Ian Kitai TB Specialist Division of Infectious Diseases Sickkids
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
TB in the world 1 new case every 3 seconds 1 TB death every 19 seconds Global statistics as based on smear positive individuals: underestimate pediatric TB World Health Statistics 2008 http://www.who.int/whosis/whostat/2008/en/index.html
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 Overlap Older child and adolescent Pulmonary and extrapulmonary protean.
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 50 30-40 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 95 5 0.5 5-10 years No disease Pulmonary disease TB meningitis or miliary disease 98 2 < 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 Dis 2004;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 notified home follow up Aunt- sputum smear numerous, AMTD positive What 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 meningitis TB EXPOSURES: The younger child the more urgent the need for prophylaxis.
X ray and PPD all children PPD negative: clinically well Preventive 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 months And ppd negative
PPD positive: Rule out disease If clinically well, Normal chest X ray Preventive Rx INH sensitive: INH 10-15mg/kg/d for 9 months Pyridoxine 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.
EXPOSURE Child exposed to bacilli from adult or adolescent More TB meningitis common in the No infection Primary complex Miliary TB young child Heals -- latent infection Progresses
ONTARIO TB: SITES OF DISEASE BY AGE 100% 80% % 60% 40% 20% 0% 0-4 4-12 13-17 Both Extrapulmonary Pulmonary Age
precx natural history 100% 90% 80% 70% 60% 50% 40% Meningitis/Miliary Pulmonary No disease 30% 20% 10% 0% < 12 months 12-23mo 2-4 5-10
1 st 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 treatment Young 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 20 th century Administered intradermally Requires reading at timed intervals Inter and intraobserver variability For standardisation see Canadian TB Standards http://www.phac-aspc.gc.ca/tbpclatb/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 2010: 137: 952-968
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 BUT great variability different BCG strains, Influence of environmental mycobacteria BCG in later life: approx 25% positive for life Positive second step tests correlate with BCG better than with disease states
Variable sensitivity in immunocompromised patients 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 M. TB specific antigens. Antigens USED DO NOT OCCUR not in BCG or in the majority of non-tuberculous mycobacteria.
No gold standard for latent TB infection active 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 cavitary disease Well child N CxR USE TST AND IGRA (if available). Any positive=positive and 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?
Case 10 Female LTBI CLOSE CONTACT 12 MM MANTOUX Normal Baseline LFT s On INH for 7 months Seen monthly Discussion of side effects and what to do x3 2 weeks after last clinic visit c/o pain and vomiting Thought 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.