describing the relationship of how diabetes complicates the TB and vice versa.

1. PRESENTER-
Dr. Divyagunjan Sahu (PT)
Cardiopulmonary Physical therapist

3. INTRODUCTION
 The burgeoning epidemic of diabetes mellitus (DM) and tuberculosis (TB) is two of the
major global health challenges.
 It is estimated that over a million TB cases among adults were affected by DM in 2012
and the rising DM epidemic would create havoc in the TB burden.
 Estimates suggest that the DM burden is increasing fastest in regions like India
where TB remains endemic.
 Therefore, strategies are needed to ensure that optimal care is provided to patients with
both diseases.

4.  Despite the decline in the mortality rate of active tuberculosis (TB)
since 1990, TB is ranked as one of the leading causes of death.
 In 2015, there were an estimated 10.4 million incident TB cases
worldwide. The “End TB Strategy” launched by the World Health
Organization (WHO) in 2016, aims to end the global TB epidemic by
2035.
 Targets set in this strategy include 90% reduction in TB deaths and an
80% reduction in TB incidence by 2030, compared with 2015.

5. Diabetes
increases
the risk of
TB three
times.
One in 3
people in
the world
also have
latent TB.
People with
TB and
coexisting
diabetes
have a six
times higher
risk of death
during TB
treatment
Dooley et al Am Troop Med Hyg 2009; 634-9

6. HISTORY
Association of
Tb & Diabeties
was
documented by
Avicenna. (1027)
TB is the shadow
of DM is long
recognised but
under
appreciated.
Susruta in
600AD “Phthsis
frequently
complicated
Diabetes” During early 20th
centaury, Autopsy of
malnourished diabetic
patients showed TB
granuloma in 50% of
the cases.

7. TB AROUND THE WORLD:
 More than 10 million people fall sick with TB around the world every year.
 India has the largest number of TB cases in the world, estimated at 2.8 million
incident cases per annumf TB Burden (2020)
Estimates of TB Burden (2020Estimates of TB Burden (202
Global Tuberculosis Report 2021

8. DIABETES AROUND THE WORLD:
 Globally, an estimated 422 million adults were living with diabetes in 2014, compared to
108 million in 1980. The global prevalence (age-standardized) of diabetes has nearly
doubled since 1980.
 Diabetes caused 1.5 million deaths in 2012. The percentage of deaths attributable to
high blood glucose or diabetes that occurs prior to age 70 is higher in low- and middle-
income countries than in high-income countries. Diabetes is no longer the disease of
affluent.
 It is predicted that globally Diabetic prevalence will be increased by 50% by 2030.
National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS)

9.  In the world, India stands second with 69.2 million people with diabetes and
another 36.5 million with prediabetes which is a high-risk condition for diabetes
and cardio-vascular disease.
 Diabetes affects children and adolescents alike. Type 1 diabetes though
uncommon is increasing at a rate of 3% every year particularly among children.
 In India alone there are more than 70,000 children with this condition, second
largest number in the world after the USA.
National Health Portal

10. India is Diabetes capital of the world and
every 5TH Diabetic is Indian.

11. CAN TB CAUSES DIABTETES:
TB can even cause diabetes in those not previously diabetic through:
 Decreased hepatic glycogenesis.
 Increased hepatic glycogenolysis and gluconeogenesis.
 Lack of insulin due to impairment of pancreatic islets.
 Tubercle bacilli suppress the sensitivity of tissue to insulin.
 Diabetic effect of INH.

13. GLOBAL ESTIMATES OF THE NUMBER OF TB CASES
ATTRIBUTABLE TO SELECTED RISK FACTORS
Global Tuberculosis Report 2021

14. CONTRIBUTION OF RISK FACTORS TO TB CASES
IN INDIA

15. PULMONARY PHYSIOLOGIC DYSFUNCTION:
 Lung is the target organ for microangiopathy in both typeI and type II.
 Thickening of alvelor capillary & pulmonary arterial walls & decrease lung
capacity blood volume in patients with type I diabetes.
 Alteration of lung connective tissue at biochemical level is responsible for
abnormal lung mechanics.
 Changes in collagen or elastin component affect the normal elastic and complaint
properties of lung.

