War on Childhood Tuberculosis

Diagnosis, Management &

Prevention

Prakash Mohan Jeena

Department of Paediatrics & Child Health

University of Kwazulu Natal

Durban

Declaration of Conflicts of Interest1. Employment by a commercial entity

2. Consultancies or Advisory Board

3. Lecture Fees/ Honoraria

4. Shares/Patent in relevant companies

5. Active or previous relationship with a tobacco entity

6. Any other potential conflicts of interest

NO

YES

YES

NO

NO

NO ☐

AREAS TO COVER• EPIDEMIOLOGY & RISK FACTORS

• DIAGNOSIS

• CLINICAL

• RADIOLOGICAL

• LABORATORY – SPECIMENS & TESTS

• MANAGEMENT

• UNCOMPLICATED AND COMPLICATED

• SPECIAL SITUATIONS

• TBM & MILIARY

• HEPATO-TOXICITY

• POOR ABSORPTION

• DRUG RESISTANCE

• HIV AND IRIS

• NEONATAL TB

• CHEMOPROPHYLAXIS

• WHY ARE WE LOSING THE WAR?????????

Current TB Epidemiology

• Global

• Incidence 10.4 million/annum – 10% in children

• Morbidity 142/100 000, Mortality 24/100 000

• South Africa

• Incidence 715/100 000 (346-1130) – decreasing

• TB-HIV co-infection 60% constant

Its estimated that out 10.4 million incident cases of

TB 10% occurred among children under 15years

~10% of the result deaths due to TB (among HIV-

negative children)

-Incidence of childhood TB & HIV2-4 X > risk of acquiring TB in HIV infected than uninfected

cure rate 60-80%, 2 year fatality rates 30%

75% of these cases occurred in the 22 highest TB-

burden countries

In many countries children comprise more than half

the population, suggesting that the reported cases of

childhood TB are likely underestimated

WHY MAKE A FIRM DIAGNOSIS OF

CHILDHOOD TB?

• Sentinel public event

• Indicates poor adult control

& identifies source case

• Marker of HIV infection

• Newly infected- recent

transmission

• TB rapidly progresses from latent infection to disease- in addition to

severe manifestations of disease such as-miliary TB and meningitis

• Most children are infected by household contacts with TB disease,

even when the adult index case is sputum negative- transmission to

children has been documented in 30-40 % of households

• Diagnosis is mainly clinically because PTB presents with pauci-

bacillary, non-cavitatory pulmonary disease

• Bacteriologic confirmation is possible only in 30-40% of patients

• Children lack sufficient tussive force to produce adequate sputum

samples by expectoration alone, thus the use of gastric aspiration

and induced sputum

Transmission dynamics

• Depends of risk factors

• Pathogen load & characteristics

• Host receptiveness

• Health system intervention

Association of Childhood Pulmonary TB

with Exposure to Indoor Air PollutionJafta N et al 2018 personal communication

Aim

• To determine the association between exposure to indoor air pollution (IAP) and childhood pulmonary tuberculosis (PTB).

Methods:

• Age and sex-matched case controlled study, children diagnosed with PTB (cases) were compared to those without PTB (controls)

• Questionnaires about children’s health, their home characteristics and activities related to household air pollution and second hand smoke (SHS) exposure were administered to all the caregivers.

• A subset of the participants’ homes was sampled for measurements of PM10over a 24-hour period (n=105), NO2 and SO2 over a period of 2 to 3 weeks (n=82). IAP concentrations of PM10 and NO2 were estimated in unsampledhomes using predictive models. Logistic regression was used to look for association between IAP concentrations, crude measures of IAP and PTB.

Results:

• 134 participants, 107 cases and 127 controls.

• Measured pollutants concentrations (µg/m3) for PM10 were GM: 50.5 (95%CI: 47.5-53.7), for NO2 were GM: 15.7 (95%CI: 15.0-16.5) and for SO2 were GM: 0.2 (95%CI: 0.2-0.3). Day-to-day variability was large.

• No significant association was observed between pollutant concentrations and PTB in children for PM10 and NO2, due to high day-to-day variability.

• Crude exposure measures of pollution viz cooking fuel type (clean or dirty fuel) and SHS, was positively associated but not statistically significant.

• Presence of dampness in the household was a significant risk factor for childhood TB with AOR from 2.1 to 2.2 for different models.

Conclusion:

• Overcrowding, HIV status, TB contact and dampness are important risk factors for PTB acquisition

• Exposure to secondhand smoke (SHS) and dirty cooking fuel suggests as risk

Careful history (including history of TB contact and symptoms

consistent with TB

Clinical examination (including growth assessment)

TST and/or IGRA (both tests, if available , to increase

sensitivity)

Bacteriologic confirmation whenever possible

Investigation relevant for suspected pulmonary and

extrapulmonary TB

HIV testing (e.g. In high prevalence areas)

Clinical disease - symptoms• Cough -persistent >14 days

• Fevers – persistent > 14 days

• Failure to thrive > 2 month without another cause

• LOW > 1 month- no other cause

• Night sweats

• Loss of appetite

• Chest pains

• Contact with an infective source

• Cough, night sweats, fever, FTT

• sensitivity 75%, specificity 50%

CONTACT• Depends on duration of exposure, transmissible bacillary load of

index, extent of exposure

• With sputum positive case- increased likelihood of transmission

• Household contact vs. non household contact

• Schools, taxis churches etc

• Susceptibility of host important for conversion of infection to disease - HIV infected risk for transmission greater than HIV uninfected

• Duration of exposure 4-8 houts

• Exposure current or less than 12 months ago

Clinical examination• General: BCG scar, TST, hypersensitivity reactions,

lymphadenopathy- painless, matted +/- sinus, FTT

• Chest: Persistent ARI, all possible respiratory signs, non-

responsive wheeze

• CNS:TBM- SIADH, Obstructive hydrocephalous, convulsions,

deficits, SOL- Tuberculoma, abscess

• Abdominal: ileum- t/v ulceration, peritonitis-omental

mass,para-aortic lymphadenopathy, ascites

• Disseminated - liver/ spleen granulomas

• Spinal: slow onset paralysis, gibbus

• Other: genito-renal TB, joint/skin, miliary

•AP and Lateral chest xrays can be very useful tool for the diagnosis of TB in children

•Most common finding is a primary complex, which consists of opacification with hilar or subcarinal lymphadenopathy, in the absence of parenchymal involvement•When adenopathy advances, consolidation or a segmental lesion may occur, leading to collapse in the setting of infiltrates and atelectasis

•In a study of 326 traced contacts under 5 years of age, 9% of

children diagnosed with intrathoracic TB were asymptomatic and

had radiographic findings only of the primary complex, a miliary

pattern of opacification is highly suspicious for TB, as is

opacification that does not improve or resolve following a course

of antibiotics

RADIOLOGY: RESPIRATORYCXR: calcified Ghon focus & primary complex

perihilar/hilarl/adenopathy, bronchial compression,atelectasis bronchopneumonia, military, pleural effusion, calcified pericardial effusion

• Reactivation-focal infiltration of the upper lobes i.e. apical or superior/posterior segments of lower lobe.

