Diabetes and TB The deadly Combo.pptx

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

1. DIABETES AND TB THE DEADLY COMBO PRESENTER- Dr. Divyagunjan Sahu (PT) Cardiopulmonary P hysical therapist

2. DIABETES TB

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 MDR 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 20 th 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 annum f 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 5 TH 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.

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

13. CONTRIBUTION OF RISK FACTORS TO TB CASES IN INDIA

14. 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.

15. PULMONARY PHYSIOLOGIC DYSFUNCTION:

16. 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.

17. 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

18. 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.

19. PATHOGENESIS:

20. 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.

21. 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,

22. Immunologic Reactions:

23. 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.

24. 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.

25. 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  kat G 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.

26. 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.

27. 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

28. 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

29. 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

30. 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.

31. 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

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

33. 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.

34. 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.

35. 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.

36. 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.

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

38. Gohn focus with hilar adenopathy and bilateral infiltrate.

39. 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

40. 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. H epatic insufficiency leads to hypovitaminosis A and D that should be supplemented.

41. 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

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

43. 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.

44. 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.

45. 62/M on chlorpropamide 250mg daily Given Rifampicin 600mg Daily Chlorpromamide increased to 400mg daily CASE REPORT Self & morris , Chest 1980

46. 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 R ifampicin discontinued, Gliclazide reduced to 80mg daily (HBA1c 5.6%) CASE REPORT Sellers & Dean, Diabetes Care 2000

47. 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

48. 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

49. 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

50. 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

51. 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.

52. 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 .

53. 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.

54. 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. E xamination 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.

55. 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 d iabetic patient should be screened for TB and vice-versa.

56. DOCTOR THANK YOU