TB Intensive San Antonio, Texas

Transcription

1 TB Intensive San Antonio, Texas November 29-December 2, 2011 Pediatric TB Andrea Cruz, MD, MPH December 2, 2011 Andrea Cruz, MD, MPH has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1

2 An Introduction to Childhood Tuberculosis Andrea T. Cruz, MD/MPH Assistant Professor of Sections of Emergency Medicine & Infectious Disease Objectives To understand the definitions we use for childhood TB To know the common clinical and radiographic manifestations of childhood TB To understand the utility and limitations of available TB diagnostics To map out a plan of care (and know how to get help) for children with TB exposure, infection, and disease Page 3 2

3 Population Distribution World map showing territory size as a proportion of the world s population Page 4 Geography of TB World map showing territory size as a proportion of the world s TB cases found there Page 5 3

4 Famous People with TB JFK* Bronte (x3) Eleanor Roosevelt Fyodor Dostoyevsky Henry David Thoreau Nelson Mandela Ralph Waldo Emerson Simon Bolivar Franz Kafka King Tut John Keats *: possibly Edgar Allan Poe R.L. Stevenson Frederic Chopin Page 6 National Epidemiology: 2010 Data MMWR 2011;60:333 Page 7 4

5 Texas Epidemiology Harris County: cases cases cases cases cases cases 4-5 times the average national incidence Page 8 Definitions we use for TB Category Age Exam PPD/ IGRA CXR Contagious Treatment Exposure < 5 Never 1 drug, usually for 2 3 months (given by health department) Infection All + Never Usually 1 drug, given 6 9 months (given by family or health department) Disease All /+ +/ +/ Rarely Multiple drugs (3 4), given 6 12 months (always givenby health department) Nopatient with nontuberculous mycobacteria is contagious Page 9 5

6 Childhood TB Disease Sites Site* % of cases Median Age (years) Pulmonary Lymphatic Pleural Meningeal Bone/joint Miliary GU Peritoneal *: United States (almost all are normal hosts) Page 10 Risk of Progression from TB Infection to Disease by Age Peds in Review 2010;31:13 Page 11 6

7 Signs and Symptoms of Pulmonary TB Peds in Review 2010;31:13 Page 12 Available Diagnostic Tools Tool Older Generation Newer Generation Radiography CXR CT* Immune response Skin test Interferon assay Specimen Gastric aspirates Induced sputa collection PCR Sputum Other body fluids *CT is not the standard of care for the diagnosis of pulmonary TB, and is not necessary for the vast majority of children with pulmonary TB disease Page 13 7

8 One difference between adults & kids Modality Culture: Solid Adult Studies* Pedi Studies* Ratio adult to pedi Year of 1 st publication x 1967 Culture: x 1966 Liquid MODS x 2000 PPD/TST x 1907 IGRA x 1999 Xpert x 2010 PCR, all x 1990 *: PubMed Queries as of 7/27/11 Page 14 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 Page 15 8

9 Intrathoracic Lymphadenopathy N.O Page 16 Lobar Infiltrates 9mo M presents to TB clinic with 23mm PPD done after grandfather diagnosed with smear positive pulmonary TB. Baby is asymptomatic, normal vital sg signs, s,go growing gwell. Admitted for LP (normal), gastric aspirates (smear negative), started on multidrug therapy for TB disease D.T Page 17 9

10 Collapse/Consolidation Pattern Lymph node collapses a bronchus, leading to distal atelectasis M.A Page 18 Calcifications Usually indicates disease present for 2 6 months W.C Page 19 10

11 Cavitary Lesions W.C Page 20 Cavitary Lesions Uncommon in children, but if see cavities, treat the child as contagious and take appropriate infection control precautions M.N Page 21 11

12 Cavitary Lesion 16yo M with very poorly controlled IDDM 2 months of productive cough, weight loss Smear-positive TB * DM is single most common predisposing medical condition in TX adults with TB disease J.A Int J Tuberc Lung Dis 2011;15:179 Page 22 Miliary Disease P.K Page 23 12

13 2003: 17yo WM with Crohn s, on anti TNFα therapy, negative baseline TST, developed miliary TB after 2 months C.A Page 24 Miliary TB with Tension Pneumothorax D.M Page 25 13

14 Miliary TB in Spleen, Liver D.M Page 26 Pleural Effusions Often, children are very well appearing (vs. Staph empyemas) J.G Page 27 14

