Published on April 4, 2014
Treatment Guidelines of Childhood Tuberculosis and RNTCP Presenter: Dr. Chinmoy Lath 1st June’12
Aims of Therapy in Tuberculosis The main objectives of anti-TB treatment are to: • Cure the patient of TB (by rapidly eliminating most of the bacilli). • Prevent death from active TB or its late effects. • Prevent relapse of TB (by eliminating the dormant bacilli). • Prevent the development of drug resistance (by using combination of drugs). • Decrease TB transmission to others.
Evolution in Treatment of TB Classical (long course) chemotherapy regimen : • 18 months duration daily regimens • Used INH with one or two bacteriostatic drugs • High failure and relapse rate • Poor compliance Short course chemotherapy regimen • Combination of 3-4 drugs used in intensive phase (2 mths) • Drugs give either daily / intermittently • Minimum duration of treatment – 6 months • Drugs – preferably given together and as single dose
Advantages • Faster, powerful bactericidal and sterilizing action • Patient exposed to toxic drugs for shorter duration • Less expensive • Reduction in emergence of drug resistant bacilli • Good tolerance and adherence
Results of six month treatment regimen for TB Author, country & year Diagnostic Criteria No. of children Regimen Results Al Dossary et al, USA, 2002 Clinical and radiological 175 2 weeks daily HRZ f/b 6 wks HRZ2 / 4RH2 81% t/t completion 1 relapse Te Water Naude et al, S. Africa, 2000 Clinical & radiological 89 117 2 RHZ2/4RH2 6RHZ t/t outcome & adherence equivalent 1 relapse Varudkar, India, 1985 Clinical & radiological 100 40 45 2 HRE/4HE 2 HZE/4HE 6 HRE3 0 failures, 0 relapses Kumar et al, India, 1990 Clinical & bacteriological 37 39 2 HRZ / 4HR2 9 HR 2 deaths not related to TB 0 relapse Ramachandran et al, India, 1998 Clinical & bacteriological 68 69 2 HRZ3 / 4RH2 3 (2%) died, 0 failures, 3 relapses
TRC studies on extrapulmonary TB Studies Rx regimen Duration (mon) No. of pts Follow- up period (months) Overall favourable response % TB spine 6 HR7 + modified HongKong Surgery 6 78 120 90 6HR7 6 78 120 94 TBM 2 HRS7/ 4HE7S2 / 6HE7 12 69 24 33 2R2 HZS7/ 10HE7 12 70 24 36 Pott’s paraplegia 2SHER7 / 7HR2 9 11 60 73 Abd TB 2HRZ7/4HR7 6 85 60 94 Brain tubeculoma 3HRZ7 / 6HR2 9 47 24 89
• Tuberculosis Research Centre (TRC) studies have clearly established efficacy of short course treatment. • Intermittent regimens proven as effective as daily regimen • Overall favourable response varied from 87-99% except in TBM (33%) and Pott’s spine (73%) • In TBM, outcome is related to stage of disease at the start of treatment and duration of symptoms prior to admission • Similarly in Pott’s spine recovery influenced by factors like initially motor power, presence or absence of bed sores and duration of kyphosis • Therefore early diagnosis and treatment is recommended for these two conditions
Management of pediatric TB under RNTCP – Diagnosis Suspected cases of pulmonary TB include • Fever and/or cough > 2 wks • Weight loss or failure to thrive • H/o contact with suspected / diagnosed case of active TB in last 2 yrs • Suspect TBM in child with neurological symptoms, irritability, refusal to feed, headache, vomiting, altered sensorium
Bacteriological testing • Sputum examination whenever possible • Gastric lavage if sputum not available (yield is 20%) • Multiple samples to be taken Tuberculin Test • Mantoux test using 1 TU PPD RT 23 Tween 80 • +ve test >10 mm induration at 48-72 hrs Radiology • CXR – suggestive findings mediastinal / hilar lymphadenitis with / without parenchymal lesions, pleural effusion, miliary and fibro-caseous pictures • Persistent pneumonia >4 wks inspite of antibiotic therapy
