paediatric tuberculosis sam walters imperial nhs trust london

PAEDIATRICTUBERCULOSIS

Sam Walters

Imperial NHS Trust

LONDON

2011 ESTIMATED TB CASES 12 MILLION

8.7 million new cases:

500,000 children (6-8%)

DEATHS: 1.43 million

60,000 children (4.2%)

[2012; 74,000 children (5.2%)]

* Up to 40% of cases in high

incidence countries are children

2011 500,000 children (6-10%)

non-HIV DEATHS:

2011 60,000 children (4.2%)

2012 74,000 children (5.2%)

2011 500,000 children (6-10%)

non-HIV DEATHS:

2011 60,000 children (4.2%)

2012 74,000 children (5.2%)

? PAEDIATRIC DEATHSUnreliable estimates;

not that bad in 2009 or, just as bad in 2011/2012;how many HIV deaths due to TB

Reliable estimates;huge improvement;

fixed dose tabs, management guidelines, linked TB/HIV care, roll-out of ARVs for children

2011 500,000 children (6-10%)

non-HIV DEATHS:

2011 60,000 children (4.2%)

2012 74,000 children (5.2%)

? PAEDIATRIC DEATHSUnreliable estimates;

not that bad in 2009 or, just as bad in 2011/2012;how many HIV deaths due to TB

Reliable estimates;huge improvement;

fixed dose tabs, management guidelines, linked TB/HIV care, roll-out of ARVs for children

Children now firmly placed on global TB agenda

PAEDIATRIC TUBERCULOSIS

Clinical Presentation

Clinical Presentation

-18 month girl

-previously well, no family history of TB

-3 weeks cough and unwell

-admitted to hospital

-low grade fever, normal examination

-appropriate investigations: all negative, Mantoux; 2mm

-gastric aspirates x 3; negative AFB

-X-ray patchy consolidation;

-Rx. 3 different antibiotic courses over 3 weeks

-gradual improvement; afebrile, less cough, looking well

-discharged home, no ∆

-6 weeks later out-patient review

-completely well, thriving, no cough

-gastric aspirates x 3; negative culture

-Rx. 3 different antibiotic courses over 3 weeks

-gradual improvement; afebrile, less cough, looking well

-continued improvement, discharged home, no ∆

-6 weeks later out-patient review

-completely well, thriving, no cough

-gastric aspirates x 3; negative culture

“Grandfather admitted to local hospital with pulmonary TB”

-repeat Mantoux; now 22 mm

-TB treatment commenced

PAEDIATRIC TB

Primary TB in children;

-spontaneous recovery is usual

CHILDHOOD EXPOSURE

PRIMARYPULMONARYINFECTION

INFECTION ≠ DISEASE

NATURALHISTORY

CHILDHOOD EXPOSURE


WELLCHILD

‘LIFELONG’IMMUNITY(live MTB)

Successfulimmuneresponse

CHILDHOOD EXPOSURE


WELLCHILD or ADULT

IMMUNITY(live MTB)

Successfulimmuneresponse 1/3 of population of planet

have been infected 2.3 billion people

1/3 of population of planet have live MTB

in them: = 2,300,000,000

Tuberculosis cases: = 12,000,000

CHILDHOOD EXPOSURE


WELL CHILD or ADULT

IMMUNITY(live MTB)


LATE REACTIVATION, RE-INFECTION

‘Immunosuppression’;age, malnutrition, infection, HIV

CHILDHOOD EXPOSURE


WELLADULT

IMMUNITY(live MTB)


LATE REACTIVATION OFADULT CAVITATING

PULMONARY DISEASE

FORMS CAVITY

CHILDHOOD EXPOSURE


WELLADULT

IMMUNITY(live MTB)


LATE REACTIVATION OF PULMONARY DISEASE

ADULT DISEASE

FORMS CAVITY

TRANSMISSION

CHILDHOOD EXPOSURE


PROGRESSIVEPULMONARY

DISEASE

MILLIARY,EXTRA-PULMONARY

DISEASE

DEATH

DEATH

Inadequateimmuneresponse

Lympho/haematogenous

spread

Paediatric TB: Adult TB: 104-106 bacteria >109 bacteria

-difficulty in confirming diagnosis-difficulty in detecting resistance

-? emergence of resistance

PAUCI-BACILLARY TBImplications of bacterial load:



-? emergence of resistance- infectivity




-? emergence of resistance- infectivity-not part of immediate public health problem


CHILDHOOD EXPOSURE


WELL CHILD

IMMUNITY( live MTB)

