Ian KitaiTB Specialist

Division of Infectious DiseasesSickkids

Review � Clinical presentation of TB disease childhood� How to assess risk for TB infection� How to assess risk for disease if infected� TST’s and IGRA’s – benefits� Discuss monitoring during therapy, side

effects and reactions to treatment

� Canadian TB Standards 2007– Google it� Excellent resource especially diagnosis section

excellent summary of literature. � Some of this talk with audio � Webber training course

� www.webbertraining.com/recordingslibraryc4.php� Frances Curry Center –excellent resources, drug

information

World Health Statistics 2008 http://www.who.int/whosis/whostat/2008/en/index.html

1 new case every 3 seconds

1 TB death every 19 seconds

Global statistics as based on smear positive individuals: underestimatepediatric TB

TB in the world

� 7 week old� Aunt visiting from endemic country� Cough – marked� History of TB treatment in past� Taken to walk in clinic, X rayed, “abnormal”

� Mom concerned re exposure of infant� Sees pediatrician

� 11 year old, Born Congo

� Crohns, growth Failure

� Failing Methotrexate

� Being considered for Infliximab

� Evaluation?

� 16 year old

� Volunteer at hospital

� Born Canada moved to Dubai, Lived in Pakistan: Returned 10 years ago. Had BCG at 18 months of age

� No known TB contact

� TST 10mm Normal Chest X ray

1. Close contacts with multibacillary and cavitary disease and cough-ADULTS or ADOLESCENTS

2. Less often: smear negative culture positive patients

� Standard response� Young children (approx <10) do not spread

TB to others� Childhood Tb is paucibacillary� Children do not generate cough to spread TB

Little role for isolation

This message is largely true-BUT there ARE a FEW exceptions which can be anticipated from the clinical circumstances

� Munoz et al- Texas children’s� Screened adult visitors of 59 consecutive

children admitted with TB� Isolation if thought have potential to be

airborne� 8 children required isolation� 16/105 (15%) screened adult visitors --

previously undetected pulmonary TB.

� Risk- mainly from adults accompanying child

� Infect Control Hosp Epidemiol. 2002 10:568-72.

� Very young < 1� Miliary , pulmonary, extrapulmonary, TB

meningitis

� Young child� Primary complex and its complications

� Older child and adolescent� Pulmonary and extrapulmonary– protean.

Overlap

�3 month old�Hx pertussis like cough �Fever�Canadian Born�Unwell

Unwell

Hemophagocytosis

Hepatosplenomegaly

ICU admission

Cavitary disease – infected close contacts.

Age at Primary Infection

Manifestations of Disease

Risk of Disease

(%)< 12 months No disease

Pulmonary disease TB meningitis or miliary disease

5030-40 10-20

12-23 months No disease Pulmonary disease TB meningitis or miliary disease

70-80 10-20 2-5

2-4 years No disease Pulmonary disease TB meningitis or miliary disease

955

0.5 5-10 years No disease

Pulmonary disease TB meningitis or miliary disease

982

< 0.5 > 10 years No disease

Pulmonary disease TB meningitis or miliary disease

80-90 10-20 < 0.5

Marais BJ, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis2004;8(4):392-402.

� 7 week old� Aunt visiting from endemic country� Cough – marked� History of TB treatment in past� Taken to walk in clinic, X rayed, “abnormal”

� Mom concerned re exposure of infant� Sees pediatrician

� Referred to TB clinic� Physical exam normal� Chest X ray normal� TB skin test 0mm at 48 hours� What to do next??

� GET SOURCE CASE DETAILS� Xray- extensive upper lobe disease� Positive skin test� No sputum sent

Public health – in clinic – notifiedhome follow upAunt- sputum smear numerous, AMTD positiveWhat next?

� “Window prophylaxis”� INH (10mg/kg/day) – in young infants use

12-15 mg/kg to allow for rapid growth and adjust monthly based on weight

� Available as suspension� Pyridoxine in breastfed- 1-2mg/kg/day is

plenty(crushed tabs)What follow up?

