MANAGEMENT OF TUBERCULOSIS IN NEONATES AND YOUNG INFANTS
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1 MANAGEMENT OF TUBERCULOSIS IN NEONATES AND YOUNG INFANTS A Bekker FIDSSA Conference, 2017
2 OUTLINE Case Perinatal TB Approach to the TB-exposed newborn
3 MOM AND BABY S Born by NVD at peripheral hospital 38 weeks - male 2605 g (5.7 lbs) Developed respiratory distress and transferred to Tygerberg Children s Hospital MOM 18 yrs old, G1P1 Uncomplicated pregnancy HIV -, RPR -
4 ARRIVAL TO NICU GENERAL oedematous + pale petechial rash RESP IPPV GIT hepatosplenomegaly (5 cm liver; 4 cm spleen) ascites
5 RADIOLOGY
6 CONGENITAL INFECTION Term baby boy Acutely ill Abnormal blood results in keeping with infection Septic work up TORCH infection Parvovirus screen
7 DETERIORATION IN FIRST WEEK IV Pen and Gentamycin Broad spectrum antibiotic cover + Acyclovir Optimal supportive therapy HFOV and vasopressors All test results were coming back negative..took a week for the penny to drop
8 MOM S HEALTH? TB screening questions No coughing No night sweats No fever Weight loss No other family members or close contacts with TB Because of high TB incidence in our area: CXR Sputum specimens for M. tuberculosis TB symptom screening tool
9
10 TB INVESTIGATIONS Date Type AFB M.tb culture Mom 01/08/08 Endometrium biopsy - Positive 22/09/08 Date Type AFB M.tb culture Baby 30/07/08 Tracheal aspirate + Positive 04/09/08 30/07/08 Urine - Positive 12/09/08 01/08/08 Ascitic fluid - Positive 12/09/08 11/08/08 Bone marrow - Positive 16/10/08
11
12 OUTLINE Case Perinatal TB Approach to the TB-exposed newborn
13 TERMINOLOGY Congenital TB + Postnatal TB = Perinatal TB
14 Congenital TB is rare: transmitted in utero by haematogenous spread via the umbilical vein or ingestion/aspiration of infected amniotic fluid during birth Postnatal infection much more common: which occurs by inhalation of bacilli spread by the airborne route from a mother or other close source case with infectious pulmonary TB
15 TYPES OF MATERNAL TB ASSOCIATED WITH PERINATAL TB Bacillaemic phase in utero transmission Typical cavitating disease post-natal transmission
16 WHEN TO CONSIDER TB IN NEONATES? - nonspecific symptoms but mother (or other source case) diagnosed with TB - pneumonia not responding to broad spectrum antibiotics, especially in TB endemic settings or if the mother/primary caregiver has TB - high lymphocyte count in CSF with no identified pathogen; - fever and hepatosplenomegaly - abdominal distension with ascites Schaaf Respirology 2010
17 Symptoms and signs in congenital TB: combined data from 75 cases of congenital TB Symptoms and signs Respiratory distress including tachypnoea Hepatomegaly, splenomegaly Fever (usually low grade) Prematurity/low birth weight Cough may be acute or chronic Poor feeding Failure to thrive Abdominal distension (including ascites) Irritability Peripheral lymphadenopathy Sepsis syndrome Skin papular/pustular or ulcerative lesions TB meningitis Jaundice (obstructive) Otorrhoea/mastoiditis Wheeze or stridor Apnoea or cyanosis attacks Facial nervepalsy Shock Occurrence Common (i.e. >40%) Frequent (i.e %) Infrequent (i.e %) Rare (i.e. <10%) Schaaf et al. Respirology 2010;15:
18 Comparison of CXR features in infants with culture-confirmed congenital tuberculosis versus those <3 months of age with mainly postnatal tuberculosis Radiographic feature Congenital TB n = 53 (%) TB in infants (<3 mo) n = 27 (%) Lymphadenopathy (hilar/paratracheal) Lobar/segmental opacification (unilateral or bilateral) 4 (8) 14 (52) 18 (34) 14 (52) Airtrapping NA 15 (56) Large airway compression NA 13 (48) Bronchopneumonia (bilateral) 17 (32) 5 (19) Miliary TB 16 (30) 7 (26) Ghon focus NA 2 (7) Cavities or cystic lesions 4 (8) NA Lobar collapse NA 4 (15) Pleural effusion 1 (2) 2 (7) Normal chest radiograph 4 (8) 1 (4) Schaaf et al. Respirology 2010;15:
