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Pediatric Tuberculosis Update J. Podgore ,DO, MPH Department of Pediatrics TCOM Dec. 19,20012 TUBERCULOSIS... The greatest killer of all time... The captain of all these men of death... ...during this century and the last, one billion people have died from tuberculosis Tuberculosis A Global Emergency • One third of the world’s population is infected • TB kills 5,000 people a day – 2-3 million each year • HIV and TB co-infection is producing explosive epidemics • Hundreds of thousands of children will become TB orphans this year • MDR threatens global TB control Leading Infectious Disease Causes of Death, 1998 3.5 2.3 2.2 1.5 1.1 WHO Report 2000 0.9 TB in USA Summary of Epidemiology of TB • Cases and case rates are on the decline • Foreign born persons account for more than 50% of U.S. cases • TB in children: – Highest risk for disease: • <5 years of age • Foreign born children – 60% of cases develop within 18 months of arrival in U.S. – Varies depending on immigration patterns, i.e., recent increases in cases among children from Sub-Saharan Africa, Asia, and the MiddleEast • Racial and ethnic minorities TB Life-Cycle TB Pathogenesis PRIMARY Infection: Lympho-hematogenous spread • 8-14 weeks after onset of TB • usually occult • Mantoux positive during this phase • body wide seeding occurs during this phase – bone, kidney, meninges etc. – 3% of children with nl CXR’s develop calcifications in lung apices (SIMON FOCI) Risk factors : infection to disease HIV Malnutrition Recent exposure Young age Short incubation period More severe Highest risk More difficult to diagnose Host factors Effect of HIV? Mantoux Tuberculin Skin Test • Specificity of the test varies depending on the prevalence of LTBI and the frequency of cross-reactions to the PPD antigen in a given population • In a population with relatively high frequency cross-reactions the specificity of the PPD is <95% – Decreases the positive predictive value of positive test in a low risk population – If the specificity is 90% in a low risk population with a prevalence of LTBI of 1%: • Positive predictive value of TST: 8% • 92% of positives are false positives – As prevalence of LTBI increases the PPV increases Huebner RE. Clin Infect Dis 1993;17:968 Purified Protein Derivative (PPD) test • Aka tuberculin sensitivity test (TST), Mantoux test, TB skin test – First described by Robert Koch in 1890 – Test further developed and refined by Charles Mantoux in 1907 • Purified protein extracts from M TB cultures are injected into skin • Immune T cells that have been sensitized to TB from prior infection migrate to the injection site • Release chemicals that produce local inflammation and induration (bumpy reaction) • After initial infection, it takes 2-10 wks (median 3-4 wks) to develop hypersensitivity to the PPD test. • At best, PPD is ~90% sensitive, ~90% specific Positive PPDs Generally, skin test conversion occurs within 2 months of contact Measure only induration, and record millimeters of induration Any induration seen only in the first 24 hours should be ignored Induration after 72 hours counts; blistering also counts What is a Positive PPD? • ≥ 5 mm: – HIV+ or other immunocompromise – Contact with suspected source case – Suspected TB disease • ≥ 10 mm: – – – – Immigrants from high-prevalence areas Children under 4 years of age Children exposed to adults in high-risk categories Other immunocompromising conditions • ≥ 15 mm: – anyone, even without risk factors 2009 Red Book BCG and TST (2) • Review of studies that compared TST responses to BCG during and after infancy • Vaccination during infancy estimated to cause false-positive TST in 6.3% overall, but only 1% of those tested more than 10 years after vaccination • Vaccination at 2 years of age or older estimated to cause false-positive TST in 40% of persons overall, 20% of those tested 10 years or more after vaccination Farhat M et al, Int J Tuberc Lung Dis 2006; 10: 1192-204 TB and BCG Vaccination • Efficacy for adult pulmonary TB 0-80% in randomized clinical trials • Best efficacy against serious childhood disease – 64% protection against TB meningitis – 78% protection effect against disseminated TB • BCG important for young children, inadequate as single strategy Colditz GA et al. JAMA 1994; 271: 698-702. PPD Limitations False positives: • Exposure to mycobacteria other than TB • BCG vaccine False negatives: • Corticosteroid usage • Other immunocompromise • Viral