• Atypical radiography common in HIV positive, adenopathy, mass (tuberculoma), fibronodular lesion (miliary), effusions-CXR (79% sensitivity)₃

• Amber CXR - reviews airways

• HRCT scan more sensitive for id

early/subtle parenchymal and nodes

HRCT

Used to further delineate the anatomy for cases in which

radiographic findings are equivocal

Able to visualize endobronchial involvement, bronchiectasis

and cavitations more readily

In tuberculous meningitis- CT scan of the head is useful:

Findings…In 80 - 90% of cases- obstructive hydrocephalus and basilar meningeal enhancement are observed, tuberculoma and brain abscess

Radiology: CNS/MS• Spine XR, Tomogram, MRI

• Cystic & lytic changes & collapse in vertebral body

• intact nucleus pulposis

• pedicle involvement

• abscess formation & destruction- Psoas abscess

• tuberculoma

• X-ray joints:

• Osteo-articular & cystic and pseudocystic changes

• granuloma formation

• Tuberculoma- gummatous lesions

Radiology: abdominal TB• Abdominal XR- Ileus & calcification

• CTS : granuloma, nodes & masses

• Barium studies

• Swallow- UGIT diseases

• Meal - thick, ulcer, stricture

• Enema – LGIT diseases

• Ultra-sound

• Para-aortic & porta hepatus l/n

• Ascites/ omental mass

• Granuloma- liver/spleen

• Excretory urography

• calcification hydronephrosis

Diagnosis Latent TB: Tuberculin skin tests• Recall of delayed type CMI hypersensitivity to MTB Ag

• 3 types of TSTs: commonly used

• Mantoux- Intradermal- 0.1 ml PPD containing 5 units

-transverse diameter of induration at 10-72 hours

• Boostering

• Occurs 1-5 weeks post vaccination (1 year) but 10 years post vaccination- 15-25% of TST still positive

• TST thresholds of positivity

• >9 mm had a 68% sensitivity and 78% specificity for infection

• >13 mm a 54% sensitivity and 90% specificity for disease.

• Interpretation

• Age: < 5 years or > 5 years

• Presence of BCG

• Degree of immunosuppression

The TST is performed by injecting 0.1 ml of tuberculin

purified protein derivative (PPD)into the inner surface

of the forearm

A tuberculin syringe should be used and the needle

bevel should face upwards

When this intradermal injection is placed correctly, the

injection should produce a pale elevation of the skin

(a wheal ) 6-10mm in diameter

Should be read after 72 hours after administration

A pt who doesn’t return within 72 hours will need to

be rescheduled for another skin test

Measured in millimeters of the induration (palpable,

raised, hardened area of swelling)

The reader must not measure erythema

The diameter of the indurated area should be

measured across the forearm (perpendicular to the long

axis)

• Non tuberculous

mycobacteria

• Previous BCG vaccination

• Incorrect method of TST

administration

• Incorrect interpretation of

the reaction

• Incorrect bottle of antigen

used

• Cutaneous anergy-inability to react to skin tests due to a weakened immune system

• Very young age(<6/12)

• HIV infected

• Immunosupression

• Recent live viral vaccination(e.g. Measles)

• Overwhelming TB dx

• Viral illness (eg. measles and chicken pox)

Since TST cannot distinguish between TB disease,

latent M.tuberculosis infection, and infection due to non-

tuberculous mycobacteria, the result must be interpreted in the context of the clinical features and history of TB exposure ~40% of immunocompetent children with culture –

confirmed TB disease may have a negative TST

In pulmonary and extrapulmonary TB, the TST is

positive 90% and 80% respectively

While in miliary TB and TB meningitis, the TST is

usually positive in only 50% of cases

IGRAs• IGRAs are in vitro blood tests of cell mediated immune response. Measure

T-cell release of IF-gamma following M.tb Ag

• Use of both TST and IGRA may increase sensitivity for evaluation of children with suspected TB

• Not affected by BCG or by most infections with non-environmental NTM

• Expensive- Can be available in 24-48hrs

• More objective interpretation of results

• Specificity>95% of latent TB.

• Sensitivity for T-SPOT higher than for QFT-GIT or TST (90%,80%,80% resp)

• Does not boost subsequent IGRA test results

• TST may boost subsequent IGRA results - If IGRA test is needed to confirm a TST result, blood should be drawn within 3 days of TST placement

• IGRAs specificity>95% of latent TB.& Sensitivity 80% - HIV uninfected - Lower in HIV infected but similar and complimentary yield to TST-

1. Recent close contact with an infectious case

2. A positive tuberculin skin test (TST) or

interferon-gamma release assay(IGRA)

3. Suggestive findings on chest radiograph or

physical examination

Laboratory Confirmation of TB

• Possible Samples: early morning gastric aspirates, stool nasopharyngeal aspirates, sputum/induced sputum, urine broncho-alveolar lavage, bone marrow aspirates, CSF,

• Sterile Body fluids –proteins, glucose, LDH concentrations compared with serum (Lights criteria), differential cell counts, MCS for bacteria & mycobacteria

• Tuberculous effusions- lymphocytosis, high protein>50% serum, low glucose but absence or presence does not exclude diagnosis

• Organism burden is low thus often negative smears and cultures. Cultures positive in <25% of cases

• Pleural fluid adenosine deaminase (ADA), > 40-70U/L highly suggestive

Other samples• Urine

• First morning MSU. Multiple specimens increase yield. AFB usually –ve, Culture more useful. LAM assay useful in 40-90%

• Fine Needle L/N Aspirate: yield over 90%

• CSF

• protein & glucose cf serum studies, differential cell counts.

• AFB smear +ve in < 30%, examine for at least 30min

• Culture may be +ve in as high as 90% of cases.

• IGRA or ADA values not reliable

• PCR -high specificity (100%) but moderate sensitivity (59%)

• Bone marrow aspirate &trephine

• Tissue biopsy Granulomatous inflammation

Gastric lavage or gastric aspirate has been the standard of care for many years but the yield is

disappointing, three consecutive –sequential day specimens for optimal yield must be taken, the procedure

is unpleasant, its relatively invasive and usually requires hospitalisation

Sputum induction has been successfully used as an alternative to GL

-PRECAUTIONS MUST BE TAKEN :

-procedure should be performed in a well –ventilated room

-enough time should be allowed between procedures

-appropriate particulate respirators should be used by staff eg. N95

ADVANTAGES OF SPUTUM INDUCTION:

-can be performed as an outpatient

-yield is higher

-relatively easy to perform

NB:

*NPA samples have a lower yield than GA

*BAL is resource-intensive and invasive , has a lower yield than GL,therefore BAL is not indicated for

microbiologic confirmation of TB

Collection of pulmonary samplesEarly morning gastric aspirates, stool nasopharyngeal aspirates, BAL, sputum/induced sputum

Sputum induction

• Undertaken after 2-3 hour fast

• Pre-treat with salbutamol via MDI + spacer

• 5% saline (5ml) nebulisation + O2 (5l/min) x 15min

• Anterior & posterior chest wall percussion

• Sputum by suctioning with mucus extractor

• Less invasive, easier, quick, outpatient procedure

• Minor adverse reactions - ↑ coughing, epistaxis, wheezing, vomiting

• Careful environmental control - ventilation, masks etc. to prevent nosocomial TB transmission

• At least 2 samples of 5mls.

