Transcript PAEDIATRIC TB

PAEDIATRIC
TUBERCULOSIS
Sam Walters
Imperial NHS Trust
LONDON
2011
8.7 million new cases:
ESTIMATED TB CASES 12 MILLION
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%)
? PAEDIATRIC DEATHS
2011
500,000 children (6-10%)
Unreliable 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
non-HIV DEATHS:
2011
60,000 children (4.2%)
2012 74,000 children (5.2%)
? PAEDIATRIC DEATHS
2011
500,000 children (6-10%)
Unreliable 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
non-HIV DEATHS:
2011
60,000 children (4.2%)
2012 74,000 children (5.2%)
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
NATURAL
HISTORY
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
INFECTION ≠ DISEASE
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Successful
immune
response
WELL
CHILD
‘LIFELONG’
IMMUNITY
(live MTB)
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Successful
immune
response 1/3 of population of planet
WELL
CHILD or ADULT
have been infected
 2.3 billion people
1/3 of population of planet have live MTB
in them:
= 2,300,000,000
IMMUNITY
(live MTB)
Tuberculosis cases: = 12,000,000
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Successful
immune
response
WELL CHILD
or ADULT
IMMUNITY
(live MTB)
LATE REACTIVATION,
RE-INFECTION
‘Immunosuppression’;
age, malnutrition, infection, HIV
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Successful
immune
response
WELL
ADULT
IMMUNITY
(live MTB)
LATE REACTIVATION OF
ADULT CAVITATING
PULMONARY DISEASE
FORMS CAVITY
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Successful
immune
response
WELL
ADULT
IMMUNITY
(live MTB)
FORMS CAVITY
TRANSMISSION
LATE REACTIVATION OF
PULMONARY DISEASE
ADULT DISEASE
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Inadequate
immune
response
PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous
spread
DEATH
MILLIARY,
EXTRA-PULMONARY
DISEASE
DEATH
PAUCI-BACILLARY TB
Implications of bacterial load:
Paediatric TB:
104-106 bacteria
Adult TB:
>109 bacteria
-difficulty in confirming diagnosis
-difficulty in detecting resistance
-?  emergence of resistance
PAUCI-BACILLARY TB
Implications of bacterial load:
Paediatric TB:
104-106 bacteria
Adult TB:
>109 bacteria
-difficulty in confirming diagnosis
-difficulty in detecting resistance
-?  emergence of resistance
-  infectivity
PAUCI-BACILLARY TB
Implications of bacterial load:
Paediatric TB:
104-106 bacteria
Adult TB:
>109 bacteria
-difficulty in confirming diagnosis
-difficulty in detecting resistance
-?  emergence of resistance
-  infectivity
-not part of immediate public health problem
PAUCI-BACILLARY TB
Implications of bacterial load:
Paediatric TB:
104-106 bacteria
Adult TB:
>109 bacteria
-difficulty in confirming diagnosis
-difficulty in detecting resistance
-?  emergence of resistance
-  infectivity
-not part of immediate public health problem
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Inadequate
immune
response
WELL CHILD
IMMUNITY
( live MTB)
Successful
immune response
LATE
REACTIVATION
Any Organ e.g. Bone,
Kidney
PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous
spread
MILLIARY,
EXTRAPULMONARY
DISEASE
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Inadequate
immune
response
Treatment
WELL
CHILD
‘LIFELONG’
IMMUNITY
(lesions sterilised)
Successful
immune response
PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous Treatment
spread
MILLIARY,
EXTRAPULMONARY
DISEASE
CHILDHOOD EXPOSURE
? WHICH PATHWAY
ORGANISM
PRIMARY
PULMONARY
INFECTION
Infecting dose
-smear +ve, log phase
-smear -ve / culture +ve,
? dormant
MTB strain differences Successful
immune
response
WELL
CHILD
LIFELONG
IMMUNITY
(live MTB)
HOST
Immunosuppression
Genetics ?
Age esp. young children
Inadequate
immune
response
PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous
spread
DEATH
MILLIARY,
EXTRA-PULMONARY
DISEASE
DEATH
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)
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
< 1 yr
Undisputed
↑risk
30%
43%
50%
Disputed
↑risk
CHILDHOOD EXPOSURE
PRIMARY
PULMONARY
INFECTION
Treatment
Successful
immune
response
WELL
CHILD
IMMUNITY
Sterile lesions
Inadequate
immune
response
Successful
immune response,
PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous Treatment
spread
MILLIARY,
EXTRAPULMONARY
DISEASE
Triple therapy: the Big Three (+ one)
ISONIAZID
RIFAMPICIN
PYRAZINAMIDE
(Ethambutol)
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
* Not CNS
?20 mg/kg/day
TREATMENT: HOW LONG?
‘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
HOW LONG TO TREAT CHILDREN?
‘SHORT COURSE’ Criteria
-pulmonary disease (TB adenopathy)
-fully sensitive organism (usually unknown in paediatrics)
- mostly adult data
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
KWAZULU
NATAL
TUGELA FERRY (KZN, SOUTH AFRICA)
TUGELA FERRY (KZN, SOUTH AFRICA)
2005 - 2006
-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!
