J Pediatr Infect Dis 2018; 13(02): 132-140
DOI: 10.1055/s-0037-1607231
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Treatment of Tuberculosis Infection in Children

Andrea T. Cruz
1   Sections of Infectious Diseases and Emergency Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
› Author Affiliations
Further Information

Publication History

13 March 2017

27 March 2017

Publication Date:
15 October 2017 (online)


The last decade has seen publication of more robust data for shorter course regimens for tuberculosis infection. These regimens are associated with higher completion rates than the traditional 6- to 9-month course of daily isoniazid (INH). These shorter regimens include 4 months of daily rifampin (RIF) and 12 once-weekly doses of INH and a long-acting rifamycin and rifapentine. In addition, a widely used regimen in the United Kingdom is 3 or 4 months of daily INH and RIF. All regimens have demonstrated efficacy in the ideal conditions of clinical studies, and all have very low rates of hepatotoxicity in children. These newer regimens likely are more effective than longer courses of INH once patient and family adherence is considered. Clinicians need to be cognizant of poor completion rates with traditional INH therapy and how the use of rifamycin-containing regimens offers more palatable options for children and their families.

  • References

  • 1 Marais BJ, Gie RP, Schaaf HS. , et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004; 8 (04) 392-402
  • 2 Dodd PJ, Prendergast AJ, Beecroft C, Kampmann B, Seddon JA. The impact of HIV and antiretroviral therapy on TB risk in children: a systematic review and meta-analysis. Thorax 2017; 72 (06) 559-575
  • 3 Webb EA, Hesseling AC, Schaaf HS. , et al. High prevalence of Mycobacterium tuberculosis infection and disease in children and adolescents with type 1 diabetes mellitus. Int J Tuberc Lung Dis 2009; 13 (07) 868-874
  • 4 Hernández-Cruz B, Ponce-de-León-Rosales S, Sifuentes-Osornio J, Ponce-de-León-Garduño A, Díaz-Jouanen E. Tuberculosis prophylaxis in patients with steroid treatment and systemic rheumatic diseases. A case-control study. Clin Exp Rheumatol 1999; 17 (01) 81-87
  • 5 Kim HA, Yoo CD, Baek HJ. , et al. Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient population. Clin Exp Rheumatol 1998; 16 (01) 9-13
  • 6 Calzada-Hernández J, Anton-López J, Bou-Torrent R. , et al; Carmen García de Vicuña Muñoz de la Nava. Tuberculosis in pediatric patients treated with anti-TNFα drugs: a cohort study. Pediatr Rheumatol Online J 2015; 13: 54
  • 7 Cruz AT, Karam LB, Orth RC, Starke JR. Disseminated tuberculosis in 2 children with inflammatory bowel disease receiving infliximab. Pediatr Infect Dis J 2014; 33 (07) 779-781
  • 8 Cruz AT, Airewele G, Starke JR. Tuberculosis in pediatric oncology and bone marrow transplantation patients. Pediatr Blood Cancer 2014; 61 (08) 1484-1485
  • 9 American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 2000; 161 (4 Pt 2): S221-S247
  • 10 Auguste P, Tsertsvadze A, Pink J. , et al. Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis. BMC Infect Dis 2017; 17 (01) 200
  • 11 Starke JR. ; Committee On Infectious Diseases. Interferon-γ release assays for diagnosis of tuberculosis infection and disease in children. Pediatrics 2014; 134 (06) e1763-e1773
  • 12 Wilson FA, Miller TL, Stimpson JP. Mycobacterium tuberculosis infection, immigration status, and diagnostic discordance: a comparison of tuberculin skin test and QuantiFERON-TB Gold In-Tube among immigrants to the U.S. Public Health Rep 2016; 131 (02) 303-310
  • 13 Howley MM, Painter JA, Katz DJ. , et al; Tuberculosis Epidemiologic Studies Consortium. Evaluation of QuantiFERON-TB gold in-tube and tuberculin skin tests among immigrant children being screened for latent tuberculosis infection. Pediatr Infect Dis J 2015; 34 (01) 35-39