15 Tuberculomas W.C At initiation of therapy Page 28 After 2 months of therapy Tuberculous Pericarditis Page 29 15

16 Lymphadenopathy + Scrofuloderma Page 30 Paed Resp Rev 2007;8:107 Comparison: Nontuberculous Mycobacterial lymphadenopathy A.J T.O Page 31 16

17 Cutaneous TB: Lupus vulgaris M.R Page 32 Skeletal TB Page 33 17

18 Pott s Disease J.M. 1/ yo F with 1yr of worsening hunchback (gibbous deformity). T5 destruction. Culture: M. bovis Clin Infect Dis 2005;41:515 Page 34 Immune System Recognition Tuberculin skin tests (PPD) Interferon gamma release assays (IGRA) Page 35 18

19 PPD Placement No controls Need to see a wheal raised Page 36 Positive PPDs Generally, skin test conversion occurs within 2 months of contact Measure only induration, and record millimeters of induration (never record + or ) Any induration seen only in the first 24 hours should be ignored Induration after 72 hours counts; blistering also counts Page 37 19

20 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 Page 38 Who does AAP Recommend Skin Testing? Universal skin testing is NOT recommended Initial PPD should be done before initiation of immunosuppressive therapy (including prolonged steroid usage, TNF-α antagonists) Annual PPDs: HIV+ or incarcerated Q2-3yr testing should be considered: high-risk Immediate PPD should be placed: As part of contact investigation CXR or clinical findings consistent with TB Children emigrating from endemic countries Children with travel history to or contact with persons from endemic countries 2009 Red Book Page 39 20

21 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 2001;107:e54; Red Book 2009 Page 40 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 Page 41 21

22 PPD: Myths surrounding BCG Myth: PPDs will be positive in all patients who received BCG vaccination Reality: R 50% of infants receiving i BCG do not react to skin tests, and most of the rest stop reacting within 5 years Myth: PPDs can be neither placed nor interpreted in BCG recipients Reality: y different cut-off points for the skin test are not recommended based upon a child s BCG status Page 42 So, What Are Alternatives? Since 2005: 2 commercially available blood tests, interferon gamma release assays (IGRA) that offer more specificity than the skin test Page 43 22

23 IGRAs Interferon-γ release assays (IGRAs) detect host response to Mycobacterium tuberculosis-specific antigens Two main tests currently FDAapproved: T-SPOT.TB QuantiFERON Q Gold In-Tube Offer several potential advantages over the tuberculin skin test (TST) MMWR 2010;59(No.RR 5):1 14 Page 44 Comparison of Skin Test & IGRA Characteristic TST IGRA Antigens studied Many -PPD ESAT-6, CFP-10, (TB-7.7) Cross-reactivity with BCG Yes Unlikely Cross-reactivity with NTM Yes Less Likely Estimated sensitivity, TB in 75-90% 75-95% immunocompetent adults Estimated specificity, TB in 70-95% % immunocompetent adults Distinguish between TB infection No No and TB disease Boosting Yes No Patient visits required Two One Page 45 Pediatr Infect Dis J 2006;25:941 23

24 IGRAs: Advantages One visit: optimal if adherence issues Decreased confusion about interpretation: one cutoff irrespective of age, immune status, and TB risk factors Enhanced specificity: optimal for BCG-immunized persons Page 46 IGRA: Limitations Indeterminate results: decrease the utility of a screening tool One cut-off: is this appropriate across risk strata? Unknown dynamics of when assays become positive Discordance: interpretation if TST and IGRA provide different results Limited pediatric data: especially for the most vulnerable risk groups Page 47 24

25 HIV-infected Children Sensitivity plummets with CD4 < 200 Sensitivity: TSPOT > QFN > TST We don t know the dynamics of IGRAs in HIV+ kids No association with QFN result and CD4 (but n=14 with + TST) Page 48 Malnourished Children 251 malnourished children, of whom 47% had helminthic infection (Ascaris, Trichuris) Test agreement: κ = 0.55 between TST and QuantiFERON 25% had indeterminate test results Degree of malnutrition and helminth infection were associated with indeterminate IGRA results 2010;126:e1522 Page 49 25

