Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis

Rishi K Gupta, Sebastian B Lucas, Katherine L Fielding, Stephen D Lawn, Rishi K Gupta, Sebastian B Lucas, Katherine L Fielding, Stephen D Lawn

Abstract

Objectives: Tuberculosis (TB) is estimated to be the leading cause of HIV-related deaths globally. However, since HIV-associated TB frequently remains unascertained, we systematically reviewed autopsy studies to determine the true burden of TB at death.

Methods: We systematically searched Medline and Embase databases (to end 2013) for literature reporting on health facility-based autopsy studies of HIV-infected adults and/or children in resource-limited settings. Using forest plots and random-effects meta-analysis, we summarized the TB prevalence found at autopsy and used meta-regression to explore variables associated with autopsy TB prevalence.

Results: We included 36 eligible studies, reporting on 3237 autopsies. Autopsy TB prevalence was extremely heterogeneous (range 0-64.4%), but was markedly higher in adults [pooled prevalence 39.7%, 95% confidence interval (CI) 32.4-47.0%] compared to children (pooled prevalence 4.5%, 95% CI 1.7-7.4%). Post-mortem TB prevalence varied by world region, with pooled estimates in adults of 63.2% (95% CI 57.7-68.7%) in South Asia (n = 2 studies); 43.2% (95% CI 38.0-48.3) in sub-Saharan Africa (n = 9 studies); and 27.1% (95% CI 16.0-38.1%) in the Americas (n = 5 studies). Autopsy prevalence positively correlated with contemporary estimates of national TB prevalence. TB in adults was disseminated in 87.9% (82.2-93.7%) of cases and was considered the cause of death in 91.4% (95% CI 85.8-97.0%) of TB cases. Overall, TB was the cause of death in 37.2% (95% CI 25.7-48.7%) of adult HIV/AIDS-related deaths. TB remained undiagnosed at death in 45.8% (95% CI 32.6-59.1%) of TB cases.

Conclusions: In resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths. Almost half of this disease remains undiagnosed at the time of death. These findings highlight the critical need to improve the prevention, diagnosis and treatment of HIV-associated TB globally.

Figures

Fig. 1
Fig. 1
Flow diagram showing study selection process and reasons for exclusions.
Fig. 2 (Continued)
Fig. 2 (Continued)
Forest plots showing post-mortem prevalence [% (95% CI)] of tuberculosis (TB) in the following as given in the legend.
Fig. 2 (Continued)
Fig. 2 (Continued)
Forest plots showing post-mortem prevalence [% (95% CI)] of tuberculosis (TB) in the following as given in the legend.
Fig. 2 (Continued)
Fig. 2 (Continued)
Forest plots showing post-mortem prevalence [% (95% CI)] of tuberculosis (TB) in the following as given in the legend.
Fig. 3
Fig. 3
Meta-regression analyses showing graphs of post-mortem prevalence of tuberculosis (Y-axis) plotted against the following.

