TB Nurse Case Management Norman, Oklahoma October 810, 2008 Tuberculosis in Children Jeffrey R. Starke, MD October 9, 2008 TUBERCULOSIS IN CHILDREN Jeffrey R. Starke, M.D. Professor and Vice Chairman of Pediatrics Baylor College of Medicine Houston, Texas USA 1
Tuberculosis is a social disease with medical implications. A Difficult Case A 7 yo HIV + girl has cough, abdominal pain, cervical and axillary adenopathy, bilateral rales and a large liver. A 10 day course of clarithromycin did not improve her symptoms. Her CD4 count was 291/20%, her hemoglobin was 8.9, but other labs were WNL. After several weeks, her cough improved, she was sweating a lot but did not have fever or weight loss. Her adult cousin had pulmonary tuberculosis 232 years ago [household contact]. Does she have tuberculosis? 2
Estimated TB incidence rates, 2000 Rate per 100 000 0 9 10 24 25 49 50 99 100 300 300 or more No estimate The boundaries and names shown and the des ignat i ons used on this map do not imply the express i on of any opinion whatsoever on the part of the World Health Organizat i on concerning the l egal status of any country, territory, c i ty or area or of its authorit ies, or concerning the del im itat i on of its front i ers or boundaries. Dotted l i nes on maps represent approx imate border l ines for which there may not yet be ful l agreement. Global Tuberculos i s Control. WHO Report 2002. WHO/CDS/TB/2002.295 3
EPIDEMIOLOGY OF TUBERCULOSIS IN THE WORLD WHO ESTIMATES 9.2 million incident cases in 2006 4.1 million of these cases were sputum AFB smear positive 14.4 million prevalent cases 0.7 million HIVinfected persons with new onset TB in 2006 0.5 million new cases of multidrug resistant TB in 2006 1.7 million deaths a/w TB in 2006 Country EPIDEMIOLOGY OF CHILDHOOD TUBERCULOSIS IN SELECTED 22 HIGH BURDEN COUNTRIES Childhood Cases Case Rate % Total Cases Children Total Afghanistan 17.540 25.3 1891 324 Brazil 23,520 20.7 47 66 China 86,978 5.3 27 129 Pakistan 61,905 25.3 103 172 South Africa 35,449 16.1 237 501 Zimbabwe 12,267 16.1 221 603 Range 2.725.3 25.3 15237 66603 Total 659,397 9.6 4
TRANSITIONS IN TUBERCULOSIS Susceptible Exposed Infected Diseased Sick Diagnosed Treated Cured TIME TABLE OF CHILDHOOD TUBERCULOSIS Site of Disease Miliary and meningeal Time to Develop 199 months Primary pulmonary 2122 months Lymph node [cervical] 2122 months Pleural effusion Skeletal Renal 399 months 6 months 2 years 155 years 5
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 s Hospitals rare case reports of transmission, all with special circumstances, none has been patient to patient 6
FEATURES OF CONTAGIOUS PEDIATRIC TUBERCULOSIS Cavitary lung lesion Sputum production Positive acidfast stain of sputum smear Bronchoscopy Draining lesions or surgical drainage of an abscess DIAGNOSIS OF TUBERCULOSIS All existing diagnostic tests for TB in children have significant 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] 7
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] Sensitivity = Specificity = 95% 90% prevalence 1% prevalence PPV= 99% (1% false+) PPV=15% (85% false+) 8
MANTOUX TUBERCULIN SKIN TEST uses 5 TU [2 TU if R23] of purified protein derivative interpret in 48 72 hours record size of induration in mm if it makes a reaction at >72 hrs, it counts! false negatives: 10% to 20% in disease FACTORS S THAT CAUSE DECREASED RESPONSE TO TUBERCULIN Hostre related Infection ions,, vaccinev accines Chronic disease, malnutrm lnutritiontion Immunosuppressive diseases (HIV, malignancy, CVD) Drugs (corti ticosteroids) Extremes es of o age, stresss Over erwhelming tuberculo ulosis Tuberculin related Improper storage or diluti tion Adsorption to glass or o plastic Administra ration relat lated Reading rela lated 9
INDURATION SIZE POSITIVE TUBERCULIN N SKIN TEST > 5 mm > 10 mm HIV coin infection Foreignborn from a HR country Immune compromisec Drug users Recent contact to TB Living in HR congregate Suspected ed disease setting Specific HR groups Children < 4 yrs y s old (AAP) > 15 mm No risk factors Previous BCG G vaccination? 10