16. PULMONARY PHYSIOLOGIC DYSFUNCTION:
Diminished
bronchial
reactivity
Reduced
Diffusion
capacity
Occult
mucus
plugging of
airways
Reduced
ventilator
response to
hypoxaemia.

17. PULMONARY COMPLICATION OF DM:
 Prolong Infection
 Pulmonary edema
 Decresead breathing during sleep
 Reduction of elastic recoil of lung
 Decreased DLCO
 Decreased bronchomotor tone.
 Increased risk of thromboembolism due to their hypercoagulable state.
 Higher risk of pulmonary embolism.

18. 1
2
3
4
5
PRODUCING LOCAL
ACIDOSIS
THAT IMPAIR REPAIR
ALTERED
CARBOHYDRATE,
FAT & PROTEIN
METABOLISM
HYPERGLYCEMIA
DISTURBING
PULMONARY
PERFUSION
IMMUNOLOGIC
REACTIONS
HOW DIABETES CAUSE TB

19. HOW DIABETES POTENTIATE TB
(Pathophysiology)
 10% of latent tubercular infection patient with normal immune system will develop active Tb
during their lifetime.
 5 % of these will develop active TB disease within first 1-2yrs of infection and another 5% later in
life.
 Diabetes might also lead to increased susceptibility to disease caused TB via multiple mechanism:
 Direct mechanism: include those directly related to hyperglycemia and cellular insulinopenia.
 Indirect mechanism: effect on macrophages and lymphocytic function, leading to diminished
ability to contain the organism.

20. PATHOGENESIS:
IMMUNOLOGIC
CHANGES
PULMONARY
PHYSIOLOGIC
DYSRUPTION
HYPERGLYCEMIC

21. Hyperglycemia:
 Hyperglycemia favours growth, viability and propagation of tubercle bacilli and hamper resistance to
repair capacity.
 Increased availability of glycerol and nitrogenous substance aid the growth of tubercle bacilli.
 High levels of insulin were associated with a decrease in T helper 1 (Th1) immunity through a
reduction in the Th1 cell to T helper 2 (Th2) cell ratio and interferon-c (IFN-c) to interleukin-4 (IL-4)
ratio.
 Leukocyte bactericidal activity was found to be reduced in people with diabetes, especially those
with poor glucose control.

22. Immunologic Reactions:
 Immune mechanisms contributing to the increased susceptibility of diabetic patients to TB
are due to the defects in bacterial recognition, phagocytic activity, and cellular activation
which results in impaired production of chemokines and cytokines.
 The initiation of adaptive immunity is delayed by impaired antigen-presenting cell (APC)
recruitment which results in reduced frequencies of Th1, Th2, and Th17 cells and its
secretion of cytokines.
 Neutrophils in people with diabetes were found with a lack in chemotaxis and oxidative
killing potential compared to non-diabetic controls.
 High levels of IL-17 and IL-8 in diabetes with TB may be related to more granulocytic
infiltration.
Birhanu Ayelign et al, Immunological Impacts of Diabetes on the Susceptibility of Mycobacterium tuberculosis Hindawi Journal of Immunology Research Volume 2019,

23. Immunologic Reactions:
m.tuberculosis
Leukocyte chemo taxis
Granuloma development
Stimulation of T-cell,Nkcell,IL-
12,IL-15,IL-18,IL-23,IL-27
Th2 cytokine expression IL-
4,IL-10,IL-27
Initiation of adaptive immunity
immunity T-cell response, IFN,
TNF, perforin, granulysin
Macrophages of dendritic cell

24. CLINICAL EFFECT OF DIABETES ON TB:
 More extensive exudation and caseation with subsequent cavitation and
toxaemia.
 More frequent pleural effusion.
 DM also increases the risk factor for hepatic toxicity of anti-TB drugs.
 Diabetic causes changes in oral absorption, decreased protein binding of
drugs, and renel insufficiency or fatty liver with impaired glucose tolerance.