26 Cancer Center Patients 34 newly diagnosed children with cancer (S. Africa) TST vs. T-SPOT vs. QuantiFERON 7 were (+) with any test (less than expected) IGRAs had 12-15% indeterminate results In 1/5 of cases, TSPOT could not be completed because of low cell counts (controls failed) Multiple discordances: Between TST and both IGRAs Between the IGRAs Conclusion: no stand-alone test helpful in this population Int J Tuberc Lung Dis 2010;14:689 Page 50 Renal Patients Conversions and reversions of IGRAs seen Conversions: 22% and 27% for QFN and T-SPOT Reversions: 16% and 30% for QFN and T-SPOT Most studies suggest QFN is better for this group Indeterminate results range from 3-15% Results can be dramatically different if blood obtained pre- or post-dialysis IGRA should be done pre-dialysis Transpl Infect Dis 2009;11:28 / J Infect 2010;61:144 Page 51 26

27 Diabetics Adult type II diabetics with culture-positive TB* QFN: 70% sensitive T-SPOT: 93% sensitive Seemed to perform as well as TST * DM is single most common predisposing medical condition in TX adults with TB disease Int J Tuberc Lung Dis 2011;15:179 Page 52 TST preferred, IGRA acceptable Children < 5 years of age IGRA preferred, TST acceptable BCG recipients Groups with historically low rates of return for TST reading MMWR 2010;59:RR 5 Page 53 27

28 Either IGRA or TST can be used Contact investigations Surveillance programs for healthcare workers MMWR 2010;59:RR 5 Page 54 Both TST and IGRA should be considered Initial IGRA indeterminate i t or borderline When initial test (TST or IGRA) is negative and: There exists clinical suspicion for TB disease Risk of infection, progression, and poor outcome higher When initial test (TST or IGRA) is positive and: Need additional evidence to increase compliance Healthy persons with low risk for both infection and disease progression MMWR 2010;59:RR 5 Page 55 28

29 What to do with discordant results? In patients in whom disease is suspected or at high risk for progression from infection, treat if any test positive For patients without risk factors, treat if the more specific test is positive Page 56 Case: A.N. (2010) 19mo M presents with fever, altered mentation. No medical history or known contacts with TB. Page 57 29

30 Case: A.N. (2010) CSF WBC RBC Protein Glucose Smear AFB Cx Source EVD 15 17, LP < 20 PPD: 0 mm QuantiFERON: indeterminate T-SPOT: wicked positive Mother s (now former) boyfriend found to have pulmonary TB after contact investigation Page 58 Acid-Fast Culture Yield Specimen Culture Yield Sputum/gastric aspirate 30-40% Lymphatic tissue 75% Pleural fluid 20-40% Cerebrospinal fluid 20-50% Pericardial fluid 0-42% Ascitic fluid 30% Skin biopsy 20-50% Skeletal biopsy 75% Paed Resp Rev 2007;8:107 Page 59 30

31 So, Our Culture Yield is Horrible; Now What? Great contact investigations to identify source cases for our patients (cultures by proxy) Try new methods of obtaining cultures Page 60 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% Page 61 31

32 Induced Sputum Outpatient procedure 2-3h fasting gperiod 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 Page 62 Page 63 Photo courtesy of Paul Mullan, M.D. 32

33 TB Infection Control In the mid-1990s, TCH began to require that adults and adolescents accompanying inpatient children with suspected tuberculosis undergo chest radiography to rule- out infectious pulmonary TB A previous report from TCH [Muñoz et al. Infect Control Hosp Epidemiol 2002;23: ] demonstrated that 15% of the adults accompanying hospitalized children with suspected tuberculosis had previously undiagnosed pulmonary TB Results from this study also showed that no healthcare worker who cared for a child with tuberculosis became infected [conversion of the TST] Infect Control Hosp Epidemiol 2002;23:568 and 2011;32:188 Page 64 When do we worry about it? Older adolescents Children with certain findings on CXR Producing sputum Any draining skin lesions Infect Control Hosp Epidemiol 2011;32:188 Page 65 33

34 If we are worried, what do we do? N95 respirator for you Simple facemask (not N95) for patient Keep patient in room Page 66 History of Drug-Resistant TB Drug Year Introduced Year of 1 st Documented Resistance Streptomycin Isoniazid Pyrazinamide Ethambutol Rifampin Fluoroquinolones Page 67 34

35 Total drugs to treat pan-susceptible TB Page 68 Total drugs to treat 1 case of multidrug-resistant (MDR)* TB *MDR: resistant to at least INH and Rifampin XDR (extensively drug resistant): Page MDR 69 + resistance to fluoroquinolones + injectable agents 35