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 noninfants who get one or more BCG vaccinations will react to a TST (usually < 15 mm), but effect wanes over 5 10 years outside infancy, positive TST more likely to indicate infection with M. tuberculosis than be residual from BCG TUBERCULINN SKIN TESTING OF FOREIGNBORN 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 t do an investigation 11
TUBERCULINN SKIN TESTING OF FOREIGNBORN 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 Interferon γ tests o o o o MTB specific antigens: Genes s in region of difference (RD1) on MTB genome Culture filtrate protein 10 (CFP10) Early secretory antigen target 6 (ESAT6) Identifies LTBI &/or disease Does not cross react with BGC vaccine or most other mycobacteria Requires: single medical visit blood collection laboratory equipment and personnel o Results in 2448 48 hrs 12
Commercial Tests QuantiFERONTB Gold Company: Cellestis, Australia US FDA approved Available in some areas of US InTube improvement o Method: Whole blood Incubated with MTB antigens (ESAT6 6 & CFP10) TCells produce INF γ Supernate removed INF γ measured by ELISA reader TSpot. Spot.TB or ELISPOT Company: Oxford Immunotec, UK FDA reviewing Available in Europe & Canada o Method: Tcells Incubated with MTB antigens (ESAT6 6 & CFP10) TCells produce INF γ IFN γ binds to antibody in wells Spots develop and are counted manually or by reader Comparison of Tuberculin Skin Test and Interferon ٢ Release Assays Antigens studied Crossreactivity reactivity with BCG Crossreactivity reactivity with NTM Estimated sensitivity, TB in immunocompetent adults Estimated specificity, TB in immunocompetent adults Distinguish between TB infection and TB disease Boosting Patient visits required Tuberculin Skin Test Many PPD Yes Yes 7590% 7095% No Yes Two IFN ٢ Release Assay ESAT6, CFP10 Unlikely Less Likely 7595% 90100% No No One 13
Sensitivity and Specificity QuantiFERONTB Gold Sensitivity* (95%CI) Mori ( 04)( 04) 89 (8294) 05) 85 (7294) 05) 80 (6790) 05) 75 (6485) Ravn ( 05)( Kang ( 05)( Pai ( 05)( Specificity+ (95%CI) Mori ( 04)( 98 (9599) Ravn ( 05)( 97 (87100) Kang ( 05)( 96 (9099) Goletti ( 05)( 90 (6899) TSpot. Spot.TB or ELISPOT Sensitivity* (95%CI) Lalvni ( 01a)( 96 (8599) Lalvni ( 01b)( 80 (6690) Pathan ( 01)( 92 (7499) Chapman ( 02)( 92 (8198) Liebeschuetz( 04) 83 (7589) Meier ( 05)( 97 (90100) Specificity+ (95%CI) Lalvni ( 01a)( 91 (8098) Pathan ( 01)( 100(89100) Meier ( 05)( 92 (62100) *Sensitivity in pts with active TB, Cx = Gold standard +Specificity in healthy low risk patients without TB Pai, Expert Rev Mol Diagn. 6(3):413422 (2006) Interferon γ tests Problems Variable sensitivity (7597%) in active TB disease Specificity reported high (95%) but no gold standard for LTBI and concordance estimates 6090% with TST and Interferon γ tests 14
TCELL ASSAYS FOR TUBERCULOSIS IN CHILDREN More data available for TSPOT. T SPOT.TBTB Appear to be more specific for tuberculosis infection, especially in low prevalence conditions Sensitivity is a bigger issue, especially in high prevalence conditions [recent contact] Dynamics of tests are largely unknown Results have been highly variable, and indeterminate results are common with QuantiFERONTB Gold TRANSITIONS IN TUBERCULOSIS Susceptible Exposed Infected *Diseased Sick Diagnosed Treated Cured 15
HOW IS TUBERCULOSIS S DIAGNOSED? Adults Mycobacterialbased based diagnosis is positive sputum AFB smear 60% 75% positive sputum culture 90% positive tuberculin skin test 80% [HIV < 50%] Childre ildren positive sputum or gastric AFB smear 10% positive sputum or gastric culture 10% 40% positive tuberculin skin test 50% 80% 16
DIAGNOSIS OF TUBERCULOSIS The diagnosis of tuberculosis in children relies on careful and thorough assessment of all the evidence derived from a careful history, clinical examination and relevant investigations, e.g. the tuberculin skin test [TST], chest radiography [CXR] and sputum smear microscopy. Stop TB Partnership Childhood TB Subgroup DIAGNOSIS OF TUBERCULOSIS Even in developed countries, the gold standard for the diagnosis 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 17
