This document summarizes key aspects of tuberculosis (TB) diagnosis and treatment under India's Revised National Tuberculosis Control Programme (RNTCP). It outlines that TB is diagnosed through sputum smear microscopy and treatment involves a short course of directly observed intermittent chemotherapy. New sputum-positive pulmonary TB patients receive a six month regimen consisting of two months of daily therapy followed by four months of thrice weekly doses.

1. Scientific Basis of Diagnosis and Treatment in RNTCP Dr Awadhesh Kumar Sharma , MD Senior resident Department of Medicine, M.L.B. Medical College, Jhansi, UP

2. Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis which is discovered by Robert Koch. Pulmonary tuberculosis is the most common form of TB. Transmission occurs by air borne spread of infectious droplets and droplet nuclei containing the tubercle bacilli. The source of infection is a person with sputum smear-positive pulmonary TB. Robert Koch

3. India is the highest TB burden country globally accounting for one fifth of the global incidence Source: WHO Geneva; WHO Report 2006: Global Tuberculosis Control; Surveillance, Planning and Financing Globally ~9 million new TB cases occur annually Non-HBCs 20% Ethiopia 3% Philippines 3% South Africa 4% Bangladesh 4% Pakistan 3% Nigeria 4% Indonesia 6% China 15% India 20% Other 13 HBCs 18%

4. Problem of TB in India Incidence of TB disease: 1.8 million new TB cases annually (0.8 million new infectious cases) Prevalence of TB disease: 3.8 million bacteriologically positive (2000) Deaths: about 370,000 deaths due to TB each year TB/HIV: ~2.5 million people with HIV & ~1 million co infected with TB-HIV About 5% of TB patients estimated to be HIV positive MDR-TB in new TB cases ≤ 3% Substantial socio- economic impact

5. Estimated Incidence of TB in India* (No. of New Smear Positive Cases per 100,000 population, per year) North West East South National 75 North Zone 95 East Zone 75 West Zone 80 South Zone 75

6. NATIONAL TUBERCULOSIS CONTROL PROGRAMME During the 1950 s & 1960 s, significant research on TB was undertaken in India & in 1962 the National TB Control Programme (NTP) was launched. In 1992, a review of the NTP found that the desired results had not been achieved. There was over dependence on X rays for diagnosis.

7. REVISED NATIONAL TB CONTROL PROGRAMME A revised strategy to control TB was pilot tested in 1993. The RNTCP applies the WHO recommended DOTS (Directly Observed, Short Course) strategy. The programme was expanded in a phased manner to cover the entire country in 2005.

8. RNTCP – Goal and Objectives Goal The goal of TB control Programme is to decrease mortality and morbidity due to TB and cut transmission of infection until TB ceases to be a major public health problem in India. Objectives: To achieve and maintain a cure rate of at least 85% amongst new smear positive cases To achieve and maintain a case detection of at least 70% of the estimated new sputum positive TB patients

9. Scientific basis of diagnosis Scientific basis of the treatment regimen Basis of intermittent chemotherapy Directly observed treatment

10. Diagnosis

11. How are TB cases diagnosed? Cough for ≥ 3 weeks ( TB suspects ) screened from OPD/clinics and referred for sputum microscopy Sputum microscopy performed at quality assured Designated Microscopy Centres (DMCs) If sputum is initially negative and remains so after a course of antibiotic, despite persisting symptoms, then X-ray chest is done Standard diagnostic algorithm for pulmonary TB Patients diagnosed as Sputum +ve and Sputum –ve PTB Extra-Pulmonary TB is diagnosed based on clinical evaluation and histopathological evidence

12. DIAGNOSTIC ALGORITHM FOR PULMONARY TB

13. Diagnosis by Microscopy of Patients Presenting to Health Facilities Microscopy is more accurate than x-ray, and correlates with infectiousness as well as with risk of death from TB Virtually all patients with multiple positive direct AFB smears have TB At least half of persons with x-rays suggestive of TB do not have TB

14. Microscopy is More Objective and Reliable than X-ray Inter-observer variability is much less with microscopy than with x-ray AFB microscopy provides information on infectiousness of the patient, which x-ray does not AFB microscopy allows prioritization of cases, which x-ray does not AFB microscopy is also an objective method to follow the progress of patients on treatment

15. Acid Fast Stain Tubercle Bacilli

16. Problems with Over-Reliance on X-ray for TB Diagnosis Misclassification of non-TB as TB, resulting in unwarranted treatment and avoidable expenditure Inability to distinguish between smear+ and smear-negative patients, resulting in inadequate priority to true smear+ patients Failure to give appropriate treatment Inability to monitor progress accurately  Lower cure rates and increased spread of TB

17. X-rays of an Dubai based NRI engineer who complaints of cough with expectoration alongwith haemoptysis for 3 months, diagnosed there as case of pulmonary tuberculosis & antituberculosis Rx started. When he did not get relief, he visited India, here on investigation his eosinophillic count and IGE level found to be elevated & diagnosed as case of Allegric Bronchopulomonary Aspergillosis and got relief by antifungal and steroids .

