CDC Immigration Requirements: Tuberculosis Screening for Children Ann M. Loeffler, M.D. Curry International TB Center San Francisco, CA March, 2013 Atlanta, Georgia
CDC Immigration Requirements: Tuberculosis Screening for Children Disclosures Personal financial relationships with commercial interests relevant to this presentation during the past 12 months: Cellestis - supported my travel to this conference Off-Label Disclosure: None
Tale of two screening strategies Prior to the 2007 Technical Instructions, children were not screened for TB prior to immigration or international adoption Meron delayed diagnosis of MDR-TB
Tale of two screening strategies Prior to currnet TI KH started on cat 1 tx 1/07 Started on MDR tx in US 10/08
Tale of two screening strategies AFTER 2007 Technical Instructions children are screened for TB in country In China alone, 7/2009 7/2010, five children were diagnosed with TB including one infant with MDR-TB California child diagnosed and appropriately treated for INH resistant TB
Children are not just small adults Pediatric TB and LTBI are sentinel events Likelihood of TB disease Signs and symptoms Radiographic findings
Children are not just small adults Pulmonary vs. extrapulmonary Contagion Bacteriologic diagnosis Treatment regimens TB drugs much better tolerated Dosing difficulties
Children at high risk for TB disease Young age 40% of infected babies <1 year develop TB disease higher risk continues until school-aged Adolescence Malnutrition Underlying conditions/intercurrent illnesses: HIV, measles, pertussis, DM, immunosuppression
Signs and symptoms of pediatric tuberculosis Most US children with TB are asymptomatic The chest x-ray findings have NO correlation with signs and symptoms Infants and adolescents are most likely to have signs and symptoms Poor weight gain Fever Cough Sluggishness
Chest radiographs Characteristic: Adults Children Location Apical Anywhere (25% multilobar) Adenopathy Rare Usual (30-90%) (except HIV) Cavitation Common Rare (except adolescents) Signs and sx Consistent Relative paucity
Sputum induction Hypertonic saline can be used to induce sputum in older children Taught to breathe deep and cough out sputum Younger children can undergo nasopharyngeal (NP) suction after sputum induction
Bacteriologic diagnosis Gastric aspirates people swallow mucus in their sleep collect gastric contents before the stomach empties www.currytbcenter.ucsf.edu/pediatric_tb Pediatric on-line course: resources Lots of forms and instructions / video Bibliography for specimen collection
Gastric aspirate yield A negative culture does not rule out TB First specimen is the very highest yield Nearly 100% yield for <3-month-olds smear rarely positive after 3 months Literature for 3 gastric aspirates: 40%
Gastric aspirate collection Have everything ready Have helper if possible Restrain the child well mark tube length to stomach with pen insert at least 10 French catheter through nose stay away from septum aim straight at the bed
Gastric aspirate collection If insignificant yield: put any yield in sterile container check tube position in stomach by instilling air and listening with stethoscope instill 20 ml sterile water re-aspirate if no good mucous advance and withdraw tube, roll the child, etc. looking for mucous continue to aspirate syringe as you withdraw tube
Gastric aspirate collection Put all yield in sterile cup or tube Immediately transport to lab for neutralize OR Neutralize at bedside Order AFB smear and culture (Bicarbonate for neutralization 2.5 grams NaHCO3 dissolved in 100 cc deionized water. Filter the solution through a 45um filter. Use 1.5 cc for each specimen. Lab should monitor and correct the ph)
Gastric Aspirate Video
Treatment Pediatric TB: A decision to treat is a decision to treat Most often, once TB treatment is begun, it must be completed Unlike adults positive cultures often not available Clinical or radiographic improvement on treatment may be attribute to TB treatment or spontaneous resolution of another process
Treatment Pediatric TB: In areas of high TB incidence OR For known TB contacts OR For children with typical radiographic findings» START TB Therapy as soon as cultures are collected!!
Treatment Pediatric TB: For children whose symptoms and radiographic changes are more consistent with asthma or community acquired pneumonia Treat first with albuterol (not steroids) or amoxicillin or a macrolide (NO fluoroquinolones) Follow up closely!!