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 activity
Streptomycin
Cycloserine
Amikacin
Rifabutin
Capreomycin
Rifapentine
Ciprofloxacin
Ethionamide
Ofloxacin
Prothionamide
Sparfloxacin
Clofazamine
Thiacetazone
Linezolid
PAS
Clarithromycin
IFN 
TNF 
2nd line for good reasons
- limited paediatric data
- complex drug interactions
-↑toxicities,↓tolerability
Promising new drugs;
Moxifloxacin
TMC-207 (Bedaquiline) Sirturo™
PA 824 (Nitroimidazol-oxazine)
(metronidazole class)
TREATMENT sensitive MTB: HOW LONG?
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)
PAEDIATRIC TB
ADHERENCE
If you don’t take the drugs,
the drugs won’t work.
DRUG TOXICITY
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
-insidious onset;
-headaches, subtle behaviour change
-progresses to convulsions, cranial nerve palsies, hemiplegia, coma, DEATH
TB MENINGITIS DIAGNOSIS
CSF (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
Neisseria
meningitidis
Haemophilus
influenzae
Streptococcus
pneumomiae
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/blood
glucose : <0.4
7
79
74
91
79
Organisms seen
on microscopy
0
65
47
85
8
Number of cases
108
140
47
34
62
Investigation
Cell count
>500x106/l
Viral
meningitis
Tuberculous
meningitis
TB Meningitis
MRI > SENSITIVITY THAN CT
ENHANCED CT SCAN
GADALLINIUM ENHANCED MRI
MRI > SENSITIVITY THAN CT
Miliary TB,
no meningitis
ENHANCED CT SCAN
GADALLINIUM ENHANCED MRI
TB MENINGITIS TREATMENT
TREATMENT
Anti TB drugs;
-duration
-sensitivity
-? CSF penetration
Adjunctive therapy;
-steroids
-SIADH
-acetazolamide
-surgery
HYDROCEPHALUS
CSF penetration of anti-TB drugs
DRUG
TYPICAL
PEAK LEVELS
PEAK LEVELS
MIC mg/ml
SERUM mg/ml
CSF mg/ml
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
% PENETRATION
? 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
ETHAMBUTOL
20 mg/kg/day
40 if < 10kg
PROGNOSIS
Coma 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
PRIMARY
PULMONARY
INFECTION
Diagnosis
Inadequate
immune
response
WELL CHILD
or ADULT
IMMUNITY
(? live MTB)
Successful
immune response,
LATE
REACTIVATION
Any Organ
PROGRESSIVE
PULMONARY
DISEASE
Lympho/
haematogenous Diagnosis
spread
MILLIARY,
EXTRAPULMONARY
DISEASE
PAEDIATRIC TUBERCULOSIS
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)
PAEDIATRIC TUBERCULOSIS
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)
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**
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
-CSF, bone marrow, lymphoid tissue, etc.
Diagnostic tests
Microbiology
Organism
smear
culture
Immunology
Histology
DNA
Host response
Tuberculin
skin test (TST)
antigen-specific
production of IFN
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;
Problems with Specificity
Low Sensitivity in young kids
-early infection, disseminated disease
-other acute infections (measles, pertussis), live vaccines
-severe malnutrition
-immunocompromised
In children negative test does not exclude TB
IGRAs
Arch Dis Child
2010:95:
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
PI: Prof B Kampmann, Imperial College; study involves 11 NHS sites in the UK
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
Design
TB house-hold-exposed children
Target: 500,
Currently: 489
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)
Results for secondary endpoint available in early 2014, primary endpoint: 2015
Clinical; but TB can do anything!
DIAGNOSIS OF TB IN CHILDREN
Family history
Epidemiology
Trial of treatment
DIAGNOSIS OF TB IN CHILDREN
HIGH LEVEL OF SUSPICION
Ask yourself
“WHY ISN’T THIS TB?”
PREVENTION
CHILDHOOD EXPOSURE
BCG
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
INAH
RIF
Avoid
contact
PRIMARY
PULMONARY
INFECTION
-does not prevent post-primary disease
if given to already infected (tuberculin
reactive) people
-can produce severe necrotising lesions
Screening high risk groups
-contact with open TB
-recent immigrants from
hyper-endemic areas
PAEDIATRIC TUBERCULOSIS
WISH-LIST
Better diagnostic tests
- differentiate between infection and disease
- global application
- cheap, robust and simple
- monitor success of therapy
Better immunisation
Better treatments
- drugs/regimens
- ? immunotherapy
- ? other
Better delivery of healthcare
PAEDIATRIC TUBERCULOSIS
WISH-LIST
More data; better understanding
Better diagnostic tests
- differentiate between infection and disease
- global application
- cheap, robust and simple
- monitor success of therapy
Better immunisation
Better treatments
- drugs
- ? immunotherapy
- ? other
Better delivery of healthcare