltrates
FIGURE 5 Higher IFN-γ secretion in response to purified after lympho-hematogenous dissemination in reactiva-
protein derivative in TB patients with high HbA1c (versus tion TB (80). However, alternative explanations for the
normal HbA1c) despite their DM status. Whole blood from TB higher frequency of lower lung lobe infiltrates in DM are
patients with and without DM was incubated with purified
protein derivative from M. tuberculosis, and after 18 to 24 h,
also possible (e.g., older age is more frequent in DM and
the secretion of IFN-γ in the culture supernatants was quan- also favors lower lung lobe infiltrates).
tified by enzyme-linked immunosorbent assay. Results are
shown in a scatter plot in which each circle represents one Immunoassays for Diagnosis of LTBI (or TB):
TB patient. Black circles, DM patients; white circles, patients Is There Immune Compromise in DM Patients?
without DM. The horizontal line indicates the median IFN-γ The in vivo tuberculin skin test (TST) and ex vivo IFN-γ
level. The vertical line at the HbA1c level of 6.2% of total he- release assays (IGRAs; namely, QuantiFERON-TB Gold
moglobin indicates the upper limits of normal (left) and ele-
vated (right) HbA1c levels. IFN-γ values are provided in natural
assays by Qiagen and T.Spot-TB by Oxford Immunotec)
log (Ln) scale (35). are used in the clinical setting to diagnose LTBI in in-
dividuals with a high risk of TB progression (targeted
testing) or to support the diagnosis of TB. These assays
for TB control by reducing the deleterious inflamma-

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detect immunological memory to M. tuberculosis (or
tion associated with immune pathology and enhancing mycobacterial species in the case of TST), and their
the antimycobacterial activity of immune cells (77). performance depends on immune function. Given the
Additional studies are required to further elucidate the contribution of these tools to TB prevention, there is
underlying relationship between metformin and M. tu- a need to determine whether the immune dysfunction
berculosis killing, with careful assessment of the risks in DM compromises their performance. In TB patients
involved in adding anti-inflammatory medications like with and without DM, most studies show that DM does
metformin to the TB regimen (78). not compromise the performance of TST and/or IGRAs,
with some contradictory findings that may be attributed
to lack of control for possible confounders (81–84).
DM AND LTBI There are few studies on the performance of the TST
Risk of LTBI in Patients with DM or IGRAs for the diagnosis of LTBI in DM patients. A
The literature often refers to DM as a risk factor for community-based study in Tanzania showed that the
reactivation of LTBI to TB, but the relative risk of pri- proportion of QuantiFERON-Gold (Qiagen) negatives
mary versus reactivation TB has never been systemati- was higher among individuals with pre-DM or DM (ver-
cally studied in the context of DM. That is, there is sus patients without DM), suggesting reduced sensitivity
scanty information on whether DM increases the risk of of these assays in these patient populations. How-
successful LTBI in close contacts and/or facilitates the ever, this difference was not significant after controlling
progression from LTBI to TB. Indirect evidence suggests for confounders (82). Among refugees in Atlanta, GA,
that both scenarios are possible. In a population-based there was a higher proportion of LTBIs among those
study with TB patients from southern Mexico, the pro- with pre-DM or DM (versus those without DM) when
portion of M. tuberculosis strains with genotypes that using QuantiFERON-Gold (85). Thus, the few available

8 ASMscience.org/MicrobiolSpectrum
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studies do not indicate a clear compromise due to DM, 5. Boucot KR, Dillon ES, Cooper DA, Meier P, Richardson R. 1952.
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income countries where TB is endemic has been identi- regional, and global trends in fasting plasma glucose and diabetes prev-
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the development of TB among DM patients? How do we International Diabetes Federation, Brussels, Belgium. http://www.idf.org
stratify among the millions of DM patients who have /diabetesatlas. Accessed 9 June 2016.
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effective recommendations for LTBI treatment? How prevalence of Mycobacterium tuberculosis infection and disease in chil-
can we reduce the prevalence of adverse TB treatment dren and adolescents with type 1 diabetes mellitus. Int J Tuberc Lung Dis
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epidemiological, clinical, and immunological studies on 11. Hu FB. 2011. Globalization of diabetes: the role of diet, lifestyle, and
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risk and adverse TB treatment outcomes (55). Glucose Kang H, Hwang S, Carroll M, Cai Y, Cho SN, Barry CE III, Via LE,
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