Treatment regimens TB disease four drugs: INH, rifampin, pyrazinamide, ethambutol for two months No proven cases of eye toxicity in pediatrics if chest radiograph is not worse, compliance good, and isolate presumed sensitive, two drugs for four more months miliary or CNS disease one year
Pediatric Treatment Treat with directly observed therapy Monitor at least monthly for:» Evidence of progression of disease» Toxicity» Adherence» Absorption» Clinical improvement» Repeat radiograph at two months / COT
Dosing difficulties Avoid liquid suspensions INH is only commercially available. High osmotic load, stomach upset others custom made poor stability, poor homogeneity
Dosing difficulties Crush or fragment tablets, open capsules onto vehicle and layer with a topping of the food
Dosing difficulties Use thick, strong flavored vehicles: jelly Nutella chocolate whipped cream syrup chocolate sauce baby foods Give a spoonful of vehicle before and after drug dose
Dosing difficulties Small amounts of non-sugary liquids Rarely, dose infants in their sleep
Technical Instructions Pediatric TB information required» TB incidence in country of screening (< 20 or > 20 / 100,000)» Age of child» HIV Status (not required, but influences management if positive)» Signs or symptoms of TB disease» Information about TB contacts
Evaluation of Applicants < 15 Years of Age CDC Culture and DOT TB TI (CDOT or 2009 TB TI) <20/100,000 TB Incidence >20/100,000 < 15 years of age < 2 years of age > 2 years of age Medical history Physical examination If signs or symptoms of TB or pediatric applicant has known HIV TST or IGRA and Chest radiograph* and Collect 3 sputum specimens by cough, induction or gastric aspirate for smears and cultures Consider TB treatment if exam or CXR highly suggestive of TB; see p. 14, CDOT TB TI Drug susceptibility testing of positive cultures *Frontal and lateral views if < 10 years of age CXR always required if documented TB history, regardless of TST or IGRA result If smear or culture positive, applicant is Class A until treatment completed and post-tests negative Medical history Physical examination TST 10 mm or IGRA + Chest radiograph * TB signs or symptoms or CXR suggestive of TB or HIV infected Three sputum smears and cultures for M. tb Consider TB treatment if exam or CXR highly suggestive of TB; see p. 14, CDOT TB TI Drug susceptibility testing of positive cultures
Details of evaluation Medical history Physical examination TST or IGRA If: TST 10 mm or IGRA + or History or exam suggestive of TB disease: Chest Radiograph (2 view for < 10 years) If medical history, P.E., or CXR suggestive of TB or HIV infected In children, may include growth delay, weight loss, cough, fever, night sweats, or symptoms of extrapulmonary disease Children are more prone to extrapulmonary TB such as meningitis, miliary / disseminated TB and disease of the middle ear and mastoid, lymph nodes, bones, joints, and skin Three sputum smears and cultures for M. tb Drug susceptibility testing of positive cultures CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Diagnosis of TB in Children WHO: Key Features The presence of three or more of the following should strongly suggest a diagnosis of TB: Chronic symptoms suggestive of TB Physical signs highly suggestive of TB Positive tuberculin skin test or IGRA Chest radiograph suggestive of TB WHO. Guidance for national tuberculosis programmes on the management of tuberculosis in children. 2006
Diagnosis of TB in Children Loeffler The presence of ONE or more of the following should strongly suggest a diagnosis of TB: Chest radiograph suggestive of TB (especially with modest symptoms) Signs or symptoms suggestive of TB without another explanation Loeffler also known as your speaker and CDC Pediatric TB expert
Details of evaluation Medical history Physical examination TST or IGRA If: TST 10 mm or IGRA + or History or exam suggestive of TB disease: Chest Radiograph (2 view for < 10 years) If medical history, P.E., or CXR suggestive of TB or HIV infected Three sputum smears and cultures for M. tb Drug susceptibility testing of positive cultures TST or IGRA should be performed unless well documented prior positive TST/IGRA If the TST is 10 mm or positive IGRA or if the applicant has signs or sx of TB or has HIV, a CXR should be performed Applicants 2-14 year of age with a documented previous history of TB disease should have a chest radiograph even if their TST < 10 mm or IGRA is negative CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Interferon-gamma Release Assays (IGRAs) Panel physicians should be advised that some experts prefer TST in children younger than 5 years of age:» Relatively few published reports documenting the performance of IGRAs in young children» Obtaining sufficient blood is more difficult» Some concern that IGRAs may perform differently in young children
Diagnosis of LTBI/household contacts: QFT:IT QFT-TB Gold-IT, Nigeria PPD Chiron (5 IU): positive = 10 mm Nakaoka, H., Emerg Inf Dis, 2006
Specificity of Diagnosis of LTBI in TB suspects: QFT-IT/ T-Spot.TB vs TST QFT-TB Gold-IT vs T-spot, Germany PPD Chiron (10 TU), positive 5 mm Detjen, et al., CID, 2007.
Specificity of Diagnosis of LTBI in TB suspects: QFT-IT/ T-spot.TB vs TST QFT-TB Gold-IT vs T-spot, Germany PPD Chiron (10 TU), positive 5 mm Detjen, et al., CID, 2007.