suppression: measles, mumps, influenza • Inter-observer variability • Sliding scale for what is considered positive can be confusing • Until very recently, lack of any confirmatory tests Factors causing decreased ability to respond to tuberculin • Factors related to the person being tested – Infections • Viral (measles, mumps, chickenpox) • Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB, • Fungal (South American blastomycosis) – Live virus vaccinations (MMR) – Metabolic derangements (chronic renal failure) – Nutritional factors (severe protein depletion) – Diseases affecting lymphid organs (Hodgkin’s lymphoma, chronic lymphocytic leukemia, sarcoidosis) – Drugs (corticosteroids, other immunosuppressive agents) – Age (newborn, elderly) – Recent overwhelming infection with M. tuberculosis – Stress (surgery, burns, mental illness, graft versus host reactions) • • • Factors related to the tuberculin used Factors related to the method of administration Factors related to reading the test and recording results Another TB screening test: the IGRA • Interferon gamma release assay – Quantiferon TB Gold most well-known • Uses specific M TB antigens to stimulate primed T cells • They release inflammatory protein: interferon gamma • IGRA antigens are more specific to M TB, not shared with NTM or BCG vaccine – Not enough data for use in children <4yrs old – Have replaced PPDs in some institutions/clinics, $$ • Requires blood sample, processing of live immune cells • Need <24 hr delivery to reference lab • Call before drawing blood sample to make sure it will get there on time Why Measure Interferon-? • • • • • • TB infection induces T-cell response (CMI) IFN- is the ‘classic’ CMI cytokine Produced in vitro in response to specific antigen Secreted in measurable and stable amounts Absent from normal circulation Extensive literature showing importance of IFN- in TB infection In Vivo and In Vitro Diagnostic Tests Presentation of mycobacterial antigens IFN- TNF- IL-8, etc. IFN- Antigen presenting cell Memory T-cell Andersen P, et al. Lancet 2000;356:1099 TNF- IL-8, etc. Interferon Gamma Release Assay o TB specific antigens: Genes in region of difference (RD1) on TB genome Culture filtrate protein 10 (CFP-10) Early secretory antigen target 6 (ESAT-6) TB-7.7 o Requires: single medical visit blood collection laboratory equipment and personnel o Results in 24-48 hrs o 2 tests: Quantiferon; T-SPOT Whole Blood IFN- Assay QuantiFERON-TB Test Stage 1 Whole Blood Culture Nil ESAT-6 CFP 10Mitogen Control Control Aliquot blood & add antigen Draw blood + heparin Stage 2 IFN-gamma ELISA Incubate → INF- from sensitized Tcells COLOR TMB Harvest plasma from above settled cells Measure [ IFN- ] in ‘Sandwich’ ELISA Computerized interpretation Cellestis T-Spot.TB: “Six easy Steps” Nil Control Infection Infection Positive Control Oxford Immunotec The IGRAs QuantiFERON®-TB Gold Test Method Advantages and Disadvantages • Advantages: – Only one visit required – Objective and reproducible; not operator-dependent – No cross reactivity with BCG, little cross-reactivity with non-tuberculous mycobacteria – Controls for low or no immune response – No chance of ulceration due to brisk skin test reaction • Disadvantages: – Blood must be received in lab within 12 hours – Labor intensive for the lab – Not much data for some patient groups IGRAs: Summary (2) • IGRAs represent an exciting new opportunity to learn more about a very old disease • IGRAs are not perfect tests, so clinicians need to be aware of their limitations • Can we replace the TST? – Not yet! Treatment of Latent Tuberculosis Infection in Children • INH 10 mg/kg (max., 300 mg) PO daily for 270 doses • Alternative: Twice weekly directly observed (DOT) INH 20-40 mg/kg (max., 900 mg) PO for 72 doses • Monitor index case isolate sensitivities • Hepatotoxicity from INH is rare in children: – A monthly assessment for clinical evidence of hepatotoxicity should be made: loss of appetite or weight, nausea, vomiting, abdominal pain, jaundice – Routine monitoring of LFTs is not indicated New 12 Dose Regimen Evaluation of the Child with a Positive TST • Evaluation of all children with a positive TST should include: – A careful history • Household investigation – Physical examination – Chest radiographs (PA & lateral) Childhood TB diagnosed by: Combination of : Contact with infectious adult case Symptoms and signs Positive tuberculin skin test Suspicious CXR Bacteriological confirmation Serology Symptom-based