25. CLINICAL EFFECT OF TB ON DIABETES:
 Worsening of diabetes state as tuberculosis might induce
glucose intolerance and worsen glycemic control with
increased insulin requirement and ketosis.
 Higher incidence of chronic chronic calcific pancreatitis occurs
in patient with concomitant diabetes and tb leading to
relative insulin deficiency.

26. MDR-TB and Diabetes:
 Increasing numbers of multi-drug resistant (MDR TB) strains, resistant to at least
isoniazid (INH) and rifampin (RIF) are a threat to success of the treatment.
 Patients with T2DM, that diabetes patients do not achieve or maintain adequate blood
levels of rifampin. This leads to failure to comply with therapy result in secondary
resistance.
 Molecular studies show that mutations in the MTB katG gene contributes to
protection of the bacterium against oxidative stress, but it also encodes a catalase-
peroxidase which transforms isoniazid into its active form.
 Strains with these mutations may be better able to thrive in patients with T2DM in
whom production of Reactive Oxygen Species may be impaired.

27. CLINICAL MANIFESTATION:
 More aggressive course, might progress rapidly.
 Less clinical manifestations.
 Typical features like cough, weight loss are less prominent.
 Prolong duration of fever.
 More complication and risk of drug resistant TB.

28.  The effect of serum from DM patients on
growth of M. tuberculosis.
 It is also seen that Diabetic mice
experimentally infected with
Mycobacterium tuberculosis have higher
bacterial loads compared to euglycemic
mice.
Qing Zhang et al Jpn J Infect Dis 2009;62:390-391

29.  Mycobacterial clearance from sputum is
delayed during the first phase of
treatment in patients with diabetes.
 Diabetes is independent risk factor for the
5 day delay in mycobacterial clearance
within first 60 days.
Restrepo et al Am J Trop Med Hyg 2008, 79(4):541-4

30. TB infection produces
glucose intolerance that
improves or normalize with
the treatment.
Glucose intolerance is not
specific to TB but also occur
in Pneumonia.
TB-DM patients are more likely to
remain sputum smear positive even
after completion of the intensive phase
of treatment.
01
02
03

31. COMPARISON OF CLINICAL FEATURES:
Clinical feature DM &TB TB only
fever 64% 98%
Night sweats 52% 85%
Cough>3wks 71% 96%
Weight loss 69% 94%
Hossain D et al, Clinical and Radiological presentation of Pulmonary Tuberculosis in Diabetic and non diabetic pateints.J Soc Heart Chest Disease 2004.

32. X-RAY FINDINGS:
 Lower lobe opacity(often misdiagnosed as pneumonia)
 Multilobular (usually in elderly)
 Cavitary lesion
 Pleural effusion
Radiological feature DM+TB TB ALONE
Upper lobe opacity 17% 56%
Lower lobe opcity 19% 7%
Multi lobe opacity 64% 36%
cavity 82% 59%
C.Perez et al 2001

33. Upper Lobe Cavitory lesion typical Xray of
primary pulmonary TB. Atypical Xray seen in TB-DM patient.

34.  A 22yrs old man presented with night
sweats, weight loss, dyspnea and
productive cough.
 Xray demonstrates a large right sided
pleural effusion.
 Pleural fluid examination demonstrates
lymphocytic population.

35. Xray of 62years old female:
 A horizontal bend-like opacity at the right
mid zone with an ill-defined thin-walled
cavity-like shadow may be tubercular.
 Blunting of costophrenic angle due to
minimal pleural effusion both side.
 Mild scoliosis of the dorsal spine with
convexity towards right side.

