Tuberculosis and Other Opportunistic Infections in HIV-Infected Children

  • Helena Rabie
  • Ben J. MaraisEmail author


Tuberculosis (TB) is the number one infectious disease killer on the planet and children living in human immunodeficiency virus (HIV)-affected households are particularly vulnerable. These children are at increased risk of TB exposure, given the high rates of TB among HIV-infected adults, and those who are very young or have HIV-induced immune compromise are at increased risk of progression to active disease. Apart from TB, HIV-infected children have increased susceptibility to a variety of other infections. Common infections such as viral and bacterial pneumonia occur with increased frequency and severity. They are also prone to opportunistic infections, which refer to organisms with low pathogenic potential that mainly cause disease in people with immune compromise. The main focus of this chapter is on tuberculosis and other opportunistic infections in HIV-infected children.


Human Immunodeficiency Virus Human Papilloma Virus Progressive Multifocal Leukoencephalopathy Tuberculin Skin Test Immune Reconstitution Inflammatory Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Bates M, Mudenda V, Mwaba P, Zumla A. Deaths due to respiratory tract infections in Africa: a review of autopsy studies. Curr Opin Pulm Med. 2013;19:229–37.CrossRefPubMedGoogle Scholar
  2. 2.
    Gupta RK, Lucas SB, Fielding KL, Lawn SD. Prevalence of tuberculosis in post-mortem studies of HIV infected adults and children in resource-limited settings: a systematic review and meta-analysis. AIDS. 2015;29:1987–2002.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Venturini E, Turkova A, Chiappini E, Galli L, de Martino M, Thorne C. Tuberculosis and HIV co-infection in children. BMC Infect Dis. 2014;14(Suppl 1):S5.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV infected infants. N Engl J Med. 2008;359:2233–44.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva: World Health Organization; 2016.
  6. 6.
    Boulware DR, Callens S, Pahwa S. Pediatric HIV immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS. 2008;3:461–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    B-Lajoie MR, Drouin O, Bartlett G, et al. Incidence and prevalence of opportunistic and other infections and the impact of antiretroviral therapy among HIV-infected children in low- and middle-income countries: a systematic review and meta-analysis. Clin Infect Dis. 2016;62:1586–94.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics. 2007;120:100–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Dankner WM, Lindsey JC, Levin MJ, Pediatric ACTGPT. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J. 2001;20:40–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children. Department of Health and Human Services.
  11. 11.
    Wolf ER, Beste S, Barr E, Wallace J, et al. Health outcomes of international HIV-infected adoptees in the United States. Pediatr Infect Dis J. 2016;35:422–7.CrossRefPubMedGoogle Scholar
  12. 12.
    World Health Organization. Global tuberculosis report 2015. WHO/HTM/TB/2015.Google Scholar
  13. 13.
    Marais BJ, Gupta A, Starke JR, El Sony A. Tuberculosis in women and children. Lancet. 2010;375:2057–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Lawn SD, Bekker LG, Middelkoop K, Myer L, Wood R. Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions. Clin Infect Dis. 2006;42:1040–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Wood R, Johnstone-Robertson S, Uys P, et al. Tuberculosis transmission to young children in a South African community: modeling household and community infection risks. Clin Infect Dis. 2010;51:401–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cotton MF, Schaaf HS, Lottering G, Weber HL, Coetzee J, Nachman S. Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting. Int J Tuberc Lung Dis. 2008;12:225–7.PubMedGoogle Scholar
  17. 17.
    Hesseling AC, Cotton MF, Jennings T, et al. High incidence of tuberculosis among HIV-infected infants: evidence from a South African population-based study highlights the need for improved tuberculosis control strategies. Clin Infect Dis. 2009;48:10.CrossRefGoogle Scholar
  18. 18.
    Gupta A, Bhosale R, Kinikar A, et al. Maternal tuberculosis: a risk factor for mother-to-child transmission of human immunodeficiency virus. J Infect Dis. 2011;203:358–63.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Marais BJ, Seddon JA, Detjen AK, et al. Interrupted BCG vaccination is a major threat to global child health. Lancet Respir Med. 2016;4:251–3.CrossRefPubMedGoogle Scholar
  20. 20.
