Clinical Aspects of Tuberculosis

1. Clinical Aspects of Tuberculosis Professor Mike McKendrick Lead Physician Department of Infection and Tropical Medicine Royal Hallamshire Hospital Sheffield Honorary Professor Division of Genomic Medicine University of Sheffield Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

2. Clinical aspects of TB • Pathogenisis • Clinical diagnosis • Treatment and monitoring and control • New issues Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

3. Clinical Aspects of Tuberculosis • Pathogenesis of tuberculosis • Infection versus disease • Host factors • Pathogen factors Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

4. Pathogenesis • Host factors include • Social e.g. • Poverty • alcoholism • Age e.g. • Baby • Teenage girl • Old age • Immunity e.g. • HIV • Gamma interferon • SCID Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

5. Pathogenesis • Organism factors e.g. • Virulence factors • [Drug resistance] Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

6. Pathogenesis • MTB into lungs (or to cervical nodes or abdo. nodes) • Replication of organisms • Primary complex (lung and mediastinal lymph nodes) • Mycobacteraemia with potential for ‘seeding’ • Consequence of tuberculous infection • Symptomatic illness – disease (minority) • immunological control (majority) with Ghon focus on Xray. Infection is ‘contained’ by granuloma but not eliminated Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

7. Pathogenesis • Tuberculous disease is a consequence of: • Primary infection e.g. in baby • Reactivation • ‘natural’ • Associated with immunosupression • Re infection Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

8. Clinical features • Clinical illness • Pulmonary • Extrapulmonary Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

9. Clinical illness • Chest • Pulmonary • Pleural • Mediastinal nodes • pericardium • Extra pulmonary • skin and soft tissues (including lymph nodes) • Bone • Abdominal • Intra cranial • other Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

10. Clinical clues for TB • Clinical symptoms – usually ‘chronic’ rather than acute • Fever • Sweats • Weight loss • Focal symptoms • Epidemiology • History of TB, HIV • Country of origin, recent travel/work • Contact with TB [England, Wales & NI 2004 • 7,176 notifications, 414 children • 70% foreign born population groups] Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

11. TB – guidelines for the clinician • Great mimicker • Low index of suspicion • Pulmonary TB usually easy to consider • Non pulmonary often requires ‘lateral thinking’ Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

12. Clinical TB • Laboratory samples • In the current era every effort must be made to obtain adequate samples likely to lead to a microbiological diagnosis before treatment is started (sometimes difficult with surgical specimens!) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

13. What can the laboratory do to help the clinician? • Awareness of TB e.g. in the patient with recurrent sputum samples for ‘chronic bronchitis’ • ‘Rapid’ diagnosis of infection and resistance • Culture and sensitivities – the clinician wants answers immediately if possible • PCR – further opportunities for development • Gamma interferon based tests?? • other Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

14. What samples? Depends on clinical scenario • Chest • Sputum – if productive • Induced sputum • Bronchoscopic alveolar lavage (BAL) • Pleural biopsy • Pleural fluid • Other • E.g. Lymph node, aspiration of abscess, mesenteric biopsy, stool, bone marrow etc. • What about EMSU? - should be done selectively where it is likely to be helpful Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

15. Induced sputum • Hypertonic saline nebuliser in negative pressure room with HEPA filter and well trained physiotherapist • Study of 27 confirmed positive patients • 13 +ve induced sputum only • 1 +ve bronchoscopy only • 13 +ve induced sputum and bronchoscopy McWilliams T et al Thorax 2002: 57; 1010-1014 Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

16. Audit of induced sputum in Department of Infection in Sheffield • Criteria for procedure • Past history TB or contact with TB in last year • Respiratory symptoms of one or more of: • Non-productive cough • Fever, Night sweats, weight loss • Haemoptysis 114 procedures, 12 positive for TB • Cohort followed up for 12 months, no cases missed - Bell et al. J Infection 2003: 47; 317-321 Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

17. Clinical cases • Cases of • pulmonary infection • Non pulmonary infection • Examples of spectrum of disease produced by TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

18. Pulmonary and non pulmonary TB disease – Sheffield 2005 • Equal numbers of patients with pulmonary and non pulmonary tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

19. Clinical presentation 1 • 35 year old African lady with fever and dry cough for 3 weeks. • Mildly unwell • Night sweats • Weight loss 4 pounds • No history of contact with TB • CXR Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