36 DOTS (directly observed therapy, short course): administration of medications to persons with TB disease by dispassionate 3 rd party Standard d d of care for TB disease in the United States Provided free of charge to patient Removes some barriers to care Increases adherence, thereby decreasing risk of selecting out for drug resistant organisms by sporadic medication usage Photos courtesy of Manish Shah, MD Page 70 Treatment TB exposure TB infection TB disease Page 71 36

37 TB Exposure Children < 5 years of age with a negative PPD, normal CXR and examination exposed to contact with suspected TB Provide chemoprophylaxis in the window period (8-10 weeks) pending repeat skin testing Children > 4 yrs of age also need sequential skin testing, but no window chemoprophylaxis Page 72 Why Do We Do This? To Prevent This: E.Q Page 73 37

38 Why do we treat TB infection? Risk of developing TB disease with untreated + PPD: 5-10% lifetime risk in most patients 40% risk in infants 5-10% annual risk in HIV-infected patients ½ of lifetime risk in 1 st 1-2 yrs after PPD conversion Remainder of risk evenly spread over lifetime We can reduce risk by 90-95% with INH Page 74 Red Book Statement on TB Infection 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 Page 75 38

39 How is LTBI different in children? Risk of disease progression Identifying time of infection Identification of source case Medication tolerance Page 76 Risk of Progression to Disease, Stratified by Patient Age Risk of disease progression in adults: 1 13% lifetime risk in Review 2010;31:13 Page 77 NEJM 2011;364:15 39

40 Pinpointing time of infection Most young children are by definition new converters So, this is best opportunity to prevent future disease: ½ of lifetime risk is in first 1-2 years after TST conversion Risk substantively higher for infants Page 78 Children have circumscribed social networks Often the person who infected the child is a caregiver/relative Easier to identify source case, and child is unlikely to have > 1 source case NEJM 2011;364:730 Page 79 40

41 Medication Tolerance : 5% risk of side effects in children Most minor abdominal pain without elevation in LFTs 3.3% 3% risk of elevated LFTs in 1970s with INH+RIF Adults: 2006;117:e148; 1983;72:491 Page NEJM ;364:15 IJTLD 2010;14:1374 Take home messages: educate families on side effects low threshold for checking LFTs if symptomatic screen for LTBI judiciously 2008;121:e1732 Page 81 41

42 Chest 2010;137:737 Page 82 TB Prevention Isoniazid (INH) = mainstay of therapy mg/kg single daily dose if given by family mg/kg twice weekly if given by health department Duration: 9 months Alternative: rifampin x 6 months If person around child with TB is known to have INH-resistant disease or if child is INH-intolerant Page 83 42

43 LTBI Treatment Pearls Use INH suspension only in children < 5 kg Otherwise, give tablets that can be crushed & mixed with food 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 Page 84 Therapy for TB Disease Start 4-drug therapy (a change from 2006 Red Book) INH, rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB); INH/RIF are the backbone of therapy Use PZA only during 1 st 2 months for susceptible TB This is your shortening agent : consolidate from 9 to 6 months of therapy Stop EMB once culture results known, if have pan-susceptible TB This is your insurance in case you have drug-resistant 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) 2009 Red Book Page 85 43

44 Notes on TB Drugs Drug Side Effects Other notes INH Peripheral neuropathy; seizures in B6 helps prevent neuropathy and is overdose only treatment for INH seizures, but doesn t prevent hepatotoxicity RIF Orange discoloration of secretions; inactivates oral contraceptives; many drug interactions Please warn of Longhorn orange urine! PZA Can increase uric acid gout symptoms; rash Of 1 st line drugs, greatest association with hepatotoxicity EMB Optic neuritis, red green color blindness Despite side effects, has very poor CNS penetrance and not used for meningitis *All primarily hepatically metabolized, except EMB, which is also renally excreted Peds in Review 2010;31:13 Page 86 Conclusions Screen all children for TB risk factors via questionnaire Traditional culture techniques are of much lower yield in children as compared with adults Newer diagnostic assays have recently become available, but are not without their own limitations IGRAs offer improved specificity, not sensitivity, compared to PPDs There is no substitute for a comprehensive history to elicit TB risk factors It is impossible to effectively manage childhood TB without close cooperation with an effective public health infrastructure Page 87 44