PCR • Low sensitivity for gastric aspirates • Routine use not recommended • May be useful in neuro TB • Sensitivity ranges from 4-80% & specificity 80-100% Serology • Low sensitivity, specificity and positive predictive value
RNTCP diagnostic algorithm for pediatric pulmonary TB
Standard Case Definitions New case • Pt. who never had treatment for TB / or taken ATT <4 wks Relapse • Pt. declared cured of TB in past after one full course of ATT, and has become sputum smear +ve Treatment failure • A pt. who while on treatment remained or become again smear positive 5 months or more after starting therapy • A pt. initially smear negative become sputum +ve after 2nd month of therapy
Treatment after interruption • Patient who interrupts t/t for 2 months or more, and return with smear +ve Chronic case • Patient who remained or become smear +ve after completing fully supervised re-treatment regimen Smear positive pulmonary TB • One or more initial sputum smear +ve for AFB
Smear negative pulmonary TB • At least 2 sputum specimen –ve for AFB • Radiological abnormality consistent with active pulm TB • No response to a coarse of broad spectrum antibiotics • Decision by clinician to treat with full course of ATT
Treatment Outcomes Cure • Initially sputum smear-positive patient who • has completed treatment and • had negative sputum smears on two occasions, one of which was at the end of the treatment. Treatment completed • Pt. who has completed t/t without proof of cure. Treatment failure • Pt. who remaining or becomes again smear +ve at 5 month / later during t/t Transfer out • Pt. transferred to other reporting unit
Treatment Regimen Treatment category Type of patients TB treatment regimens Intensive phase Continuation phase Category I New sputum smear-positive PTB Seriously ill sputum smear-negative PTB Seriously ill extrapulmonary tuberculosis (EPTB) 2H3R3Z3E3 4H3R3 Category II Sputum smear-positive relapse, Sputum smear-positive treatment failure, Sputum smear-positive treatment after default 2S3H3R3Z3E3/ 1H3R3Z3E3 5H3R3E3 Category III Sputum smear-negative and EPTB not serious ill 2H3R3Z3 4H3R3
New RNTCP Classification
• Seriously ill sputum smear negative pulm. TB: all forms of PTB other than primary complex • Seriously ill EPTB: TBM, disseminated miliary TB, TB pericarditis, TB peritonitis and intestinal TB, B/L or extensive pleurisy, spinal TB with or without neurological complications, genitourinary tract TB, bone & joint TB • Not seriously ill EPTB: lymph node TB and U/L pleural effusion • In pts with TBM on category I treatment, 4 drug use during intensive phase should be HRZS instead of HRZE. Continuation phase to be given for 7 months. Total duration of treatment 9 months • Steroids to be used initially in hospitalized cases of TBM and TB pericarditis for 6-8 weeks.
Suggested pediatric dosages for intermittent therapy Drug Dosage (mg/kg) Weight range in kg 6-10 11-17 18-25 26-30 Isoniazid 10 75 150 225 300 Rifampicin 10 75 150 225 300 Pyrazinamide 30-35 250 500 750 1250 Ethambutol 30 200 400 600 1000 Streptomycin 15
• During intensive phase, patient swallows drug under supervision of Health worker 3 times a week • In continuation phase, pt is issued medicine for 1 wk in multiblister combipack of which 1st dose swallowed in presence of health worker Chemoprophylaxis • Asymptomatic children <6 yrs exposed to infectious TB should be given 6 month of INH (5 mg/kg daily) Monitoring & evaluation • Sputum examined after 2 month of intensive phase in Category I, after 3 months in Category II, if +ve IP given for 1 more month.