LATEREACTIVATION

Any Organ e.g. Bone, Kidney


DISEASE

MILLIARY,EXTRAPULMONARY

DISEASE


Successfulimmune response Lympho/

haematogenousspread

CHILDHOOD EXPOSURE


WELLCHILD

‘LIFELONG’IMMUNITY

(lesions sterilised)


DISEASE


DISEASE


Successfulimmune response Lympho/

haematogenousspread

Treatment

Treatment

CHILDHOOD EXPOSURE


WELLCHILD

LIFELONGIMMUNITY(live MTB)



DISEASE

MILLIARY,EXTRA-PULMONARY

DISEASE

DEATH

DEATH



spread

HOSTImmunosuppressionGenetics ?Age esp. young children

ORGANISMInfecting dose -smear +ve, log phase -smear -ve / culture +ve, ? dormantMTB strain differences

? WHICH PATHWAY

AGE WHEN INFECTED PUERTO RICAN data SOUTH AFRICAN data

ADOLESCENT 15% 5 – 10%

5 yr - ADOLESCENT 5 – 10%

5 – 10 yr 2%

3 – 5yr 5%

1 – 5 yr 24%

1 – 2 yr 30%

< 1 yr 43% 50%

Age related risk of progression to disease:Adult 5 – 10%/lifetime (HIV 10%/yr)

Risk is life long, but concentrated in first 12-24 months after infection (approximately 80% of risk)

Undisputed ↑risk

Disputed ↑risk

CHILDHOOD EXPOSURE


WELLCHILD

IMMUNITYSterile lesions


DISEASE


DISEASE


Successfulimmune response,


spread Treatment

Treatment Successfulimmuneresponse

ISONIAZID

RIFAMPICIN

PYRAZINAMIDE

(Ethambutol)

Triple therapy: the Big Three (+ one)

September 2009

Probably correct dose but taken 40 yrs!

PAEDIATRIC DRUG DOSES

ISONIAZID 10-15 mg/kg/day

RIFAMPICIN 15 mg/kg/day

PYRAZINAMIDE 30-40 mg/kg/day

ETHAMBUTOL ?20 mg/kg/day

* Not CNS

‘SHORT COURSE’ 6 months chemotherapy;

-Pyrazinamide 2 months, Ethambutol 2 months

-INAH 6 months, Rifampicin 6 months

Good data in adults-East African/British MRC studies 1970s

-Singapore Tuberculosis Service/British MRC 1970s & 1980s

-Hong Kong Chest Service/British MRC 1970s & 1980s

Criteria-pulmonary disease (TB adenopathy)

-fully sensitive organism

TREATMENT: HOW LONG?

‘SHORT COURSE’ Criteria-pulmonary disease (TB adenopathy)

-fully sensitive organism (usually unknown in paediatrics)

- mostly adult data

HOW LONG TO TREAT CHILDREN?

RESISTANT TB

MDR TB (2-3 decades) - resistant to rifampicin + isoniazid

XDR TB (2006) – resistant to -Rifampicin +-Isoniazid +-any 2nd line anti-TB injectable +-any fluoroquinolone

2008-2011: % CONFIRMED MDR-TB from ISOLATES

Resistance to at least INAH and Rifampicin(2010 global prevalence; 650,000 cases)

Very few children

XDR-TB: EXTENSIVE DRUG RESISTANT TB-resistance to INAH and Rifampicin, any fluoroquinolone and 1 of the

injectable drugs (amikacin, capreomycin, kanamycin)Countries that had reported at least one XDR-TB case by Oct 2012

KWAZULUNATAL

TUGELA FERRY (KZN, SOUTH AFRICA)

-544 TB patients

-221 MDR TB

-53 XDR TB (55% primary infection)

-44 HIV tested; ALL +ve

-52 died within 25 days diagnosis

transmission

mortality

association with HIV

Must have spread to children but no data; culture negative or not public health threat!

TUGELA FERRY (KZN, SOUTH AFRICA)2005 - 2006

MDR and XDR TB

HOW MANY ARE CHILDREN?

Not an immediate public health threat but many will be infectious in the future.

