2. 2
”علما فيه يلتمس طريقا سلك من
إلى طريقا به له ا سهل
.“الجنة
Double Trouble:
Diabetes and Tuberculosis
BYBY
ProfessorProfessor DrDr Magdy EmaraMagdy Emara
ProfessorProfessor of Pulmonologyof Pulmonology,,
Faculty of Medicine,Faculty of Medicine,
TaibahTaibah UniversityUniversity
3. 3
OBJECTIVESOBJECTIVES
• Discuss the national and state epidemiology ofDiscuss the national and state epidemiology of
tuberculosis disease (TB), diabetes mellitus (DM) andtuberculosis disease (TB), diabetes mellitus (DM) and
co-infection.co-infection.
• Discuss the increased risk of individuals with latent TBDiscuss the increased risk of individuals with latent TB
infection (LTBI) and diabetes mellitus progressing toinfection (LTBI) and diabetes mellitus progressing to
active TB disease.active TB disease.
• Discuss how diabetes Mellitus potentiates TB?Discuss how diabetes Mellitus potentiates TB?
• Discuss how tuberculosis predispose to Hyperglycemia.Discuss how tuberculosis predispose to Hyperglycemia.
• Discuss screening and treatment recommendations forDiscuss screening and treatment recommendations for
individuals with LTBI and DM.individuals with LTBI and DM.
• Discuss prevention & treatment recommendations forDiscuss prevention & treatment recommendations for
individuals with TB and DM.individuals with TB and DM.
4. 4
Tuberculosis and Diabetes:Tuberculosis and Diabetes: Historically “TheHistorically “The
tubercular diabetic”tubercular diabetic”
• TB IS THE SHADOW OF DMTB IS THE SHADOW OF DM is long recognized butis long recognized but
underappreciated.underappreciated.
• Indian physician Susruta, in 600 A.D.Indian physician Susruta, in 600 A.D.
““phthisis frequently complicated diabetes”phthisis frequently complicated diabetes”
• Autopsy of diabetics in 1883 showed presence of TBAutopsy of diabetics in 1883 showed presence of TB
granuloma in 50% of diabetics.granuloma in 50% of diabetics.
The association between DM and TB was documented
by Avicenna (who lived form 980 through 1027).
5. 5
• Prior to the insulin era: Diagnosis of DM was a deathPrior to the insulin era: Diagnosis of DM was a death
sentence.sentence.
– Leading cause of death was: Tuberculosis.Leading cause of death was: Tuberculosis.
• During the early 20th century, it was said that a patientDuring the early 20th century, it was said that a patient
with diabetes who did not die in a diabetic coma waswith diabetes who did not die in a diabetic coma was
likely to die of TB, particularly if the patient was poor.likely to die of TB, particularly if the patient was poor.
6. 6
Global Burden of DM and TBGlobal Burden of DM and TB
Diabetes Mellitus: 2008Diabetes Mellitus: 2008
• 250 million people living with250 million people living with
DMDM
• 6 million new cases each6 million new cases each
yearyear
• 3.5 million people died of DM3.5 million people died of DM
during the yearduring the year
[World Diabetes Foundation 2009][World Diabetes Foundation 2009]
Tuberculosis: 2009Tuberculosis: 2009
• 14.0 million people living14.0 million people living
with TBwith TB
• 9.4 million new cases each9.4 million new cases each
yearyear
• 1.7 million people died of TB1.7 million people died of TB
during the yearduring the year
[WHO- Global TB Control 2010][WHO- Global TB Control 2010]
7. 7
The Global Increase in DMThe Global Increase in DM
• 20102010 285 million with DM285 million with DM
• 20302030 440 million with DM440 million with DM
• It is predicted that global diabetes prevalence willIt is predicted that global diabetes prevalence will
increase by 50% by 2030.increase by 50% by 2030.
• Hidden epidemic – estimated that ¼ of people withHidden epidemic – estimated that ¼ of people with
diabetes don’t know they have it.diabetes don’t know they have it.
[Diabetes Atlas: International Diabetes federation, 2009][Diabetes Atlas: International Diabetes federation, 2009]
8. 8
DefinitionsDefinitions
Latent Tuberculosis Infection (LTBI):Latent Tuberculosis Infection (LTBI):
• Persons are infected with M. tuberculosis, but do notPersons are infected with M. tuberculosis, but do not
have active TB disease.have active TB disease.
