TB Nurse Case Management

TB Nurse Case Management San Antonio, Texas March 2-4, 2011 Pediatric TB Andrea T. Cruz, MD, MPH March 2, 2011 Andrea Cruz, MD, MPH has the following disclosures to make: No conflict of interests No relevant financial relationships with No relevant financial relationships with any commercial companies pertaining to this educational activity 1

TUBERCULOSIS IN CHILDREN Andrea T. Cruz, MD/MPH Assistant Professor of Pediatrics Baylor College of Medicine Houston, Texas Tuberculosis is a social disease with medical implications. 2

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THE GREAT PARADOX OF TUBERCULOSIS A CAUTIONARY TALE By the use of drugs and BCG vaccines, we can Cure tuberculosis disease [for less than 75 dollars] Prevent progression of tuberculosis infection into disease Prevent a significant proportion of life-threatening childhood tuberculosis [by BCG vaccination] Yet tuberculosis remains one of the three greatest Yet, tuberculosis remains one of the three greatest infectious disease menaces for humans, and our inability to control it is our biggest public health failure. 4

Definitions TB exposure: a young child (< 4 y.o.) with a negative PPD or interferon gamma release assay (IGRA), negative CXR, and normal exam who has been in contact with an adult with contagious TB (Latent) TB infection (LTBI): positive TST or IGRA in a child with a negative CXR and normal physical examination TB disease: a positive culture for TB or combination of at least 2 of the following: Epidemiological link to a suspected source case Positive PPD or IGRA Abnormal chest radiograph (or other imaging) TUBERCULOSIS CASES IN THE UNITED STATES CHILDREN 0-14 YEARS OLD 1,800 1,600 1,400 1,200 1,000 800 600 400 200 0 1980 2000 5

RISK FACTORS FOR TUBERCULOSIS Increased risk of acquiring or having infection Foreign born from high prevalence country Intravenous drug or crack cocaine user Family history of TB (2-3 generations) Contact with HIV- infected individuals Contact with inmates of prison or jail (past or present) Some nursing homes, residential living Some healthcare workers Increased risk of developing disease after infection HIV infected Immune suppression - drugs or disease Recent (<3 years) infection Certain diseases: silicosis, diabetes mellitus Extremes of ages: infants, elderly SOME REASONS WHY TUBERCULOSIS SURGED IN THE UNITED STATES HIV co-epidemic Immigration increased pool of infection and disease Congregate settings Poor tuberculosis control 6

MONOCLONAL ANTIBODIES TUBERCULOSIS Remicade (Infliximab) monoclonal antibody against TNF-α black box warning for tuberculosis 84 cases by 10/01 severe pulmonary, G-I and disseminated tuberculosis must do at least a TB risk assessment and TST prior to use Humira (adalimumab), Enbrel (etanercept) less information known strong warning to assess for TB risk and place a TST TIME TABLE OF CHILDHOOD TUBERCULOSIS Site of Disease Time to Develop Miliary and meningeal Primary pulmonary Lymph node [cervical] Pleural effusion Skeletal Renal 1-9 months 2-12 months 2-12 months 3-9 months 6 months 2 years 1-5 years 7

Average age specific risk for disease development following primary infection (pre- BCG) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0-1 year 1-2 years 2-5 years 5-10 years >10 years Miliary or TBM Pulmonary No disease Adapted from Marais B, et al. Int J Tuberc Lung Dis 2004 TRANSITIONS IN TUBERCULOSIS Susceptible Exposed Infected Diseased Sick Diagnosed Treated Cured 8

ARE CHILDREN WITH TUBERCULOSIS EVER CONTAGIOUS? Difficult to answer in the community Orphanages caretaker with TB led to transmission; a child with TB did not Schools only 2 reported epidemics caused by children <13 years old Children s Hospitals rare case reports of transmission, all with special circumstances, none has been patient - to - patient 9

FEATURES OF CONTAGIOUS PEDIATRIC TUBERCULOSIS Cavitary lung lesion Sputum production Positive acid-fast stain of sputum smear Bronchoscopy Draining lesions or surgical drainage of an abscess NEJM 1999;341:1491 10

DIAGNOSIS OF TUBERCULOSIS All existing diagnostic tests for TB in children have significant ifi shortcomings Most tests are not available in settings where the vast majority of TB cases are diagnosed The utility of most tests is further diminished in children with immune compromise [especially HIV infection] 11