36.  Xray of 40yr male diabetic patient who
presented with weight loss, night sweats,
productive cough since 2months.
 Xray demostrates a large cavity in the
right upper lobe with an effusion and air-
fluid level at the base.
 Aspirate confirms the m tuberculosis
infection.

37.  Chest radiograph shows multiple
randomly scattered circumscribed nodules
distributed around the lung parenchyma
evenly .
 Miliary TB- 6 months after the primary
infection in immunocompromised patient.

38. Newly diagnosed TB patient with pre-
existing DM
Chest radiograph showing Right hilar
Adenopathy in TB-DM patient.

39.  Gohn focus with hilar adenopathy and
bilateral infiltrate.

40. General management:
 There should be glucose meter in every TB clinic and blood glucose should be frequently
checked in the clinic for those with DM.
 Moderate intensity weight training 2-3days/wk and aerobic training like walking 5days/wk is
important for muscle health and diabetic control.
 It is permissible to maintain a blood glucose of 120-150mg/dl TB-DM group,and glycosylated HB
7.5%.
 Oral hypoglycemic drugs should be given only in case of mild diabetes.
 Insulin is clearly the preferred agent of choice in Diabetes due to its anabolic action, improving
appetite and promoting weight gain especially in undernourished.
Heaton TG . Can Med Asso J 1932, 498-501

41. Dietary management:
 High calorie high protein diet is necessary which
doesnot increase blood glucose levels or LDL.
 Diet should include eggs, tofu, fish, yoghurt, beans,
legumes, whole grains, millets, milk, banana, ginger,
garlic, blackpepper, drumsticks and leafy veggies.
 Get some sun light and vit B and iron supplements.
 Hepatic insufficiency leads to hypovitaminosis A and D
that should be supplemented.

42. PHARMACOLOGICAL ISSUES IN THE
COMANAGEMENT OF DIABETES AND TB
 Patient should be admitted to hospital for glycemic control.
 Tb treatment can be extended for 9-12 months in case for severe diabetes.
 Rifampicin potent Cytp450 inducer lowers the serum level of sulphonylureas & metformin.
Guptan & Asha IND J Tub 2000

43. Rifampicin reducing the plasma glimepiride
concentration.
Niemi et al BR J cli pharmacol 2000, 50-591-595

44. Rifampicin
decreases
concentration of
rosiglitazone by
54-65% and
pioglitazone by
54%.
Rifampicin
causes early
phase
hyperglycemia
& associated
insulinopenia
even in non-
diabetics.
Rifampicin a
CytP450
inducers that
lowers the
level of
Sulphonyl
ureas &
worsen
glycemic
control.
.
Isoniazid
inhibits the
metabolism of
sulphonyl
ureas
& increase their
plasma levels.

45. Gliptins
(Dipetidyl Protease
Inhibitors)
have a possibility of
reducing immune-
competence, this
could worsen the
outcome in Tb
Patients.
Isoniazid impairs
the release &
action of insulin
leading to
hyperglycemia
even in
non-diabetic.
Isoniazid causes
cholelisthesis.
It also cause
peripheral
neuropathy.

46. 62/M on chlorpropamide
250mg daily
Given Rifampicin
600mg Daily
Chlorpromamide increased to 400mg
daily
Self & morris, Chest 1980

47. 65/M on gliclazide 80mg daily
FPG 6.4 mmol/L
HBA1c 5.4%
Atypical mycobacteriosis
Rifampicin,Isoniazide,ethambutol,clarithromycin
FPG increased to 11.3mmol/L
Gliclazide increased upto 160mg daily
When Rifampicin discontinued, Gliclazide reduced to
80mg daily (HBA1c 5.6%)
CASE REPORT
Sellers & Dean, Diabetes Care 2000

48. INSULIN 01
To prevent Drug
interaction and GI
disturbances.
FG-120mg/dl &
HBA1c <7% 02
To maintain the goals
of treatment
More patient
compliance and
better treatment
outcome
03
To decrease pill
burden
Guptan & Asha IND J Tub 2000