• About 90% of people who get infected with TB develop aAbout 90% of people who get infected with TB develop a
latent TB infection. Some bacteria survive and remainlatent TB infection. Some bacteria survive and remain
dormant (inactive) but viable for years (latent TBdormant (inactive) but viable for years (latent TB
infection, or LTBI).infection, or LTBI).
Active TB Disease:Active TB Disease:
– Persons infected with M tuberculosis bacteria thatPersons infected with M tuberculosis bacteria that
progress from latent TB infection to develop theprogress from latent TB infection to develop the
disease.disease.
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RISK: LTBI Progression to TBRISK: LTBI Progression to TB
10% of LTBI persons with normal immune system will develop10% of LTBI persons with normal immune system will develop
active TB disease during their life-time.active TB disease during their life-time.
5% of these will develop active TB disease within first 1-2 yrs of5% of these will develop active TB disease within first 1-2 yrs of
infection and another 5% later in life.infection and another 5% later in life.
Diabetes increases risk for progression from latent TB infectionDiabetes increases risk for progression from latent TB infection
(LTBI) to active TB disease and complicates treatment of active(LTBI) to active TB disease and complicates treatment of active
TB. Studies suggest that infected persons with DM may be ≈ 3TB. Studies suggest that infected persons with DM may be ≈ 3
times more likely to progress to TB disease.times more likely to progress to TB disease.
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HOW Does DiabetesHOW Does Diabetes potentiatepotentiate Tuberculosis ?Tuberculosis ?HOW Does DiabetesHOW Does Diabetes potentiatepotentiate Tuberculosis ?Tuberculosis ?
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Diabetes Mellitus potentiates TB through:Diabetes Mellitus potentiates TB through:
1.1. Diabetes, especially when poorly-controlled, causes relativeDiabetes, especially when poorly-controlled, causes relative
immunocompromise and increases likelihood of reactivation ofimmunocompromise and increases likelihood of reactivation of
TB.TB.
2.2. Diabetes might also lead to increased susceptibility to diseaseDiabetes might also lead to increased susceptibility to disease
caused bycaused by M tuberculosisM tuberculosis via multiple mechanisms:via multiple mechanisms:
– Direct mechanism:Direct mechanism: include those directly related to hyperglycaemia andinclude those directly related to hyperglycaemia and
cellular insulinopenia, as well ascellular insulinopenia, as well as
– Indirect effects on macrophage and lymphocyte function, leading toIndirect effects on macrophage and lymphocyte function, leading to
diminished ability to contain the organism.diminished ability to contain the organism.
1.1. Producing local tissue acidosis and electrolyte imbalance thatProducing local tissue acidosis and electrolyte imbalance that
impair repair.impair repair.
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Diabetes Mellitus potentiates TB through:Diabetes Mellitus potentiates TB through:
4.4. Disturbed carbohydrate metabolism leading toDisturbed carbohydrate metabolism leading to
hyperglycemia with subsequent increase of sugar,hyperglycemia with subsequent increase of sugar,
glycerol and nitrogen substances in the blood thatglycerol and nitrogen substances in the blood that
favor the growth and viability of tubercle bacilli.favor the growth and viability of tubercle bacilli.
5.5. Disturbed protein metabolism with subsequentDisturbed protein metabolism with subsequent
decrease of antibodies formation.decrease of antibodies formation.
6.6. Disturbed fat metabolism leading to:Disturbed fat metabolism leading to:
– Ketosis decrease the bactericidal effect of lactic acid.Ketosis decrease the bactericidal effect of lactic acid.
– Increase of glycerol in the blood that favor the growth ofIncrease of glycerol in the blood that favor the growth of
tubercle bacilli.tubercle bacilli.
7.7. Associated hepatic insufficiency as a result of fattyAssociated hepatic insufficiency as a result of fatty
liver leads to hypovitaminosisliver leads to hypovitaminosis A & D that decreases theA & D that decreases the
integrity of epithelial tissue.integrity of epithelial tissue.
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Diabetes Mellitus potentiates TB through:Diabetes Mellitus potentiates TB through:
8.8. Associated stress increases ACTH and the resultingAssociated stress increases ACTH and the resulting
increase in corticosteroids aids in flaring up ofincrease in corticosteroids aids in flaring up of
tuberculosis.tuberculosis.