� High risk of drug resistance� Need to get source case sensitivities� Turnaround typically 1-2 weeks for culture� 2-3 weeks or sensitivities

� INH resistant--?� INH and rifampin resistant?

� Rapid progression to TB disease� Often disseminated � May be miliary, TB meningitisTB EXPOSURES: � The younger child the more urgent the need for prophylaxis.

X ray and PPD – all childrenPPD negative: clinically wellPreventive Rx to all < 5 (varies)

Repeat TST 10 weeks (8-12 weeks) after “break in contact”

D/c Rx if repeat –ve. Infant<6months –treat until age 6 monthsAnd ppd negative

PPD positive: Rule out disease

If clinically well, Normal chest X rayPreventive Rx

INH sensitive: INH 10-15mg/kg/d for 9 monthsPyridoxine 1-2mg/kg. Adults 25-50mg/kg

� INH resistant contacts: Refer if possible� EXCLUDE DISEASE!!� Rifampin 10mg/kg/day until proven negative� If LTBI --for 4 to 6 months� No RCT but theoretically better drug than INH

� MultiDrug resistant contacts– no data, need referral/discussion.

� A few bacilli� Sequestered somewhere� Undetectable clinically� Able to reactivate� Vey cunning strategy to sustain an epidemic

over centuries.

EXPOSUREChild exposed to bacilli from

adult or adolescent

No infection Primarycomplex

Miliary TB

TBmeningitis

Heals -- latentinfection

Progresses

More

common

in the

young child

0%

20%

40%

60%

80%

100%

%

0-4 4-12 13-17

Age

ONTARIO TB: SITES OF DISEASE BY AGE

Both

Extrapulmonary

Pulmonary

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

< 12 months 12-23mo 2-4 5-10

precX natural history

Meningitis/Miliary

Pulmonary

No disease

� 1st Step to disease

� Lifetime risk of developing TB 1:10-1:20

� Prevent TB by reducing pool of infectious adults who transmit to the next generation

� Young children , immunocompromised, at high risk of rapid progression to severe disease

� Approximately 10% Lifetime risk of developing disease.

UPHS trial 1957

� Most disease (about 40%) occurs within first 2 years of infection

� Several factors increase risk of disease.

� Well patient- asymptomatic� Poor tests� No gold standards� Outcome if not treated usually curable� Sequelae/fatalities especially in young and

immunocompromised� Rare but serious toxicity of treatment

� How likely is the child to have been infected? �Close contact

� Endemic country

� What might happen if the patient really is infected?� Immunocompromised

� HIV infection

� Renal failure

� Diabetes – 2 fold risk but very prevelant risk factor

� Young age

� AIDS 110–170x

� HIV infection 50–110x

� Transplantation 20–74x

� CRF hemodialysis 10–15x

� Recent TB infection (<2yrs) 15x

� Age<6 months ?

Risk� Rx with glucocorticoids 4.9x� TNF-alpha inhibitors 1.5–4x� Diabetes mellitus (all types) 2.0–3.6x� Underweight (90% <IBW); 2.0-3x� Age < 4 2.2–5.0x� Abnormal CxR– granuloma 2x

� Treatment is for the patient’s benefit. � Patient needs to understand the risks,

benefits and intention of treatment� In their own language. � And accept treatmentYoung infants with significant exposures or LTBI may be exception

� If for the public good- where’s the no fault compensation and legislation?