  • 14 Taylor EM, Painter J, Posey DL, Zhou W, Shetty S. Latent tuberculosis infection among immigrant and refugee children arriving in the United States: 2010. J Immigr Minor Health 2016; 18 (05) 966-970
  • 15 Centers for Disease Control and Prevention. CDC immigration requirements: technical instructions for tuberculosis screening and treatment using cultures and directly observed therapy. Issued 1 October 2009 . Available online at: https://www.cdc.gov/immigrantrefugeehealth/pdf/tuberculosis-ti-2009.pdf . Accessed March 11, 2017
  • 16 Horsburgh Jr CR, Rubin EJ. Clinical practice. Latent tuberculosis infection in the United States. N Engl J Med 2011; 364 (15) 1441-1448
  • 17 Cruz AT, Starke JR. Increasing adherence for latent tuberculosis infection therapy with health department-administered therapy. Pediatr Infect Dis J 2012; 31 (02) 193-195
  • 18 Powell DA, Perkins L, Wang SH, Hunt G, Ryan-Wenger N. Completion of therapy for latent tuberculosis in children of different nationalities. Pediatr Infect Dis J 2008; 27 (03) 272-274
  • 19 Stuurman AL, Vonk Noordegraaf-Schouten M, van Kessel F, Oordt-Speets AM, Sandgren A, van der Werf MJ. Interventions for improving adherence to treatment for latent tuberculosis infection: a systematic review. BMC Infect Dis 2016; 16: 257
  • 20 Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95 (06) 935-943
  • 21 Comstock GW, Baum C, Snider Jr DE. Isoniazid prophylaxis among Alaskan Eskimos: a final report of the bethel isoniazid studies. Am Rev Respir Dis 1979; 119 (05) 827-830
  • 22 Hsu KH. Isoniazid in the prevention and treatment of tuberculosis. A 20-year study of the effectiveness in children. JAMA 1974; 229 (05) 528-533
  • 23 Getahun H, Matteelli A, Abubakar I. , et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J 2015; 46 (06) 1563-1576
  • 24 Menzies D, Long R, Trajman A. , et al. Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial. Ann Intern Med 2008; 149 (10) 689-697
  • 25 Skinner D, Mandalakas AM. Pasting together the preventive therapy puzzle. Int J Tuberc Lung Dis 2013; 17 (02) 175-177
  • 26 Hong Kong Chest Service/Tuberculosis Research Center, Madras/British Medical Research Council. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. Am Rev Respir Dis 1992; 145 (01) 36-41
  • 27 Villarino ME, Ridzon R, Weismuller PC. , et al. Rifampin preventive therapy for tuberculosis infection: experience with 157 adolescents. Am J Respir Crit Care Med 1997; 155 (05) 1735-1738
  • 28 Lee SH, Yim JJ, Kim HJ. , et al. Adverse events and development of tuberculosis after 4 months of rifampicin prophylaxis in a tuberculosis outbreak. Epidemiol Infect 2012; 140 (06) 1028-1035
  • 29 Cruz AT, Starke JR. Safety and completion of a 4-month course of rifampicin for latent tuberculous infection in children. Int J Tuberc Lung Dis 2014; 18 (09) 1057-1061
  • 30 Munsiff SS, Kambili C, Ahuja SD. Rifapentine for the treatment of pulmonary tuberculosis. Clin Infect Dis 2006; 43 (11) 1468-1475
  • 31 Sterling TR, Villarino ME, Borisov AS. , et al; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011; 365 (23) 2155-2166
  • 32 Bliven-Sizemore EE, Sterling TR, Shang N. , et al; TB Trials Consortium. Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. Int J Tuberc Lung Dis 2015; 19 (09) 1039-1044 , i–v
  • 33 Villarino ME, Scott NA, Weis SE. , et al; International Maternal Pediatric and Adolescents AIDS Clinical Trials Group; Tuberculosis Trials Consortium. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr 2015; 169 (03) 247-255
  • 34 Blake MJ, Abdel-Rahman SM, Jacobs RF, Lowery NK, Sterling TR, Kearns GL. Pharmacokinetics of rifapentine in children. Pediatr Infect Dis J 2006; 25 (05) 405-409
  • 35 Hatzenbuehler LA, Starke JR, Smith EO. , et al. Increased adolescent knowledge and behavior following a one-time educational intervention about tuberculosis. Patient Educ Couns 2017; 100 (05) 950-956