2nd line drugs with anti-TB activityStreptomycin CycloserineAmikacin RifabutinCapreomycin RifapentineCiprofloxacin EthionamideOfloxacin ProthionamideSparfloxacin ClofazamineThiacetazone LinezolidPAS ClarithromycinIFN TNF

2nd line for good reasons- limited paediatric data- complex drug interactions-↑toxicities,↓tolerability

Promising new drugs;

Moxifloxacin PA 824 (Nitroimidazol-oxazine)

TMC-207 (Bedaquiline) Sirturo™ (metronidazole

class)

EXTRA PULMONARY DISEASE (paucity of data)(2 months intensive treatment)

Joint / bone

-? 9-12 months

CNS

-12 months at least, ? 18-24 months if tuberculomata

-steroids for 1 month

-4th drug initially ethambutol

But why should it take longer to sterilise extrapulmonary lesions?

HIV

-?12 months (relapse with same organism: SA children treated for 6/12)

TREATMENT sensitive MTB: HOW LONG?

PAEDIATRIC TB

ADHERENCE

If you don’t take the

drugs,

the drugs won’t work.

HEPATITIS

-rare in children

-usually with predisposing co-morbidity e.g. HIV, viral hepatitis

? Only routinely measure LFTs at start of therapy

BUT with newer ↑in recommended doses need to be vigilant

DRUG TOXICITY

-insidious onset;-headaches, subtle behaviour change-progresses to convulsions, cranial nerve palsies, hemiplegia, coma, DEATH

TB MENINGITIS DIAGNOSISCSF (textbook description)

-lymphocytes, low sugar, high protein, AFB visible

But, Mycobacteria don’t read textbooks

Early disease;

-often polymorphs

-protein can be normal initially

-sugar can be normal initially

Usually -no visible organisms

CSF ABNORMALITIES IN MENINGITIS (%)Donald et al. 1987; J Trop Ped; 33: 213-216 Viral Neisseria Haemophilus Streptococcus Tuberculous

Investigation meningitis meningitidis influenzae pneumomiae meningitis

Cell count >500x106/l 12 81 74 70 3

Protein >0.8 g/l 7 83 84 97 76

Glucose< 2.2mmol/l 1 76 73 75 64

CSF/bloodglucose : <0.4 7 79 74 91 79

Organisms seenon microscopy 0 65 47 85 8

Number of cases 108 140 47 34 62

ENHANCED CT SCAN GADALLINIUM ENHANCED MRI

MRI > SENSITIVITY THAN CTTB Meningitis

MRI > SENSITIVITY THAN CT

ENHANCED CT SCAN GADALLINIUM ENHANCED MRI

Miliary TB, no meningitis

TB MENINGITIS TREATMENTTREATMENT

Anti TB drugs;

-duration

-sensitivity

-? CSF penetration

Adjunctive therapy;

-steroids

-SIADH

-acetazolamide

-surgeryHYDROCEPHALUS

DRUG TYPICAL

MIC mg/ml

PEAK LEVELS

SERUM mg/ml

PEAK LEVELS

CSF mg/ml

% PENETRATION

INAH 0.025-0.5 4.4 3.2 80

RIFAMPICIN 0.006-0.2 11.5 0.78 6.8

PYRAZINAMIDE 12.5 50 50 100

ETHAMBUTOL* 1 1.2-8 0.9-4.2 52-75

STREPTOMYCIN 2.1-10 30 2 6.6

MOXIFLOXACIN** 0.37 5.49 4.07 74

* poor penetration of ethambutol across non-inflamed meninges**Kanellakopoulou k et al. J Anti microb Chemo. 2008 61; 1328-31

CSF penetration of anti-TB drugs

? PAEDIATRIC CNS DRUG DOSES

ISONIAZID 15 mg/kg/day ?20 if < 10kg

RIFAMPICIN 15 mg/kg/day ?20 if < 10kg

PYRAZINAMIDE 30-40 mg/kg/day 40 if < 10kg

ETHAMBUTOL 20 mg/kg/day

PROGNOSISComa divided into 3 stages (MRC 1948);

Stage I -early signs of meningeal irritation-no focal neurology-complete recovery if treated

Stage II -focal neurology; CN palsies, hemiparesis, confusion-if treated recover but majority have physical or

intellectual handicap

Stage III -comatose, unable to localise pain-30% mortality, most survivors have severe physical

or intellectual handicap

EARLY TREATMENT: EARLY DIAGNOSIS

CHILDHOOD EXPOSURE


WELL CHILD or ADULT

IMMUNITY(? live MTB)

LATEREACTIVATION

Any Organ


DISEASE


DISEASE


Successfulimmune response,


spreadDiagnosis

Diagnosis

Difficulty in diagnosis–Primary TB

• Non-specific symptoms• Tuberculin reaction -ve• X-ray changes non-specific

–Progressive primary• Non-specific symptoms• Pauci-bacillary• Tuberculin reaction ve• X-ray changes non-specific

–Post-Primary, late reactivation (Adult)• Cavitating pulmonary disease (any organ

involved)• Tuberculin reaction +ve (usually)


Difficulty in diagnosis–Primary TB

• Non-specific symptoms• Tuberculin reaction -ve• X-ray changes non-specific

–Progressive primary• Non-specific symptoms• Pauci-bacillary• Tuberculin reaction ve• X-ray changes non-specific

–Post-Primary, late reactivation (Adult)• Cavitating pulmonary disease (any organ

involved)• Tuberculin reaction +ve (usually)


Easy for adult TB colleagues !

