TB IN CHILDREN & PREGNANT WOMEN Picture of CPG Cover TB IN CHILDREN & PREGNANT WOMEN by Dr. Suryati Adnan & Dr. Jumeah Shamsuddin

LEARNING OBJECTIVES To update current management of TB in children & pregnant women To highlight latest antiTB regimens & dosages in children To address evidence-based management of BCG lymphadenitis To strengthen LTBI & contact management in children

TB IN CHILDREN TB in children is increasing in Malaysia High risk of active disease in infants & children under 5 years of age Active TB usually develops within 2 years of infection but can be as short as a few weeks in infants TBIS, 2011; WHO, 2006 TBIS, 2011; WHO 2006 Data from TBIS 2011 showed TB in children is increasing in Malaysia. History of contact is a strong factor to suspect TB in a symptomatic child Infants & young children under 5 years are at higher risk of developing active disease Active TB usually develops within 2 years of infection but the time lag can be as short as a few weeks in infants

TB IN CHILDREN PTB & lymph node TB - commonest presentations PTB & LN TB are the commonest presentations of TB in children Most children with PTB are sputum negative

COMMON CLINICAL PRESENTATIONS OF TB IN CHILDREN Prolonged fever Failure to thrive Unresolved pneumonia Persistent lymphadenopathy Symptoms of TB in children are usually non-specific The common clinical presentations are : Prolonged fever , FTT, unresolved pneumonia & persistent LN , which may be the presenting features of by many other illnesses. Hence, other chronic diseases must be ruled out especially if there is no history of contact

DIAGNOSTIC TESTS FOR ACTIVE TB AFB smear & culture from clinical specimens CXR - PTB, pleural, hilar LN disease TST (Mantoux test) compounded by false positive/negative Other relevant diagnostic procedures & imagings for PTB & EPTB in children are similar to adults The diagnostic tests for active TB in children are similar to adults . AFB smear & culture from clinical specimens, sputum , LN bx etc must be taken : For infants & young children who are unable to expectorate sputum , Gastric lavage or gastric aspiration should be performed . for better diagnostic yield, it should be done following standard protocols . Others: CT , MRI , scopes etc.

TST (MANTOUX TEST) False positive Mantoux False negative Mantoux BCG vaccination Non-TB mycobacterium infection False negative Mantoux Immunosuppression False negative results may be seen in those who have compromised immune system like severe malnutrition, premature infants, intercurrent viral illness, TB meningitis or disseminated disease Immunocompetent children with TB: 10%

RECOMMENDATION 18 Children suspected of PTB should have sputum examination, CXR & TST performed. (Grade C) Gastric lavage/aspiration should be performed in infants & children who are unable to expectorate sputum. (Grade C)

TREATMENT FOR TB DISEASE IN CHILDREN TB cases Regimen* Remarks Intensive phase Continuation phase New smear positive PTB New smear negative PTB Less severe EPTB 2HRZ 4HR Ethambutol can be added in the intensive phase of suspected isoniazid-resistance or extensive pulmonary disease cases. Severe concomitant HIV disease 2HRZE Severe form of EPTB TB meningitis/ spine/bone 10HR *Direct observation of drug ingestion is recommended especially during the initial phase of treatment & whenever possible during the continuation phase. WHO , 2010; WHO, 2006

TREATMENT FOR TB DISEASE IN CHILDREN TB cases Regimen* Remarks Intensive phase Continuation phase Previously treated smear positive PTB including relapse & treatment after interruption 3HRZE 5HRE All attempt should be made to obtain culture & sensitivity result. In those highly suspicious of MDR-TB, refer to paediatrician with experience in TB management. Treatment failure TB Refer to paediatrician with experience in TB management. MDR-TB Individualised regimen *Direct observation of drug ingestion is recommended especially during the initial phase of treatment & whenever possible during the continuation phase. WHO , 2010; WHO, 2006

ANTITB DRUGS IN CHILDREN Dose (range) in mg/kg Maximum dose Isoniazid 10 (10 - 15) 300 mg Rifampicin 15 (10 - 20) 600 mg Pyrazinamide 35 (30 - 40) 2 g Ethambutol 20 (15 - 25) 1 g Take note that the dosages of antiTB drugs in children are higher than previously recommended. The doses previously were extrapolated from adult pharmacokinetic studies, recent data showed that the doses did not achieve adequate desired serum level. Optic neuritis was a concern with ethmabutol, a SR showed that ethambutol can be used safely in children. (Donald PR et al., Int J Tuberc Lung Dis. 2006) Pyridoxine 5 - 10 mg daily need to be added if isoniazid is prescribed.