9.9. Enhancing atherosclerosis disturbing pulmonaryEnhancing atherosclerosis disturbing pulmonary
perfusion and increasing VA/Q that increasesperfusion and increasing VA/Q that increases
alveolar O2 tension that help organism multiplication.alveolar O2 tension that help organism multiplication.
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Diabetes Mellitus potentiates TB through:Diabetes Mellitus potentiates TB through:
10.10. Disturbed endocrinal function at late stages:Disturbed endocrinal function at late stages:
– Thyroid dysfunction leads to decreased antibodiesThyroid dysfunction leads to decreased antibodies
formation.formation.
– Pituitary dysfunction leads to increase in ACTH withPituitary dysfunction leads to increase in ACTH with
subsequent increase of cortisol level which leads to:subsequent increase of cortisol level which leads to:
• Decreased formation of granulation tissue leading toDecreased formation of granulation tissue leading to
exudative inflammation and spread of infection.exudative inflammation and spread of infection.
• Worsening of diabetic state (insulin antagonism) as lackWorsening of diabetic state (insulin antagonism) as lack
of insulin receptors on macrophages and monocytesof insulin receptors on macrophages and monocytes
suppress the immunity.suppress the immunity.
16. 16
Tuberculosis predispose to HyperglycemiaTuberculosis predispose to Hyperglycemia
Studies suggest that TB can even cause diabetes inStudies suggest that TB can even cause diabetes in
those not previously known to be diabetic:those not previously known to be diabetic:
1.1. Decreased hepatic glycogenesis.Decreased hepatic glycogenesis.
2.2. Increased hepatic glycogenolysis andIncreased hepatic glycogenolysis and
gluconeogenesis.gluconeogenesis.
3.3. Lack of insulin due to impairment of pancreatic islets.Lack of insulin due to impairment of pancreatic islets.
4.4. Tubercle bacilli suppress the sensitivity of tissues toTubercle bacilli suppress the sensitivity of tissues to
insulin.insulin.
5.5. Tuberculosis causes tissue destruction .Tuberculosis causes tissue destruction .
6.6. Diabetogenic effect of INH.Diabetogenic effect of INH.
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Effect of Diabetes Mellitus on pulmonary TB.Effect of Diabetes Mellitus on pulmonary TB.
1.1. More extensive exudation and caseation withMore extensive exudation and caseation with
subsequent cavitation and toxaemia.subsequent cavitation and toxaemia.
2.2. More frequent haemoptysis and pleural effusion.More frequent haemoptysis and pleural effusion.
3.3. Predilection to hilar and basal regions.Predilection to hilar and basal regions.
4.4. Less frequent extrapulmonary TB and fibrousLess frequent extrapulmonary TB and fibrous
adhesions.adhesions.
5.5. DM may also be a risk factor for hepatic toxicity ofDM may also be a risk factor for hepatic toxicity of
anti-TB drugs.anti-TB drugs.
6.6. Diabetes cause changes in oral absorption, decreasedDiabetes cause changes in oral absorption, decreased
protein binding of drugs, and renal insufficiency orprotein binding of drugs, and renal insufficiency or
fatty liver with impaired drug clearance.fatty liver with impaired drug clearance.
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Effect of DM on treatment outcomes of TBEffect of DM on treatment outcomes of TB
• DM associated with:-DM associated with:-
– Possible delay in sputum culture conversion.Possible delay in sputum culture conversion.
– Increased risk of death.Increased risk of death.
– Increased risk of recurrent TB.Increased risk of recurrent TB.
19. 19
Effect of TB on Diabetes MellitusEffect of TB on Diabetes Mellitus
• Worsening of diabetic state as tuberculosis mightWorsening of diabetic state as tuberculosis might
induce glucose intolerance and worsen glycaemicinduce glucose intolerance and worsen glycaemic
control with increased insulin requirement and ketosis.control with increased insulin requirement and ketosis.
