Gary Reubenson 16 October 2012 PAEDIATRIC TUBERCULOSIS: AN OVERVIEW IN 40 MINUTES!!

DECLARATION No relevant conflicts of interest to declare

OVERVIEW Burden of disease & epidemiology Pathogenesis (not covered) Clinical presentation of childhood TB Diagnosis of paediatric TB Categorizing TB infections in children Anti-tuberculous therapy in children Miscellaneous issues BCG

THE BURDEN OF TB Every year, about 9 million develop active TB and 1.4 million die 99% of all TB sufferers live in developing countries Between 2000 and 2020, nearly 1 billion additional people will be newly infected, 200 million will become sick and 35 million will die Globally, the economic costs of TB to the poor are estimated to be US$12 billion per year

GLOBAL TB INCIDENCE (2010)

HIV CO-INFECTION IN NEW TB CASES (2010)

THE BURDEN OF PAEDIATRIC TB 1 million clinical cases (11%) occur annually in children, many more infections 450 000 childhood deaths each year Children who develop disease tend to do so in first two years after exposure to open adult case

THE BURDEN OF PAEDIATRIC TB Risk of developing disease after infection with Mycobacterium tuberculosis increases with younger age 5 to 10% 15% 24% 43% adults adolescents children 1 to 5 years of age infants < 1 year of age Risk of progression to TB disease = 10% per year in HIV-positive adults (possibly even higher in HIV-positive children)

THE BURDEN OF PAEDIATRIC TB Most common age at presentation is 1 to 4 years Children usually develop Primary TB Some may develop post-primary TB Reactivation Re-infection Relative contributions determined by baseline prevalence

DIFFERENCES BETWEEN CHILDHOOD AND ADULT TB Children have paucibacilliary disease Cavitation is rare in children: only 6% of cases Extrapulmonary TB more often occurs in children Disseminated disease occurs especially in children <3 years of age Children develop fewer anti-tb drug side effects

INTRA-THORACIC TB IN CHILDREN

DIAGNOSIS OF TB IN CHILDREN: HISTORY BUT, many cases of Smear positive household contact, often unrecognised confirmed paediatric Symptoms TB will have none of Cough: unremitting, > 21 days Fever: > 38 C for 14 days Weight loss or failure to thrive: RTHC Fatigue Very unlikely if none of: Poor weight gain, current cough or fever these!!

DIAGNOSIS OF TB IN CHILDREN Physical signs strongly suggestive of Extrapulmonary TB: Gibbus virtually pathognomonic for spinal TB Non-painful cervical adenopathy with fistula formation

DIAGNOSIS OF TB IN CHILDREN Clinical features requiring further investigation: Meningitis not responding to appropriate antibiotic therapy Pleural effusion Non-painful enlarged nodes without fistula formation Pericardial effusion Ascites Non-painful enlarged joint Hypersensitivity phenomena e.g. Erythema nodosum, phlyctenular conjunctivitis

DIAGNOSIS OF TB IN CHILDREN: TUBERCULIN SKIN TEST Positive test suggests infection with M. tuberculosis, not necessarily TB disease Mantoux method: 2 new tuberculin units (TU) of PPD-S Equivalent to 5 old TU High-risk children: HIV-infected Severely malnourished 5 mm Other children (irrespective of BCG): 10mm

DIAGNOSIS OF TB IN CHILDREN: FALSE NEGATIVE TST Incorrect technique Expired PPD Viral infections: measles, varicella Live viral vaccine within 6 previous weeks Malnutrition Bacterial infections: pertussis, typhoid Immunosuppressive therapy Neonatal patient Primary immunodeficiencies Diseases of lymphoid tissues Low protein states Severe/disseminated TB

DIAGNOSIS OF TB IN CHILDREN: FALSE POSITIVE TST Incorrect interpretation of test BCG vaccination Non-tuberculous mycobacterial infection Incorrect technique