18. Case- I This chest X-ray of Pt. mrs. Vimla 25 yrs. old lady admitted on 7 th April 08 with complaints of high grade fever with productive cough. Treated on the line of right lower lobe pneumonitis with IV antibiotics for 2 weeks but did not get reliefed. Later her sputum examination was done and found to be AFB positive and treated on line of cat. I regimen.

19. Case- II This chest X-ray of Pt. Mr. Gopesh Kumar 50 yrs. old male admitted on 8 th April 08 with complaints of high grade fever with productive cough with chest pain and dyspnoea. TLC was 42000 /cmm and polymorphs were 92%.Treated on the line of right upper lobe lung abcess with IV antibiotics for 2 weeks but did not get relief. Later his sputum examination was done and found to be AFB positive and on repeat chest X-ray the cavity size increased & involved whole of the right upper and middle lobe and treated on the lines of cat. I regimen. After that pt. improved.

20. A systematic evaluation of well-functioning District TB Centres by the National TB Institute, Bangalore found that nearly 70% of the cases diagnosed and put on treatment on the basis of x-ray, did not have tuberculosis at all The proportion of cases diagnosed on the basis of x-ray alone and put on treatment unnecessarily is likely to be even higher in many centres NTI, IJT, 1974 Over- diagnosis

21. Three sputum Samples collected - SPOT – Early Morning – SPOT

22. Three sputum smears are optimal

23. Diagnosis of tuberculosis Tools Merits Demerits Tuberculin test Can identify infection Good epidemiological tool Cannot differentiate infection & disease X-ray Sensitive Not specific Sputum Sm. Microscopy Definitive diagnosis Easy to perform at the periphery Replicability Less costly Sensitivity 60-80% Culture for MTB Highly sensitive & specific Costly, not freely available long waiting period

24. Treatment

25. Aims of TB treatment To decrease mortality, long-term morbidity and transmission To effect a permanent cure, prevent relapses and decrease transmission To minimize development of drug resistance To achieve the above while minimizing drug side effects

26. Need for standardized treatment To treat sm+ PTB patients as priority To prevent under-treatment of sm+ cases prevent spread of TB in the community prevent acquired drug resistance To avoid over-treatment To minimize side effects To be able to monitor and compare treatment outcomes

27. Some definitions …….. Smear positive patient - A patient with at least 2 initial sputum smear examination (direct smear microscopy) positive for acid-fast bacilli (AFB). - Or A patient with one sputum examination positive for AFB and radiographic abnormalities consistent with active pulmonary TB. - Or A patient with one sputum specimen positive for AFB and culture positive for M tuberculosis.

28. Some definitions …….. Smear negative patient - A patient having symptoms suggestive of TB with at least 3 sputum examinations negative for AFB and radiographic abnormalities consistent with active pulmonary TB. - Or A patient whose diagnosis is based on culture positive for M. tuberculosis but sputum smear examinations negative for AFB.

29. Types of Tuberculosis Patients New: A TB patient who has never had treatment for TB or one who has taken anti TB drugs for less than one month. Relapse: A TB patient who was declared cured or treatment completed by a physician, but who reports back to the health service and is now found to be sputum smear-positive. Transferred in : A TB patient who has been received for treatment in one Tuberculosis unit, after starting treatment in another unit (TU) where(s) he has been registered.

30. Treatment after default: A TB patient who received anti TB treatment for one month or more from any source and returns to treatment after having defaulted, i.e., not taken anti TB drugs consecutively for two months or more, and who is found to be sputum smear positive. Failure: Any TB patient who is smear positive at 5 months or more after starting treatment. Failure also includes a patient who was treated with category III regimen but who becomes smear positive during treatment. Chronic: A TB patient who remains smear positive after completing a re-treatment regimen.

31. Treatment Outcomes Cured: Initially sputum smear positive patient who has completed treatment and had negative sputum smears, on at least two occasions, one of which was at the end of treatment. Treatment Completed: A sputum smear positive patient who has completed treatment, with negative smears at the end of Intensive phase but none at the end of treatment, or A sputum snear negative patient who has received a full course of treatment and has not become smear positive during or at the end of treatment.

