Clinical Manifestations of HIV-Associated Tuberculosis in Adults

  • Sean WassermanEmail author
  • David Barr
  • Graeme Meintjes


HIV-associated tuberculosis is a heterogenous disease that confronts clinicians with substantial diagnostic challenge. Clinical syndromes are frequently non-specific in terms of symptoms, physical examination, routine laboratory testing, and chest radiography. Further complicating management is the possibility of co-infection with other severe opportunistic infections, all of which may have clinical presentations that mimic tuberculosis. Early recognition and treatment is urgent because of more severe manifestations and rapid progression, particularly at low CD4 counts. This chapter describes clinical manifestations and diagnostic approaches for HIV-associated tuberculosis in adults, with an emphasis on practice in resource-limited, high-burden settings. Advanced immunosuppression and disseminated disease are considered separately from ambulant patients with preserved CD4 cell counts in order to highlight differences in clinical phenotype, differential diagnosis, and management strategies. Clinical features and evaluation of common extra-pulmonary manifestations are also covered.


HIV-associated tuberculosis Mycobacteraemia Disseminated tuberculosis Extra-pulmonary tuberculosis Lipoarabinomannan GeneXpert Rapid diagnostics 


  1. 1.
    Barry CE 3rd, Boshoff HI, Dartois V et al (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7:845–855PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Gupta RK, Lucas SB, Fielding KL et al (2015) Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis. AIDS (London, England) 29:1987–2002CrossRefGoogle Scholar
  3. 3.
    Getahun H, Kittikraisak W, Heilig CM et al (2011) Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med 8:e1000391PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Hamada Y, Lujan J, Schenkel K et al (2018) Sensitivity and specificity of WHO’s recommended four-symptom screening rule for tuberculosis in people living with HIV: a systematic review and meta-analysis. The Lancet HIV 5:e515–ee23PubMedCrossRefGoogle Scholar
  5. 5.
    Wood R, Middelkoop K, Myer L et al (2007) Undiagnosed tuberculosis in a community with high HIV prevalence: implications for tuberculosis control. Am J Respir Crit Care Med 175:87–93PubMedCrossRefGoogle Scholar
  6. 6.
    Lawn SD, Kerkhoff AD, Vogt M et al (2013) Diagnostic and prognostic value of serum C-reactive protein for screening for HIV-associated tuberculosis. Int J Tuberc Lung Dis 17:636–643PubMedCrossRefGoogle Scholar
  7. 7.
    Drain PK, Mayeza L, Bartman P et al (2014) Diagnostic accuracy and clinical role of rapid C-reactive protein testing in HIV-infected individuals with presumed tuberculosis in South Africa. Int J Tuberc Lung Dis 18:20–26PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Wilson D, Badri M, Maartens G (2011) Performance of serum C-reactive protein as a screening test for smear-negative tuberculosis in an ambulatory high HIV prevalence population. PLoS One 6:e15248PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Nyamande K, Lalloo UG (2006) Serum procalcitonin distinguishes CAP due to bacteria, Mycobacterium tuberculosis and PJP. Int J Tuberc Lung Dis 10:510–515PubMedGoogle Scholar
  10. 10.
    Yoon C, Davis JL, Huang L et al (2014) Point-of-care C-reactive protein testing to facilitate implementation of isoniazid preventive therapy for people living with HIV. J Acquir Immune Defic Syndr 1999 65(5):551–556CrossRefGoogle Scholar
  11. 11.
    Mendelson F, Griesel R, Tiffin N et al (2018) C-reactive protein and procalcitonin to discriminate between tuberculosis, Pneumocystis jirovecii pneumonia, and bacterial pneumonia in HIV-infected inpatients meeting WHO criteria for seriously ill: a prospective cohort study. BMC Infect Dis 18:399PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Van Dyck P, Vanhoenacker FM, Van den Brande P et al (2003) Imaging of pulmonary tuberculosis. Eur Radiol 13:1771–1785PubMedCrossRefGoogle Scholar
  13. 13.