DIAGNOSIS OF TB IN CHILDREN: MICROBIOLOGICAL Microbiological examination for AFBs: Sputum Gastric aspirates Body fluids Mycobacterial culture: Suspected drug-resistant TB HIV infection Complicated or severe disease Uncertain diagnosis Histological or cytological evidence of TB in extrapulmonary sites

DIAGNOSIS OF TB IN CHILDREN: RESPIRATORY TRACT SPECIMENS Expectoration Gastric aspiration Difficult to obtain in children < 5 years old Bacterial yields higher in older children 2 sputum specimens, previously 3 Children unwilling or unable to expectorate 3 consecutive morning samples Sputum induction Bacterial yields better than that of gastric aspirates Slow uptake, but requires no new skills

SPUTUM INDUCTION Low-risk procedure Contraindications Procedure Coughing, mild wheezing, nose-bleeds Attention to Infection Control Fasting <3 hours Severe respiratory distress Intubated Bleeding Reduced level of consciousness Significant asthma Administer nebulised bronchodilator Administer hypertonic (3%) saline for 15 minutes or 5 mls Chest physiotherapy (if necessary) Expectorate or suction nose/nasopharynx

DIAGNOSIS OF TB IN CHILDREN: SUSPECTED PULMONARY TB Good quality CXR Persistent opacification in the lung (>6 weeks) Enlarged hilar lymph nodes Miliary pattern is useful in HIV-uninfected children Cavitation Pleural effusion CXR notoriously unreliable, especially with HIV

INTERFERON-γ RELEASE ASSAYS Immune-based tests for TB infection, not currently disease 2 commercially- available: T-Spot.TB (ELISPOT) Quantiferon-TB Gold In-tube (ELISA) Both measure response to ESAT-6 and CFP-10 Not affected by prior BCG exposure and many environmental mycobacteria High risk of indeterminate results in HIV-positive children Require only 1 clinical visit No boosting effect Expensive Exact role in diagnosing paediatric TB not entirely clear, but not recommended in our setting

DIAGNOSIS OF TB IN CHILDREN: OTHER TESTS Interferon-γ Release Assays Serology not recommended Nucleic Acid amplification Antigen-based tests e.g. lipoarabinomannan Newer culture techniques Phage-based tests New skin tests Require further research HIV testing is recommended in all patients in whom TB has been diagnosed HIV PCR HIV ELISA Work up for ART if HIV-infected

GENE XPERT

DEVELOPMENT PIPELINE FOR NEW DIAGNOSTICS

CATEGORIZING TB INFECTIONS IN CHILDREN: CASE DEFINITIONS Site of disease Result of microbiological investigations Severity of disease History of previous TB treatment Register each case with the National TB Programme when suspected

CATEGORIZING TB INFECTIONS IN CHILDREN: PULMONARY TB, SPUTUM SMEAR-POSITIVE 2 initial sputum smears positive for AFBs 1 sputum smear positive for AFB plus CXR consistent with TB OR OR 1 sputum smear positive for AFBs plus culture positive for M. tuberculosis

CATEGORIZING TB INFECTIONS IN CHILDREN: PULMONARY TB, SPUTUM SMEAR-NEGATIVE Cases that do not meet the criteria for smear-positive disease, including those with no smear results: At least 3 sputum specimens negative for AFBs AND Radiological changes consistent with pulmonary TB AND No response to broad spectrum antibiotics AND Decision by clinician to treat with a full course of anti-tb therapy

CATEGORIZING TB INFECTIONS IN CHILDREN: EXTRAPULMONARY TB Children with only extrapulmonary TB, and no pulmonary involvement If the case has concomitant pulmonary disease, it should be classified as a Pulmonary TB case

CATEGORIZING TB INFECTIONS IN CHILDREN: DRUG-RESISTANT TB Suspect drug resistance if: Source Case Known to have drug-resistant TB Sputum smear positive after 3 months of Rx History of previously treated TB History of Treatment interruption Child Contact with a known drug-resistant TB case Not responding to anti-tb treatment regimen Recurrence of TB after adherence on treatment