32. Died: Patient who died during the course of treatment, regardless of the cause of death. Failure: Any TB patient who is smear positive at 5 months or more after starting treatment or A patient who was treated with category III but who becomes smear positive during treatment. Defaulted: A patient who has not taken anti TB drugs for 2 months or more consecutively after starting treatment. Transferred out: A patient who has been transferred to another TB unit or district and for whom the treatment result (outcome) is not known.

33. Intensive Phase Aims for a rapid killing of bacilli A state of non-infectiousness within 2 weeks Quick relief of symptoms Smear negativity by 2 months Prevent development of drug resistance  multi-drug regimens and DOT

34. Continuation Phase Aims to eliminate remaining bacilli Killing of “persisters” prevents relapses Multi-drug regimens and DOT necessary even though risk of emergence of drug resistance is less as fewer bacilli remain

35. Treatment Regimens 2H 3 R 3 Z 3 / 4H 3 R 3 New smear negative and extra-pulmonary, not seriously ill Cat III 2H 3 R 3 Z 3 E 3 S 3 / 1H 3 R 3 Z 3 E 3 / 5H 3 R 3 E 3 Previously treated smear positive (relapse, failure, treatment after default) Cat II 2H 3 R 3 Z 3 E 3 / 4H 3 R 3 New smear positive; seriously ill smear negative; seriously ill extra-pulmonary Cat I

36. Side Effect of Anti-TB Drugs Symptom Drug Action to be taken Gastrointestinal upset Any oral medication Reassure patient Give drugs with less water Do not give drugs on empty stomach. Itching Burning in the hands and feet Isoniazid Give pyridoxine 100 mg/day until symptoms subside Joint pains Pyrazinamide evaluate Impaired vision Ethambutol STOP ethambutol and evaluate Ringing in the ears Loss of hearing Streptomycin STOP streptomycin and evaluate Jaundice Isoniazid, Rifampicin, Pyrazinamide STOP if liver enzymes elevated 5 times of normal.

37. Domiciliary treatment Short course chemotherapy Intermittent chemotherapy Directly observed treatment

38. Advantages of domiciliary chemotherapy Domiciliary chemotherapy is as effective as sanatorium treatment No additional benefit by bed rest, special diet etc No need for routine hospitalisation Economic benefit

39. Short Coures Chemotherapy (SCC) Six months of chemotherapy gives favourable results when compared with longer terms of treatment for new sputum positive TB patients. Duration of treatment are adequate to prevent emergence of drug resistance. SCC is more convenient and economical than conventional treatment with longer durations. The shorter period of time makes direct observation more feasible and improves patient adherence to tretment.

40. Intermittent Treatment As effective as daily treatment Less adverse reactions Total drugs consumed is less Less costly Less number of doses  facilitates treatment observation as less number of patient visits required and prevents concealed irregularity

41. D irectly O bserved T reatment DOT ensures the best possible results in treatment of TB. Here an observer watches and supports the patient in taking their drugs, thereby ensuring that the patient receives the medication. Direct observation ensures treatment for the entire course with the right drugs in the right doses at the right intervals

42. Patients swallows drugs in presence of observer

43. Why is it necessary to directly observe treatment? At least 1/3 of patients on self-administered Rx fail to adhere to Rx Impossible to predict which patients will take medicines DOT necessary at least in the IP of Rx to ensure adherence and smear conversion TB patient missing 1 attendance can be traced immediately and counseled

44. “ This use of supervised treatment ( now known as directly observed treatment ) in which patients are observed taking their anti-TB medications, was shown to be essential in India” Fox W. 1961 Based on studies from TRC

45. D irectly O bserved T reatment is the Standard of Care “ Every patient with TB in this country should receive DOT” (Iseman, NEJM, 1993) “ DOT has emerged as the standard of care” (Bayer, Lancet, 1995) “ DOT seems imperative … where the disease has become epidemic” (Chaulk, JAMA, 1996)

46. DOTS- Plus The WHO working group on DOTS- Plus for MDR-TB was established in 1999 to lead the global effort to control MDR-TB (Cat. IV) (Whose sputum culture isolates are resistant to at least isoniazid and rifampicin). Treatment is for a minimum duration of 18 months beyond sputum conversion (At least to sets of consecutive negative smears and cultures taken 30 days apart). Regimens should consist of at least four drugs with either certain, or almost certain, effectiveness.

47. Drugs are administered at least six days a week. In most cases, an injectable agent and a fluoroquinolone form the core of the regimen. An injectable agent (an aminoglycoside or capreomycin) is used for a minimum of 6 months.

48. XDR- TB: XDR – TB is defined as …….. MDR Plus resistance to any fluoroquinolone, And at least one of the second line injectable drugs, capreomycin, kanamycin or amikacin. Such extensive resistance markedly limits treatment options because few effective and reasonably well tolerated alternative drugs are available.

49. Tuberculosis in Children TB in children represents 5-15% of all TB cases. Diagnosis Younger children with pulmonary TB rarely cough out sputum as they usually swallow it. Diagnosis of pulmonary TB by sputum microscopy is therefore very unlikely among smaller children. Gastric lavage or laryngeal swabs are difficult to carry out. Bacteriological confirmation is not possible in most cases.

50. Children will be suspected of having pulmonary TB if they present with fever and/or cough for more than 3 weeks, with or without weight loss or no weight gain. TB should also be suspected if there is a history of contact with a suspected or diagnosed case of active TB disease in the last 2 yrs. Diagnosis of TB in children should be based on a combination of clinical presentation, sputum examination (wherever possible), chest X-ray, mantoux test and history of contact.

51. Treatment Intermittent short-course chemotherapy given under direct observation as for adult patients, based on the weight of the children. For children with TB meningitis on cat I regimen, the 4 drugs used during intensive phase should be H, R,Z and S (instead of HRZE) as ethambutol does not cross the blood brain barrier easily. Steroids are recommended during the early part of the treatment of TB meningitis, with the doses being tapered off over 6 to 8 weeks.

52. Chemoprophylaxis Asymptomatic children under 6 yrs of age, exposed to a patient with infectious (smear positive) TB from the same household, need to be given 6 months of daily isoniazid (5 mg/kg) as chemoprphylaxis against the disease.

53. Monitoring & Evaluation Whenever possible , follow up sputum examination is to be performed with the same frequency as in adults. Since this may not be possible for the majority of children with pulmonary TB, clinical or symptomatic improvement is to be assessed at the end of the intensive phase of treatment and at the end of the treatment. Improvement should be judged by absence of fever or cough, a decrease in the size of lymph node(s), weight gain, radiological assessment etc.

54. Diagnostic Algorithm for Pediatric Tuberculosis

55. Pulmonary TB Suspect Fever and/or cough 3 weeks Loss of wt./No wt. gain History of contact with suspected or diagnosed case of active TB Is expectoration present? If yes, examine 3 sputum smears If no, then diagnosed based on a combination of Clinical presentation Chest X-ray Mantoux test History of contact 2 or 3 positives 3 negatives Antibiotics 10-14 days Cough Persists Repeat 3 sputum examinations Sputum positive TB 1 Positive X- Ray Suggestive of TB Negative of TB Non TB Negative 2 or 3 positives X-Rays + Mantoux Sputum Positive TB Suggestive of TB Sputum negative TB

56. Algorithm for clinical monitoring

57. Patient on treatment Review at 2 months shows satisfactory response assessed by: - improvement in symptoms - no weight loss and or weight gain Review at 2 months shows non - satisfactory response assessed by - poor or non adherence to treatment - weight loss - worsening of symptoms Follow up clinically Clinical assessment and X-ray at completion of treatment Refer to for assessment (Consider sputum examination) Sputum positive Failure Category II Sputum negative or not available Review diagnosis Extend IP by 1 month No improvement = Paediatric non-responder

58. TB treatment in HIV infected patients All new TB cases known to be HIV positive are classified as seriously ill and treated with category I regimen. The retreatment cases are to be treated with category II regimen. The HIV positive status should not be mentioned in any RNTCP records. Routine HIV testing of all TB suspected patients is NOT the national policy. Treatment interruption, due to higher occurrence of adverse drug reactions or intercurrent opportunistic infections, could also lead to an increased risk of relapse of TB.

59. The current recommendations on ART are to use a triple drug combination. A combination of stavudine/zidovudine plus lamivudine plus Efavirenz/Nevirapine is usually used. Co-administration of Rifampicin with any of the protease inhibitors or non-nucleoside reverse transcriptase inhibitors should be avoided as Rifampicin induces cytochrome P450 and substantially decrease blood levels of these antiretroviral drugs. In TB patients co-infected with HIV, TB treatment should be completed prior to starting ART, unless there is a high risk of HIV disease progression and death during the period of TB treatment (i.e. a CD4 count <200/cmm or the presence of disseminated TB)

60. Conclusion RNTCP diagnosis and treatment strategies are based on scientific evidence In addition It is consistent with international WHO guidelines It is consistent with International Standards of TB Care Well documented and good RNTCP treatment outcomes in millions of patients supports the soundness of the treatment strategies

61. Thank You