IGRA in culture proven TB Among 6 studies 2007-2009 52-100% positive TST (depending on definition) 53-100% positive IGRA tests
Pediatric IGRA guidelines Use interchangeably in children > 5 yrs Use with caution in younger children Ann s practical use Use IGRA for families who do not / will not believe a positive TST AND will believe an IGRA Use both tests for TB suspects. Any positive is helpful
Travel Clearance Applicants 2-14 years of age who have a TST 10 mm or a positive IGRA, are without HIV infection, have no clinical findings of TB disease, and have a normal CXR can be cleared for travel (Class B2 TB, LTBI Evaluation) CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Travel Clearance Immediate initiation of definitive TB treatment should be strongly considered if TB is suspected on exam or chest radiograph, especially if travel is not imminent» After culture collection Parents of children with Class A TB may apply for a waiver of the Class A condition. The waiver application requires» acceptance by a US treating physician» acceptance by the local health department CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Travel Clearance Applicants 10 years of age who require sputum cultures, regardless of HIV infection, may travel to U.S., immediately after sputum smear analysis if none of the following conditions exist» Sputum smears are positive» CXR findings include 1 cavities OR extensive disease» Respiratory symptoms include forceful and productive cough» Known contact with a person with MDR-TB who was infectious at the time of contact CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Treatment of Tuberculosis Children Children with drug-susceptible TB disease should be treated with a 4-drug regimen:» Isoniazid» Rifampicin» Pyrazinamide» Ethambutol Duration of treatment:» HIV uninfected 6 months» HIV infected 9 months» Disseminated disease or meningitis 9-12 months
Tuberculosis Treatment Recommended Doses for Children Drug Isoniazid Rifampicin Pyrazinamide ATS/CDC/IDSA Daily Dose (max) 10-15 mg/kg (300 mg) 10-20 mg/kg (600 mg) 15-30 mg/kg (2.0 g) AAP Daily Dose (max) 10-15 mg/kg (300 mg)* 10-20 mg/kg (600 mg)* 30-40 mg/kg (2.0 g) Ethambutol 15-20 mg/kg 20-25 mg/kg (2.5 g) Streptomycin 20-40 mg/kg/d (1.0 g) 20-40 mg/kg/d (1.0 g) *Hepatotoxicity increases with INH >10 mg/kg or RIF > 15 mg/kg in combination See nationaltbcenter.edu/drtb for pediatric drug dose tables by weight
Tuberculosis Treatment Children Evidence of TB disease? Yes No Yes (or highly suggestive of TB disease clinically) Begin directly observed therapy (DOT) Smear or culture positive? No Consider not initiating therapy prior to departure if travel is imminent and child is asymptomatic with minimal disease * What would you do if it were your child? CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Tuberculosis Treatment Monitoring Drug Susceptibility Pattern Drug-susceptible Resistant to only one drug Resistant to > 1 drug (but susceptible to INH and rifampin) MDR-TB No drug susceptibility results (culture negative) Monitoring Recommendations* Collect 2 sputum specimens once a month until cultures are negative for 2 consecutive months As above As above Collect 2 sputum specimens once a month during therapy Collect 1 sputum specimen once a month during therapy *Specimens should be submitted for AFB microscopy and mycobacterial culture All cases should have 2 sputum specimens collected at the end of therapy CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Tuberculosis Treatment Monitoring Children < 10 years of age with drugsusceptible or culture-negative TB who cannot provide sputum specimens will not need to provide induced sputum or gastric aspirate specimens during treatment, unless their clinical course warrants an evaluation. CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Waivers Applicants undergoing treatment for pulmonary or laryngeal TB can petition for a Class A waiver Because TB disease in young children can be challenging, CDC supports the filing of waiver requests for young children with TB disease CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Contacts to TB Cases Children < 4 years of age or HIV infected Contact to known pulmonary TB case? Yes No Negative evaluation for TB disease Yes No Begin directly observed preventive therapy (DOPT), regardless of TST or IGRA results Begin directly observed therapy (DOT) Another slide at the end of the handout CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Contacts to TB Case Children < 4 years of age or HIV infected Re-test with TST or IGRA 8 weeks after conclusion of exposure TST < 5 mm or IGRA negative TST 5 mm or IGRA positive Stop DOPT Continue DOPT Cleared for travel to U.S. Cleared for travel to U.S. Class B3 TB, Contact Evaluation CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Preventive Therapy INH is the preferred drug for treatment of latent infection (except in known exposures to TB cases with drug resistance) Advice on other preventive regimens should be sought from experts identified by DGMQ If an applicant does not complete DOPT prior to departure, a 30-day supply of medication and instructions should be given to the applicant s parent or responsible adult traveling with the applicant Another slide at the end of the handout CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Conclusions Pediatric TB Large global problem Higher rates of progression to TB Children have: fewer signs and symptoms different radiographic findings more extrapulmonary TB less contagion