Lacunae in RNTCP • Children can’t appreciate symptoms / bring out sputums difficulty in diagnosis • CXR – intra and interreader variations, not available at primary health centres • Tubeculin test, gastric lavage and FNAC – limited to hospitals, not available in primary health centres • Problem in direct observation of t/t – non-availability of child due to clash with school timing, non-availability of parents due to work • Social stigma, especially for female pts
Consensus Statement Recommendations of IAP, 2010
Diagnostic algorithm for tubercular lymphadenitis
Recommended doses of antitubercular drugs • All drugs to be given empty stomach single dose • Vit B6 – not needed in children taking INH • Daily treatment regimen is advised • Fixed dose combination of INH and rifampicin acceptable • Use pyrazinamide separately
Prednisolone Indications • Tubercular meningitis. • Tubercular pericarditis. • Mediastinal compression syndrome due to Tuberculosis. • Endobronchial tuberculosis. • Pleurisy with severe dystress. • Milliary disease with alveolocapillary block. • Dose:2-4 mg/kg/day for 2-4 wks then tapper over 2 weeks.
Microbiological Basis of Treatment Types of bacterial population • Group I – metabolically active continuously growing bacilli in neutral pH present extracellularly, killed by INH f/b rifampicin and streptomycin • Group II – intermittent multiplying organisms (semidormant) in hypoxic environment of cacious material killed by rifampicin • Group III – intracellular bacilli in acidic pH killed by pyrazinamide • Group IV – drug resistant mutants, acted upon by rifampicin and INH
Pharmacological principles • Drugs are divided in three categories 1. Early bactericidal activity – ability to kill bacilli in first few days of t/t, max. in INH f/b Etham. and Rifampicin 2. Sterilizing activity – ability to eradicate persisters - intracellular bacilli, seen with Rifampicin & Pyz 3. Prevention of drug resistance to companion drug, seen in INH and Rifampicin
CLASSIFICATION OF ANTITUBERCULAR DRUGS
Tuberculocidal Tuberculostatic Isoniazid, Rifampicin Streptomycin, Amikacin Pyrazinamide Capreomycin, Quinolones, Rifamycin Ethambutol (except in inflamed meninges) Thiacetazone, Ethionamide Para-aminosalicyclic acid Cycloserine
TRADITIONAL CLASSIFICATION FIRST LINE DRUGS: INH (H) RIFAMPICIN (R) PYRAZINAMIDE (Z) ETHAMBUTOL (E) STREPTOMYCIN (S) SECOND LINE DRUGS: AMIKACIN, KANAMYCIN FLUOROQUINOLONES PAS, CYCLOSERINE
RECENT WHO CLASSIFICATION GROUP 1 (FIRST LINE ORAL AGENTS) – INH GROUP 2 (INJECTABLE AGENTS) – KANAMYCIN GROUP 3 (FLUOROQUINOLONES) – LEVOFLOXACIN GROUP 4 (ORAL BACTERIOSTATIC AGENTS) – ETHIONAMIDE GROUP 5 (AGENTS WITH UNCLEAR EFFICACY) – LINAZOLID, AMX-CLV
ANTI-TB DRUGS USED IN RNTCP FIRST LINE DRUGS: INH (H) RIFAMPICIN (R) PYRAZINAMIDE (Z) ETHAMBUTOL (E) STREPTOMYCIN (S) SECOND LINE DRUGS: AMIKACIN, KANAMYCIN, FLUOROQUINOLONES, CAPREOMYCIN, ETHIONAMIDE PAS, CYCLOSERINE, etc…
Adverse effects of ATT drugs Drug Adverse effects Isoniazid Hepatotoxicity, peripheral neuritis, hypersensitive reactions may precipitate epilepsy, drug induced lupus, psychotic changes Rifampicin Hepatotoxicity, gastrointestinal, autoimmune reactions (more with intermittent administration), which include flu syndrome, thrombocytopenias, purpura, respiratory shock syndrome, acute hemolytic anemia, ARF) Pyrazinamide Hepatotoxicity, arthralgia, hyperuricemia, gastrointestinal, allergic reactions Ethambutol Optic neuritis, colour blindness, gastrointestinal, allergic reactions, hyperuricemia Streptomycin Vestibular dysfunction, deafness, nephrotoxicity, neuromuscular blockade, peripheral neuritis
Adverse effects of ATT drugs (contd…) Drug Adverse effects Thioacetazone Exfoliative dermatitis, Steven Johnson syndrome Quinolones GI symptoms, CNS, phototoxicity, tendinopathy & tendinitis, nephrotoxicity, skin rash Ethionamide GI symptoms, psychiatric (hallucination & depression), hepatitis, hypothyroidism, Gynaecomastia Cycloserine CNS (convulsions), psychiatric (depression, suicidal tendency) PAS GI symptoms, hepatic dysfunction, hypokalemia, hypothyroidism