� TST: 200 antigens� Developed early 20th century� Administered intradermally� Requires reading at timed intervals� Inter and intraobserver variability� For standardisation see Canadian TB

Standards� http://www.phac-aspc.gc.ca/tbpc-

latb/pubs/pdf/tbstand07_e.pdf page 55

�Induration > 5 mm� Close contact with infectious TB

� Suspected TB disease

� immunosuppressive Rx immunocompromised (including HIV)

�Induration > 10 mm (including BCG)� increased risk of disseminated disease

� < 4 years of age� medical risk factors: malnutrition, malignancy…

� increased environmental TB exposure� Child/parents born in high prevalence area� travel to high prevalence area� Adult contact is HIV positive/ homeless/ IVDU/

institutionalized

� False negatives: � very young children, � Immunocompromised� malnutrition, concurrent chronic medical

conditions, � other viral and parasitic infections.

� Sensitivity in active and or disseminated TB –only 77% recent meta-analysis.

- Deil CHEST 22010: 137: 9952-968

� Unknown: PPV a real problem for low risk populations

� Size matters (>20mm more significant than >10mm)

� BCG given at birth: most lose reactivity by 10 years BBUT great variability� different BCG strains, � Influence of environmental mycobacteria

BCG in later life: approx 25% positive for lifePositive second step tests correlate with BCG better

than with disease states

� Variable sensitivity in immunocompromisedpatients and in active disease

� Poor/variable specificity in BCG vaccinated populations

� Poor standardization� Inter and intra-observer variability� Need for a return visit within 48-72hrs for

interpretation

.....Reluctance to look for and screen for LTBI

� Validated as marker for progression to active disease

� USPHS trials from 1957 � showed about 5-10% risk of developing TB disease

over a lifetime in TST positive� (and marked reduction in risk with 6-12 months

INH)

� Controlled chemoprophylaxis trials in tuberculosis. A general review.Ferebee SH - Bibl Tuberc - 01-JAN-1970; 26: 28-106

�measure the in vitro production of interferon gamma by sensitized lymphocytes in response to MM. TB specific antigens.

�Antigens USED DO NOT OCCUR not in BCG or in the majority of non-tuberculousmycobacteria.

�No gold standard for latent TB infection – aactive disease used as a surrogate when quantifying specificity

�IGRA specificity (93-99%) consistently >> TST (60%) in BCG vaccinated populations

�IGRA correlates better with gradients of exposure to infectious source cases that the TST in low incidence settings

�A positive IGRA may be indicative of TB infection– however “low level”positives that revert and convert are described and are of uncertain significance

� Sensitivity of the IGRA is variable across studies, high vs. low incidence settings, pediatric vs. adult data, active vs. LTBI

� In active TB, the sensitivity of the IGRA 75-90% (QFT less sensitive than T-SPOT TB)

� In clinical LTBI, overall agreement between TST and IGRA in children is 55-95%, Majority of discordant values TST+/IGRA-

� To date no longitudinal studies on the predictive value of a negative IGRA on children who do not receive chemoprophylaxis as a result.� A negative IGRA does not rule out TB disease� Many reports of IGRA’s failing to detect TB in

children and adults � Very Limited data in children<5: Redbook- don’t

use <5 but can use >5 in most situations where TST is used.

� Few data� No longitudinal data� Reasonable agreement with TST� Less influenced by BCG� Sensitivity--?� Seem fairly specific� Low level positives may be false positives

� In children may be used in addition to TST to support diagnosis of infection which is sometimes used to help support diagnosis of disease. Does NOT take the place of collection of clinical specimens.

� May increase sensitivity in immunocompromised when combined with the TST: T spot better than QFT

� Confirmatory rule out test for patients not thought to be at high risk for TB infection.

� Research tool for population surveys

� Not recommended for staff , immigration screening.– but this is under review

� Alberta PHL does them� Ontario- not routine� Commercial Laboratory: 2 sites; $90 per test

� 2 year old

� Mother found to have smear positive cavitarydisease

� Well child N CxR

USE TST AND IGRA (if available). Any positive=positiveand needs treatment for LTBI. Repeat TST +IGRA

8-12 weeks after break in contact

�

� 16 year old � Volunteer at hospital� Born Dubai, Lived in Pakistan: Immigrated 10

years ago. Had BCG� No known TB contact

� TST 10mm Normal Chest X ray

� Low risk. May use negative IGRA to help decide against prophylaxis.