    Perlman DC, el-Sadr WM, Nelson ET et al (1997) Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. Clin Infect Dis 25:242–246PubMedCrossRefGoogle Scholar
  14. 14.
    Pedro-Botet J, Gutierrez J, Miralles R et al (1992) Pulmonary tuberculosis in HIV-infected patients with normal chest radiographs. AIDS (London, England) 6:91–93CrossRefGoogle Scholar
  15. 15.
    Organization WH (2007) Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents. WHO, GenevaGoogle Scholar
  16. 16.
    Ngwira LG, Corbett EL, Khundi M et al (2019) Screening for tuberculosis with Xpert MTB/RIF versus fluorescent microscopy among adults newly diagnosed with HIV in rural Malawi: a cluster randomized trial (Chepetsa). Clin Infect Dis 68(7):1176–1183PubMedCrossRefGoogle Scholar
  17. 17.
    Hermans SM, Babirye JA, Mbabazi O et al (2017) Treatment decisions and mortality in HIV-positive presumptive smear-negative TB in the Xpert MTB/RIF era: a cohort study. BMC Infect Dis 17:433PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Calligaro GL, Theron G, Khalfey H et al (2015) Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial. Lancet Respir Med 3:621–630PubMedCrossRefGoogle Scholar
  19. 19.
    Sigel K, Makinson A, Thaler J (2017) Lung cancer in persons with HIV. Curr Opin HIV AIDS 12:31–38PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Hanifa Y, Toro Silva S, Karstaedt A et al (2019) What causes symptoms suggestive of tuberculosis in HIV-positive people with negative initial investigations? Int J Tuberc Lung Dis 23(2):157–165PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Kaplan R, Hermans S, Caldwell J et al (2018) HIV and TB co-infection in the ART era: CD4 count distributions and TB case fatality in Cape Town. BMC Infect Dis 18:356PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Osler M, Hilderbrand K, Goemaere E et al (2018) The continuing burden of advanced HIV disease over 10 years of increasing antiretroviral therapy coverage in South Africa. Clin Infect Dis 66:S118–Ss25PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Crump JA, Reller LB (2003) Two decades of disseminated tuberculosis at a university medical center: the expanding role of mycobacterial blood culture. Clin Infect Dis 37:1037–1043PubMedCrossRefGoogle Scholar
  24. 24.
    Janssen S, Schutz C, Ward A et al (2017) Mortality in severe human immunodeficiency virus-tuberculosis associates with innate immune activation and dysfunction of monocytes. Clin Infect Dis 65:73–82PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Griesel R, Stewart A, van der Plas H et al (2018) Optimizing tuberculosis diagnosis in HIV-infected inpatients meeting the criteria of seriously Ill in the WHO algorithm. Clin Infect Dis 66(9):1419–1426PubMedCrossRefGoogle Scholar
  26. 26.
    Gupta-Wright A, Corbett EL, van Oosterhout JJ et al (2018) Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial. Lancet 392:292–301CrossRefGoogle Scholar
  27. 27.
    Maartens G, Willcox PA, Benatar SR (1990) Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med 89:291–296PubMedCrossRefGoogle Scholar
  28. 28.
    Jacob ST, Pavlinac PB, Nakiyingi L et al (2013) Mycobacterium tuberculosis bacteremia in a cohort of HIV-infected patients hospitalized with severe sepsis in Uganda-high frequency, low clinical suspicion [corrected] and derivation of a clinical prediction score. PLoS One 8:e70305PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Muchemwa L, Shabir L, Andrews B et al (2017) High prevalence of Mycobacterium tuberculosis bacteraemia among a cohort of HIV-infected patients with severe sepsis in Lusaka, Zambia. Int J STD AIDS 28:584–593PubMedCrossRefGoogle Scholar
  30. 30.
    Gleeson LE, Sheedy FJ, Palsson-McDermott EM et al (2016) Cutting edge: Mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication. J Immunol 196:2444–2449PubMedCrossRefGoogle Scholar
  31. 31.