Gastric lavage aspirate

• Useful in children

• Early morning, after overnight fast ≥ 4hrs

• Prior to brushing teeth or breakfast

• NGT passed & gastric contents aspirated

• Minimum of 20ml aspirate

• Placed in sterile tube containing sodium carbonate

• 2 samples 8-24hr intervals/at least one early morning sample

Limitations of GLA

• Need for overnight fast

• Repeated specimens

• Admission

• Time-consuming

• Unpleasant for both child & health worker

•Microscopy is also the oldest test•Useful in assessing infectivity and cure

•Advantages: -inexpensive*& simple

•Disadvantages: -requires adequate training,-time consuming

quality control processes to ensure high quality results

•There is two types of microscopy: light microscopy and

-fluorescent microscopy has clear advantages over LM

*more sensitive than LM

*has a higher throughput

-disadvantages:

*equipment and bulbs are expensive

*Bulbs need monitoring and frequent replacement

*fluorescent debris may be confused with TB bacteria

Smear microscopy• At least 5000 to 10,000 bacilli needed for detection on smears vs. 10-

100 organisms for positive culture.

• Sensitivity & PPV of AFB smear microscopy is +/-30% (multiple samples & concentration procedures)

• AFB on smears may represent Non TB mycobacteria, thus culture for species identification & DST+/- NAA

• Fluorochrome technique (using auramine-O or auramine rhodaminedye with fluorescence microscopy) up to 10 fold more sensitive than the carbofuschin method (Z-N & the Kinyoun methods)

• Smear AFB positive yield:

• gastric aspirates 20.4%, sputum 37.0%, induced sputum32.0%₁

Rapid diagnosis of TB and rifampicin and other anti-

tuberculosis resistance in pulmonary sputum smear positive

specimens have high specificity and good sensitivity

WHO (Dec 2010) endorsed assay for rapid diagnosis of PTB

with sputum (as a replacement for smear microscopy) in settings

with high rates of HIV associated TB & MDR TB

Molecular Xpert MTB/RIF assay•Rapid molecular diagnostic test & result within 2 hours

•1-10 organisms/ml needed for a positive result

• False positive -dead bacteria, lab errors, contamination

•Detects the presence of MTB and resistance to rifampicin

•Distinguishing TB from non-tuberculous mycobacteria.

•Specifically developed for sputum samples but children inability of produce expectorate sputum

• 25% of children with culture confirmed TB were – ve on MTB/RIF testing (even higher in smear – ve culture + ve children)- therefore must also send for culture and DST

• Testing 2 specimens = ↑ diagnostic yield for smear – TB

• Other molecular tests-Haines test- Line probe assay

• 1st & 2nd generation - detects MTB and resistance to INH & Rifampicin & PZA and FQs

WHO (Dec 2010) endorsed assay for rapid diagnosis of PTB with sputum (as a replacement for smear microscopy) in settings with high rates of HIV associated TB & MDR TB

Sensitivity of MTB/RIF molecular test in different samples vs. culture HIV negative pop, 97-100% specificity , culture =gold std

Study Sample Number sensitivity 2nd sample

yield

Overall TB

id rate

Cape Town Induced

sputum

N=452 75.9% 13.8% 16%

Tanzania Sputum +IS N=280 66.6% 16% 17.1%

Cape Town NPA+ IS N=535 65% - 16.3%

Zambia GA + IS N=930 68.8% - 6.2%

Cape Town GA + Stool N=23 75% - 17%

India/Italy Pleural fluids Mixture of

studies

25-50% - -

South Africa FNA N=18 96.6% - -

India Tissue

Biopsy

N=250 80.6% - -

Other fluids and testing• Sterile Body fluids –proteins, glucose, LDH concentrations compared with serum (Lights

criteria), differential cell counts

• Tuberculous effusions- lymphocytosis, high protein>50% serum, low glucose but absence or presence does not exclude diagnosis

• Cultures positive in <25% of cases

• Pleural fluid adenosine deaminase > 40-70U/L =suggestive

• Urine

• First morning MSU. Multiple specimens increase yield. AFB usually –ve, Culture more useful. LAM assay useful in 40-90%

• Fine Needle L/N Aspirate: yield over 90%

• CSF

• protein & glucose cf serum studies, differential cell counts.

• AFB smear +ve in < 30%, examine for at least 30min

• Culture may be +ve in as high as 90% of cases.

• PCR -high specificity (100%) but moderate sensitivity (59%)

• Bone marrow aspirate & trephine= smear and culture

• Tissue biopsy= Granulomas

• It is an automated nucleic acid amplification test that can simultaneously identify M.tuberculous and detect rifampicinresistance

• Performs better than smear microscopy

• While GeneXpert MTB/RIF test appears to be highly specific, its sensitivity for sputum smear negative TB in children remains low

• It may be a rapid diagnostic test that may take the place of sputum microscopy but not mycobacterial culture

• A negative result should be interpreted in the context of the child’s clinical and x-ray findings

• 25% of children with culture confirmed TB were – ve on MTB/RIF testing (even higher in smear – ve culture + ve children)- therefore must also send for culture and DST

• Testing 2 specimens = ↑ diagnostic yield for smear – TB

• Sputum culture remains a more sensitive test and is required to detect the full drug susceptibility of the infecting organism

Other molecular tests: Haines test- Line probe assay1st & 2nd generation - detects MTB and resistance to INH,Rifampicin, PZA and FQs

Rapid tests that can be used to detect the presence of MTB as

well as genetic mutations that confer drug resistance

Three types of LPA’s are available:

*INNO-LiPA Rif.TB detects only RMP resistance

*GenoType MTB DR/MTBDRplus detects both RMP and

INH resistance

*GenoType MTB-DRsl detects resistance to FQs, injectable

2nd line drugs and ethambutol

High sensitivity(90-97%) and specificity (99%) compared to DST

NB: evidence mainly from adult studies Assays still cannot replace the culture for TB or conventional

drug susceptibility testing(DST)

oDETECTION OF ANTIBODIES:

-although detection of antibodies against M.tuberculosis in the blood is relatively cost

effective and simple, a recent meta-analysis and systematic review concluded that

commercial serological tests provided inconsistent results

-WHO currently recommends against their use for the diagnosis of pulmonary and

extra-pulmonary TB

oDECTECTION OF ANTIGENS:

-Lipoarabinomannan(LAM) was identified as a promising target for antigen detection for

TB diagnosis due to its temperature stability; it could be detected in urine, which is

normally easier to collect and safer to handle than sputum

-LAM- based assays are included in the WHO TB diagnosis re-tooling programme and

forms part of a Foundation for Innovative New Diagnostics(FIND) funded TB project

Microbiology - culture• Culture detects as few as 10 bacteria/ml by 3-8 weeks

• Negative smear or molecular test can be culture positive

• Negative culture can still have TB - bacteriologic confirmation is never established in 15-20% of cases. Sensitivity/specificity for sputum 80/98% respectively

• Methods• Solid-egg based (Lowenstein Jensen), agar based (Middle brook).

• Liquid: Bactec-RIA method, growth 13-16 days, expensive. Time to positivity dependent on bacillary load

• L-J slants a useful backup for rare mycobacterial strains.

• Species identification. Performed using nucleic acid hybridization with DNA/RNA probe, high pressure liquid chromatography(HPLC) or biochemically

• DST- disc dilution method for resister

• Culture + smear -ve: 74.7% sensitive (95% CI, 64.6%-82.8%)₁

Reliability of our current criteria to diagnose TB

1

• Contact – used extensively but lacks clear definition

• Cough, night sweats, fever, FTT (sensitivity 75%, specificity 50%)

• CXR (79% sensitivity)

• TST thresholds of positivity

• >9 mm had a 68% sensitivity and 78% specificity for infection

• >13 mm a 54% sensitivity and 90% specificity for disease.