• The endocrine function of pancreas has also beenThe endocrine function of pancreas has also been
found to be adversely affected in severe tuberculosis,”found to be adversely affected in severe tuberculosis,”
and a higher incidence of chronic calcific pancreatitisand a higher incidence of chronic calcific pancreatitis
occurs in patients with concomitant diabetes andoccurs in patients with concomitant diabetes and
tuberculosistuberculosisleading to an absolute or relative insulinleading to an absolute or relative insulin
deficiency state. deficiency state.
20. 20
Diagnosis of TB and DMDiagnosis of TB and DM
• Any diabetic- who suddenly develops prolongedAny diabetic- who suddenly develops prolonged
coughcough > 2 weeks> 2 weeks , prolonged duration of fever,, prolonged duration of fever,
loss of weight, abnormal chest radiograph orloss of weight, abnormal chest radiograph or
needs increasing doses of insulin to controlneeds increasing doses of insulin to control
blood glucose should be investigated forblood glucose should be investigated for
presence of tuberculosispresence of tuberculosis as per nationalas per national
guidelinesguidelines..
21. 21
Screening for DM in persons with TBScreening for DM in persons with TB
• Every patient with TB over the age of 18 should beEvery patient with TB over the age of 18 should be
screened for DM:screened for DM:
– A fasting plasma glucose > 126mg/dl = DM.A fasting plasma glucose > 126mg/dl = DM.
– A random plasma glucose > 200 mg/dl = DM.A random plasma glucose > 200 mg/dl = DM.
– A Hemoglobin A1c > 6.5% = DM.A Hemoglobin A1c > 6.5% = DM.
– Ask about polyuria/polydipsia at TB clinic visits.Ask about polyuria/polydipsia at TB clinic visits.
• Abnormal glucose values should be repeated in patientsAbnormal glucose values should be repeated in patients
who have no symptoms of DM.who have no symptoms of DM.
• Glucose should be repeated after 2-4 weeks of TB Rx orGlucose should be repeated after 2-4 weeks of TB Rx or
if symptoms of hyperglycemia develop.if symptoms of hyperglycemia develop.
– Rifampin and INH can markedly elevate glucose levels.Rifampin and INH can markedly elevate glucose levels.
22. 22
Radiographic Findings in TuberculousRadiographic Findings in Tuberculous
Diabetic patientsDiabetic patients
Radiographic Findings in TuberculousRadiographic Findings in Tuberculous
Diabetic patientsDiabetic patients
23. 23
• TB in diabetics presented with an atypical radiographicTB in diabetics presented with an atypical radiographic
pattern and distribution, particularly lower-lungpattern and distribution, particularly lower-lung
involvement especially in older individuals.involvement especially in older individuals.
• This is important because lower-lobe tuberculosis:This is important because lower-lobe tuberculosis:
– Misdiagnosed as community-acquired pneumonia or cancer.Misdiagnosed as community-acquired pneumonia or cancer.
– Less likely to have positive sputum smears and cultures.Less likely to have positive sputum smears and cultures.
• Recent studies found that multilobar disease orRecent studies found that multilobar disease or
multiple cavities was more common in diabetics, whilemultiple cavities was more common in diabetics, while
lower-lung disease is more in patients > 40 years.lower-lung disease is more in patients > 40 years.
• Lower lobe involvement with cavitation is a patternLower lobe involvement with cavitation is a pattern
which, when encountered, should raise the possibilitywhich, when encountered, should raise the possibility
of co-existing diabetes in the patient with pulmonaryof co-existing diabetes in the patient with pulmonary
TB.TB.
29. 29
Management of PulmonaryTuberculousManagement of PulmonaryTuberculous
Diabetic patientsDiabetic patients
Management of PulmonaryTuberculousManagement of PulmonaryTuberculous
Diabetic patientsDiabetic patients
30. 30
Prevention of TB in persons with DMPrevention of TB in persons with DM
Persons with diabetes mellitus (DM) who are at increased
risk of tuberculosis (TB) should be screened for latent TB
infection (LTBI): Just as we recommend screening TB
patients for HIV, screen for DM when TB is
diagnosed.
•TST or IGRA should be done at time of DM diagnosis.
•TST –ve BCG.
• CXR and sputum examination: If sudden weight loss,
prolonged cough or increased insulin requirement are
observed in diabetic patients.
31. 31
Treatment for LTBITreatment for LTBI
• Treating LTBI reduces the risk thatTreating LTBI reduces the risk that M. tuberculosisM. tuberculosis
infection will develop into TB disease.infection will develop into TB disease.