DIAGNOSIS OF TB IN CHILDREN

Microscopy / culture ‘gold standard’

(pauci-bacillary, prolonged culture)-respiratory secretions

-sputum (need > 5000/ ml to see AFB)-gastric washings > BAL-?induced sputum vs gastric washings**

-CSF, bone marrow, lymphoid tissue, etc.

Paediatric TB: 104-106 bacteria

**Induced sputum >> gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. H J Zar et al. Lancet, 2005; 365:130-134

**Induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis? Showed equivalence. M Hatherill, H J Zar et al. Arch Dis Child, 2009;94:195-201

Diagnostic testsImmunology

Host response

Tuberculin antigen-specific skin test (TST) production of IFN

Microbiology

Organism

smear culture DNA

Histology

TUBERCULIN SKIN TEST (used since 1890)-measures;

-degree of hypersensitivity to PPD

-does not measure; -immunity to tuberculosis

-time of infection

-presence or extent of disease

-poor specificity, does not distinguish between; -TB disease and TB infection

-BCG

-atypical mycobacteria

-poor sensitivity, can be falsely negative in;-early infection, disseminated disease

-other acute infections (measles, pertussis), live vaccines

-severe malnutrition

-immunocompromised

In children negative test does not exclude TB

Problems with SpecificityLow Sensitivity in young kids

Arch Dis Child2010:95:180-186

Conclusions:

-TST more sensitive for culture proven TB

-a negative IGRA does not exclude active TB

-a combination of IGRA + TST increases sensitivity of diagnosis

-negative IGRAs should not deter treating presumed active TB

-IGRAs would significantly reduce treatment of LTBI in UK

-but would it be safe?

→ NIKS (NIHR IGRA Kids Study) - to assess predictive value of IGRA for LTBI

Aims of the project

1. To determine if it is safe to withhold chemoprophylaxis from children exposed to TB with negative IGRA but positive TST

Prospective cohort study

2. To link TB exposure, infection and outcome in children via a national contact tracing module, linked to TB register

Contact module

PI: Prof B Kampmann, Imperial College; study involves 11 NHS sites in the UK

Design

TB house-hold-exposed children

TST and IGRA at screening and 2 months later

TST+ve/IGRA-ve followed for 1-2 years

Primary endpoint: Development of active TB(? NICE: how safe are the guidelines)

Secondary endpoint: how concordant are TST and IGRA(? NICE: is the step-wise screening approach justified)

Target: 500, Currently: 489

Results for secondary endpoint available in early 2014, primary endpoint: 2015

Clinical; but TB can do anything!


Family history

Epidemiology

Trial of treatment


HIGH LEVEL OF SUSPICION

Ask yourself

“WHY ISN’T THIS TB?”

CHILDHOOD EXPOSURE


Only validated effect- protection against overt primary TB if given to un-infected (tuberculin negative) infants, children or young adults

- ? prevents dissemination of bacilli from initial site of infection

-? protects against TBM and disseminated disease

- does not prevent post-primary disease if given to already infected (tuberculin reactive) people

-can produce severe necrotising lesions

BCG

Avoidcontact

PREVENTION

Screening high risk groups-contact with open TB-recent immigrants

from hyper-endemic areas

INAHRIF

WISH-LISTBetter diagnostic tests

- differentiate between infection and disease

- global application- cheap, robust and simple

- monitor success of therapyBetter immunisationBetter treatments

- drugs/regimens- ? immunotherapy- ? other

Better delivery of healthcare


WISH-LISTMore data; better understandingBetter diagnostic tests

- differentiate between infection and disease

- global application- cheap, robust and simple

- monitor success of therapyBetter immunisationBetter treatments

- drugs- ? immunotherapy- ? other

Better delivery of healthcare


Better understandingMore dataMore research

paediatric tuberculosis sam walters imperial nhs trust london

Documents