DIAGNOSTIC TESTS FOR CHILDHOOD TUBERCULOSIS The sensitivity and specificity of the available tests are inherent in the tests However, the positive and negative predictive values are inherent in the population on whom the tests are used Therefore, all tests are more accurate when used on children with a high index of suspicion [epidemiology HISTORY OF RECENT CONTACT TO A TB CASE - or suspicious symptoms] 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 12

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 Bo FACTORS THAT CAUSE DECREASED RESPONSE TO TUBERCULIN Host-related Infections vaccines Infections, vaccines Chronic disease, malnutrition Immunosuppressive diseases (HIV, malignancy, CVD) Drugs (corticosteroids) Extremes of age, stress Overwhelming tuberculosis Tuberculin - related Tuberculin related Improper storage or dilution Adsorption to glass or plastic Administration - related Reading - related 13

Sensitivity = Specificity = 95% 90% prevalence 1% prevalence PPV= 99% (1% false+) PPV=15% (85% false+) 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 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 14

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 INTERACTION OF BCG VACCINES WITH THE TUBERCULIN SKIN TEST 50% of vaccinated infants do not react to a TST; most of the rest stop reacting within 5 years most non-infants who get one or more BCG vaccinations will react to a TST (usually < 15 mm), but effect wanes over 5 10 years CURRENT DOGMA: outside infancy, positive TST more likely to indicate infection with M. tuberculosis than be residual from BCG 15

TUBERCULIN SKIN TESTING OF FOREIGN-BORN ADOPTEES On one hand, most children have received a BCG vaccine within the past year, which can cause reaction to a TST On the other hand, many have lived in conditions conducive to transmission of M. tuberculosis and we can t do an investigation TUBERCULIN SKIN TESTING OF FOREIGN-BORN ADOPTEES General Guidelines 1. Assess for symptoms of tuberculosis disease prolonged (>2 wk) cough, weight loss, fevers 2. Note a BCG scar and/or immunization records 3. Place and read a 5 TU TST without controls 4. Delay or repeat the TST if the child is significantly malnourished 5. Positive TST reaction is 10mm, though this will result in some overtreatment due to recent BCG vaccination 6. Treat LTBI with isoniazid unless specific evidence of INHresistance is uncovered 16

Interferon tests o o o o o MTB specific antigens: Genes in region of difference (RD1) on MTB genome Culture filtrate protein 10 (CFP-10) Early secretory antigen target 6 (ESAT-6) TB7.7(p4) in QuantiFERON Gold In-Tube Identifies LTBI &/or disease Does not cross react with BGC vaccine or most other mycobacteria Requires: single medical visit [for LTBI, not for exposure] blood collection laboratory equipment and personnel Results in 24-48 hrs Commercial Tests QuantiFERON-TB Gold Company: Cellestis, Australia US FDA approved for adults but not for children In-Tube improvement o Method: Whole blood Incubated with MTB antigens (ESAT-6, CFP-10, TB7.7 7 {p4}) T-Cells produce INF- Supernatant removed INF- measured by ELISA reader T-Spot.TB or ELISPOT Company: Oxford Immunotec, UK USFDA approved for adults but not for children o Method: T-cells Incubated with MTB antigens (ESAT-6 & CFP-10) T-Cells produce INF- IFN- binds to antibody in wells Spots develop and are counted manually or by reader 17

Comparison of Tuberculin Skin Test and Interferon- ٢ Release Assays Tuberculin Skin Test IFN- ٢ Release Assay Antigens studied Many -PPD ESAT-6, CFP-10 Cross-reactivity with BCG Yes Unlikely Cross-reactivity with NTM Yes Less Likely Estimated sensitivity, TB in immunocompetent adults Estimated specificity, TB in immunocompetent adults 75-90% 75-95% 70-95% 90-100% Distinguish between TB infection and TB disease No No Boosting Yes No Patient visits required Two One Sensitivity and Specificity QuantiFERON-TB Gold Sensitivity* (95%CI) Mori ( 04) 89 (82-94) Ravn ( 05) 85 (72-94) Kang ( 05) 80 (67-90) Pai ( 05) 75 (64-85) Specificity+ (95%CI) Mori ( 04) 98 (95-99) Ravn ( 05) 97 (87-100) Kang ( 05) 96 (90-99) 99) Goletti ( 05) 90 (68-99) T-Spot. Spot.TB or ELISPOT Sensitivity* (95%CI) Lalvni ( 01a) 96 (85-99) Lalvni ( 01b) 80 (66-90) Pathan ( 01) 92 (74-99) Chapman ( 02) 92 (81-98) Liebeschuetz( 04) 83 (75-89) Meier ( 05) 97 (90-100) Specificity+ (95%CI) Lalvni ( 01a) 91 (80-98) Pathan ( 01) 100(89-100) 100) Meier ( 05) 92 (62-100) *Sensitivity in pts with active TB, Cx = Gold standard +Specificity in healthy low risk patients without TB Pai, Expert Rev Mol Diagn. 6(3):413-422 (2006) 18