ANTI-TB THERAPY: OBJECTIVES OF TREATMENT Rapidly kill bacilli (bactericidal) Effect cure and prevent relapse (sterilizing) Prevent progression of disease Prevent transmission of infection Elimination of dormant bacilli Minimal side effects Prevent drug resistance Combination of anti-tb drugs

RECOMMENDED REGIMENS Intensive Phase Continuation Phase Rapidly eliminate organisms Prevent emergence of drug resistance Eradicate dormant organisms Drug (WHO 2010) Dose and Range (mg/kg body weight) Isoniazid H 10-15 300 Rifampicin R 10-20 600 Pyrazinamide Z 30-40 2000 Ethambutol E 15 25 1200 Streptomycin S Not Recommended Maximum daily dose (mg)

PAEDIATRIC TREATMENT REGIMENS Regimen 3A: 2HRZ, 4HR New smear negative PTB with minimal parenchymal involvement Less severe forms of extra pulmonary TB Regimen 3B: 2HRZE, 4HR TB meningitis: 2RHZEth, 7RHEth Younger than 8 years or weigh less than 30kg Complicated forms of TB: New smear positive PTB Smear negative PTB with extensive parenchymal involvement Severe forms of EPTB SASPID and 2012 SAMF: HIV-infected children Not entirely consistent with other guidelines Reflects consensus opinion & lack of high quality evidence rather than a superior regimen

REGIMEN 3A Body weight kg Intensive Phase (2 months) Treatment given 7 days a week RHZ* 60,30,150 Additional isoniazid (5 mg/kg to make total RHZ* 60,60,150 isoniazid dose to 10 15 mg/kg) Isoniazid 100 mg tablet 2 2.9 kg ½ tablet ¼ tablet ½ tablet 3 5.9 kg 1 tablet ¼ tablet 1 tablet 6 8.9 kg 1½ tablets ½ tablet OR 1½ tablets 9 11.9 kg 2 tablets ½ tablet 2 tablets 12 14.9 kg 2½ tablets 1 tablet 2½ tablets 15 19.9 kg 3 tablets 1 tablet 3 tablets 20 24.9 kg 4 tablets 1 ½ tablet 4 tablets 25 29.9 kg 5 tablets 1 ½ tablet 5 tablets 30 35.9 kg 6 tablets 1 tablet 6 tablets 36 40 kg 7 tablets 7 tablets

REGIMEN 3A Body weight kg Continuation phase (4 months) Treatment given 7 days a week RH 60,30 Additional isoniazid (5 mg/kg to make total RH 60,60 isoniazid dose to 10 15 mg/kg) Isoniazid 100 mg tablet 2 2.9 kg ½ tablet ¼ tablet ½ tablet 3 5.9 kg 1 tablet ¼ tablet 1 tablet 6 8.9 kg 1½ tablet ½ tablet OR 1½ tablets 9 11.9 kg 2 tablets ½ tablet 2 tablets 12 14.9 kg 2½ tablets 1 tablet 2½ tablets 15 19.9 kg 3 tablets 1 tablet 3 tablets 20 24.9 kg 4 tablets 1 ½ tablet 4 tablets 25 29.9 kg 5 tablets 1 ½ tablet 5 tablets 30 35.9 kg 6 tablets 1 tablet 6 tablets 36 40 kg 7 tablets 7 tablets