    Fordham von Reyn C. Routine childhood Bacille Calmette Guerin immunization and HIV infection. Clin Infect Dis. 2006;42:559–61.CrossRefPubMedGoogle Scholar
  21. 21.
    Hesseling AC, Rabie H, Marais BJ, et al. Bacille Calmette-Guerin (BCG) vaccine-induced complications and HIV infection in children. Clin Infect Dis. 2006;42:548–58.CrossRefPubMedGoogle Scholar
  22. 22.
    Hesseling AC, Cotton MF, Marais BJ, et al. BCG and HIV reconsidered: moving the research agenda forward. Vaccine. 2007;25:6565–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Hessling AC, Cotton MF, Fordham von Reyn C, Graham SM, Gie RP, Hussey GD. Consensus statement on the revised World Health Organization recommendations for BCG vaccination in HIV-infected infants. Int J Tuberc Lung Dis. 2008;12:1376–9.Google Scholar
  24. 24.
    Walters E, Cotton MF, Rabie H, Schaaf HS, Walters LO, Marais BJ. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on antiretroviral therapy. BMC Pediatr. 2008;8:1.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dangor Z, Izu A, Hillier K, et al. Impact of the antiretroviral treatment program on the burden of hospitalization for culture-confirmed tuberculosis in South African Children: a time-series analysis. Pediatr Infect Dis J. 2013;32:972–7.CrossRefPubMedGoogle Scholar
  26. 26.
    UNAIDS. 90–90–90 An ambitious treatment target to help end the AIDS epidemic. UNAIDS/JC2684; 2014.Google Scholar
  27. 27.
    Marais BJ, Ayles H, Graham SM, Godfrey-Faussett P. Screening and preventive therapy for tuberculosis. Clin Chest Med. 2009;30:827–46.CrossRefPubMedGoogle Scholar
  28. 28.
    Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007;334:136.CrossRefPubMedGoogle Scholar
  29. 29.
    Frigati LJ, Kranzer K, Cotton MF, et al. The impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with HIV in a high tuberculosis incidence setting. Thorax. 2011;66:496–501.CrossRefPubMedGoogle Scholar
  30. 30.
    Madhi SA, Nachman S, Violari A, et al. Effect of primary isoniazid prophylaxis against tuberculosis in HIV-exposed children. N Engl J Med. 2011;365:21–31.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Crook AM, Turkova A, Musiime V, et al. Tuberculosis incidence is high in HIV infected African children but is reduced by co-trimoxazole and time on antiretroviral therapy. BMC Med. 2016;14:50.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Marais BJ, Graham SM, Cotton MF, Beyers N. Diagnostic and management challenges of childhood TB in the era of HIV. J Infect Dis. 2007;196(Suppl 1):S76–85.CrossRefPubMedGoogle Scholar
  33. 33.
    Marais BJ, Gie RP, Schaaf HS, et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics. 2006:e1350–9.Google Scholar
  34. 34.
    Moore DP, Klugman KP, Madhi SA. Role of Streptococcus pneumoniae in hospitalization for acute community-acquired pneumonia associated with culture-confirmed Mycobacterium tuberculosis in children: a pneumococcal conjugate vaccine probe study. Pediatr Infect Dis J. 2010;29:1099–104.CrossRefPubMedGoogle Scholar
  35. 35.
    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;8:392–402.PubMedGoogle Scholar
  36. 36.
    Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med. 2012;367:348–61.CrossRefPubMedGoogle Scholar
  37. 37.
    Roya-Pabon CL, Perez-Velez CM. Tuberculosis exposure, infection and disease in children: a systematic diagnostic approach. BMC Pneumonia 2016;8:23.Google Scholar
  38. 38.
    Marais BJ, Pai M. New approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatr Respir Rev. 2007;8:124–33.CrossRefPubMedGoogle Scholar
  39. 39.
    Schaaf HS, Krook S, Hollemans DW, et al. Recurrent culture-confirmed tuberculosis in human immunodeficiency-virus infected children. Pediatr Infect Dis. 2005;24:685–91.CrossRefGoogle Scholar
  40. 40.