• Before beginning treatment for LTBI:Before beginning treatment for LTBI:
– Exclude diagnosis of TB.Exclude diagnosis of TB.
– Ensure patient has no history of adverse reactionsEnsure patient has no history of adverse reactions
resulting from prior LTBI treatment.resulting from prior LTBI treatment.
• Patients with DM who are found to have LTBI should bePatients with DM who are found to have LTBI should be
encouraged to take INH for 9 months.encouraged to take INH for 9 months.
33. 33
Treatment for TB DiseaseTreatment for TB Disease
• Ensure that TB treatment is appropriately adjusted inEnsure that TB treatment is appropriately adjusted in
persons with DM:persons with DM: BothBoth PZA and EMBPZA and EMB needneed
adjustmentadjustment for renal impairment.for renal impairment.
– Check creatinine for diabetic nephropathy.Check creatinine for diabetic nephropathy.
– Check liver function to avoid hepatic toxicity.Check liver function to avoid hepatic toxicity.
• Preferred regimen:Preferred regimen:
– Initial phase: 2 months isoniazid (INH), rifampin (RIF),Initial phase: 2 months isoniazid (INH), rifampin (RIF),
pyrazinamide (PZA), and ethambutol.pyrazinamide (PZA), and ethambutol.
– Continuation phase: 4 months INH and RIF.Continuation phase: 4 months INH and RIF.
34. 34
Treatment of TB in persons with DMTreatment of TB in persons with DM
– Consider extending treatment to 9 months for patientsConsider extending treatment to 9 months for patients
with cavitary pulmonary TB with DM and positivewith cavitary pulmonary TB with DM and positive
culture results at end of initiation phase.culture results at end of initiation phase.
– Upon completion of therapy, obtain smear and cultureUpon completion of therapy, obtain smear and culture
for AFB.for AFB.
– Follow up the patient at 6 months and one year afterFollow up the patient at 6 months and one year after
treatment completion.treatment completion.
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Pharmacological issues in the Co-Pharmacological issues in the Co-
Management of Diabetes MellitusManagement of Diabetes Mellitus
and Tuberculosisand Tuberculosis
Pharmacological issues in the Co-Pharmacological issues in the Co-
Management of Diabetes MellitusManagement of Diabetes Mellitus
and Tuberculosisand Tuberculosis
36. 36
Drugs used to treat tuberculosis might:Drugs used to treat tuberculosis might:
•Overlapping toxicities in co-managing tuberculosis and diabetes.Overlapping toxicities in co-managing tuberculosis and diabetes.
– Peripheral neuropathy caused by isoniazid.Peripheral neuropathy caused by isoniazid.
– Give Pyridoxine (B6) to prevent INH induced peripheralGive Pyridoxine (B6) to prevent INH induced peripheral
neuropathy.neuropathy.
•Worsen glycemic control.Worsen glycemic control.
– Rifampicin directly causes early-phase hyperglycaemia withRifampicin directly causes early-phase hyperglycaemia with
associated hyperinsulinaemia even in non-diabetics. orassociated hyperinsulinaemia even in non-diabetics. or
indirectly worsen glycemic control via interactions with OADindirectly worsen glycemic control via interactions with OAD
((It lowers the serum levels of sulphonyl ureas andIt lowers the serum levels of sulphonyl ureas and
biguanidesbiguanides).).
– Rifampicin decreases concentrations of rosiglitazone by 54–Rifampicin decreases concentrations of rosiglitazone by 54–
65% and of the related drug pioglitazone by 54%.65% and of the related drug pioglitazone by 54%.
– Insulin requirements might increase when on rifampicin.Insulin requirements might increase when on rifampicin.
37. 37
Management of DM in patients receivingManagement of DM in patients receiving
TB treatmentTB treatment
– There should be a glucose meter in every TB clinic andThere should be a glucose meter in every TB clinic and
blood glucose should be frequently checked in the clinic forblood glucose should be frequently checked in the clinic for
those with DM.those with DM.
– All clinical staff should reinforce lifestyle changes at TBAll clinical staff should reinforce lifestyle changes at TB
clinic visits. Dietary changes and physical activity are mostclinic visits. Dietary changes and physical activity are most
important in this effort.important in this effort.