    Keiper MD, Beumont M, Elshami A et al (1995) CD4 T lymphocyte count and the radiographic presentation of pulmonary tuberculosis. A study of the relationship between these factors in patients with human immunodeficiency virus infection. Chest 107:74–80PubMedCrossRefGoogle Scholar
  32. 32.
    Greenberg SD, Frager D, Suster B et al (1994) Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 193:115–119PubMedCrossRefGoogle Scholar
  33. 33.
    Wasserman S, Engel ME, Griesel R, Mendelson M (2016) Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: a systematic review and meta-analysis. BMC Infect Dis 16:482PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Rupali P, Abraham OC, Zachariah A et al (2003) Aetiology of prolonged fever in antiretroviral-naive human immunodeficiency virus-infected adults. Natl Med J India 16:193–199PubMedGoogle Scholar
  35. 35.
    Kerkhoff AD, Meintjes G, Burton R et al (2016) Relationship between blood concentrations of hepcidin and anaemia severity, mycobacterial burden and mortality in patients with HIV-associated tuberculosis. J Infect Dis 213(1):61–70PubMedCrossRefGoogle Scholar
  36. 36.
    Andrews B, Semler MW, Muchemwa L et al (2017) Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial. JAMA 318:1233–1240PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kerkhoff AD, Meintjes G, Opie J et al (2016) Anaemia in patients with HIV-associated TB: relative contributions of anaemia of chronic disease and iron deficiency. Int J Tuberc Lung Dis 20:193–201PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kerkhoff AD, Lawn SD, Schutz C et al (2015) Anemia, blood transfusion requirements and mortality risk in human immunodeficiency virus-infected adults requiring acute medical admission to hospital in South Africa. Open Forum Infect Dis 2:ofv173PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Janssen S, Schutz C, Ward AM et al (2017) Hemostatic changes associated with increased mortality rates in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study. J Infect Dis 215:247–258PubMedGoogle Scholar
  40. 40.
    World Health Organization (2017) Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. WHO, GenevaGoogle Scholar
  41. 41.
    Griesel R, Stewart A, van der Plas H et al (2018) Optimizing tuberculosis diagnosis in human immunodeficiency virus-infected inpatients meeting the criteria of seriously ill in the World Health Organization algorithm. Clin Infect Dis 66:1419–1426PubMedCrossRefGoogle Scholar
  42. 42.
    Lawn SD, Kerkhoff AD, Burton R et al (2015) Rapid microbiological screening for tuberculosis in HIV-positive patients on the first day of acute hospital admission by systematic testing of urine samples using Xpert MTB/RIF: a prospective cohort in South Africa. BMC Med 13:192PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Gupta-Wright A, Corbett EL, Wilson D et al (2019) Risk score for predicting mortality including urine lipoarabinomannan detection in hospital inpatients with HIV-associated tuberculosis in sub-Saharan Africa: derivation and external validation cohort study. PLoS Med 16:e1002776PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kerkhoff AD, Barr DA, Schutz C et al (2017) Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays. Sci Rep 7:10931PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Gupta-Wright A, Peters JA, Flach C et al (2016) Detection of lipoarabinomannan (LAM) in urine is an independent predictor of mortality risk in patients receiving treatment for HIV-associated tuberculosis in sub-Saharan Africa: a systematic review and meta-analysis. BMC Med 14:53PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Shah M, Variava E, Holmes CB et al (2009) Diagnostic accuracy of a urine lipoarabinomannan test for tuberculosis in hospitalized patients in a High HIV prevalence setting. J Acquir Immune Defic Syndr (1999) 52:145–151CrossRefGoogle Scholar
  47. 47.
    Lawn SD, Kerkhoff AD, Burton R et al (2017) Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort. BMC Med 15:67PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    World Health Organization (2015) Guidelines on the management of latent tuberculosis infection. WHO, GenevaGoogle Scholar
  49. 49.
    Lawn SD, Kerkhoff AD, Vogt M et al (2013) HIV-associated tuberculosis: relationship between disease severity and the sensitivity of new sputum-based and urine-based diagnostic assays. BMC Med 11:231PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Iseman MD (2000) A clinician’s guide to tuberculosis. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  51. 51.