  • 36 Hatzenbuehler LA, Starke JR, Graviss EA, Smith EO, Cruz AT. School-based study to identify and treat adolescent students at risk for tuberculosis infection. Pediatr Infect Dis J 2016; 35 (07) 733-738
  • 37 Sterling TR, Moro RN, Borisov AS. , et al; Tuberculosis Trials Consortium. Flu-like and other systemic drug reactions among persons receiving weekly rifapentine plus isoniazid or daily isoniazid for treatment of latent tuberculosis infection in the PREVENT tuberculosis study. Clin Infect Dis 2015; 61 (04) 527-535
  • 38 Cruz AT, Starke JR. Safety and adherence for 12 weekly doses of isoniazid and rifapentine for pediatric tuberculosis infection. Pediatr Infect Dis J 2016; 35 (07) 811-813
  • 39 Bright-Thomas R, Nandwani S, Smith J, Morris JA, Ormerod LP. Effectiveness of 3 months of rifampicin and isoniazid chemoprophylaxis for the treatment of latent tuberculosis infection in children. Arch Dis Child 2010; 95 (08) 600-602
  • 40 Ena J, Valls V. Short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis. Clin Infect Dis 2005; 40 (05) 670-676
  • 41 Spyridis NP, Spyridis PG, Gelesme A. , et al. The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study. Clin Infect Dis 2007; 45 (06) 715-722
  • 42 Jasmer RM, Saukkonen JJ, Blumberg HM. , et al; Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002; 137 (08) 640-647
  • 43 van Hest R, Baars H, Kik S. , et al. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment. Clin Infect Dis 2004; 39 (04) 488-496
  • 44 McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest 2003; 123 (01) 102-106
  • 45 Centers for Disease Control and Prevention (CDC); American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52 (31) 735-739
  • 46 Sánchez-Albisua I, Vidal ML, Joya-Verde G, del Castillo F, de José MI, García-Hortelano J. Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children. Pediatr Infect Dis J 1997; 16 (08) 760-763
  • 47 World Health Organization. Global Tuberculosis Report 2016. Available online at: http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 . Accessed March 11, 2017
  • 48 Dodd PJ, Sismanidis C, Seddon JA. Global burden of drug-resistant tuberculosis in children: a mathematical modelling study. Lancet Infect Dis 2016; 16 (10) 1193-1201
  • 49 Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 2002; 109 (05) 765-771
  • 50 Seddon JA, Hesseling AC, Finlayson H. , et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis 2013; 57 (12) 1676-1684
  • 51 Seddon JA, Garcia-Prats AJ, Kampmann B, Schaaf HS, Hesseling AC. Toxicity and tolerability of fluoroquinolone-based preventive therapy for childhood contacts of multidrug-resistant tuberculosis. Pediatr Infect Dis J 2014; 33 (10) 1098-1099
  • 52 Bamrah S, Brostrom R, Dorina F. , et al. Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009-2012. Int J Tuberc Lung Dis 2014; 18 (08) 912-918
  • 53 Molton JS, Pang Y, Wang Z. , et al. Prospective single-arm interventional pilot study to assess a smartphone-based system for measuring and supporting adherence to medication. BMJ Open 2016; 6 (12) e014194
  • 54 Chuck C, Robinson E, Macaraig M, Alexander M, Burzynski J. Enhancing management of tuberculosis treatment with video directly observed therapy in New York City. Int J Tuberc Lung Dis 2016; 20 (05) 588-593
  • 55 Story A, Garfein RS, Hayward A. , et al. Monitoring therapy compliance of tuberculosis patients by using video-enabled electronic devices. Emerg Infect Dis 2016; 22 (03) 538-540
  • 56 Shemesh E, Shneider BL, Savitzky JK. , et al. Medication adherence in pediatric and adolescent liver transplant recipients. Pediatrics 2004; 113 (04) 825-832
  • 57 Nobili V, Alkhouri N, Alisi A. , et al. Nonalcoholic fatty liver disease: a challenge for pediatricians. JAMA Pediatr 2015; 169 (02) 170-176