    Marais B. The global tuberculosis situation and the inexorable rise of drug-resistant disease. Adv Drug Deliv Rev. 2016;102:3–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Schaaf HS, Marais BJ. Management of multidrug-resistant tuberculosis in children: a survival guide for paediatricians. Paediatr Respir Rev. 2011;12(3):1–8.Google Scholar
  42. 42.
    Isaakidis P, Casas EC, Das M, Tseretopoulou X, Ntzani EE, Ford N. Treatment outcomes for HIV and MDR-TB co-infected adults and children: systematic review and meta-analysis. Int J Tuberc Lung Dis. 2015;19:969–78.CrossRefPubMedGoogle Scholar
  43. 43.
    Rabie H, Gousaard P. Tuberculosis and pneumonia in HIV infected children, an overview. Pneumonia. 2016;8:19.CrossRefGoogle Scholar
  44. 44.
    Meintjes G, Rabie H, Wilkinson RJ, Cotton MF. Tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. Clin Chest Med. 2009;30:797–810.CrossRefPubMedGoogle Scholar
  45. 45.
    Link-Gelles R, Moultrie H, Sawry S, Murdoch D, Van Rie A. Tuberculosis immune reconstitution inflammatory syndrome in children initiating antiretroviral therapy for HIV infection: a systematic literature review. Pediatr Infect Dis J. 2014;33:499–503.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    van Toorn R, Rabie H, Dramowski A, Schoeman JF. Neurological manifestations of TB-IRIS: a report of 4 children. Eur J Paediatr Neurol. 2012;16:676–82.CrossRefPubMedGoogle Scholar
  47. 47.
    Chintu C, Bhat GJ, Walker AS, et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet. 2004;364:1865–71.CrossRefPubMedGoogle Scholar
  48. 48.
    Morrow BM, Samuel CM, Zampoli M, Whitelaw A, Zar HJ. Pneumocystis pneumonia in South African children diagnosed by molecular methods. BMC Res Notes. 2014;7:26.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Graham SM, Mtitimila EI, Kamanga HS, Walsh AL, Hart CA, Molyneux ME. Clinical presentation and outcome of Pneumocystis carinii pneumonia in Malawian children. Lancet 2000; 355:369–73.Google Scholar
  50. 50.
    Pitcher RD, Daya R, Beningfield SJ, Zar HJ. Chest radiographic presenting features and radiographic progression of pneumocystis pneumonia in South African children. Pediatr Pulmonol. 2011;46:1015–22.CrossRefPubMedGoogle Scholar
  51. 51.
    Zar HJ, Langdon G, Apolles P, et al. Oral trimethoprim-sulphamethoxazole levels in stable HIV-infected children. S Afr Med J. 2006;96:627–9.PubMedGoogle Scholar
  52. 52.
    Mankahla A, Mosam A. Common skin conditions in children with HIV/AIDS. Am J Clin Dermatol. 2012;13:153–66.CrossRefPubMedGoogle Scholar
  53. 53.
    Guidelines on the Treatment of Skin and Oral HIV-Associated Conditions in Children and Adults. Geneva: World Health Organization; 2014.Google Scholar
  54. 54.
    Van der Wouden JC, van der Sande R, van Suijlekom-Smit LWA, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2009;7(4):CD004767.Google Scholar
  55. 55.
    Jones V, Smith SJ, Omar HA. Nonsexual transmission of anogenital warts in children: a retrospective analysis. Scientific World Journal. 2007;7:1896–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Moscicki AB, Farhat S, Yao TJ, Ryder MI, et al. Oral human papillomavirus in youth from the pediatric HIV/AIDS cohort study. Sex Transm Dis. 2016;43:498–500.CrossRefPubMedGoogle Scholar
  57. 57.
    Levin MJ, Moscicki AB, Song LY, et al. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11,16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010;55(2):197–204.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Weinberg A, Song LY, Saah A, et al. Humoral, mucosal and cell-mediated immunity against vaccine and non-vaccine genotypes after administration of quadrivalent human papillomavirus vaccine to HIV-infected children. J Infect Dis. 2012;206:1309–18.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Jura E, Chadwick EG, Josephs SH, et al. Varicella-zoster virus infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J. 1989;8:586–90.CrossRefPubMedGoogle Scholar
  60. 60.
