Pediatrics

New Guidelines About Latent Tuberculosis Infection in Children and Adolescents: A Welcome Advancement Lisa J. Nelson, John A. Jereb and Kenneth G. Castro Pediatrics 2004;114;1084 DOI: 10.1542/peds.2004-1525

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/114/4/1084.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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The American Academy of Pediatrics policy issued in December 2003 considered both the opportunity to reduce the incidence of RSV hospitalizations in infants and children at greatest risk and the cost of prophylaxis when recommending that “in most seasons and in most regions of the Northern Hemisphere, the first dose of palivizumab should be administered at the beginning of November, and the last dose should be administered at the beginning of March, which will provide protection into April.”11 Changes from this recommendation require careful consideration of the benefits and costs as well as data on timing of RSV outbreaks and associated disease using appropriate diagnostic criteria. H. Cody Meissner, MD Pediatric Infectious Disease Division Tufts-New England Medical Center Tufts University School of Medicine Boston, MA 02111 Larry J. Anderson, MD Division of Viral and Rickettsial Diseases National Center for Infectious Disease Centers for Disease Control and Prevention Atlanta, GA 30333 Larry K. Pickering, MD National Immunization Program Centers for Disease Control and Prevention Atlanta, GA 30333 REFERENCES 1. The IMpact-RSV study group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998; 102:531–537 2. Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr. 2003;143:532–540 3. Romero JR. Palivizumab prophylaxis of respiratory syncytial virus disease from 1998 to 2002: results from four years of palivizumab usage. Pediatr Infect Dis J. 2003;22(2 suppl):S46 –S54 4. Mohan AK, Braun MM, Ellenberg S, Hedje J, Cote TR. Deaths among children less than two years of age receiving palivizumab: an analysis of comorbidities. Pediatr Infect Dis J. 2004;23:342–345 5. Gardner P, Pickering LK, Orenstein WA, Gershon AA, Nichol KL. Guidelines for quality standards for immunization. Clin Infect Dis. 2002; 35:503–511 6. Mullins JA, Lamonte AC, Bresee JS, Anderson LJ. Substantial variability in community respiratory syncytial virus season timing. Pediatr Infect Dis J. 2003;22:857– 862 7. Stensballe LG, Devasundaram JK, Simoes EAF. Respiratory syncytial virus epidemics: the ups and downs of a seasonal virus. Pediatr Infect Dis J. 2003;22(2 suppl):S21–S32 8. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalization among US children, 1980 –1996. JAMA. 1999;282:1440 –1446 9. Johnson S, Oliver C, Prince GA, et al. Development of humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis. 1997;176: 1215–1224 10. Hendrickson KJ. Advances in the laboratory diagnosis of viral respiratory disease. Pediatr Infect Dis J. 2004;23(1 suppl):S6 –S10 11. American Academy of Pediatrics. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. 2003;112:1442–1446

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New Guidelines About Latent Tuberculosis Infection in Children and Adolescents: A Welcome Advancement ABBREVIATIONS. LTBI, latent tuberculosis infection; TB, tuberculosis.

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n a supplement to this month’s issue of Pediatrics, comprehensive new guidelines are being published on finding and treating latent tuberculosis infection (LTBI) in children and adolescents.1 The collaborative group responsible for the guidelines is composed of health professionals from US health departments, the National Tuberculosis Model Centers, academic institutions, and the Centers for Disease Control and Prevention. With these guidelines, pediatricians have a single comprehensive reference about preventing tuberculosis (TB) in their patients. The guidelines are founded on a paradigm that is evolving with the TB epidemiology for US children and adolescents. Although TB rates have been declining overall since 1992, infections and cases have become even more concentrated among high-risk groups such as children born outside the United States. Thus, these guidelines recommend that children should be screened for risk factors for TB and LTBI and tested with the tuberculin skin test only if at least 1 risk factor is present. These guidelines discourage the use of administrative or mandated tuberculin skin tests for entry to child care, school, or summer camp, because these they are likely to consume limited resources but yield very little in finding current cases or preventing future ones. For these settings and most others, testing should be undertaken only if (1) preceded by screening for risk factors as described in the guidelines and (2) coupled to systems that start children who have LTBI on treatment and help them to complete it. The authors of the guidelines begin by reviewing the recent epidemiology of TB in children and adolescents, and they situate pediatric TB prevention within a hierarchy of TB-control activities managed by health departments. They provide the scientific rationale, with references, for the recommendations. They define differences among contact, source-case, and associate investigations, and they summarize research on risk-assessment questionnaires; a sample questionnaire is included in the article.1 They review new data on the TB risks for internationally adopted children, particularly those from orphanages in China and Russia. They also highlight the lack of Accepted for publication Jul 16, 2004. doi:10.1542/peds.2004-1525 The use of trade names does not imply endorsement by the US Public Health Service or the Department of Health and Human Services. Reprint requests to (L.J.N.) Division of TB Elimination, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS E-10, Atlanta, GA 30333. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.