• IGRAs (Interferon-gamma release assays)- CMI response. Specificity>95% of latent TB.& Sensitivity 80% - HIV uninfected

• Lower in HIV infected but similar and complimentary yield to TST

• Smear AFB positive yield:

• gastric aspirates 20.4%, sputum 37.0%, induced sputum32.0%₁

• Culture + smear -ve:74.7% sensitive (95% CI, 64.6%-82.8%)₁

CLASSES of TB DRUGS• 1: FIRST LINE ORAL ANTI-TB AGENTS

• E.g. RIPE/E

• 2: INJECTABLES

• E.g. Aminoglycosides, capreomycin

• 3: FLUOROQUINOLONES

• E.g. ofloxa, levo, moxi, gatifloxacin

• 4: ORAL BACTERIOSTATIC SECOND-LINE ANTI-TB AGENTS

• E.g. PAS, terizidone, cycloserine, thioacetazone

• 5: ANTI-TB AGENTS with unclear efficacy

• e.g. clofazamine, co-amoxiclavunate, linezolid, clarithromycin

• NB Newer agents= Bedaquiline and Delaminid

First-line Anti-TB Therapy• Isoniazid(H)

� Discovered in 1912◦ anti-depressant properties

◦ Used in TB therapy since 1952

• Rifampin(R)

• Semi-synthetic derivative of rifamycin;

first produced in 1959

• Use in TB therapy 1960s

• Pyrazinamide(Z)

• Discovered in 1956

• Ethambutol(E)

• Discovered in 1961

• Replaced streptomycin in 1980s

Intensive phase

(2months)

Continuation

phase

(4 months)

RHZE RH

INH(MW 137) � Prodrug-activated by KatG

� Activated form inhibits Mycolic

acid synthesis

� Highest early bactericidal

activity in first few days

� Active against intra-and

extracellular bacilli

� Toxicity: clinical hepatitis,

peripheral neuropathy

� Mutation in KatG gene is

one mechanism of resistance

Absorption Readily absorbed; peak serum level 1-2hrs post dose; decreased with food intake

Distribution 0.57 to 0.76 L/kg

Metabolism Hepatic(N-acetylation)

Excretion 75-95% renal

• Inhibits RNA synthesis

• Unique ability of rapid killing of bacilli in tuberculosis lesions

• Maintains activity against sporadically dividing bacilli(“persisters”)

• Resistance develops due to point mutations in the rpoB gene

• Issues with drug-drug interaction

• Induces hepatic enzymes(CYP 2C9, 2C19 and 3A4)

• Lowers levels of ART, specifically PIs, NNRTIs

Absorption Good

absorption

Distribution 1.6L/kg

Metabolism Hepatic; active

metabolite

Excretion Enterohepatic

circulation; fecal-

65%; metabolite

renally

Rifampin(MW 823)

• One of the essential sterilizing anti-TB drugs

• Shortened treatment duration from

9mo6mo

• Pro-drug activated by pnc A

• Needs acidic medium for activity

• Has activity against slowly dividing bacilli

• Mode of action is not elucidated

• Toxicity: Hepatitis, hyper-uricaemia

Absorption Rapidly &

completely

absorbed; food

intake reduces

Cmax

Distribution 0.75-1.65 L/kg

Metabolism Hydrolysis;

active metabolite

Excretion Renal:70%

PZA (MW 123)

• Bacteriostatic at the therapeutic dosages used

• Prevent resistance development of companion drugs

• Inhibits arabinosyl transferase disrupts arabino-glycan synthesis (cell wall)

• In adults, dose-dependent efficacy ; associated with ocular toxicity (retrobulbar neuritis)

Absorption Time to peak 2-4hrs

Distribution

Metabolism Oxidation

Excretion Renally: 50% unchanged15 % metaboliteFecal: 22%

ETHAMBUTOL

(MW 204)

Pharmacodynamics and

Pharmacokinectics

• Dosage of anti-TB originally tested in healthy adults and

doses extrapolated to children

• Response to Therapy related to clinical and crude

microbiological response (negative culture) not MIC or time

to negative culture

• No therapeutic drug levels monitoring or attainment of

therapeutic drug levels

• Drug concentrations vary in different tissues

Kearns et al. Developmental Pharmacology-Drug Disposition, Action and Therapy in Infants and Children. N ENGL J

MED 2003;349: 1157-67

Concerns with drug dosageFor example anti tuberculosis treatment in children: Isoniazid

Plasma Concentrations in South African Children with Tuberculosis

• McIlleron et al…. INH concentration in

56 hospitalized children treated with

previous WHO recommended dosages

for INH (4-6mg/kg)

• 70% of children had peak

concentrations that were <3mg/L

• Resulted in change in WHO

recommendations: recommended

dosage for INH for children to

10mg/kg

Therefore – TB in children

Maximum doses: PZA 2 g & ETHAM – 1200mg

In silico children & the glass mouse model: clinical trial

simulations to identify and individualized optimal doses

in children with tuberculosis. Jeena PM, Bishai WR, Pasipanodya JG, Gumbo T. AAC. 2011; 55(2): 539-45.

• Pharmacokinetics of Anti-TB medications in South

African Children (PHATISA STUDY)

• Characterize pharmacokinetics of the four 1st line anti-TB drugs( isoniazid, rifampin, pyrazinimide, ethambutol) in children

• Identify differences and sources of variation in the pharmacokinetics of these drugs in children

METHOD

• Pt sample Centrifuge

Buffy layer stored

for SNP analysis

Pharmacokinetics of Anti-TB medications in 31South African

Children on recommended doses(PHATISA STUDY)

Using previous WHO standardized therapeutic doses

Dosage within the WHO

Rec. Range

Therapeutic plasma levels

achieved

INH 26/31 26/31

RIF 28/31 3/31

PZA 13/31 20/31

EMB 11/13 4/11

Therapeutic plasma

achieved

INH 24/26

RIF 3/28

PZA 7/13

EMB 3/11

RESULTSWHO Dosage Recommendation,

mg/kg

Dosages in

the study

Cmax*

in ug/ml

(SD)

Tmax**

in hrs

(SD)

AUC0-24

In ug.hr/ml

(SD)

INH 10-15 4.67-21.8 6.88(3.73) 1.32(0.93) 33.93(24.7)

RIF 10-15 8.6-21.8 4.38(3.4) 3.63(5.5) 23.56(15.67)

PZA 30-40 19.8-55.5 29.08(14.28) 2.04(1.01) 296.26(163.54)

EMB 15-25 10-25 1.72((0.87) 3.18(2.32) 12.57(5.68)