    Srugo I, Israele V, Wittek AE, et al. Clinical manifestations of varicella-zoster virus infections in human immunodeficiency virus-infected children. Am J Dis Child. 1993;147:742–5.PubMedGoogle Scholar
  61. 61.
    Wood SM, Shah SS, Steenhoff AP, Rutstein RM. Primary varicella and herpes zoster among HIV-infected children from 1989 to 2006. Pediatrics. 2008;121:e150–6.CrossRefPubMedGoogle Scholar
  62. 62.
    Kao C, Goldman DL. Cryptococcal disease in HIV-infected children. Curr Infect Dis Rep. 2016;18:27.CrossRefPubMedGoogle Scholar
  63. 63.
    Meiring ST, Quan VC, Cohen C, et al. A comparison of pediatric- and adult-onset cryptococcosis detected through population surveillance in South Africa, 2005–2007. AIDS. 2012;26:2307–14.CrossRefPubMedGoogle Scholar
  64. 64.
    WHO. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. 2011.
  65. 65.
    Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med. 2016;374:542–54.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Beardsley J, Wolbers M, Day JN, CrptoDex Investigators. Dexamethasone in cryptococcal meningitis. N Engl J Med. 2016;375:189–90.PubMedGoogle Scholar
  67. 67.
    Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children: Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Department of Health and Human Services.
  68. 68.
    Schwenk H, Ramirez-Avila L, Sheu SH, et al. Progressive multifocal leukoencephalopathy in pediatric patients: case report and literature review. Pediatr Infect Dis J. 2014;33(4):e99–105.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266:1865.CrossRefPubMedGoogle Scholar
  70. 70.
    Orem J, Otieno MW, Remick SC. AIDS-associated cancer in developing nations. Curr Opin Oncol. 2004;16:468.CrossRefPubMedGoogle Scholar
  71. 71.
    Gantt S, Orem J, Krantz EM, Morrow RA, et al. Prospective characterization of the risk factors for transmission and symptoms of primary human herpesvirus infections among Ugandan infants. J Infect Dis. 2016;214:36.CrossRefPubMedGoogle Scholar
  72. 72.
    Butler LM, Were WA, Balinandi S, Downing R, et al. Human herpesvirus 8 infection in children and adults in a population-based study in rural Uganda. J Infect Dis. 2011;203:625.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Rohner E, Wyss N, Heg Z, et al. HIV and human herpesvirus 8 co-infection across the globe: systematic review and meta-analysis. Int J Cancer. 2016;138:45–54.CrossRefPubMedGoogle Scholar
  74. 74.
    Bohlius J, Maxwell N, Spoerri A, Wainwright R, et al. Incidence of AIDS-defining and other cancers in HIV-positive children in South Africa: record linkage study. Pediatr Infect Dis J. 2016;35:e164–70.CrossRefPubMedGoogle Scholar
  75. 75.
    Rohner E, Valeri F, Maskew M, Prozesky H, et al. Incidence rate of Kaposi sarcoma in HIV-infected patients on antiretroviral therapy in Southern Africa: a prospective multicohort study. J Acquir Immune Defic Syndr. 2014;67:547–54.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Luppi M, Barozzi P, Rasini V, et al. Severe pancytopenia and hemophagocytosis after HHV-8 primary infection in a renal transplant patient successfully treated with foscarnet. Transplantation. 2002;74:131–2.CrossRefPubMedGoogle Scholar
  77. 77.
    Vaz P, Macassa E, Jani I, et al. Treatment of Kaposi sarcoma in human immunodeficiency virus-1-infected Mozambican children with antiretroviral drugs and chemotherapy. Pediatr Infect Dis J. 2011;30:891–3.CrossRefPubMedGoogle Scholar
  78. 78.
    World Health Organization. Guidelines on the treatment of skin and oral HIV-associated conditions in children and adults. Geneva; 2014.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Paediatrics and Child Health and KIDCRU Pediatric Infectious Diseases Clinical Research UnitStellenbosch University, Tygerberg Children’s HospitalCape TownSouth Africa
  2. 2.Clinical School, The Children’s Hospital at Westmead and the Marie Bashir Institute for Infectious Diseases and BiosecurityWestmeadAustralia
  3. 3.University of SydneySydneyAustralia

Personalised recommendations