19 TB treatment - Factors affecting drug absorption and disposition in newborns Kearns N Engl J Med 2003
20 2010 REVISED HIGHER WHO-RECOMMENDED TB DOSES INH RMP PZA EMB 10 (7-15) mg/kg/d 15 (10-20) mg/kg/d 25 (20-30) mg/kg/d 20 (15-25) mg/kg/d Strong recommendation, moderate quality of evidence WHO Guidance of national TB programmes on the management of TB in children 2014
21 ISONIAZID PHARMACOKINETICS IN 20 LOW BIRTH WEIGHT (LBW) INFANTS To determine the PK parameters of isoniazid (INH) given at the WHO- recommended 10 mg/kg/daily dose in LBW-infants To define the PK of INH in relation to the N-acetyltransferase-2 (NAT2)-genotype. Low Birth Weight infants N=20 (%) or # median and IQR Male Sex 14 (70) Postnatal age (days) 14 (9-29) # Gestational age (weeks) 35 (34-38) # Term (> 37 weeks) 7 (35) Preterm (< 37 weeks) 13 (65) Birth weight (g) 1575 ( ) #
22 ISONIAZID CONCENTRATIONS IN LOW BIRTH WEIGHT INFANTS (N=20) All 20 LBW infants obtained target INH plasma concentrations with 10 mg/kg/day
23 INH CONCENTRATIONS IN RELATION TO THE NAT-2 GENOTYPING (N=20) p-values: C max AUC t 1/ Reduced clearance was shown in slow acetylators and smaller infants
24 Key findings When dosing with INH at 10 mg/kg/day (lower range of recommended dose), all 20 LBW infants obtained target INH plasma concentrations Reduced clearance was shown in slow acetylators and smaller infants (caveat 15 mg/kg) Limited safety data reassuring
25 OUTLINE Case Perinatal TB Approach to the TB-exposed newborn
26 APPROACH TO THE TB-EXPOSED NEWBORN Infectious mother non-infectious mother Well baby unwell baby
27 WHICH MOTHERS ARE AN INFECTION RISK? A recently diagnosed mother with TB Received < 2 months of TB treatment at time of delivery OR Sputum smear/culture has not yet converted to negative/ results are unknown at time of delivery
28 APPROACH TO THE TB-EXPOSED NEWBORN Infectious mother non-infectious mother Well baby unwell baby
29 Well baby & non-infectious mother Observe and f/up Unwell baby TB-screening Well baby & infectious mother TB-screening
30 1. Well baby and non-infectious mother Observe and follow-up BCG at birth Monthly follow-up Ask about TB symptoms at each visit Screen for TB in the presence of any TB symptoms
31 Well baby & non-infectious mother Observe and f/up Unwell baby TB-screening Well baby & infectious mother TB-screening
32 2. Unwell baby TB Screening Gastric aspirates (x2) Xpert and culture Chest radiology Perform TB-screening If indicated: Abdominal ultrasound CSF Blood culture
33 Well baby & non-infectious mother Observe and f/up Unwell baby TB-screening Well baby & infectious mother TB-screening
34 3. Well baby TB Screening Gastric aspirates (x2) Xpert and culture Chest radiology Perform TB-screening If indicated: Abdominal ultrasound CSF Blood culture
35 2. Unwell baby 3. Well baby with infectious mother Perform TB screening No TB TB Prevention versus Observation Treatment
36 IPT PREVENTION No BCG at birth INH 10 mg/kg/day for 6 months - Monthly follow-up Ask about TB symptoms at each visit Screen for TB in the presence of any TB symptoms At IPT completion BCG administration
37 Unwell baby Well baby with infectious mother Perform TB screening No TB TB Prevention Treatment
38 TB - TREATMENT Intensive phase 2 months (3/4 drugs) INH RMP PZA EMB (ETH) Continuation phase 4 months (2 drugs) INH RMP
39 KEY MESSAGES High index of suspicion is required in high burden TB/HIV settings Neonates and young infants may have an atypical TB presentation TB investigations in the mother can guide management of newborn Do not delay IPT or TB treatment when indicated
40 ACKNOWLEDGEMENTS Anneke Hesseling, Simon Schaaf, Robert Gie, Mark Cotton, DTTC team: BCH PK unit, TBH, KDH and KBH Tygerberg neonatal team Harry Crossley funding Families that participated
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