RECOMMENDATION 19 All children with TB should be given standardised treatment regimens & dosages according to the relevant diagnostic categories. (Grade C)

LATENT TB INFECTION (LTBI) IN CHILDREN LTBI: infected with M.tuberculosis but patient is asymptomatic Active TB disease: Symptomatic TB infection Children younger than 5 years old with LTBI has 10 - 20% risk of developing active TB disease. (Horsburgh C et al., N Engl J Med, 2004)

DIAGNOSTIC TESTS FOR LTBI IN CHILDREN LTBI is suspected in children exposed to active TB person For child contact: perform CXR & TST Sputum AFB smear is not required in asymptomatic child being investigated for LTBI Symptomatic child: examine & investigate for active TB & other diseases as indicated CXR & TST should be done for all child contacts. Symptomatic child must be thoroughly examined & investigated for active TB & other diseases as indicated

INTERFERON GAMMA RELEASE ASSAY (IGRA) IN CHILDREN The amount of Interferon Gamma (IFN-y) released is correlated directly with age (p<0.0001). (Lighter J et al., Pediatrics. 2009) IGRA test is less likely to be positive in children < 2 years of age. The sensitivity of both IGRAs & TST are reduced in young or HIV-positive children. (WHO, 2011) Both positive IGRA & TST responses are strongly associated with increasing likelihood of TB. However, children ≤12 months of age are more likely to have positive TST results rather than IGRA. WHO states that the sensitivity of both IGRAs & TST are reduced in young or HIV-positive children. (WHO, 2011)

RECOMMENDATION 20 TST should be used as a standard test to diagnose LTBI in children. (Grade C) IGRA should not be used as a replacement for TST in diagnosing LTBI in children. (Grade C)

TREATMENT OF LTBI IN CHILDREN Active TB must be ruled out before starting LTBI treatment. Therapeutic regimens: Isoniazid: 6 months Isoniazid plus rifampicin : 3 months WHO, 2006 Panickar JR et al., Eur Respir J, 2007 Spyridis NP et al ., Clin Infect Dis, 2007 6-month of isoniazid for children with LTBI is recommended by WHO,however studies of LTBI in adults showed that 12-month was better than 6-month treatment of INH in reducing the number of active TB cases i.e. 75% & 65% respectively. However, the 6-month isoniazid is recommended considering the problem of adherence & hepatoxic effects of longer duration of isoniazid. In a cross-sectional study on LTBI in children, 3-month isoniazid plus rifampin (3HR) regimen had a low failure rate of 0.85%. Short course 3HR & 4HR had equal minor side effects as 9H which did not warrant discontinuation or modification of treatment NICE guideline recommends either regimen US: 9H

RECOMMENDATION 21 Non-HIV infected children with LTBI should be treated with 6-month of isoniazid or 3-month of isoniazid plus rifampicin. (Grade C) There is no retrievable evidence of treatment for LTBI in HIV-infected children. Hence, we follow WHO recommendation of 6-months isoniazid therapy.

MANAGEMENT OF CHILD TB CONTACT Mantoux test may be negative in children who are malnourished & immunocompromised. Contact tracing & investigations in children are to be done within six weeks of diagnosis of the index patient. Source: World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva: WHO; 2006

CXR IN CHILD CONTACT CXR is important:- TST is not specific & sensitive enough Need to exclude active TB Suboptimal clinical assessment Some areas have high TB burden e.g. OA population, immigrants etc. high degree of exposure language barrier CXR IS IMPORTANT TO EXCLUDE ACTIVE PTB TST is not specific & sensitive enough to be the sole determinant of LTBI or active TB in children History taking (exposure & s/s of active TB) & physical examination may be done suboptimally by inexperienced health staff or face communication barrier. These are important factors to decide diagnosis of LTBI or active TB

CXR IN CHILD CONTACT CXR can be omitted:- If the health staff are able to exclude active TB   Adequate history & physical examination Considering the risk factors of severity of exposure age of the child disease burden in community logistics for follow-up for 2 years     

BCG LYMPHADENITIS Develop 2 - 4 months after vaccination Usually self-limiting No evidence of benefit from medical therapy Erythromycin, isoniazid & rifampicin Suppuration can occur in 30 - 80% If LN >3 cm & fluctuant: needle aspiration surgical excision (if recurring) Banani SA et al., Arch Dis Child, 1994 Goraya JS et al., Postgrad Med J, 2002 BCG lymphadenitis tends to occur 2 - 4 months after vaccination & suppuration can occur in 30 - 80% of lymphadenitis. It is normally self-limiting, medical therapy has no evidence of benefit. Medical therapy such as erythromycin, isoniazid and rifampicin have been used, but no proper trials have shown that it can reduce suppuration or shorten duration of healing.123, level III Surgical intervention, aspiration or excision is advised if the node is >3 cm in diameter, fluctuant & the overlying skin is inflammed; needle aspiration reduces rate of spontaneous rupture. Surgical excision is curative & reduces healing time when aspiration fails or if multiple nodes are involved. I&D is not recommended.