Criteria* Pulmonary Disease • Persistent cough x ≥ 2 weeks • Failure to thrive x 3m • Fatigue • Sensitivity: 82% • Specificity: 90% • In HIV(-) children > 3 yrs old Lymphadenopathy • > 4 wks of adenopathy • > 2 x 2 cm • No response to antibiotics • Sensitivity: 89% • Specificity: 98% • In HIV(-) children > 1 yr old Pediatrics 2006;118:e1350 *: all performed in TB endemic regions Pediatr Infect Dis J 2006;25:142 CXR Findings in Pediatric TB • Hilar or mediastinal adenopathy • Segmental/lobar infiltrates • Calcifications (seen in 75-80% of children with pulmonary TB) • Miliary disease • Pleural effusions • 15% of patients with TB disease will have normal CXRs Common Pediatric Finding in TB CXR vs. CT • How to interpret a newer technology that is more sensitive, but less specific than the gold standard? • Not routinely recommended, but may be helpful in immunocompromised patients • Difficult to know the significance of findings that are only apparent on CT So, your pediatric patient has active TB (+PPD and +CXR) • We need to find the bugs – Establish definitive diagnosis-a challenge in pediatric TB – Obtain drug sensitivities from M TB culture • Sputum AFB smear and culture is the gold standard – Children <8yrs don’t do sputum very well – Often sputum smear and culture negative: low bacterial burden • Gastric aspirates: they cough up the TB bacilli, then swallow them into the stomach – Perform every morning for 3 days-need admission – Alternative: bronchoalveolar lavage (BAL) – Isolation in negative-pressure room with Airborne TB precautions (fitted N95 mask) – Isolation during BAL , induced sputum, gastric aspirate procedures • Exception: children <10yrs with non-cavitary disease and negative sputum smears (Red Book 2009 p 697-8) PCR for Childhood TB • Primary use in adults has been for determining if patients with positive acid-fast smears have TB or environmental mycobacteria • Limited utility in children – Much decreased sensitivity in extrapulmonary TB cases • A negative test does not exclude TB • As false positive tests can be seen due to laboratory contamination, a positive assay alone should not call off the search for alternative diagnoses (especially if the story doesn’t fit with TB) Clin Infect Dis 2009;49:46 Specimen Collection Induced Sputum: Gastric Aspirates: Outpatient procedure Inpatient procedure 2-3h fasting period Overnight fasting Lavage with NS if volume < 20cc Pretreated with salmeterol; nebulized saline, then CPT given Nasopharynx suctioned Generally done qAM x3 Inpatient costs substantial AFB smear yield: minimal AFB Culture yield: 20-30% One specimen sufficient Minimal costs AFB smear yield: 50% AFB Culture yield: 25-30% Lancet. 2005;365:130 Gastric Aspirates • Inpatient procedure • Overnight fasting • Lavage with NS if volume < 20cc • • • • Generally done qAM x3 Inpatient costs substantial AFB smear yield: minimal AFB Culture yield: 20-30% Sputum collection in young children by nebulization procedure Induced Sputum • Outpatient procedure • 2-3h fasting period • Pretreated with salmeterol; nebulized saline, then CPT given • Nasopharynx suctioned • • • • One specimen sufficient Minimal costs AFB smear yield: 50% AFB Culture yield: 25-30% Lancet. 2005;365:130 Microscopic-observation drugsusceptibilty assay Traditional MODS 6-8 weeks 7-10 days Cost per specimen High $3 Separate step for identifying species? Separate step for susceptibility testing? Feasible in developing countries? Yes No Yes No No Yes Total Time Field Trial of Rapid Xpert System Xpert compared to microscpy Therapy for TB Disease • Start 4-drug therapy (a change from 2006 Red Book) – INH, rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) • Use PZA only during 1st 2 months for susceptible TB • Stop EMB once culture results known, if have pan-susceptible TB • Anticipate minimum 6 month therapy, and we often extend it to longer periods, especially for extrapulmonary disease • Always administered by directly observed therapy (DOT) XDR-TB Outbreak S Africa History of Drug-Resistant TB Streptomycin 1944 Year, 1st Documented Resistance 1948 Isoniazid 1952 1952 Pyrazinamide 1952 1964 Ethambutol 1960 1965 Rifampin 1966 1968 Fluoroquinolones 1988 1992 Drug Year Introduced Multi-Drug Resistant TB Worldwide Multiple Drug Resistant Tuberculosis Treatment of MDR-TB in Children Conclusions • Screen all children for TB risk factors via questionnaire • Children with risk factors should be evaluated by either PPD or IGRA – Immunocompetent