49. MANAGEMENT WITH INSULIN:
Indication of Insulin:
 Chronic and severe tb.
 Loss of tissue and function of pancrease.
 Requirement of high protein, high calorie diet.
 Adverse reactions with anti tb drugs.
 Associated hepatic diseases.
 Aging.
 Contraindication to oral diabetic medication.
Rao PV Int. J Diab Dev Counteries 1999

50. WHO SHOULD BE STARTED ON INSULIN:
 On metformin with HBA1c>8.5%
 Not reaching A1c target of OHA combination therapy.
 Kidney liver diseases contra-indicted for oral diabetic medication.
 severe uncontrolled diabetes with catabolism.
ADA-FASD 2008 Alogorithm Diabetes Care 31: 1-11, 2008

51. WHO SHOULD BE STARTED IMMEDIATELY
STARTED ON INSULIN:
 Fasting BG >13.9mmol/L (250mg/dl)
 Random BG>300mg/dl
 A1c>10%
 Presence of ketouria.
 Diabetes symptoms: polyuria, polydypsea, weight loss.
ADA-FASD 2008 Alogorithm Diabetes Care 31: 1-11, 2008

52. CLINICAL STUDIES: Case1
 A 45-year-old woman, with 10-year history of T2DM
treated with metformin, arrived with complaints of dry
cough for the past 3 months.
 Interview also revealed unintentional weight loss, night
sweats, occasional unquantified fever and general malaise
but denied bloody sputum.
 Physical examination showed a thin body habitus, with
stable vital signs, presenting solely right middle lung field
ronchi up on auscultation.
 Imaging showed a right upper lobe cavitation. Positive
sputum for AFB disclosed active pulmonary TB in our
patient, prompting therapy.

53.  Laboratories yielded no leukocytosis or monocytosis.
 However, LDH (997units/L), ESR (80mm/h), hsCRP
(71.2mg/L) and HbA1C (12.4 – avg blood glucose
309mg/dL) were elevated.
 CXR right lung cavitary lesion with fluid levels suspicions for
lung abscess.
 Gram stain positive for AFB.
 Sputum culture positive for Mycobacterium tuberculosis.

54. Treatment
 The patient was started on four-drug regimen:
ethambutol, rifampin, isoniazid and
pyrazinamide, and deescalated to rifampin and
isoniazid once susceptibility was available for
6months total.
 In addition to TB therapy, patient was treated
with regular and basal Insulin requiring
considerable doses to achieve DM control.
 Hospital course complicated with hyperglycemia
despite frequent insulin dose escalation even
after clearance of AFB sputum.

55. CASE 2
 A 40-year-old man, with 10-year history of T2DM treated with oral hypoglycemic
drugs, arrived with complaints of productive cough, fever, generalised weakness,
left side chest pain for the past 3 weeks.
 Examination showed a thin body habitus, with desaturation and sinus tachycadia,
restriction on chest expansion also noted with shallow abdominal breathing
pattern, on auscultation crepitations were heard.
 Laboratories yielded no leukocytosis or monocytosis. Blood sugar was elevated
353mg/dl and Hba1c 8.7%. Ct scan revealed rt. Side Sympneumonic effusion and
left lower lobe consolidation.
 Bronchial Alveolar Lavage was done as AFB test was inconclusive and the sputum
collected confirmed the m.tuberculi through CBNAAT.
 Although the patient was treated with anti-Tb, oxygen therapy, mucolytics &
insulin.

57. CONCLUSION:
 A large proportion of people with diabetes as well as TB remain undiagnosed, or are
diagnosed at a late stage.
 Cases should be dealt with High index of suspicion.
 Aggressive treatment & robust intervention can help to improve care and control of
this Twin epidemic.
 MDR-TB outweighs the overall burden with overall mortality and morbidity.
 Insulin remains the cornerstone of the treatment owing towards the pharmacological
aspects.
 Every diabetic patient should be screened for TB and vice-versa.