RECOMMENDATION 22 Medical therapy should not be offered routinely in BCG lymphadenitis. (Grade C)

CONGENITAL & PERINATAL TB Congenital TB is rare Active maternal TB during delivery: take samples or biopsy for MTB culture & HPE Perinatal TB infection is suspected when infant does not respond to standard treatment Coulter JB et al., Ann Trop Paediatr, 2011 Whittaker et al., Early Hum Dev, 2008 Smith KC et al., Curr Opin Infect Dis, 2002 Congenital TB is a rare complication of in-utero tuberculosis infection. If maternal TB is suspected during delivery, obtain placenta/vaginal/endometrial samples or biopsy for MTB culture and histopathological examination. Perinatal TB infection should be considered in all infants with sepsis, pneumonia unresponsive to standard antimicrobial treatment.

MANAGEMENT OF NEWBORNS Defer BCG at birth & perform full TB investigations if: mother diagnosed <2 mths before delivery or did not receive adequate treatment mother is sputum positive just before delivery the newborn is symptomatic Treat as active TB if indicated WHO, 1998

MANAGEMENT OF NEWBORNS INH as prophylaxis: 2 regimens INH for 6 mths INH for 3 mths & followed by mantoux test: <5 mm - stop INH, give BCG ≥5 mm - complete INH for 6 mths, give BCG Any symptoms suggestive of TB disease: repeat TB work up, treat as TB After active TB is ruled out, babies at risk of infection from their mothers should be given isoniazid preventive therapy.

PROPHYLAXIS FOR INFANTS OF MATERNAL TB For infants of mothers diagnosed after delivery , exclude active TB from examination & Ix , even if all are negatives, commence prophylactic therapy : INH for 6 m or INH+rifampicin for 3 mth , in view of very close contact. If BCG was given less than 2 mths before therapy , the baby must be reimmunised.

RECOMMENDATION 23 BCG should not be given to babies on prophylactic TB treatment. (Grade C) Prophylactic TB treatment should be given to babies born to mothers with active PTB except those diagnosed more than 2 months before delivery who have documented smear negative before delivery. (Grade C)

TB IN PREGNANCY & LACTATION Increased risk of maternal & perinatal morbidity First-line antiTB drugs are safe in pregnancy & breastfeeding Streptomycin: avoid during pregnancy risk of foetal ototoxicity Ormerod P, Thorax, 2001 TB in pregnancy is associated with increased risk of maternal & perinatal morbidity such as prematurity, SGA/LBW, etc. First-line antiTB i.e. INH, rifampicin, ethambutol & pyrazinamide are safe in pregnancy & BF. Streptomycin: avoid during pregnancy due to risk of foetal ototoxicity.

TB IN PREGNANCY & LACTATION Breastfeeding should be continued Surgical mask should be used if the mother is still infectious Pyridoxine should be given to mothers taking isoniazid Infant-mother separation is considered if the mother has MDR-TB or is non-compliant to treatment Ormerod P, Thorax, 2001

ORAL CONTRACEPTIVE PILLS (OCPs) & ANTITB DRUGS Rifamycin (rifampicin & rifabutin) reduces the efficacy of both combined oral contraceptives & progesterone-only pills Alternative contraceptive method should be used during & for 1 month after stopping rifamycins MOH NZ, 2010

RECOMMENDATION 24 All women of child bearing age suspected of TB should be asked about current or planned pregnancy. (Grade C) First-line antiTB drugs except streptomycin can safely be used in pregnancy. (Grade C) First-line antiTB drugs can safely be used in breastfeeding. (Grade C) Pyridoxine supplementation should be given to all pregnant & breastfeeding women taking isoniazid. (Grade C) Patient on rifampicin should use alternative contraception methods other than oral contraceptives & progesterone-only pills. (Grade C)

TAKE HOME MESSAGES - TB IN CHILDREN Children <5years old have high risk of developing active TB disease. Defer BCG in newborns at risk of perinatal TB until INH completed. TST & CXR should be performed in all child TB contacts. BCG lymphadenitis does not require antibiotic.

TAKE HOME MESSAGES - MATERNAL TB First-line antiTB drugs are safe in pregnancy & lactation. Streptomycin must be avoided in pregnancy. Rifamycins reduce the efficacy of OCPs.

THANK YOU drsuryati_adnan@phg.moh.gov.my jaynachi@gmail.com jumeah70@yahoo.com