Second-line anti-TB drugs for t/t of MDR-TB in children Drug Mode of action Recommended daily dose Range (mg/kg bw) Max (mg) Ethionamide or prothionamide Bacteriostatic 15-20 1000 Fluoroquinolones Ofloxacin Bactericidal 15-20 800 Levofloxacin Bactericidal 7.5-10 - Moxifloxacin Bactericidal 7.5-10 - Gatifloxacin Bactericidal 7.5-10 - Ciprofloxacin Bactericidal 20-30 1500 Aminoglycosides Kanamycin Bactericidal 15-30 1000 Amikacin Bactericidal 15-22.5 1000 Capreomycin Bactericidal 15-30 1000 Cycloserine terizidone Bacteriostatic 10-20 1000
Contraindications for anti TB drugs Isoniazid • Known hypersensitivity to isoniazid • Active hepatic disease Rifampicin • Hypersensitivity to rifampicin • Hepatic dysfunction Pyrazinamide • Known hypersensitivity to pyrazinamide • Severe hepatic impairment • Gout Streptomycin • Hypersensitivity • Auditory nerve impairment • Myasthenia gravis • Pregnancy Ethambutol • Hypersensitivity • Preexisting optic neuritis • Pts with creatinine clearance of <50 ml/min
Important side effects with clinical implications Hepatotoxicity • Hepatotoxicity drugs include INH, rifampicin, PYZ • Chances if higher doses / combination are used • Children with severe disease like TBM, miliary TB are at greater risk • Children with preexisting liver dysfunction and malnutrition more predisposed • Routine lab monitoring needed in high risk cases
Hepatotoxicity (clinically evident jaundice / ALT >5 times normal) Stop IHN, Rifamp & Pyz, start Etham & Strepto Repeat AST, ALT If they stay as normal / or show a declining trend Rifamp 10. mg/kg/day + add INH 2.5 mg/kg/d (repeat LFT) PZA (30 mg/kg/d) + INH (5 mg/kg/d) (7 days)
Ocular toxicity • Seen in 5%, if doses of Ethambutol b/w 25-50 mg/kg/d. • Rare in dose of 15 mg/kg/day. • Result in reversible optic neuritis, blurred vision, scotoma, colour blindness. • Literature review suggests it is safe in children at a dose of 15-25 mg/kg/day. Peripheral neuritis • Clinically manifest peripheral neuritis is rare in children. • Manifest and pins and needle sensation in hands and feet. • More common in malnourished children, HIV +ve, breastfeeding infants. • Supplemental pyridoxine 5-10 mg/kg/day is recommended in the predisposed population.
Role of Surgery in TB Pulmonary TB Indications • Major airway obstruction due to – Extraluminal LN compression – nodal curettage – Intraluminal granulation tissue - bronchoscopy • Post-TB pulmonary destruction – lung resection • Late pleural fibrosis – decortication • Release of post-tubercular constrictive pericarditis • Drainage of active TB lung abscess
Neuro TB Indications • Failure of medical management • TB with hydrocephalus and uncontrolled raised ICT • Cerebral abscess • Tuberculoma – for diagnosis of difficulty cases / features of SOL • Tubercular spinal arachnoiditis compressing cord Early VP shunts for mild to mod. Hydrocephalus, morbidity & mortality, no effect on stage III pts prognosis
Abdominal TB Indications • Diagnostic in case of peritoneal abd. TB • Exploratory laparotomy in acute abdomen • Management of complications like stricture, adhesion, fistula, bleeding Peritoneal Wet / Ascitic Dry / Sclerosing Laparoscopy and biopsy Open biopsy
Intestinal Ulcers MassStricture Perforation Local resection Local resection (ileoceocotomy) Minimal narrowing Local resection / enterostomy (rarely) Significant narrowing Multiple or very long stricture ATT Stricturoplasty Local resection
Genitourinary TB For complications like • Ureteral stricture, abscesses and non-functioning kidneys Radical procedures • Nephrectomy • Partial nephrectomy • Epididymectomy Reconstructive procedures • Strictures – For PUJ obstruction: Pyeloplasy, percutaneous nephrostomy – Ureteric strictures: Double J stenting, resection anastomosis – Vesicoureteric junction obstruction: ureteric reimplantation
Potts spine Indications for surgery • Paraplegia despite conservative treatment • Sudden acute paraplegia • Paraplegia accompanied by uncontrolled spasticity • Paraplegia in flexion • Flaccid paraplegia • Surgical procedure – anterolateral decompression
MDR-TB An MDR TB SUSPECT Whose SPUTUM Is CULTURE POSITIVE for M.Tb that are invitro resistant to Isoniazide AND rifampicin with or without resistant to other drugs from an RNTCP accredited laboratory.