20. Case 1 – miliary tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

21. Pulmonary TB typically affects the upper zones of the lung Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

22. Case 1 • Investigation • FBC normal • ESR 53 • U and E normal • LFT – albumen 31 • CRP 40 • Induced sputum – smear negative Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

23. Case 1 • Progress • Clinical diagnosis of TB • 4 drug treatment • Clinical improvement • TB culture • positive at week 3 • fully sensitive (week 5) • Modified anti TB drug regime in light of lab results Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

24. Case 1 • What about HIV testing? – who to test? • Strong association between HIV and TB • Universal testing or selective testing? • What about testing for vitamin D? • Vitamin D has role in activating macrophages to destroy mycobacteria • Vitamin D deficiency in ethnic populations in UK often low Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

25. Case 1 • Cured after standard 6 months therapy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

26. Clinical presentation 2 • 28 year old African lady with backache for 6 weeks • Diagnosed initially as non specific • Developed fever – no obvious cause • ID opinion sought • Investigation with MRI scan Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

27. Clinical case 2 • Diagnosis • Vertebral osteomyelitis with soft tissue mass impinging on the cord • Investigation • Biopsy and culture • Treatment • 4 anti TB drugs and antibiotic therapy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

28. Clinical case 2 What will happen if diagnosis or treatment for TB spinal osteomyelitis is delayed? Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

29. What will happen if treatment delayed? – gibbus formation (acute angulation of spine with or without neurological damage) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

30. The physical appearance – Potts disease of spine - gibbus Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

31. Clinical case 2 • Progress • Increasing back pain and neurological symptoms – mild leg weakness • Repeat MRI – changes similar • Treatment • Continue therapy • consider surgical decompression Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

32. Clinical case 2 • Further progress • Weakness of legs • Neurosurgery and internal splinting • Other considerations - clinical • Has she got HIV? • Is her vitamin D level normal? • Other considerations - epidemiological • From where has she got infection? • To whom might she have given it? Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

33. TB may affect any tissue of the body including: • Skin and soft tissue • Lymph nodes • Bones and joints • Intra abdominal structures including • peritoneum • Kidneys • Adrenal glands • Lymph nodes • Central nervous system • Tuberculoma • meningitis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

34. Skin and soft tissue Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

35. 25 male African. Expanding non painful lesion in neck - Cervical lymph node TB progressing to abscess (beware deep extension – collar stud abscess) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

36. TB node in neck with deep extension Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

37. 35 female African – systemically well - hand and foot lesions present for 6 months – MTB grown on biopsy by plastic surgeons(HIV neg) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

38. Bony tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

39. Astute radiologist should enable the appropriate further investigation Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

40. Often associated with delay in diagnosis – any chronic discharging lesion must be considered possibly TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

41. Abdominal Tuberculosis Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

42. Renal tuberculosis (may have few or no symptoms) leading to autonephrectomy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

43. 30 middle eastern asylum seeker - abdo pain, fever, sweats – CT scan - peritoneal TB confirmed on biopsy – may mimic malignancy Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

44. Intracranial TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

45. miliary TB on MRI scantuberclomas on CT scan Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

46. meningitis – diagnosis usually made on clinical grounds • Clinical • Acute or subacute • Prognosis related to severity of disease at onset of treatment • Commonly delay between presentation and diagnosis • Common in children • c100 cases per year in England • CSF • Cell count 50-500 (50% lymphs, 50% polys) • High protein ++ • Low glucose • Micro often negative (PCR/culture important) Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

47. Treatment of TB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

48. BTS guidelines – 1999 Thorax 2000: 55; 210-218 • NICE guidelines – 2006 • Sensitive TB – 4 drugs for 2 months 2 drugs for 4 months • Resistant TB - 6 drugs for 24 months (second line drugs are not so effective) [Eng, Wales & NI 2004, 6.8% Isoniazid resistant, 1% MDR TB (R to Isoniazid and rifampicin)] Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

49. Problems of TB therapy • Toxicity e.g. liver • Multiple therapy • Prolonged treatment • Drug interactions e.g. anti HIV drugs Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

50. Compliance • Treatment will not work if not taken • DOTS (Directly Observed Therapy) if: • Likely poor compliance • MDRTB Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals