Unit 9: Diagnosis and Treatment of Paediatric Tuberculosis

1. Unit 9: Diagnosis and Treatment of Paediatric Tuberculosis Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. Objectives At the end of this unit, participants will be able to: • Diagnose TB in children • Discuss the use of the tuberculin skin test (TST) • Explain treatment regimens for children • Explain the interaction between ART and TB treatment

3. Worldwide Burden of Paediatric Tuberculosis • 8.3 million new cases of TB in 2000* • 884,019 (10.7%) were in children • Est. 9 million new cases in 2006** • 1 million (11%) in children • varies from 3-25% depending on the country • 75% occurs in 22 high-burden countries Sources: *Nelson LJ, et al. Int J Tuber Lung Dis, 2004. ** WHO, 2006.

4. Botswana Paediatric TB • In 2000, 12% of all reported TB in Botswana occurred among children <15 years of age, though children represented only 2% of smear positive cases* • Reported cases in children 0–9 years of age • 1996: 813 (case rate 199/100 000) • 2000: 1029 (case rate 229/100 000) • An increase of 15% from 1996-2000 Source: *B Koosimile, BNTP, 2005.

5. TB Notification Rates by Sex and Age Group, Botswana 2005 Source: BNTP, 2005.

6. Lung Diseases at Autopsy in African Children Dying from Respiratory Illnesses, 1997-2000, Zambia Diagnosis Source: Chintu C, et al. The Lancet, 2002.

7. Key Risk Factors for TB in Children Household contact with newly diagnosed smear-positive case Fewer than 5 years old HIV infection Severe malnutrition • Source: WHO, 2006.

8. Young Children Exposed to TB Children should be evaluated for illness If not ill and < 5 years old: INH preventive therapy If ill, evaluate for need of TB treatment Courtesy of: Hampton G, Lung Health Image Library, 2003.

9. TB Prevention and Control from Smear Positive Mother-to-Child Infants should take INH prophylaxis for 6 months The infant receives BCG after completion of INH prophylaxis

10. Recommended Approach to Dx in Children: Assessment Patient history Contact to PTB+ Symptoms consistent with TB Clinical Exam TST Investigations for PTB and EPTB HIV test Source: WHO, 2006.

11. Diagnosis of TB in HIV-Infected Children TST less reliable (false-negatives) More extrapulmonary disease- harder to diagnose Broader differential diagnosis with poor tests Culture yield- similar to non-HIV-infected children

12. Symptoms of Pulmonary TB in Children Clinical manifestations may include: Chronic cough not improving and present for 2-3 weeks Night sweats Fever of > 38 degrees for 2 weeks Weight loss or failure to thrive Fatigue* Blood-streaked sputum Shortage of signs and symptoms relative to chest radiograph findings *Source: Marais B, et al. Pediatrics, 2006.

13. Radiographic Manifestations of Pulmonary TB in Children Prominent hilar and/or mediastinal adenopathy (not always discernable on plain radiographs) Any lobe of lung involved; 25% multilobar Collapse-consolidation or segmental pattern common Obstructive signs/symptoms with endobronchial lesions Not contagious

14. Source: Botswana-Baylor Children’s Clinical Centre of Excellence

15. Bacteriological Confirmation If sputum can be obtained, 3 samples should be sent for smear microscopy Perform gastric aspirate smear and culture Perform sputum induction TEST SENSITIVITY AFB smear – gastric aspirate 5-10% Mycobacteria culture – gastric aspirate 0-40% Mycobacteria culture – infants Up to 75% Source: Botswana-Baylor Children’s Clinical Centre of Excellence

16. Triad Approach Contact with a case + Positive TST + Consistent clinical and/or radiographic evidence THIS IS HIGHLY SUGGESTIVE OF TB

17. Differential Diagnoses of Pulmonary TB (1) Bacterial pneumonia Lymphocytic interstitial pneumonitis (LIP) Pneumocystis carinii (jeroveci) pneumonia Bronchiectasis Others Fungal pneumonia Pulmonary lymphoma Pulmonary Kaposi’s Sarcoma

18. Differential Diagnoses of Pulmonary TB (2) Asthma Cardiac disease Severe gastro-oesophageal reflux Aspirated foreign body Pertussis Cystic fibrosis Bronchiectasis

19. Extra-Pulmonary TB: Signs (1) Non-painful, enlarged cervical lymphadenopathy without fistula formation Meningitis not responsive to antibiotic treatment Distended abdomen with ascites Pleural effusion Gibbus deformity of the spine

20. Extra-Pulmonary TB: Signs (2) • Pericardial effusion • Bone or joint swelling • Signs of tuberculin hypersensitivity, such as erythema nodosum • Subacute CNS disease, such as change in behaviour progressing to seizures or coma Courtesy of: Merck & Co., Inc. 2006.

21. Time from Infection to Disease Miliary and Meningeal 2 – 6 months Intrathoracic 2 – 12 months Lymph node 2 – 12 months Pleural effusion 3 – 12 months Skeletal 6 months – 2 years Renal 1 – 5 years Source: Botswana-Baylor Children’s Clinical Centre of Excellence

22. TB Cervical Lymphadenitis Most common form of extra-thoracic TB Courtesy of: B. Marais, Stellenbosch University

23. Lymphadenitis Caused by Mycobacterium Tuberculosis Often unilateral, sometimes bilateral Chest x-ray usually normal Usually non-tender, enlarged, fixed, matted nodes Absence of systemic findings Often progress and “break down”: suppuration, sinus tracts Major differential diagnosis = malignancy Source: Botswana-Baylor Children’s Clinical Centre of Excellence

24. Tuberculous Meningitis Inflammation of the meninges as a result of infection with M. tuberculosis Presents with headache, fever, irritability, convulsions, altered mental status High-pitched cry Bulging fontanelle Suspected clinically & confirmed with CSF

25. Classic Findings in Cerebrospinal Fluid Source: Botswana-Baylor Children’s Clinical Centre of Excellence

26. CT Scan/MRI Findings in Meningeal (CNS) Tuberculosis Basilar enhancement Hydrocephalus (communicating) Vasculitis Infarct “Paradoxical” tuberculomas-- while on ultimately successful chemotherapy Ring-enhancing lesions, single or multiple Source: Botswana-Baylor Children’s Clinical Centre of Excellence

27. Disseminated (Miliary) Tuberculosis in Childhood • Usually slow, subtle appearance, but may show rapid progression • CXR usually normal early, then classic miliary appearance • Other common features: hepatosplenomegaly, lymphadenopathy, cutaneous lesions • TST negative in up to 50% of cases Source: Botswana-Baylor Children’s Clinical Centre of Excellence

28. Source: Botswana-Baylor Children’s Clinical Centre of Excellence

29. What Do You See? © Slice of Life and Suzanne S. Stensaas

30. What Do You See? © Slice of Life and Suzanne S. Stensaas

31. Tuberculous Pleural Effusion in Pediatrics • Primarily in adolescents • Uncommon before age five • Rare before age two • Usually unilateral, but can be bilateral • Usually presents with: fever, chest pain, SOB Source: Marais B, Stellenbosch University

32. Botswana-Baylor Children’s Clinical Centre of Excellence

33. Investigations for Suspected EPTB

34. Tuberculin Skin Test (TST) Latent TB uncommon in children, therefore a positive skin test is more likely to represent recent infection and the presence of TB disease Used in tandem with other diagnostic tests in children Mantoux method is recommended test

35. Applying the TST (PPD or Mantoux Test) TST useful in young children who have low prevalence of latent TB infection Placed by intradermal injection similar to BCG application Courtesy of: Knobloch G, CDC, 2004

36. Reading the TST (Mantoux) A positive reaction occurs when a cell-mediated immune response to tuberculin antigens produces firm swelling at the intradermal site after 48-72 hours Courtesy of:Kopanoff D, CDC, 1969

37. Interpreting the TST • Positive Result • Infection with MTB • Does not prove active tuberculosis disease • Negative Result • No infection with MTB • Cannot exclude active TB disease (20-25% of HIV patients with active TB have negative TST)

38. Incorrect TST Results False Negative Incorrect placement Incorrect reading HIV infection and other immunosuppression Viral Infections, e.g. measles Vaccinated with live viral vaccines (w/in last 6 weeks) False Positive Incorrect interpretation of test Infection with M. bovis or MOTT Recent BCG

39. BCG Vaccination BCG vaccine prevents severe forms of TB in infants (up to 85% reduction) and is recommended for newborns TB meningitis Miliary TB Negligible effect on TB epidemiology Does not prevent infection Little effect on reactivation disease

40. BCG Dosages

41. BCG Vaccination in Children

42. Normal Reaction Course to BCG Vaccination At vaccination Approximately 3 wk post-vacc Approximately 1 yr post-vacc Approximately 6 wk post-vacc Courtesy of: Kim SJ, Korean Institute of Tuberculosis, 2001

43. Complications of BCG Swelling of lymph nodes adjacent to vaccination site Subcutaneous abscess in babies Excessive ulceration Local ulcers and BCG adenitis persisting for more than 8 weeks Note: Routine follow-up of infants is recommended for early identification and treatment of any BCG-related complication

44. Interaction of BCG Vaccines with the Tuberculin Skin Test 79% of vaccinated children ages 3-60 months did not react to a TST (MMWR 1997) Most non-infants who get one or more BCG vaccinations will react to a TST (usually <15 mm), but effect wanes over 5 – 10 years Outside infancy, “positive” TST more likely to indicate infection with M. tuberculosis than be residual from BCG Source: Lockman S, et al., Int J Tuberc Lung Dis, 1999.

45. HIV Testing In Botswana, HIV testing is part of the diagnostic work-up for ALL TB suspects (including children) In HIV positive children: Lymph node and pulmonary TB are Clinical Stage 3 EPTB other than lymph node is Clinical Stage 4

46. Impact of HIV on Diagnosis and Management of TB in Children HIV makes diagnosis and management of TB in children more difficult for the following reasons: Other HIV-related disease, such as lymphocytic interstitial pneumonitis, may present in a similar way to PTB or miliary TB Interpretation of tuberculin skin testing and CXR is less reliable Pill burden of TB treatment and ART can be difficult for children to tolerate Drug-drug interactions between rifampicin and NNRTIs and PIs Source: WHO, 2003

47. Anti-tuberculosis Drug Dosing in Children

48. Recommended Treatment Regimens for Children Category I Children with severe disease, such as disseminated TB: 2HRZE/4HR Children with TB meningitis: 2SHRZ/4HR Category II 2SHRZ/1HRZ/5HR Category III 2HRZ/4HR

49. Role of Adjuvant Steroid Therapy TB meningitis 2mg/kg/day for 4 weeks and then taper over 6 weeks TB pericarditis 2mg/kg/day for 4 weeks then 1mg/kg/day for 4weeks then taper for 6 weeks Massive lymphadenopathy with airway obstruction 2mg/kg/day for 4 weeks then taper over 6 weeks

50. Tuberculosis in Children: Drug-Resistance Usually must link the child with an adult case to identify it Adults with drug-resistant TB are as contagious as those with susceptible disease Disease expression in children the same as with susceptible strains Children tolerate and respond well to second-line drugs Source: Botswana-Baylor Children’s Clinical Centre of Excellence