Conclusions Pediatric TB Gastric aspirates insensitive, but best culture method Treatment regimens limited for LTBI, similar to adult TB regimens Children are difficult to dose with TB medications; require patience and positive creativity
Conclusions Pediatric TB Technical Instructions require TB incidence based on WHO estimates Patient age HIV status (if known can offer to family if signs or symptoms of HIV disease) History and physical exam
THANKS To CDC for the invitation To Cellestis for the travel support To Drs Debbie Lewinsohn and Chuck Daley for the use of their slides and ongoing support
Extra slides See also: Currytbcenter.ucsf.edu/pediatric_tb Currytbcenter.ucsf.edu/drtb For specific questions can e-mail for clinical advice through the RTMCC Medical Consultation Service link on the CDOT TB Technical Instruction webpage
Bronchoscopy / Bronchoalveolar Lavage (BAL) Valuable for evaluation of other diagnoses Evaluation / treatment of airway compression AFB culture collection
BAL Culture Yield Author Year Region % + cx BAL % + gastric Cakir 2008 Turkey 12.8% 10% Bibi 2002 Israel 4% ---- Singh 2000 India 22% 12% Somu 1995 India 12% 32% Abadco 1992 USA 10% 50% Norrman 1988 Scandanavia 21% 12%
All Applicants < 15 Years of Age TB Incidence < 20/100,000 History and Physical Examination Those with signs and symptoms of TB OR who have HIV infection» TST or IGRA and» Chest radiograph (2 view <10 yrs) and» Three sputum specimens for microscopy and culture CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Applicants 2 Years of Age Countries with TB Incidence 20/100,000
Applicants 2 Years of Age Countries with TB Incidence 20/100,000 Medical history Physical examination TST or IGRA If: TST 10 mm or IGRA + or History or exam suggestive of TB disease: Chest Radiograph (2 view for < 10 years) If medical history, P.E., or CXR suggestive of TB or HIV infected Three sputum smears and cultures for M. tb Applicants 10 years of age: standard posteroanterior view Applicants < 10 years of age: standard anteroposterior or standard posteroanterior view and lateral view Posteroanterior views should be labeled PA Chest radiographs should be read by a radiologist and reviewed by the panel physician Drug susceptibility testing of positive cultures CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Applicants 2 Years of Age Countries with TB Incidence 20/100,000 Medical history Physical examination TST or IGRA TST 10 mm or IGRA + Chest Radiograph Medical history, P.E., or CXR suggestive of TB or HIV infected Laboratory testing should consist of at least three sputum specimens which should undergo microscopy for AFB culture for mycobacteria species identification (at least to M. tuberculosis complex level) drug susceptibility testing Three sputum smears and cultures for M. tb Drug susceptibility testing of positive cultures CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Applicants 2 Years of Age Countries with TB Incidence 20/100,000 Medical history Physical examination TST or IGRA TST 10 mm or IGRA + Chest Radiograph Medical history, P.E., or CXR suggestive of TB or HIV infected Sputum induction with 3-15% hypertonic saline Induction can be used for children as young as 3 years of age Gastric aspirates can be used for all children but are especially helpful for young children Three sputum smears and cultures for M. tb Drug susceptibility testing of positive cultures CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
All Applicants < 2 Years of Age TB Incidence 20/100,000 History and physical exam should be performed An applicant with signs or symptoms of TB or HIV infection should have a» TST or IGRA and» 2 view Chest radiograph and» Provide 3 sputum specimens CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment
Contacts to TB Cases > 4yrs of age Contact to known pulmonary TB case? Yes No Place TST or IGRA TST < 5mm or IGRA negative TST 5mm or IGRA positive If the contact is not started on prophylaxis: Repeat TST or IGRA every 3 months until 8 weeks after contact ends, the index case has negative sputum smears for 2 consecutive months, or TST becomes 5mm or IGRA positive Evaluate for evidence of TB disease CDC/DGMQ: CDOT Technical Instructions for Tuberculosis Screening and Treatment No evidence of TB disease and contact not started on preventive therapy Evaluate for evidence of TB disease (history, PE, CXR) every 3 months until departure
Preventive Therapy Efficacy of isoniazid therapy approaches 100% for children with appropriate adherence Isoniazid should be given daily (10-15 mg/kg) although twice weekly (20-30 mg/kg) DOPT can be considered Recommended duration of therapy is 9 months (270 doses) ATS/CDC/IDSA. Am J Resp Crit Care Med 2000;161:S221-S247 Am Academy of Peds, Red Book Online (2009)
Low Levels of Pyrazinamide and Ethambutol in Children with Tuberculosis and Impact of Age, Nutritional Status, and HIV Infection S. M. Graham, D. J. Bell, S. Nyirongo, R. Hartkoorn, S. A. Ward, and E. M. Molyneux ANTIMICROB AGENTS & CHEMOTHERAPY, Feb. 2006, p. 407 413 Vol. 50, No. 2 407 413.2006 Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (Cmax) failed to reach the MIC for Mycobacterium tuberculosis. The Cmax of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The Cmax of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the Cmax was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.