Summary of findings

• Rifampicin levels are subtherapeutic

• Should adjust dosing schedule accordingly

• Need to look at weight bands more closely

• INH dose adjustment have shown benefit in in

plasma levels but may still need fine tuning

• Ultimately the impact of this sub-therapeutic levels

on clinical outcome needs evaluation

Treatment Dosages

• Isoniazid (H),10-15mg/kg-max300mg

• Rifampicin (R),10-20mg/kg-max600mg

• Pyrazinamide (PZA/Z), 30-40mg/kg - max 2g

• Ethambutol (EMB/E),15-25mg/kg-max 1200mg

Dosages for meningitis and miliary TB

• INH – 20mg/kg/day

• RIF – 20mg/kg/day

• PZA – 40mg/kg/day

• ETH – 20mg/kg/day

New WHO Treatment of initial

phase of PTB

• Uncomplicated

• Rifampicin (10-20mg/kg) new recommended dose 15mg/kg Max 600mg

• INH (10-15mg/kg) recommended dose 15mg/kg-max 300mg

• PZA (25-40mg/kg) recommended dose 35mg/kg –max 2g

• OR

• Ethambutol (15-25mg/kg) recommended dose 25mg/kg- max 1200mg

• Complicated

• Add: Ethambutol (15-25mg/kg) recommended dose 25mg/kg

vs. New FDC FORMULATION for children Rif/INH/PZA 90/60/150

(3:2:5 ratio) vs 60/30/150 (2:1:5 ratio)

FORMULATIONS

• Concern pK with FDC (Rif 60, INH 30, PZA 150) –suboptimal therapeutic levels

• Impact of crushing tablets

• Impact of NGT tube delivery of drugs into duodenum

• Per rectal therapy vs IV therapy

• Children: impact of stability of active ingredients in liquid vs dispersible sachets vs tablets must be considered

• Therapeutic drug monitoring should it be routine

Challenges of administrating Anti-TB Rx

in infants and preschool childrenPinemo-Peres R Ann Pediatr 2016

Method

• X-sectional/multicenter nationwide

• N=54 of 67 respondents

• Most use crushed tablets

• Composite formulation –variability available

• 83% = essential for FDC to be developed

Conclusion

• Great diversity in anti TB prescription in children

• Lack of suitable formulation

UNCOMPLICATED TBLow bacillary load

COMPLICATED TB < 8 YEARS

UN/COMPLICATED TB > 8YEARS EXTENSIVE TB,ABDOMINAL,PLEURAL EFFUSION,

OSTEOARTICULAR AND SPINAL

Therapeutic Surgical management

• Often only performed after 6 months of anti-tuberculosis therapy Why?

• Healing is generally good on anti-tuberculosis allows localization of infection and may oviate need for surgery

• Healing with fibrosis and cavity formation

• Can rarely occur spontaneously – auto pneumo-ectomy

• Indicated for

• TB bronchiectasis

• TB cavity & abscess with lack of penetration of medication- try nebulized aminoglycosides

• MDR TB because poor response to anti TB drugs

• Rarely Chest drain with decortication

TUBERCULOSIS MENINGITIS

TBM

Anti-tuberculosis Rx in Children3A (without E) Low bacillary load

New SS- PTB without parenchymal

involvement

Less severe EPTB

2HRZ, 4HR

3B (high bacillary load)

New SS+ PTB /HIV

New SS- with parenchymal involvement

Severe EPTB

2HRZE, 4HR

3C

All other forms of severe TB: extensive pulmonary TB, spinal or, osteo-articular TB or abdominal TB.

For children under 8 years

Previously treated SS+ PTB

2HRZE, 4HR

OR

longer depending on cure rate

3D

TB meningitis/miliary

2HRZEth, 7-10 HR Or

6 HRZEth – may prolonge

THERAPEUTIC TRIAL

• CONTROL: STRICT

• RE-EVALUATION: IMPERATIVE

• LACK OF CLINICAL IMPROVEMENT i.e. improved appetite, weight gain, partial resolution of signs: NECESSIATATES INVASIVE TESTING

• RADIOLOGICAL EVALUATION HELPFUL IN HIV UNINFECTED BUT MAY BE LATER THAN 8 WEEKS IN HIV INFECTED

Monitoring & Rx for Adverse effects

• Peripheral neuropathy

• INH- substitute with alternatives

• Hepatic toxicity

• Withdraw all TB drugs if enzymes >5x normal & introduce one drug/week

• If liver toxicity again- change to FQ, aminoglycosides, ethambutol

• Abdominal TB- poor absorption

• Mx: INH suppositories, IV FQ, IV/neb aminoglycosides

• Rash- Steven Johnson Syndrome

• Rifampicin, INH, PZA

• Mx: stop drugs and undertake test dosing- Supportive therapy

• D-D interaction esp rifampicin with PIs

• Mx: add Ritonavir –do not increase dose of Kaletra

Rx outcomes & tolerability of revised

WHO anti-tuberculosis drug dosesNansumba M et al IUATLD doi.org/105588/ijtld17.0535

Design:

• Prospective Ugandan study: n=-144 (33.3% HIV +) with 12 FU

Results:

• Efficacy (no relapse)

• 83.3% success, 13.2% died, 2.8% LFU, 2.1% treatment failure, 0.7% transfer out

• Treatment adherence = 85%

• Safety = Increased ALT 0.7%, Peripheral neuropathy 0.7%

• 22% moderate-severe malnourished – predictor of MR 8.76 (CI 1.59-48.25)

Conclusions:

Good adherence and tolerability - MR related to Malnutrition

Childhood TB: management and treatment

outcomes among children in NW EthiopiaKebede ZT et al Pan Afr Med J 2017;27: 25

Design

• Cross-sectional study of children who completed TB Rx

• TB diagnosed clinical and CXR: Site: University & 6 satellite health centers

Results

• 98.7% lack of compliance, 22.5% poor adherence, 1.8% inadequate TB Rx

• Factors for good Rx outcome

• Adherence to anti TB Rx OR 0.003 (0.001-0.002)

• Factors for poor Rx outcome

• No permanent home OR 8.3 (4.1-16.7%), ARV co-treatment OR 4.5(1.2-16)

Overall low success but health centers/hospital follow up improves outcome

DOTS THERAPY

• VARIABLE BENEFIT

• South East Asia: huge difference

• Parts of Africa no benefit

• South Africa

• Non DOTS: rates 33 & 16% respectively

• DOTS cure 52% & interrupted rate 8 % better than unsupervised

treatment but control of TB Poor compared to WHO targets

Rx outcome of TB patients under DOT(sc) and factors affecting outcome in Sothern Ethiopia

Gebrezgabiher G et al Plos ONE 2016;11:2Methods:

• 5 year retrospective study n= 1537 (smear +ve n=544(35.4%); 66% rural 11.5% extra-pulmonary TB)

Results

• Outcomes

• 73.5% completed treatment +11.8% cured = 85.2% treatment success

• Rx success due to DOTS improve between 2008-2013 = 80.5% to 84.8%

• 11.1 defaulted treated, 3.4% mortality & 0.3% Rx failure

• Risk factors poor outcome

• Rural vs urban AOR 1.68(1.21-2.2), EPTB VS PTB 2.07(1.28-3.37)

• PTB-ve vs PTB +ve AOR =1.77(1.26-2.50)

Patient Centered Care• Patient centered adherence support vs. DOT - better

• Cochrane review 2015;5:CD003343

• Care giver education

• HIV indicator and multi-modal approach

• Environmental control

• Natural ventilation- avoid overcrowding

• No dampness

• Germicidal UV AIR DISINFECTION-LED technology-Air filtration

• Second hand smoke and dirty fuels

• Respiratory protection

• Cough rooms

• Surgical mask= 50% protective effective

• N95= 70-80%

• Powered air purifying respirators

Therapy issues- Re-infection disease

• Previously successfully treated for PTB = increased risk for re-infection with TB.