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risk-factor data specific to adolescents; because of this lack of data, some risk-assessment questionnaires have performed relatively poorly when applied to this population. Low rates of TB disease (⬍0.02%) and LTBI (⬍2%) were found in recent studies of universal schoolbased screening. However, several studies have found rates of LTBI that were 6 to 24 times higher for foreign-born students, particularly older children and adolescents.2,3 Associate investigations, which include close contacts of children with LTBI, generally have found a low rate of active TB disease but a substantial rate of LTBI. These contrasts reinforce the importance of methodically planning testing programs and interpreting the epidemiologic implications of the results. Evaluation for LTBI has distinct significance for children and adolescents who are at high risk of developing disease if infected. Medical conditions that predispose to progression of TB infection include human immunodeficiency virus infection, diabetes, organ transplantation, chronic renal failure, and malignancies. In addition, medications such as high-dose steroids and other immunosuppressive medications (eg, infliximab) enhance the likelihood that LTBI will progress to active TB. Children who have these risks should receive a tuberculin skin test and treatment for LTBI if infected. The tuberculin skin test is notorious for its limitations, and the authors present background on both its characteristics and the factors associated with false-positive and false-negative results. The rationale for the 3 cut-off levels (ⱖ5, ⱖ10, and ⱖ15 mm) to improve test sensitivity and specificity is provided. Newer tests for Mycobacterium tuberculosis infection such as QuantiFERON-TB1 might prove to have better sensitivity and specificity, but they have been inadequately studied in children and adolescents and they have not been approved yet for use in this population.4 The authors describe the diagnostic work-up for children with LTBI to rule out active TB disease. In particular, they contrast the utility of chest radiography with that of computed tomography, a diagnostic study not recommended for routine management of LTBI. A 9-month regimen of isoniazid currently is recommended for children who have LTBI believed to be susceptible to isoniazid or when the specific source of infection is unknown. The treatment recommendations are based on trials done by the US Public Health Service, which are reviewed in the text of the guidelines. Alternative regimens and the treatment of LTBI with drug-resistant organisms are covered also. The section on treatment regimens covers drug toxicity as well as strategies to improve adherence. The public health aspects of TB prevention are crucial, and in the guidelines, the roles of the health department, other health care providers, and schoolbased programs are delineated. Annual skin tests are recommended only for children with human immunodeficiency virus/acquired immunodeficiency syndrome and for incarcerated adolescents. The latter recommendation is not supported by published evi-

dence for adolescents. A skin test should be administered before starting immunosuppressive therapy, because these children have a high risk of developing disease if infected and immunosuppressive therapy can cause loss of sensitivity to tuberculin later on. Priorities for future research are also outlined in detail. For adolescents specifically, few data exist for guiding recommendations about TB prevention, and to some extent we still are left to create amalgams from the current recommendations for children and those for adults. Adolescents probably differ from younger children in risk factors for TB infection/disease, in clinical manifestations of TB, and in social issues related to treatment. We need more research to allow for specific recommendations for this population. Besides their value to pediatricians, the new guidelines provide a valuable reference for other groups with an interest in preventing TB in children and adolescents, including health departments, schools, general primary care providers, and a wide variety of organizations (such as summer camps, child care facilities, international adoption organizations, and juvenile detention facilities). However, putting these comprehensive guidelines into practice is certain to present challenges. As the authors make clear, specific risk factors for LTBI vary by geographic settings and by groups of children, which necessitates the use of locally tailored risk-assessment questionnaires as well as locally tailored strategies that are founded on epidemiologic analysis. A TB-prevention strategy that is based on diagnosing and treating LTBI is unfeasible in the resourcepoor countries that suffer most of the global TB burden. The intricacy of the new pediatric guidelines reinforces the discrepancies of what can be offered to children in resource-rich and resource-poor countries. Widespread BCG vaccination has failed to bring the global TB epidemic under control, but recent vaccine discoveries give us greater hope of preventing TB among children worldwide.5 Although LTBI and active TB in children are sentinel events for recent M tuberculosis transmission, health departments (as well as other agencies) must set priorities for their diverse TB-control activities while they adjust for their increasingly limited resources. Thus, we all will be challenged to make use of these valuable new guidelines when formulating local strategies. Children with LTBI represent the future reservoir from which adult cases will arise, and detecting and treating LTBI in children and adolescents will contribute to the long-term goal of TB elimination in the United States. Lisa J. Nelson, MD, MPH, MS John A. Jereb, MD Kenneth G. Castro, MD Division of Tuberculosis Elimination National Center for HIV, STD, and TB Prevention Centers for Disease Control and Prevention Atlanta, GA 30333 ACKNOWLEDGMENT This work was funded by the Division of Tuberculosis Elimination, Centers for Disease Control and Prevention.