CLINICAL SCORING SYSTEMS FOR TUBERCULOSIS IN CHILDREN 17 scoring systems published since 1950 point systems (5) diagnostic algorithms (2) diagnostic classifications (5) combinations (5) 7 systems evaluated [none in HIV+ children] 5 prospective, 2 retrospective, none controlled OBTAINING CULTURE AND AFB SMEAR SAMPLES FROM CHILDREN Traditional method is gastric aspiration, performed as an inpatient t on 3 consecutive mornings expensive, invasive Bronchioalveolar lavage has no advantage Nasopharyngeal aspiration few studies Other sites yields usually 0% 25% culture positive, <10% smear positive 18
INDUCED SPUTUM COLLECTION N IN CHILDREN Zar et al. Lancet 2005; 365: 130. 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 INTERPRETING CHILDREN S 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 xray x is usually sicker than the patient! 19
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 xray is too white or too black 20
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TUBERCULOSIS IN HIVINFECTED INFECTED CHILDREN Clinical and Radiographic Presentation in children with prese eserved d immunocompetence, ce, presenp resentation tion isi indistinguishable from HIVuninfec uninfected d children most common on symptoms s remain malnutri nutrition, tion, fever, night sweats, s, lymphadenopath mphadenopathy and cough extrapulmonary disease (meningitis s and a tuberculo uloma, a, abdominal) is i more common on TB meningiti tis s has the same clinical cal and a CSF findings ngs as in HIV uninfected children excee xcept that intra tracerebral mass lesions s are more common on chest t radiograph findings s are typical, but more extensiv tensive e and a broader diffe fferential ential diagnosis 23
TUBERCULOSIS IN HIVINFECTED INFECTED CHILDREN Diagnostic Considerations Diagnosis of TB remains a problem, even in the best of centers broader differential diagnosis Culture yields y are about the same s for HIVinfected and HIVuninfected children when controlled for extent of disease Tuberculin skin test is useful u in immunocompetent HIVinfected children but usefulness u diminished with worsening immunocompromise Interferon release assays no data for HIVinfected children TUBERCULOSIS IN HIVINFECTED INFECTED CHILDREN BCG Disease Hesseling et al. Clin Infect Dis 2006; 42:548 BCG disease diagnosed in 25 children over 3 years 17/25 were HIVinfected; 2 had other immunocompromise Overall, 22 (88%) had local disease, 8 (32%) had distant or disseminated disease; 5 (20%) had d both Of HIVinfected children, 6 (35%) had disseminated disease Mortality y rate for disseminated disease 75% 24
IRIS AND MYCOBACTERIA Socalled paradoxical reactions occur in 2% to 23% of HIVnegative adult patients receiving treatment for tuberculosis Most common features are fever and lymph l node enlargement, though respiratory failure anda neurologic deterioration also occur Median time is 4090 days after TB treatment is started Abnormality is at the orig iginalinal site of infection ion in 75% of cases, at a new location in 25% Mechanism: increased tumor necrosis factor IRIS IN CHILDREN Puthanakit t et e al. Pediatr Infect Dis J 2006; ; 25:532 32/153 3 (21%) HIVinfected Thai children developed IRIS after starting ting HAART 14/32 (44%) ) episodes associa sociated with h mycobacteria [3TB, 22 BCG, 7MAC Complex, 2other other] In 11 of o 14 patients, the mycobacteri cobacterial l infec fections had not been diagnosed priorp to startis ting HAART 7 varicellav ricellazo zoster,, 7HSV, 3 Cryptoco yptococcus, cus, 1 Guillain lainba Barre Children who o developed IRIS had d significantly lower r baseline CD4 lympho mphocyte counts 25
NEEDED IMPROVEMENTS IN DIAGNOSIS OF CHILDHOOD TUBERCULOSIS Further characterize the Tcell T assays Refine and validate clinical scoring systems Study all tests in HIVinfected children Make chest radiography more readily available much more important role for children than for adults Pediatricians must advocate for resources MOST IMPORTANT Design TB control programs to link children with likely source cases CONTACT TRACING!!! 26