• Imperative to exclude drug-resistant TB by carrying out sputum GeneXpert and culture with drug susceptibility testing (DST) on the index cases, and to determine DST of any known TB source case...

• If the above does not indicate resistant TB, treat as drug susceptible TB (high bacillary load ) with close monitoring of response. An extension of the duration of the continuation phase of therapy in these retreatment cases may be considered....

DRTB

• Single Drug-resistant TB- Common , can be innate (primary) or acquired (secondary).

• Multi-drug resistant TB disease indicates resistance to both Rifampicin and INH with or without resistance to any other anti-tuberculosis drug

• Extensive drug resistant TB disease is defined as MDR- TB and in vitro resistance to any of the fluoroquinolones and any injectable or intensive second line anti TB drug.

• Total drug resistance indicates resistance to all classes of TB drugs.

TB drug resistance

• Resistance in new patient (primary): ab-initio around 3-6%

• Resistance in re-treatment (acquired): increasing -poor adherence

• MDR: rifampicin and INH resistance +/- other drugs

• XDR: Resistance to Rif/INH/FQ & at least one of injectables

• New classification

• Category 1(no previous TB Rx),

• Category II (TB Rx with 1st line agents),

• Category III (H/O MDR with second line Rx)

• Resistance - transmission of resistant strains: disease in 12m

RISK FACTORS FOR DRTB

• A known source or contact with drug-resistant TB case or High-risk source case, e.g. on TB Rx & released from prison;

• A smear positive case after 2 months of TB Rx

• Who failed (or deteriorated on) first-line anti-TB treatment

to which they were adherent (treatment failure or relapse within 6 months of treatment).

• Any severely ill TB case that got worse on TB Rx.

• Who defaulted TB Treatment(Rx interruption)

• Who relapsed while on or at the end of TB Rx

• With recurrent TB disease after completion of TB treatment (retreatment case)

MDRTB -diagnosis

• GeneXpert tests for rifampicin mono-resistance & Haines LPA tests for other resistant. False positive results recorded & clinical and radiological correlation required

• All samples that test positive on molecular PCR must have samples submitted for DST but therapy for MDR TB must be instituted while awaiting results.

• Drug regimen currently recommended by the National TB directorate for children < 8years with MDR TB

• 5 drugs for 6 months or more during the intensive phase for at least 6 days a week and 4 drugs for a further18 months or less during the continuation phase for at least 6 days a week.

• Exact duration for the intensive phase is 4 months after the first date of sampling of a negative culture result while the total of therapy duration should be 18 months after that date.

Management strategy

• Confirmed drug-resistant TB should be managed in a dedicated MDR TB unit with appropriate infection control measures to prevent nosocomial transmission.

• Treatment could be initiated in consultation with a designated expert while awaiting referral to the designated MDR TB centre.

• An uninterrupted medical supply, direct supervision with proper education and counselling is necessary.

• Attempts of decentralising care of MDR TB cases is currently being planned

Standardized MDR regimen • Challenge: confirm microbiological diagnosis

• Treatment

• Amikacin less ototoxicity vs. kanamycin = deafness- suicide

• PZA – joint pains, unstable- difficult to measure levels)

• Ethionamide -metallic taste- poor adherence, no susceptibility tests

• Ethambutol variable sensitivity, replaced by terizidone or cycloserine

• Ofloxacillin/clofazamine/BDQ/DELAMANID

• Intensive phase 5-7 drugs for 4-6 m & continuation phase 3-5 drugs for (drop amino & PZA) 18-24 months

• Seroconversion to negative cultures =12 months

• Cure rate 30-50%; 2 year CFR: 30-50%

MDR Therapy

• Levofloxacillin (<8 years) < 5 years 10mg/kg twice daily (max 1000mg) & > 5 years 10mg/kg daily OR

Moxifloxacin replaces levofloxacin at a dose of 400mg daily

• amikacin 15-22.5mg/kg daily

• Terizidone 15-20mg/kg daily

• Ethionamide 15-20mg/kg daily

• PZA 30-40mg/kg daily

• Injectable anti-tuberculosis therapy (aminoglycoside) is stopped during continuation phase of therapy

The only novel drug since 1970..no data

in children

Bedaquline was approved in Dec 2012

for MDR TBScience 2005; 307:214, 223

Extreme drug resistance TB

• Major issues

• Isolation for prevention of spread

• Majority in HIV infected adults - need studies in children

• Treatment & Adverse effects

• PAS –diarrhoea

• Capreomycin – hypokalaemia

• Cycloserine – seizures, depression, decreased LOC-10 to 15%

• Terizidone – no sensitivity

• PZA ,ethionamide, ethambutol

• Not proven: Clarithromycin, augmentin, high dose INH

• Current susceptibilities

• BDQ, DELMANID, ETHIONAMIDE, CAPREO, CYCLOSERINE .-LONG TERM

Challenges: Treating drug resistant TB• Cost

• Outcome- improved recently > 80%

• Optimal duration uncertain – new Bangladesh regimen 6 month induction and 5 months maintainane

• Managing adverse effects- reduced with new regimen

• Ensuring QOL

• Poor adherence 22% default rate

• Need education of health care workers

• Counseling of patients/relatives (omission of injections)

• Prevention of spread – air filter mask

• Management of treatment failure

• Decentralised program vs. Creating new facilities

• Personnel, training

Special issues with TB and ARVs

cART with Rifampicin/rifamycin

• Rifampicin stimulates cytochrome P450- drug interactions

• decreases PI by up to 80%

• Use additional dose of Ritonavir alone - not increasing dose of LOP/r

• Use higher doses for 2 weeks after stopping Rifampicin

• NNRTI based regimens

• EFV decreased AUC by 22-26%- 50% for children but no dose adjustment

• NVP decreased AUC by 37-58%- increase dose (toxic) vs. change

• EFV not < 3 years or in post pubertal girls =NOT teratogenicity

• Integrase inhibitors RAL/DTG also have interaction with TB drugs bid dosing

Drug resistant and cART

• Criteria for testing – cost expensive

• Virologic failure >1000-30000 copies after second line regimen

• Two samples (one month apart) with increasing viral loads

• Clear evidence of good adherence (diary cards, pill counts)

• Drug resistance patterns

• Low rate of ab initio resistance

• High rate of resistance with STI or poor adherence

• Often multiple mutations with varying penetrance

• Mutation with class effect or single drug effect

• Common mutations K184V & K103N against 3TC & NVP

• Triple NRTIs regimen resistance due to ineffective control

Children on HAART who develop TB

• On what HAART regimen

• On first line therapy (ABC+3TC+LOP/r or EFV):

• May indicate

• Failure of ARV treatment failure if >12-24 months of therapy

• Primary, reactivation/reinfection or drug resistant TB

• IRIS first 6 months after onset of cART

• Other OIs

• PCP/Bacterial Pneumonia, Disseminated Fungal Infection, MOTTs

• Continue cART but increase dose of Ritonavir equivalent to Lopinavir (foul taste) or triple NRTIs

When to start cART in children on

anti-tuberculosis therapy• Issues : age, pill burden, D-D interactions, IRIS, overlapping

toxicities, progression of immune suppression

• In TBM/Miliary TB highest mortality immediate therapy but best complete anti-TB treatment before ARVs especially if good initial response to therapy …