Treatment of Multi-Drug Resistant TB • Prevalence of primary MDR in India – <3% • Prevalence of MDR TB among treated cases – 12-17% (Paramsivan et al, IJMR 2004; 277-86) Initial drug resistance • INH – 20-30%, Streptomycin <10%, Rifampicin – 2-3% Acquired drug resistance • INH – 50-60%, Rifampicin – 20-30%, Streptomycin – 15- 30% (Amdekar YK. Indian Pediatr 1998; 35: 715-18)
Drug-resistant TB should be suspected if any of the features are present • Features in the source case suggestive of drug-restating TB – Contact with a known case of drug-resistant TB – Remains sputum smear-negative after 3 months of t/t – H/o previously treated TB – H/o treatment interruption • Features of child suspected of having drug-resistant TB – Contact with a known case of drug-resistant TB – Not responding to the anti-TB treatment regimen – Recurrence of TB after adherence to treatment
Types of resistance Natural resistance • Species specific resistance to drug without strain being ever exposed to it Primary resistance • Pt infected with drug-resistant population without having received prior treatment Secondary (acquired) drug resistance • Pt harbous organisms which were previously drug susceptible but resistance developed during course of t/t
Alternative method of grouping ATT drugs Grouping Drugs (abbreviation) Group 1: First line oral Anti TB agents Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Group 2: Injectable Anti TB agents Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vi) Group 3: Fluoroquinolones Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lfx); Moxifloxacin (Mfx); Gatifloxacin (Gfx) Group 4: Oral bacteriostatic second-line anti TB agents Ethionamide (Eto); Protionamide (Pto); Cycloserine (Cs); Terizidone (Trd); p- aminosalicylic acid (PAS); Thioacetazone (Th) Group 5 – Anti TB agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB pts) Clofazimine (Cfz); Amoxicillin / Clavulanate (Amx / Clv); Clarithromycin (Clr); Linezolid (Lzd)
Principles of Treatment • Never add one drug to a failing regimen. • Treat child according to the drug susceptibility pattern and using t/t history of source case strain if isolate from child is not available • Use at least 4 drugs with certain effectivity • Use daily treatment, directly observed • Use bactericidal drugs as far as possible • Use all oral 1st line drug to which isolate is sensitive • An injectable agent is used for minimum of 6 months after culture conversion
Principles of Treatment contd.. • Oral quinolone used for entire duration of therapy • t/t to be given for at least 18 months after cultures are –ve • Drug dosing to be determined by body weight • Counsel caregiver regarding adverse events & compliance • Follow-up is essential – clinical, radiological and bacteriological • Monitor LFT, KFT, hearing periodically
Concept of DOTS plus Individualized treatment regimen • Regimen designed as per resistance pattern of strain infecting pt. • Heavily dependent on drug sensitivity testing • Unlikely to fail • Less applicable in resource poor countries Standardized regimen • Based on common resistance pattern identified in a given population • Low cost, simpler implementation, less dependent on laboratories
Management of MDR TB under RNTCP • RNTCP will be using a Standardized Treatment regimen RNTCP CATEGORY IV REGIMEN: 6 (9) Km Lvx Eto Cs Z E / 18 Lvx Eto Cs E • Minimum recommendation is that intensive phase to be given for 6 months • After 6 months – continuation phase started if 4th month culture are negative • If 4th month culture is still awaited after 6 months of t/t, IP is extended • After maximum of 9 months CP started for 18 months