    World Health Organization. Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy update. Geneva, 2013Google Scholar
  52. 52.
    Lawn SD, Mwaba P, Bates M et al (2013) Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 13:349–361PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Batungwanayo J, Taelman H, Allen S et al (1993) Pleural effusion, tuberculosis and HIV-1 infection in Kigali, Rwanda. AIDS (London, England) 7:73–79CrossRefGoogle Scholar
  54. 54.
    Aljohaney A, Amjadi K, Alvarez GG (2012) A systematic review of the epidemiology, immunopathogenesis, diagnosis, and treatment of pleural TB in HIV-infected patients. Clin Dev Immunol 2012:842045PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Luzze H, Elliott AM, Joloba ML et al (2001) Evaluation of suspected tuberculous pleurisy: clinical and diagnostic findings in HIV-1-positive and HIV-negative adults in Uganda. Int J Tuberc Lung Dis 5:746–753PubMedGoogle Scholar
  56. 56.
    Aggarwal AN, Agarwal R, Sehgal IS et al (2019) Adenosine deaminase for diagnosis of tuberculous pleural effusion: a systematic review and meta-analysis. PLoS One 14:e0213728PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Baba K, Hoosen AA, Langeland N et al (2008) Adenosine deaminase activity is a sensitive marker for the diagnosis of tuberculous pleuritis in patients with very low CD4 counts. PLoS One 3:e2788PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Heyderman RS, Makunike R, Muza T et al (1998) Pleural tuberculosis in Harare, Zimbabwe: the relationship between human immunodeficiency virus, CD4 lymphocyte count, granuloma formation and disseminated disease. Tropical Med Int Health 3:14–20CrossRefGoogle Scholar
  59. 59.
    Sharma MP, Bhatia V (2004) Abdominal tuberculosis. Indian J Med Res 120:305–315PubMedGoogle Scholar
  60. 60.
    Riquelme A, Calvo M, Salech F et al (2006) Value of adenosine deaminase (ADA) in ascitic fluid for the diagnosis of tuberculous peritonitis: a meta-analysis. J Clin Gastroenterol 40:705–710PubMedCrossRefGoogle Scholar
  61. 61.
    Magula NP, Mayosi BM (2003) Cardiac involvement in HIV-infected people living in Africa: a review. Cardiovasc J South Afr 14:231–237Google Scholar
  62. 62.
    Mayosi BM, Wiysonge CS, Ntsekhe M et al (2006) Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry. BMC Infect Dis 6:2PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Mayosi BM, Wiysonge CS, Ntsekhe M et al (2008) Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa. S Afr Med J 98:36–40PubMedGoogle Scholar
  64. 64.
    Reuter H, Burgess LJ, Doubell AF (2005) Role of chest radiography in diagnosing patients with tuberculous pericarditis. Cardiovasc J South Afr 16:108–111Google Scholar
  65. 65.
    George S, Salama AL, Uthaman B et al (2004) Echocardiography in differentiating tuberculous from chronic idiopathic pericardial effusion. Heart 90:1338–1339PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Liu PY, Li YH, Tsai WC et al (2001) Usefulness of echocardiographic intrapericardial abnormalities in the diagnosis of tuberculous pericardial effusion. Am J Cardiol 87:1133–1135. a10PubMedCrossRefGoogle Scholar
  67. 67.
    Pandie S, Peter JG, Kerbelker ZS et al (2014) Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study. BMC Med 12:101PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Mayosi BM, Burgess LJ, Doubell AF (2005) Tuberculous pericarditis. Circulation 112:3608–3616PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of MedicineUniversity of Cape TownCape TownSouth Africa
  2. 2.Division of Infectious Diseases and HIV Medicine, Department of MedicineUniversity of Cape TownCape TownSouth Africa
  3. 3.Institute of Infection and Global Health, University of LiverpoolLiverpoolUK

Personalised recommendations