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REFERENCES 1. Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics. 2004;114(4 pt 3);1175–1201 2. Driver CR, Valway SE, Cantwell MF, Onorato IM. Tuberculin skin test screening in schoolchildren in the United States. Pediatrics. 1996;98: 97–102 3. Mohle-Boetani JC, Miller B, Halpern M, et al. School-based screening for tuberculosis infection: a cost-benefit analysis. JAMA. 1995;274:613– 619 4. Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep. 2003;52(RR-2):15–18 5. Fruth U, Young D. Prospects for new TB vaccines: Stop TB Working Group on TB Vaccine Development. Int J Tuberc Lung Dis. 2004;8:151–155

Supporting Vulnerable Preschool Children: Connecting the Dots Before Kindergarten

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orty-one years ago, the infant son of President John F. Kennedy died at Children’s Hospital in Boston after being born 5.5 weeks prematurely and weighing 2.1 kg.1 At that time, there were no regional systems of maternal transport and neonatal care, no National Institute of Child Health and Human Development or program projects supporting research in developmental biology, no screening for genetic disorders that cause mental retardation, no Head Start programs, and no laws ensuring that children with challenges would have the supports required to succeed in school and the community. Three decades later President George H.W. Bush, who had lost a daughter to leukemia and had a son who struggled with reading, convened a conference of governors from all 50 states. These leaders unanimously agreed on a most ambitious goal that by 2000 all children who entered kindergarten would be ready to learn.2 Now in a decade of revolutionary advances in molecular, developmental, and systems biology, we as a pediatric community face 2 major challenges. First, how can we ensure that developmental and behavioral supports exist for families after benefiting from advances in pediatric care? Second, how can we ensure that young children in families struggling with poverty access quality health and preschool developmental supports?3 The study by Roth et al4 in the September issue of Pediatrics builds on advances of regionalization of Florida’s nurseries, collaboration between health professionals and social scientists to link information on birth certificates to subsequent school success, and policy initiatives of the Chiles Center for Healthy Mothers and Babies. Of the 120 554 children born in 1990 –1991 with links to kindergarten data, biomedAccepted for publication Aug 2, 2004. doi:10.1542/peds.2004-1655 Reprint requests to (M.E.M.) University of Chicago Pritzker School of Medicine, Comer Children’s and LaRabida Children’s Hospitals, 5841 S Maryland Ave, MC0900, Chicago, IL 60637. E-mail: [email protected]. uchicago.edu PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.

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ical risk included 0.3% with birth weights of ⬍1000 g, 0.7% with birth weights of 1000 to 1499 g, 6.1% with birth weights of 1500 to 2499 g, and 1.3% with congenital anomalies. These medical conditions contributed $19 300 000 to extra kindergarten costs. The social risks were much higher: 37% were born into poverty, 28% had parents who did not complete high school, 15% had teen mothers, and 7% had less than optimal prenatal care. These social risk factors were responsible for almost $129 000 000 in extra kindergarten educational resources. It is tragic that at this time ⬍1 in 3 children in poverty had access to Head Start. Similarly, there are major gaps for children in poverty with all degrees of low birth weight to accessing comprehensive early intervention services.5 In an era of debates about health and educational reform, this study has an important lesson to teach: poverty is not a developmental enhancer. If we are going to test all elementary school children, we must also release report cards that examine gaps in accessing quality medical homes and home visiting, early intervention, early start, and early childhood programs. We must work together to connect the dots of biopsychosocial supports that will allow all children in 2010 to enter kindergarten healthy and ready to learn. Michael E. Msall, MD Department of Pediatrics University of Chicago Pritzker School of Medicine Comer Children’s and LaRabida Children’s Hospitals Chicago, IL 60637 REFERENCES 1. Blair WM. 2d Son born to Kennedys; has lung illness. New York Times. August 8, 1963;P1 2. Goals 2000: Educate America Act of 1994. Pub L No. 103-227, 20 USC §§5801 et seq 3. Shonkoff JP, Phillips D, eds. From Neurons to Neighborhoods: The Science of Early Child Development. Washington, DC: National Academy Press; 2000 4. Roth J, Figlio DN, Chen Y, et al. Maternal and infant factors associated with excess kindergarten costs. Pediatrics. 2004;114:720 –728 5. Msall ME, Tremont MR, Ottenbacher KJ. Functional assessments of preschool children: optimizing developmental and family supports in early intervention. Infants Young Child. 2001;14:46 – 66

Management of Hyperbilirubinemia: Quality of Evidence and Cost ABBREVIATION. AAP, American Academy of Pediatrics.

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ernicterus is associated with early hospital discharge, reduced concern about jaundice in otherwise healthy newborns, and breastfeeding.1–3 To compensate for early discharge, the AmerAccepted for publication Aug 11, 2004. doi:10.1542/peds.2004-1753 Address correspondence to Neil A. Holtzman, MD, MPH. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.


New Guidelines About Latent Tuberculosis Infection in Children and Adolescents: A Welcome Advancement Lisa J. Nelson, John A. Jereb and Kenneth G. Castro Pediatrics 2004;114;1084 DOI: 10.1542/peds.2004-1525 Updated Information & Services

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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