MDR patient referred to state level DOTS plus site with DTS result DOTS plus site decides on whom to start Rx Pt admitted at DOTS plus site for 1 month Discharged with 1 wk drug supply Given treatment at a facility near to home
Indications for Surgery in MDR-TB • As adjuvant may improve results of chemotherapy in selected cases • Ideally operate early in therapy, b/w 6-9 month • After surgery continue therapy for 18 months • If disease is resectable, surgery considered in following – Absence of response despite 6-9 mon of t/t – High risk of failure or relapse due to high degree of resistance – Morbid complications e.g. haemoptysis, bronchiectasis, bronchopleural fistula – Recurrence of positive smear or culture during t/t – Relapse after completion of anti-TB treatment
MDR TB in special situations MDR-TB in pts with renal failure • Drugs requiring dose or interval adjustment in renal failure are – ethambutol, quinolones, aminoglycosides, cycloserine, PAS, ethionamide • Monitor blood urea, nitrogen and creatinine frequently • In mild renal failure – dose of aminoglycoside reduced • In severe renal failure – aminoglycosides are discontinued
Drug Method of modi- fication GFR (ml/min) >50 10-50 <10 Kanamycin D, I 7.5-15 mg/kg/24 hr 4-7.5 mg/kg/24 hr 3 mg/kg/48 hr Ethambutol I 20 mg/kg/24 hr 20 mg/kg/24-36 hr 20 mg/kg/48 hr Pyrazinamide D 30 mg/kg/24 hr 30 mg/kg/24 hr 15-30 mg/kg/24 hr Ofloxacin D 100% 50-75% 50% Ethionamide D 100% 100% 50% Cycloserine D 100% 50-100% 50% PAS D 100% 50-75% 50 D = dose adjustment; I = interval adjustment; *%age of recommended dose to be given
MDR-TB in pts with pre-existing liver disease • In category IV regimen, PYZ, PAS and ethionamide are hepatotoxic • Most of the 2nd line drugs can be safely used in mild impairment as they are less hepatotoxic than 1st line drugs • PYZ should be avoided in such patients MDR-TB in pts with seizure disorders • If seizures are not under control, initiation of anti-seizure drugs will be needed prior to start of MDR-TB therapy • Cycloserine, ethionamide, quinolone have been associated with seizures, use carefully • Pyridoxine should be given with cycloserine to prevent seizures
• Avoid cycloserine in pts with uncontrolled seizures • Anti-epileptic drugs may have interaction with cycloserine and quinolones, monitoring of serum levels may be needed MDR-TB in pts with psychosis • High baseline incidence of depression and anxiety in pts with MDR-TB due to chronicity and socioeconomic factors • Quinolones, ethionamide – associated with psychosis • Pyridoxine prophylaxis recommended • Cycloserine causes severe psychosis but not abs. C/I • If pt. on cycloserine develop psychosis, stop cycloserine and start anti-psychotics • Resume cycloserine once pt is stabilized
XDR TB (extensively drug resistance TB) • XDR TB is resistance to at least INH and rifampicin (i.e. MDR TB) + resistance to any fluoroquinolones and any one of the second line anti-TB injectable drugs (Am, Cm, Km) • Worldwide noted in 41 countries till date • Isolated reports indicate existence of XDR TB in India, but it is not possible to estimate its magnitude from present data • Effective treatment of MDR pts through DOTS plus can prevent XDR TB generation • Extremely difficult to treat with poor outcomes
SUMMARY(RNTCP) DIAGNOSIS OF PTB • DURATION OF COUGH 3 WEEKS 2 WEEKS – NUMBER OF SPUTUM SMEARS TO BE COLLECTED 3 SMEARS 2 SMEARS – NUMBER OF + SMEARS REQUIRED FOR DX OF PTB+ 2 SMEARS 1 SMEAR
• CATEGORY III HAS BEEN PHASED OUT • NEW (DOTS) • PREVIOUSLY TREATED (DOTS) • CATEGORY IV FOR MDRTB • CATEGORY V FOR XDRTB SUMMARY(RNTCP) TREATMENT OF PTB