T-CELL ASSAYS FOR TUBERCULOSIS IN CHILDREN More data available for elispot technique Appear to be more specific for tuberculosis infection, especially in low prevalence conditions Correlate better with degree of exposure in contact investigations than does the TST: likely many false-positive TSTs in BCG- vaccinated children Dynamics of tests are largely unknown Results have been highly variable, and indeterminate results are common with QuantiFERON-TB Gold INTERFERON-GAMMA RELEASE ASSAYS - 2010 CDC expert panel recommends: 1. No preference for one test over the other 2. Should replace the TST for most adults and older children, except, perhaps, for immune compromised; less clear for children < 5 years of age 3. Can be used in contact investigations [even in contact investigations, many adults with a positive TST and history of BCG likely do not have LTBI] 19

IGRAs IN CHILDREN SOME UNANSWERED QUESTIONS Should +TST in a BCG-vaccinated child always be followed by an IGRA? Should only IGRAs be used in a previously BCGvaccinated child? Low risk child, TST > 15 mm, IGRA neg. Treat or no treat? High risk child [contact], TST > 10 mm, IGRA neg. Treat or no treat? Are IGRAs sufficiently sensitive for contact investigation of young children? Should we use IGRA for TB exposure in children [means two blood draws]? IGRAs AND THE 2009 AAP RED BOOK Can use IGRAs in immunocompetent children > 4 years of age in all situations when a TST would be used Particularly useful/preferred for children who have received a BCG vaccination Use with caution in children < 5 years of age, immunocompromised children Neither IGRAs nor the TST are perfect; always need clinical judgment! 20

TRANSITIONS IN TUBERCULOSIS Susceptible Exposed Infected *Diseased Sick Diagnosed Treated Cured 21

HOW IS TUBERCULOSIS DIAGNOSED? Adults Mycobacterial-based diagnosis positive sputum AFB smear - 60-75% positive sputum culture - 90% positive tuberculin skin test - 80% [HIV < 50%] Children positive sputum or gastric AFB smear - 10% positive sputum or gastric culture - 10-40% positive tuberculin skin test - 50-80% DIAGNOSIS OF TUBERCULOSIS Even in developed countries, the gold standard d for the diagnosis i of tuberculosis in children is the triad of: 1. a positive TST 2. an abnormal CXR and/or physical exam 3. a history of recent contact to an infectious adult case of TB 22

OBTAINING CULTURE AND AFB SMEAR SAMPLES FROM CHILDREN Traditional method is gastric aspiration, performed as an inpatient t on 3 consecutive mornings expensive, invasive Bronchoalveolar lavage has no advantage Nasopharyngeal aspiration few studies Other sites yields usually 0% - 25% culture positive, <10% smear positive Specimen Acid-Fast Culture Yield AFB Culture Sputum/gastric t 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 23

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 Explore non-culture methods (PCR) Inpatient procedure Overnight fasting Lavage with NS if volume < 20cc Gastric Aspirates Generally done qam x3 Inpatient t costs substantial ti AFB smear yield: minimal AFB Culture yield: 20-30% 24

INDUCED SPUTUM COLLECTION IN CHILDREN Can be done inpatient or outpatient Infection control precautions important Salbutamol, followed by 15 minutes of 5% hypertonic saline solution Sputum obtained via suction with a nasopharyngeal catheter Yield: 30% to 40% culture positive Zar et al. Lancet 2005;365:130 Outpatient procedure 2-3h fasting period Pretreated with salmeterol; nebulized saline, then CPT given Nasopharynx suctioned Induced Sputum One specimen sufficient Minimal costs AFB smear yield: 50% AFB Culture yield: 25-30% Lancet. 2005;365:130 25

Photo courtesy of Paul Mullen, M.D., Baylor International Pediatric AIDS Initiative INTERPRETING CHILDREN S CHEST RADIOGRAPHS FOR TB Rarely available in highest prevalence areas Marked inter- and intra- observer variability Reliable in expert hands and in the presence of suspicious symptoms Commonest picture is persistent opacification together with enlarged hilar or subcarinal lymph nodes [though nodes not always discernable] The x-ray is usually sicker than the patient! 26

CHEST RADIOGRAPH TECHNIQUE FOR CHILDREN Check for three important features 1. Rotation can make mediastinum be wider 2. Inspiration when inadequate, can cause mass effect of mediastinum, hilum 3. Penetration difficult to interpret if x-ray is too white or too black 27