children > 4 years old can have IGRAs performed • IGRAs offer improved specificity, not sensitivity, compared to PPDs • Children < 4 years old are at high risk for progressing from TB exposure to disease, and therefore need prophylaxis in window period • Children with TB infection should receive a course of therapy to prevent future disease • Children with TB disease need multidrug therapy coordinated by an infectious disease specialist through the health department to ensure adherence and decrease the risk of developing drug-resistant TB Summary and Pearls • Clinical manifestations in pediatric TB may be non-specific • TB is much more difficult to diagnose in children • Undiagnosed or untreated TB in a child is potentially serious, – More likely to develop severe or disseminated disease • Diagnosis of TB in a child is a sentinel event – Contact investigation is critical • Knowing how to administer and read PPDs, and to contextually interpret PPDs and CXRs is vital • Our low-prevalence status in ND does not let us off the hook • We are less experienced than other states because of low volume of cases Drugs for MDR TB in Pediatrics Targeted Tuberculin Testing Risk-Assessment Questionnaire • Was your child born outside the United States? – Africa, Asia, Eastern Europe, Latin America • Has your child traveled outside the United States? >1 week • Has your child been exposed to anyone with TB disease? TB or LTBI, nature of contact • Does your child have close contact with a person who has a positive TB skin test? Pediatrics 2004;114:1175, supplement AAP Recommendations: Tuberculin Skin Testing • Children for whom immediate TST is indicated: – Contacts of persons with confirmed or suspected infectious tuberculosis (contact investigation) – Children with CXR or clinical findings suggesting TB – Children immigrating from endemic countries (e.g., Asia, Middle East, Africa, Latin America) – Children with histories of travel to endemic countries and/or significant contact with indigenous persons from such countries Red Book AAP Recommendations: Tuberculin Skin Testing • Children who should be considered for TST at 4-6 and 11-16 years of age: – Children whose parents immigrated (with unknown TST status) from regions of the world with high prevalence of tuberculosis – Children with continued potential exposure by travel to endemic areas and/or household contact with persons from endemic areas (with unknown TST status) Validated Questions to Determine LTBI Risk • • • • Has a relative or contact had TB disease? Has a family member had a positive TB skin test? Was the child born in a high-risk country? Has your child traveled to a high-risk country for > 1 week? • Should consider screening for risk factors at the initial visit and every 6 months thereafter in first 2 years of life Pediatrics 2001;107:e54; Red Book 2009 What Does an Indeterminate Mean? • Indeterminate can occur as a result of low mitogen response (due to patient immunocompromise, poor specimen handling or storage, lab error, etc.) or high nil response (due to patient illness, recent vaccinations, etc.) • Estimated rate of indeterminates for QGT-G: approximately 1-2% among HCW, about 5-10% among patients • Upon retesting, approximately ½ of the indeterminates come out with a definitive result (unpublished data) • Retesting indeterminates once, and if indeterminate again, stop • Indeterminate rate much higher among children What Does the Red Book Say? • “The correct interpretation of a negative IGRA test result in a child with a positive PPD result remains challenging because of the current absence of longitudinal studies.” • “At this time, neither an IGRA nor the PPD can be considered a ‘gold standard’ for diagnosis of LTBI.” Red Book 2009, p687 Conclusions • Screen all children for TB risk factors via questionnaire • Children with risk factors should be evaluated by either PPD or IGRA – Immunocompetent children > 4 years old can have IGRAs performed • IGRAs offer improved specificity, not sensitivity, compared to PPDs • Children < 4 years old are at high risk for progressing from TB exposure to disease, and therefore need prophylaxis in window period • Children with TB infection should receive a course of therapy to prevent future disease • Children with TB disease need multidrug therapy coordinated by an infectious disease specialist through the health department to ensure adherence and decrease the risk of developing drug-resistant TB Red Book Statement on LTBI • “All infants, children, and adolescents who have a positive PPD result but no evidence of TB disease and who have never received antituberculosis therapy should be considered for INH unless resistance to INH is suspected or a specific contraindication exists” Red Book 2009, p691 LTBI Treatment Pearls • Use INH suspension only in children < 5 kg • Compliance with 9 months of INH averages a bit over 50%; be skeptical • Use health department to administer medications to high-risk patients: infants, immunocompromised children, recent contacts • When children aren’t tolerating INH, the problem is more often with the parent than the child • Routine LFTs not indicated unless: concomitant administration of other hepatotoxic drugs; pre-existing liver disease; or signs/symptoms of hepatitis Tuberculosis A Global Emergency • One third of the world’s population is infected • TB kills 5,000 people a day – 2-3 million each year • HIV and TB co-infection is producing explosive epidemics • Hundreds of thousands of children will become TB orphans this year • MDR threatens global TB control Notes on TB Drugs* Side Effects INH Peripheral neuropathy; seizures in overdose RIF Orange discoloration of secretions; inactivates oral contraceptives; many drug interactions Can increase uric acid gout symptoms; rash Optic neuritis, red-green color blindness PZA EMB *All primarily hepatically metabolized, except EMB, which is also renally excreted Positive TST Results: Infants, Children, and Adolescents • TST considered positive at >5 mm induration when: – In close contact with known or suspected contagious cases of tuberculosis – Suspected to have tuberculosis disease: • CXR consistent with active or previously active tuberculosis • Clinical evidence of tuberculosis – Receiving immunosuppressive therapy – With immunosuppressive conditions – With HIV infection Treatment Required Tuberculosis in Children Pediatric TB Algorithm Treatment of TB BCG and TST (1) • General teaching is that reactivity from BCG wanes after a few years and is unlikely to persist > 10 years, but may be boosted by PPD. • Study done in Switzerland* suggests that false positives due to BCG may be much more common than we thought: – 40% of 5000 HCW had positive TST – Prior BCG strongest risk factor for positive TST among those less than age 40 with TSTs <18 mm (was not as strong a risk factor for those > 40 years old and those with TSTs > 20 mm) *CID 2005; 40:211 – 217. QuantiFERON® (QFT) History • First generation (QuantiFERON ® – TB) test FDAapproved in 2001 • 2003 CDC guidelines advise use of test in selected groups only • Second generation test (QuantiFERON® - TB Gold) FDA-approved March 2005 • CDC guidelines December 2005* allow use of QuantiFERON® - TB Gold (QFT-G) in any situation in which a TST would be used; however, points out lack of data in many groups (pediatrics, immunocompromised, etc.) *MMWR 2005, 54 (RR-15): 49-55 TB Epidemiology: US • As of 2009, TB rates have dropped significantly in the US • TB cases with HIV co infection dropped to ~10% • Total ~12,000 TB cases, down 11.4% from 2008 rate, across all age and racial groups. • Foreign-born and racial/ethnic minorities rates still higher – 11x in foreign-born compared to US-born – Compared to Caucasians, 8x higher in Hispanics and Blacks, 26x in Asians – ~5x higher in Native Americans • Children <15 yrs: 6% of 2008 TB cases MMWR March 19, 2010 AAP Recommendations: Tuberculin Skin Testing • Children for whom immediate TST is indicated: – Contacts of persons with confirmed or suspected infectious tuberculosis (contact investigation) – Children with CXR or clinical findings suggesting TB – Children immigrating from endemic countries (e.g., Asia, Middle East, Africa, Latin America) – Children with histories of travel to endemic countries and/or significant contact with indigenous persons from such countries Red Book Childhood TB • Why neglected? – Not considered important in global program or contributing to immediate transmission – Not regarded as public health risk – Difficult to diagnose • Why is it important? – Health problem in children – May later contribute to epidemic Newer Regimens (NOT Yet AAP Recommended) • 3 months of INH + Rifampin • 4 months of Rifampin • 3 months of INH + weekly Rifapentine Advantages: • Improved adherence • More effective if have high rates of INH resistance in the community • Cost effective Pediatrics 2009;123:816 Clin Infect Dis 2007;45:715 Semin Resp Crit Care Med 2008;29:532