– If available, refer persons with diabetes to a diabetesIf available, refer persons with diabetes to a diabetes
specialty clinic or clinician comfortable with treating DM.specialty clinic or clinician comfortable with treating DM.
– Maintenance of blood sugar level atMaintenance of blood sugar level at normal or near normalnormal or near normal
level, is one of the most fundamentallevel, is one of the most fundamental aspects in patientaspects in patient
care (normoglycaemia ensures better control).care (normoglycaemia ensures better control).
38. 38
Management of DM in patients receivingManagement of DM in patients receiving
TB treatmentTB treatment
Again, it is permissible to maintain a level of bloodAgain, it is permissible to maintain a level of blood
glucose from 120 to 150 mg/dl in the TB-DM group ofglucose from 120 to 150 mg/dl in the TB-DM group of
patients, or glycosylated haemoglobin less than 7%.patients, or glycosylated haemoglobin less than 7%.
Insulin is clearly the preferred agent of choiceInsulin is clearly the preferred agent of choice inin
Diabetes with TB (of any type) due to its anaboilic action,Diabetes with TB (of any type) due to its anaboilic action,
improving appetite, andimproving appetite, and promoting weight gainpromoting weight gain
especially in the intensive phase of antiTB chemotherapyespecially in the intensive phase of antiTB chemotherapy
apart from it lowering the pill burden.apart from it lowering the pill burden.
But, oral hypoglycemics can be used in mild DM.But, oral hypoglycemics can be used in mild DM.
39. 39
Can TB Vaccine Stop Type 1 Diabetes?Can TB Vaccine Stop Type 1 Diabetes?
• In the study, three insulin-dependent adults withIn the study, three insulin-dependent adults with
type 1 diabetes received either two doses of BCGtype 1 diabetes received either two doses of BCG
four weeks apartfour weeks apart.. and they were compared to oneand they were compared to one
control group without diabetes and one with thecontrol group without diabetes and one with the
diabetesdiabetes.. The patients were followed for 20 weeksThe patients were followed for 20 weeks..
• Results:Results: two of the three were found to have antwo of the three were found to have an
increase in the death of insulin-harming T-cellsincrease in the death of insulin-harming T-cells
and New "good" regulatory T cells increasedand New "good" regulatory T cells increased
documented by a rise indocumented by a rise in C-peptide levelsC-peptide levels,,
suggesting the production of insulin.suggesting the production of insulin.
• The vaccine works byThe vaccine works by triggering the production oftriggering the production of
increasing levels of tumor necrosis factor (TNF).increasing levels of tumor necrosis factor (TNF).
40. 40
The “Take Home” MessageThe “Take Home” Message
Tuberculosis increases the severity of diabetes and makes theTuberculosis increases the severity of diabetes and makes the
latter disease more difficult to control. When the two diseaseslatter disease more difficult to control. When the two diseases
co-exist, the diabetes usually precedes the tuberculosis.co-exist, the diabetes usually precedes the tuberculosis.
Thus, pulmonary tuberculosis should be considered in patientsThus, pulmonary tuberculosis should be considered in patients
with diabetes mellitus who have weight loss, fever and generalwith diabetes mellitus who have weight loss, fever and general
debility that cannot be fully explained by poor diabetic control.debility that cannot be fully explained by poor diabetic control.
We advocate checking fasting and postprandial blood sugar inWe advocate checking fasting and postprandial blood sugar in
all newly diagnosed TB patients.all newly diagnosed TB patients. RepeatRepeat serum glucose afterserum glucose after
one month.one month.
Persons with DM should have an known TST status.Persons with DM should have an known TST status.
DM persons with +TST should complete LTBI treatment becauseDM persons with +TST should complete LTBI treatment because
they are at higher risk of developing TB disease.they are at higher risk of developing TB disease.
Insulin is clearly the preferred agent of choiceInsulin is clearly the preferred agent of choice in Diabetes within Diabetes with
TB as optimal glycemic control aided by insulin has clearlyTB as optimal glycemic control aided by insulin has clearly
improved outcomes of anti TB therapy and relapses/improved outcomes of anti TB therapy and relapses/
recurrences. But, oral hypoglycemics can be used in mild DM.recurrences. But, oral hypoglycemics can be used in mild DM.