CXR Findings in Pediatric TB Hilar or mediastinal adenopathy Segmental/lobar infiltrates t Calcifications (seen in 75-80% of children with pulmonary TB) Miliary disease Pleural effusions 15% of patients with TB disease will have normal CXRs Intrathoracic Lymphadenopathy 28

Collapse/Consolidation Pattern Lymph node collapses a bronchus, leading to distal atelectasis 29

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Calcifications Usually indicates disease present for 2-6 months Cavitary Lesions Uncommon in children, but if see cavities, treat the child as contagious and take appropriate infection control precautions 31

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Miliary Disease Pleural Effusions Often, children are very well-appearing 33

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 CT SCANS AND PULMONARY TB Can be valuable when it is not certain that an abnormality on CXR is due to TB define the anatomy Not valuable when CXR is normal! Example: Child with a 20 mm TST after a known exposure has a normal CXR. A CT scan shows two 1 cm nodes in the right hilum. How do you interpret? My answer: So what? INH will take care of this very nicely, and decision rules are based on CXR, not CT scan. 34

TUBERCULOSIS IN HIV-INFECTED INFECTED CHILDREN Clinical and Radiographic Presentation in children with preserved immunocompetence, presentation is indistinguishable from HIV-uninfected children most common symptoms remain malnutrition, fever, night sweats, lymphadenopathy and cough extrapulmonary disease (meningitis and tuberculoma, abdominal) is more common chest radiograph findings are typical, but more extensive and a broader differential diagnosis TREATING EXPOSED CHILDREN Very high rate of infection Takes up to 3 months for the skin test to turn positive U.S. studies 10% to 20% of childhood TB cases can be prevented if children exposed in a household receive isoniazid WHO standards children <5 years old in a TB household should be treated 35

Why Do We Do This? To Prevent This: How long do you treat exposed kids? It depends Repeat TST 8-10 weeks after broke contact t Physically breaking contact Microbiologically breaking contact But, if a young infant, we sometimes use TSTs on others in the home by proxy If no one in home converts, may feel more comfortable stopping meds If everyone in home converts, then may extend child s therapy 36

TREATMENT OF LTBI IN CHILDREN 9 months of isoniazid (daily or twice weekly under DOT) is only accepted regimen INH-resistance or intolerance rifampin for 6 months Multidrug-resistance consult an expert Use isoniazid unless there is documented exposure to a specific case of drug-resistant TB 37

PEARLS OF WISDOM FOR TREATING LTBI IN CHILDREN Use INH suspension only in children 5 kg Compliance with 9 months of INH averages 50% - be vigilant and skeptical Use DOPT for: recent contacts, infants, immune compromised When children aren t tolerating INH, the problem is more often with the parent than the child Route LFTs only for: other liver toxic drugs, liver disease, signs or symptoms of hepatitis Newer Regimens (NOT Yet AAP Recommended) 3 months of INH + Advantages: Rifampin 4 months of Rifampin 3 months of INH + weekly Rifapentine 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 38

DIRECTLY OBSERVED THERAPY FOR TUBERCULOSIS means a dispassionate 3rd party is actually present when medications are taken with every dose standard of care in U.S. for treating tuberculosis disease desirable for high risk infections - newborns and infants, household contacts, HIV - infected or immune compromised TREATMENT OF TUBERCULOSIS DISEASE IN CHILDREN Pulmonary INH, RIF for 6 months + PZA for first 2 months + EMB for 2 months or until isolate known to be susceptible Can be every day or twice/thrice weekly therapy INH-resistant: RIF+PZA+EMB for 6 to 9 months MDR - depends on susceptibility - at least 18 months CNS, Disseminated usually start with 4 drugs (INH, RIF, PZA + ETH or injectable agent) usual length: 9-12 months Every day initially, may use twice/thrice weekly later 39

FOLLOW-UP EVALUATIONS FOR CHILDREN WITH TUBERCULOSIS skin test stays positive forever frequent chest x-rays unnecessary - at diagnosis, 1-2 months, end of therapy follow growth & development closely adequate nutrition routine liver enzyme monitoring not necessary routine vitamin B 6 not necessary except breastfeeding, pregnant adolescents, poor diet WHAT WE REALLY NEED FOR BETTER TB CONTROL IN CHILDREN? A better vaccine Better diagnostic tests New drugs with pediatric pharmacokinetics Shorter durations of therapy Sustained public health funding for contact investigation and DOT 40

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 p 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 41