� 11 year old� Crohns, Growth Failure� Failing Metotrexate, NSAID’s� Being considered for Infliximab

� Evaluation?

� Immunocompromised and at high risk� USE TST AND IGRA. Any positive=positive and

needs treatment for LTBI.

� Interferes with mycolic acid production� Keep at room temperature� Fatty meal- 50% less absorption� Penetrates well into inflamed meninges� B6 important in adults� S/E Hepatic, CNS, Peripheral neuropathy. � Validated in RCFT’s to prevent TB disease in

infected. 9 months standard Rx -80%+protection

� Inform patient of S/E and to D/C if Anorexia, Nausea, Jaundice, Abdominal Pain, Vomiting.

� Provide contact numbers and plan� See monthly� Ask about side effects

Routine LFT’s not considered necessary but do if ANY S/E

Is this enough?

� Case10 FemaleLTBI – CLOSE CONTACT 12 MM MANTOUXNormal Baseline LFT’sOn INH for 7 monthsSeen monthlyDiscussion of side effects and what to do x32 weeks after last clinic visit c/o pain and vomitingThought – to be wanting to avoid school

� Continued to c/pain� Presented jaundiced Very lively and active� No hepatic tenderness� HIGH bilirubin. � AST 3000’s ALT 3000� INR 1.6� Admitted…. Listed for liver transplant� Ultimately recovered� A VERY near miss

� All US pediatric transplant centers 1987-1997

� 20 cases severe liver disease� 4 recovered� 6 died awaiting OLT� 10 transplanted

� Estimated incidence 3.2/100 000 INH courses� 14% of drug induced liver disease needing Tx

� Wu Transplantation 2007

4 year old no risk factors

Kindergarten entry—tested

INH Information sheet. Well at 3 weeks

10 weeks- vomiting, thought to have stomach flu

11 weeks—jaundice, AST 4200, Liver transplant

� MMWR� State health departments� about 200 000 patients start therpy per year� 17 cases 2-9 months after initiating therapy� Most followed according to guidelines� 5 transplants� 5deaths (1Tx)� 8 recovered� Taking INH while symptomatic– risk factor

What are the public health implications for public health practice?

� Patients receiving INH therapy for LTBI should be told categorically by medical providers to stop taking their medication immediately if they have symptoms such as nausea, vomiting, abdominal discomfort, or unexplained fatigue and to contact their providers for further evaluation.

Your child has been prescribed a drug called Isoniazid to prevent Tuberculosis disease from developing. This medicine usually has few or no side effects. Very rarely the medicine can affect the liver. If this occurs your child may:�Vomit�Complain of tummy ache�Not want to eat�Feel very tired�Become yellow around the white part of the eyes

If these symptoms or signs occur STOP GIVING THE MEDICINE and call us. Patricia Malloy can be reached at 416 813 8273 and the clinic nurse can be reached at 416 813 6609. Otherwise call 416 813 7500 and ask to speak to the infectious diseases fellow on call. Don’t start the medicine again until the child has been checked.

1. Children generally acquire TB from adolescents and adults. Most children are not infectious to others

2. Risks of and presentation of TB disease changes with age.

3. The younger child the more urgent the need for evaluation and prophylaxis

4. Extrapulmonary disease is common in children and adolescents in Canada and North America

5. INH toxicity is rare but can be fatal. Counsel patients carefully and accurately in patient’s language. Always monitor according to guidelines. D/C if any side effects

Public Health gives all/ almost all the info!� Source case: Smear and culture results� PHL specimen # helpful .� Update sensitivities when they become

available� Break in contact date NBB.

� Local epidemiology helpful- how many contacts are positive and # tested

� Ongoing smear results from index case:� Break in Contact

Use smear negative plus 2 weeks.