REGIMEN 3B NOT CONSISTENT WITH 3A?? Body weight (kg) Intensive Phase (2 months) Directly Observed Treatment (DOT) given 7 days a week Continuation Phase (4 months) Directly Observed Treatment (DOT) given 7 days a week RHZ E 400 RH (60,30) (60,30,150) 2 2.9 ½ tab Use Ethionamide in ½ tab 3 5.9 1 tab children <4kg 1 tab 6 8.9 1 ½ tabs ¼ tab 1 ½ tabs if weight 4 7.5 kg 9 11.9 2 tabs ½ tab 2 tabs If weight 7.5 11.9kg 12 14.9 2 ½ tabs ¾ tab 2 ½ tabs 15 19.9 3 tabs 1 tab 3 tabs 20 24.9 4 tabs 1 tab 4 tabs 25 29.9 5 tabs 1 ½ tabs 5 tabs

WHO: TBM AND MILIARY TB Miliary TB cases have 60 70% chance of having meningeal involvement Use drugs with good blood-brain-barrier penetration 2HRZE 4HR (or 10HR with TBM) OR 6HRZEth (high dose therapy)

ETHAMBUTOL IN CHILDREN

CORTICOSTEROIDS In management of complicated forms of TB TBM Adenopathy compressing airways Pericarditis Prednisone 2mg/kg/day (maximum 60mg per day) or dexamethasone May need higher doses in TBM as rifampicin will decrease corticosteroid drug levels Steroids for 4 weeks, tapering to stop over 2 weeks

PYRIDOXINE (VITAMIN B6) INH causes peripheral neuropathy by interfering with pyridoxine metabolism Recommend daily pyridoxine supplementation in children on TB treatment if: Adolescent Breastfeeding infant HIV on HAART Malnourished

DEVELOPMENT PIPELINE FOR NEW DRUGS

TB TREATMENT: PRACTICAL CONSIDERATIONS Every case has to be notified No other way to monitor epidemic Treatment access through clinics No directly observed treatment if accessed through hospitals or private sector Non-standard regimens, with associated risk of drugresistance e.g. India, USSR Seek expert input early Best outcomes with 1 st treatment efforts!!

HIV CO-INFECTED CHILDREN 40 60% of childhood TB patients are HIV co-infected Most HIV-infected children respond well to a 6 month course of therapy HIV-TB co-infected children should be evaluated for ART If child not already on ART and diagnosis of TB has been made, initiation of TB therapy is the priority

HIV CO-INFECTED CHILDREN ABC, D4T, 3TC, FTC, AZT, ddi NVP EFV No significant interactions High risk of hepatotoxicity and sub-therapeutic levels Preferably avoid Reduced levels, but little clinical significance PIs Never unboosted PI Not double-dose (600mg/m 2 ) LPV/r unless adult 1:1 ratio of LPV/r

FOLLOW-UP 2 weeks after initiation of therapy At end of Intensive Phase Follow-up smear for AFB if patient was smear positive at start of treatment Every 2 months until treatment completion Symptom assessment Assess adherence Assess for adverse events Weight measurement Adjust doses to accommodate weight gain

CONTACT TRACING WHO recommends that for all TB patients Screen household contacts Offer INH preventive therapy to children < 5 years Risk of infection greatest when contact is close and prolonged Risk of progression to TB disease greater in children < 5 years Most progression to disease occurs in first 2 years after infection

IPT After exclusion of TB disease, INH prophylaxis should be given to: All children under 5 years of age and HIV-infected children (irrespective of age) in contact with an infectious case of TB (drug susceptible TB and MDR- TB) All children under 5 years of age with a positive Mantoux (10 mm in diameter or greater) All HIV-infected children, irrespective of their age, with a positive Mantoux (5 mm in diameter or greater) SA National TB Guidelines 2009

BCG Live, attenuated strain of M bovis Only licensed TB vaccine Developed 1908, first administered 1921 Number of related strains In SA: Danish Efficacy: 0-80%, probably ± 50% Protects children against severe TB? Decreases non-tb morbidity & mortality

BCG Protects against leprosy? Role of intestinal helminths & environmental mycobacteria in reducing protection Local complications Disseminated BCG Contra-indicated in HIV-infected individuals Urgent need for better vaccine in various stages of testing