Treatment of Congenital TB As per IAP • Continue breastfeeding • BCG given at birth • If CXR normal – 6 HR • If CXR abnormal – 2 HRZ/7HR • Congenital TB – 2 HRZ/7 HR
As per WHO – active pulm TB diagnosed after delivery <2 months after >2 months after Treat mother, breastfeed, INH x 6 m (5 mg/kg/d), BCG after stopping INH Treat mother, breastfeed, INH x 6 m (5 mg/kg/d), if BCG not given at birth give after stopping INH >2 month <2 month before Smear-ve just before delivery Smear +ve just before delivery Treat mother, breastfeed, INH x 6 m (5 mg/kg/d), BCG after stopping INH Treat mother, breastfeed, no preventive CT, BCG at birth Treat mother, breastfeed, INH x 6 m (5 mg/kg/d), BCG after stopping INH As per WHO – active pulm TB diagnosed before delivery
As per RNTCP Treat mother Continue breast feeding Mother Sputum +ve Sputum -ve Chemotherapy to infant x 3 months BCG given No chemotherapy MTx at 3 months +ve -ve BCG givenBCG not given continue CT x 6 mths
As per National Neonatology Forum (NNF) If child has clinical features of perinatal TB Start ATT • 2 HRZ + 7 HR • May add streptomycin for first 2 months • HIV co-infection – 2 HRZS + 7 to 10 HR • Extra pulmonary TB – 2 HRZS + 7 to 10 HR • MDR TB – 12 to 18 HRZS or RHZE Add steroids (prednisolone 1-2 mg/kg/d for 4-8 wks) if • Meningitis, neuro TB, miliary TB, TB involving serous layers, endobronchial / segmental lesions, genitourinary TB, sinus formation Breastfed infants / neonates on INH must be supplemented with B6
If the child is clinically normal but mother high risk Mother Mx negative (induration <10 mm) Symptomatic Asymptomatic CXR abnormal CXR normal Presumed uninfected Investigate & treat mother No investigations No t/t Investigate & treat mother, no t/t of baby Screen baby Normal Abnormal Chemoprophylaxis (6 HR) T/t as perinatal TB
If the child is clinically normal but mother high risk Mother Mx Positive (induration >10 mm) Abnormal Normal CXR No active TB Active TB Screen mother Continue breastfeed Follow-up T/t mother Screen baby Normal Abnormal Chemoprophylaxis (6 HR) T/t as perinatal TB Symptomatic Asymptomatic Screen mother Breastfeed, no t/t
High risk mothers • Old case of TB and on irregular t/t • Sputum +ve • Having signs and symptoms • Miliary TB or CXR • TBM General instructions • Continue breastfeeding • Give BCG at birth • Separation not needed • Follow-up both mother and child
Discontinue breastfeeding + separation • Mother so sick to need admission • MDR TB suspected • Proven default • Sputum +ve mother not put on ATT
TB and HIV • 60% of PLHA develop TB • 16-18% of children with TB have HIV • Active TB is commonest OI among HIV infected individuals Diagnosis of TB in HIV infected children 3 or more of following • Chronic symptoms s/o TB • Physical signs s/o TB • CXR s/o TB • Positive Mx >5 mm induration
Problems in treatment • Potential for drug interactions, esp. b/w rifampicin and anti- retroviral agents • Problems of drug toxicity and adverse effects • IRIS • Pill burden, adherence Key therapeutic principles • Treatment of TB takes precedence over t/t of HIV infection • In pts already on HAART, continue same with modification in both HAART and ATT • If pt. not receiving HAART, timing of initiation of ART decided on basis of immune suppression and CD4 counts and type of TB
WHO recommends ART be given to • All pts with extrapulmonary TB (stage 4) • All those with pulm TB unless CD4 count >350 cells/mm3 • ART recurrence and fatality rates in TB Classification of HIV-associated immunodeficiency in children Classification of HIV-associated immunodeficiency Age-related CD4 values 11 months (%) 12-35 months (%) 35-59 months (%) 5 years (cells/mm3) Not significant >35 >30 >25 >500 Mild 30-35 25-30 20-25 350-499 Advanced 25-30 20-25 15-20 200-349 Severe <25 <20 <15 <200