• But if no response or WHO stage 4 or if CD4% (5% above of age specific CD4 threshold for severe or advance immune deficiency) or count (<200mm3) …start TB first & then HAART as soon as TB treatment tolerated(2-8weeks)

• WHO stage 3 or if CD4% (5-15%) or count (200-349mm3) = start TB treatment for initiation phase (2-8 weeks) and commence HAART during continuation phase (>8weeks)

Immune Reconstitution inflammatory Syndrome

• Definition: Paradoxical deterioration with worsening pulmonary infiltrates, peripheral & mediastinal lymphadenopathy despite good viral and immunological responses - lasts 10-40 days

• Due to Jarish herxheimer/Lepra like reaction

• Can occur in the absence of HAART and with TB treatment alone

• Occurs weeks up to 6 months after initiation of HAART

• Diagnosis requires

• Identification of offending antigen

• Change in host immunity

• Exclusion of other possible explanations for clinical syndrome-

• Pathogenesis unclear

• Restoration of CD4 and CD8 cells, Cytokine mediated responses

• Increased expression of mycobacterial antigens (paradoxical worsening)

Immune Reconstitution inflammatory Syndrome• Can occur in the absence of HAART and with TB treatment alone

• Occurs weeks to 3 -6 months after initiation of HAART

• Paradoxical deterioration with worsening pulmonary infiltrates, pheripheral & mediastinal lymphadenopathy despite good viral and immunological responses - lasts 10-40 days

• Diagnosis of exclusion vs. reactivation or re-infection TB disease

• Pathogenesis unclear

• Restoration of CD4 and CD8 cells

• Cytokine mediated responses

• Increased expression of MTB antigens (paradoxical worsening)

• Treatment

• Prednisone 1 mg/kg/day for 1-2 weeks, then taper

• Continue HAART therapy

• Close Monitoring

SOMETIMES CONSIDER TEMPORARY STOPPING HAART

Treatment• Mild

• If typical presentation - Observe, continue cART & NSAID

• If unsure of the diagnosis of IRIS, treat OI

• Severe

• Add: corticosteroids (local or systemic)

• Stop HAART only is condition is life threatening

• Prevention

• Avoid : delay commencement of cART at VERY low CD4

count as are a risk for acquiring IRIS

• Screen for OI in TB endemic areas before commencing

Shared side effects of ARVs and

Anti-TB medications

• Nausea & vomiting• ddI, AZT, Ritonavir, SQ

• PZA

• Pheripheral neuropathy• d4t, ddI

• INH

• Hepatic• Rifampicin, INH, PZAs

• EFV, NVP

• Rash• NVP, EFV, ABC Incidence: 5-9% (3% in “placebo”)

• Rifampicin, INH, PZA

Special issues with anti-TB Rx and ARVs

• Don’t switch from 1st to 2nd line TB treatment if on HAART

• Rifampicin - significant interactions – but most effective

• With INH use in malnourished on HAART - add Pyridoxine

• Streptomycin does not cross BBB, not used in pregnancy

• Thioacetazone avoided due to S-J Syndrome

• Adverse effects less common in children

• Less concerned in renal failure but must monitor if on TDF

• Non hepatotoxic TB drugs – ethambutol, aminoglycosides, FQ

Treatment of Newborn with TB

Determinant of TB Rx completion among

newborn in high burden setting in Cape TownBekker A IJTLD 2014;18(3):335-40

• N=56- 63%HIV exposed mean GA 36 weeks

• 44/56 -79% FU @ 6 MONTHS

• 29/44- Completed Rx without intervention

• Appropriate referral= improves completion

• In adequate referral = HR 0.34(0.12-0.93) for poor response

Chemoprophylaxis of TB Contact

• WHO: use if prevalence of TB < 30%

• In SA prevalence = 60% : not recommended: why? chances of missing active disease which is possible if 1 or more symptoms/signs are present!

• Cough > 2 weeks

• Fever > 2 weeks

• Night sweat

• Weight loss > 1.5 kg in the past 4 weeks

• These patients must be investigated

Send 3 sputum samples & if samples are negative, then chemoprophylaxis

TB CHEMOPROPHYLAXISWho should receive chemoprophylaxis ?

• All children < 5 years- high risk : start prophylaxis

• HIV infected > 5years eligible for prophylaxis if TST positive, clinical asymptomatic and CXR normal

• INH prophylaxis reduced all cause mortality but the post mortem findings in those without prophylaxis did not TB (Zar 2005 Lancet)

What should be given?

INH 10mg/kg for 6 months or

INH 5mg/kg + Rifampicin 5mg/kg for 3 months

Why prophylaxis?

• HIV infected children at a high risk of contracting TB

• Incidence of 24 cases per 100 HIV infected children per year was documented in Cape Town during a period of limited access to ART [1]

• For children, fewer data on the role of IPT in HIV+

• HIV positive individuals – risk for TB exceeds 10% each year, depending on degree of immunodeficiency and prevailing socioeconomic conditions

• After HIV sero-conversion, the risk doubles or trebles within the first 2 years of infection and continues to increase as the CD4 count drops [2]

Efficacy of prophylaxis• Cochrane Review – 12 clinical trials

• Total of 8578 randomised participants > TB preventative therapy [any anti Tb drug] Vs. Placebo

• Lower incidence when prophylaxis used RR 0.68, CI 0.54- 0.85

• Benefit pronounced in positive skin test RR 0.38 CI 0.25-0.57

• Efficacy was similar for all regimens

• However, compared to INH monotherapy, short–course multi-drug regimens were much more likely to require discontinuation of treatment due to side effects

• A 2nd Cochrane systematic review found that IPT had 60% efficacy in the reduction of incident TB

• Only 22% of the subjects were children

• Since young and/or HIV –infected children are at considerably greater risk for disease progression following M Tuberculosis, this meta-analysis is likely to underestimate the protective effect of IPT in children [3]

Routine Pre-exposure IPT

Method

• Multi-centred, randomized, double-blind trial comparing INH to placebo, in HIV-exposed-uninfected and HIV-infected African infants in the absence of any documented TB exposure.

• 548 HIV- infected and 804 - uninfected infants were randomized to daily INHormatching placebo for 96 weeks

Results

• 22 total culture-confirmed TB cases were seen BUT there was no difference in the 2 groups and there were no cases in infancy

• 18/22 cases had DST & in 14% INH resistance was seen but it is difficult to correlate failure of INH prophylaxis to resistance

Conclusion:

• Lack of efficacy of primary prophylaxis in reducing TB latent or active or mortality in HIV infected, unexposed & uninfected South African children MadhiS et al. NEJM 2012

Decrease in incidence and MortalityIncidence:

- Incidence of Tb in Isoniazid group 4% [5/132]

- incidence in placebo group 10% 13/131

- Hazard ratio 0.28-0.10 - P=0.005

Mortality:

• Deaths in Isoniazid group 8% [11/132] vs placebo group 16% [21/131]-95% CI 0.22-0.95

• Zar HJ et al BMJ 2007

Combined effect with ART

• INH alone 0.22 [95% CI 0.09 to 0.53]

• ART alone 0.32 [95% CI 0.07 to 1.55]

• INH reduced the risk of TB disease by 0.23 [95% CI 0.05 to 1.00]

Conclusion:

IPT offers additional protection to children on HAART

• LJ Frigati, K Kranzer, MF Cotton, HS Schaaf, CJ Lombard, HJ Zar

So why then prophylaxis?• Risk of progression from latent to active disease

• < 12 months- 50%

• 12-24 months- 10-20%

• 24 to 60 months - 5-10%

• 5 to 10 years –< 2%

• Adolescents –10-20%

• HIV infected children @ high risk of contracting TB• Incidence of 24 cases/100 HIV infected children per year was recorded in Cape

Town during period of limited ARV access

• HIV positive individuals – risk for TB exceeds 10% each year- depends on degree of immunodeficiency & S-economic conditions

• After HIV sero-conversion, the risk doubles/trebles within the first 2 years of infection & continues to increase as CD4 count drops [2]

• However, little data on IPT in HIV infected children

Paediatric Essential Drug Committee

• In HIV positive infected children ART should start as early as possible in infancy, for protective effect against developing TB disease after infection.

• Post-exposure INH Prophylactic Therapy (IPT) 10mg/kg daily for six months is recommended after exclusion of TB disease (normal CXR, no symptoms in HIV un-infected children under the age of 5 years old, and in all HIV infected children

NB. Post exposure = close contact with infectious pulmonary TB case ( smear-positive or culture-positive or Genexpertpositive) or the child is PPD (mantoux ≥10mm of induration).

PEDL CONTINUED

• IPT should be repeated with every significant new exposure (INH has no post-antibiotic effect). All HCWs should enquire about any new TB contact at every follow-up visit, as well as caregivers health

• Pre-exposure IPT is not recommended in any HIV-infected or un-infected child.

• Post-TB disease IPT is not recommended in all cases. Ensure TB cure is complete – if incomplete resolution exclude drug-resistant TB disease or prolonging the continuation phase to 7 months if no resistant TB is found

Post exposure Chemoprophylaxis

• Any positive case must have active contact screening

• Must exclude active disease before chemoprophylaxis

• Chemoprophylaxis regimen to non diseased contacts

• All <5 years, TST + highest risk for progression:

• 2 drugs (RI or RZ) for 3 months or INH for 6 mths

• RIFAPENTINE WEEKLY INJECTION FOR 3 MONTHS

• All HIV infected any age with exposure and active disease excluded- prophylaxis with INH 6 month

• Prophylaxis for MDR TB

• 3 Drugs (FQs + PZA+ Ethionamide) or high dose INH or regular monthly follow up

• INH dose 10mg/kg/d normal dose or 20 mg/kg/d

• Prophylaxis only protects while on therapy- if new exposure even 1 day after completion recommence IPT

CONCERNS WITH THESE

STUDIES

• Lack of knowledge on the rate of exposure to a TB CONTACT

case

• Severity of illness and whether the difference in mortality was

related to TB or other HIV related diseases

• Variability in the duration of the INH prophylaxis

• Inability to monitor adherence to therapy closely

• Sample size and design (open labelled) especially in the

continuation phase of the primary study

Prophylaxis in Drug Resistant Cases

• Post Exposure prophylactic therapy for drug-resistant infectious TB cases with and without HIV infection who are exposed to

• True rifampicin (RIF) mono-resistant contacts (based on culture sensitivity results NOT GeneXpert RIF resistance) - INH 10mg/kg daily for six months should be provided.

• INH mono-resistant contacts - Rifampicin 10-15mg/kg for four months as single drug.

• Multidrug-resistant and extensive drug-resistant TB contacts -preventive therapy

• 3 drug therapy (FQ, Ethambutol, High dose INH 20mg/dose or chose according to sensitivity 6 months or

• Close follow up- 2 weekly/monthly x 2 years

• Burden of disease is substantial even in the neonatal or early infancy

• Presumed diagnosis is just as bad as under-diagnosis- make effort to

confirm a diagnosis

• Health systems issues

• Therapy is poorly preformed by HCWs and patients (parents)

• Missed opportunity for prophylaxis

• Challenges with DR TB is substantial

• Vaccination with BCG or MVA85A inadequate-limited proven benefit

Why we are failing TB control in children ?

Program and policy issues

• Integration: one patient, one file, one health-care worker

• Decentralization: take treatment to patient

• Supportive health-care : make care-seeking a positive experience

• Improved diagnosis and treatment

• Holistic approach – supportive environment

• Look at risk factors for transmission

How do we measure response to anti-

tuberculosis therapy and adherence?

Response

• Time to negative culture

• Variability in pK and therapeutic drug monitoring

• MICs of anti-tuberculosis therapy

• Cytokine responses

Adherence

• No gold standard but must have pill counts - low cost & reliable

• Therapeutic drug level monitoring

Finally Some interesting thoughts

going forward ……….

• What about developing a model to quantify TB bacillary load like that for bacterial infections?

• Can we use Time to Positive TB culture as a marker bacillary load?

• What about drug sensitivity assays that determine MICs of anti-TB drugs that allow dose adjustments?

• What about shorter course intensive and maintenance TB therapies?

• What about an individual treatment program determined by whole genome sequencing vs. standardized dosing and drug Rx policy ?

• Should we adopt a ‘HIT EARLY HIT HARD, THROW YOUR BEST PITCH FIRST, APPROACH’?

CONCLUSIONS

• Fundamental changes in diagnosis, management and prevention of TB in children is necessary

• Based on PK (higher doses) and appropriate formulations

• Monitoring for response, drug interactions, adverse effects and adherence

• Ensuring adherence and appropriate follow up is essential

• Chemoprophylaxis is mandatory

• Novel thoughts for research in childhood TB

The end

Case presentation

Case evaluation-set 1

• A 24 month old female S-N, presents with cough,

loss of appetite, loss of weight for 15 days. He was

vaccinated at birth with BCG but there is no BCG

scar. Her grandpa has TB has completed treatment

for 5 months with Anti-tuberculosis therapy.

• Answer true or false in each of these statements by

show of hands

Statements-set 1• For the diagnosis of TB to be considered, the duration of

symptoms is usually >14 days but can be as little as 3 days

• the family history of TB in this case is a risk factor for

acquiring TB

• the absence of a BCG scar is indicative of lack of protection

from the vaccination

• BCG vaccination is protective against pulmonary tuberculosis

in 80% of cases

• the 5 month therapy - the grandpa received makes him still

likely to be infectious

Set 2• On examination is found to have weight for age between 60-

80%, clubbing, lymphadenopathy, parotid enlargement,

hepatosplenomegaly and oral candidiasis. There is bilateral

wheeze but the child is not distress. He also has weakness of

both lower limbs.

• For each of the following statement indicate by show of

hands whether the statement is true or false

Statements Set 2• Clubbing is a common feature in TB

• Wheezing is due to bronchial compression by lymph-nodes

• Weakness of the lower limbs could be caused by TB

• Lymphadenopathy due to TB is single discrete and rubbery

• Parotid enlargement is due to lymphoid hyperplasia in TB

Set 3

You consider the following diagnoses

• Tuberculosis

• HIV

• Lymphoid interstitial pneumonitis

• Lymphoma

• Bronchiectasis

Are the following features supportive of the diagnosis for each of these statements

Statements Set 3TB – FTT, persistent cough > 14 days, unremitting fever for >14

days, LOW, night sweats

HIV- HSM, L/N, FTT, persistent recurrent bacterial infection

LIP- HIV infected with clubbing and parotid enlargement

Lymphoma- LOW, Firm hepatosplenomegaly, mediastinal masses.

Bronchiectasis- halitosis, clubbing, chest deformity, bilateral

crackles