Initiation of first-line ART in relation to anti-TB therapy WHO pediatric clinical stage Timing of ART following start of anti-TB t/t Recommended ART regimen 4 (extrapulm TB other than LN TB) Start ART soon after anti-TB t/t (b/w 2 & 8 wks following start of anti-TB t/t) In children aged <3 yrs • preferred: triple NRTI first line regimen – d4T or AZT + 3 TC + ABC • Alternative: standard first-line regimen – two NRTIs + NVP In children aged 3 yrs • Preferred: triple NRTI first-line regimen – two d4T or AZT + 3TC + ABC • Alternative: standard firstline- line regimen – two NRTIs + EFV 3 (pulm TB and LN TB) With clinical management alone •Start ART soon after start of anti-TB t/t (b/w 2-8 wks following start of ATT) •Consider delaying start of ART until anti-TB t/t is completed – if excellent clinical response to ATT in first 2-8 wks and child is stable
WHO pediatric clinical stage Timing of ART following start of anti-TB t/t Recommended ART regimen 3 (pulm TB and LN TB) When CD4 values are available • Severe immunodeficiency CD4 <200 – start ART b/w 2- 8 wks as soon as ATT tolerated • Advanced immunodeficiency (CD4 200-350) – start ART 8 wks after starting ATT • Mild or no immunodeficiency (CD4 >350) – consider delaying start of ART until ATT completed Regimens as recommended above
• EF V is not currently recommended for <3 yrs / <10 kg and not given to postpubertal adolescent girls who are sexually active and not using contraception ART recommendations for pts who develop TB within 6 months of starting a first-line ART regimen 1st line or 2nd line ART regimen ART regimen at the time of TB occurs Management options 1st line ART (AZT or D4T) + 3TC + EFV Continue with two NRTIs + EFV (AZT or D4T) + 3TC + NVP Substitute NVP with EFV, or Substitute with triple NRTI regimen AZT + 3TC + TDF Continue with triple NRTI regimen 2nd line ART Two NRTIs + PI Substitute or continue with LPV/r – containing regimen and adjust the dose of RTV
Immune reconstitution inflammatory syndrome • Characterised by clinical deterioration after initial improvement • Occurs in 1/3rd of pts on ATT who have started ART • Presents within 3 months of ART initiation • Fever, worsening of pre-existing LAP + resp disease • Most cases resolve without intervention • Serious reactions may require use of steroids ART failure • If TB occurs within 6 months of initiation of ART, it should not be considered as failure of t/t • If episode occurs after 6 months of ART, with no other clinical / immunological evidence of disease progression, it should not be considered ART failure • Extrapulm TB should be considered ART failure
Drug interactions and toxicity • Thiacetazone is contraindicated in HIV pts • HIV pts more prone to develop INH induced peripheral neuritis therefore given pyridoxine supplementation • Both ATT and NVP – cause hepatotoxicity close monitoring needed • Rifampicin induces cyt p450 enzymes and reduces conc of PI by 80%, NVP level by 20-58%, EFV level by 25% • PI resistant mutants of HIV may emerge if unboosted PIs are used with rifampicin
Chemoprophylaxis (6HR) • All HIV pts with MTx >5 mm given prophylaxis • Also in anergic pts exposed to active TB BCG vaccination • WHO recommends all asymptomatic HIV infected children should receive BCG except those with symptoms of AIDS related complex / AIDS. This is especially true for high TB prevalent countries like India • BCG should not be given to HIV-infected children in low TB prevalence countries
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