References

    1. World Health Organization. World Health Organization Global TB Report 2014. Geneva, Switzerland. [Accessed 28 January 2015]
    1. UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2013. 2013. [Accessed 28 January 2015]
    1. World Health Organization. WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders. Geneva, Switzerland. 2012. [Accessed 28 January 2015]
    1. Mudenda V, Lucas S, Shibemba A, O’Grady J, Bates M, Kapata N, et al. Tuberculosis and tuberculosis/HIV/AIDS-associated mortality in Africa: the urgent need to expand and invest in routine and research autopsies. J Infect Dis 2012; 205 Suppl:S340–S346.
    1. Lucas S. Causes of death in the HAART era. Curr Opin Infect Dis 2012; 25:36–41.
    1. Beadsworth MBJ, Cohen D, Ratcliffe L, Jenkins N, Taylor W, Campbell F, et al. Autopsies in HIV: Still identifying missed diagnoses. Int J STD AIDS 2009; 20:84–86.
    1. Lawn SD, Meintjes G, McIlleron H, Harries AD, Wood R. Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review. BMC Med 2013; 11:253.
    1. Cox JA, Lukande RL, Lucas S, Nelson AM, Van Marck E, Colebunders R. Autopsy causes of death in HIV-positive individuals in sub-Saharan Africa and correlation with clinical diagnoses. AIDS Rev 2010; 12:183–194.
    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; 19:229–237.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6:e1000097.
    1. Marques LP, Rioja LS, Oliveira CA, Santos OD. AIDS-associated renal tuberculosis. Nephron 1996; 74:701–704.
    1. Ikeogu MO, Wolf B, Mathe S. Pulmonary manifestations in HIV seropositivity and malnutrition in Zimbabwe. Arch Dis Child 1997; 76:124–128.
    1. Chakraborty R, Pulver A, Pulver LS, Musoke R, Palakudy T, D’Agostino A, et al. The postmortem pathology of HIV-1-infected African children. Ann Trop Paediatr 2002; 22:125–131.
    1. Wong EB, Omar T, Setlhako GJ, Osih R, Feldman C, Murdoch DM, et al. Causes of death on antiretroviral therapy: a post-mortem study from South Africa. PLoS One 2012; 7:e47542.
    1. Cox JA, Lukande RL, Nelson AM, Mayanja-Kizza H, Colebunders R, Van Marck E, et al. An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala. Uganda PLoS One 2012; 7:e33685.
    1. Cohen T, Murray M, Wallengren K, Alvarez GG, Samuel EY, Wilson D. The prevalence and drug sensitivity of tuberculosis among patients dying in hospital in KwaZulu-Natal, South Africa: a postmortem study. PLoS Med 2010; 7:e1000296.
    1. Siika AM, Chumba D, Buziba N, Ayikukwei R, Mwangi A, Smith J, et al. Causes of death in HIV-positive Africans on antiretroviral therapy [Abstract THPE046]. Programme and Abstracts of the XIX International AIDS Conference, July 2012, Washington, DC. Geneva, Switzerland: International AIDS Society 2012.
    1. Chintu C, Mudenda V, Lucas S, Nunn A, Lishimpi K, Maswahu D, et al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002; 360:985–990.
    1. Ansari NA, Kombe AH, Kenyon TA, Mazhani L, Binkin N, Tappero JW, et al. Pathology and causes of death in a series of human immunodeficiency virus-positive and -negative pediatric referral hospital admissions in Botswana. Pediatr Infect Dis J 2003; 22:43–47.
    1. Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N’Gbichi JM, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993; 7:1569–1579.
    1. Rana FS, Hawken MP, Mwachari C, Bhatt SM, Abdullah F, Ng’ang’a LW, et al. Autopsy study of HIV-1-positive and HIV-1-negative adult medical patients in Nairobi, Kenya. J Acquir Immune Defic Syndr 2000; 24:23–29.
    1. Abouya YL, Beaumel A, Lucas S, Dago-Akribi A, Coulibaly G, N’Dhatz M, et al. Pneumocystis carinii pneumonia: an uncommon cause of death in African patients with acquired immunodeficiency syndrome. Am Rev Respir Dis 1992; 145:617–620.
    1. Amarapurkar AD, Sangle NA. Histological spectrum of liver in HIV: autopsy study. Ann Hepatol 2005; 4:47–51.
    1. Ansari NA, Kombe AH, Kenyon TA, Hone NM, Tappero JW, Nyirenda ST, et al. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997-1998. Int J Tuberc Lung Dis 2002; 6:55–63.
    1. Borges AS, Ferreira MS, Nishioka S, da A, Silvestre MT, Silva AM, Rocha A. Agreement between premortem and postmortem diagnoses in patients with acquired immunodeficiency syndrome observed at a Brazilian teaching hospital. Rev Inst Med Trop Sao Paulo 1997; 39:217–221.
    1. Cury PM, Pulido CF, Furtado VMG, da Palma FMC. Autopsy findings in AIDS patients from a reference hospital in Brazil: analysis of 92 cases. Pathol Res Pract 2003; 199:811–814.
    1. Eza D, Cerrillo G, Moore DAJ, Castro C, Ticona E, Morales D, et al. Postmortem findings and opportunistic infections in HIV-positive patients from a public hospital in Peru. Pathol Res Pract 2006; 202:767–775.
    1. Hsiao CH, Huang SHF, Song CL, Su IJ, Chuang CY, Yao YT, et al. Autopsy findings on patients with AIDS in Taiwan. Zhonghua Min. Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1997; 30:145–159.
    1. Jessurun J, Angeles-Angeles A, Gasman N. Comparative demographic and autopsy findings in acquired immune deficiency syndrome in two Mexican populations. J Acquir Immune Defic Syndr 1990; 3:579–583.
    1. Mohar A, Romo J, Salido F, Jessurun J, Ponce de Leon S, Reyes E, et al. The spectrum of clinical and pathological manifestations of AIDS in a consecutive series of autopsied patients in Mexico. AIDS 1992; 6:467–473.
    1. Lanjewar DN. The spectrum of clinical and pathological manifestations of AIDS in a consecutive series of 236 autopsied cases in Mumbai, India. Patholog Res Int 2011; 2011:547618.
    1. Nelson AM, Perriens JH, Kapita B, Okonda L, Lusamuno N, Kalengayi MR, et al. A clinical and pathological comparison of the WHO and CDC case definitions for AIDS in Kinshasa, Zaire: is passive surveillance valid?. AIDS 1993; 7:1241–1245.
    1. Bhoopat L, Thamprasert K, Chaiwun B, Attasiri C, Vithayasai P, Chaimongkol B, et al. Histopathologic spectrum of AIDS-associated lesions in Maharaj Nakorn Chiang Mai Hospital. Asian Pac J Allergy Immunol 1994; 12:95–104.
    1. Drut R, Anderson V, Greco MA, Gutierrez C, de Leon-Bojorge B, Menezes D, et al. Opportunistic infections in pediatric HIV infection: a study of 74 autopsy cases from latin America: the Latin American Aids Pathology Study Group. Pediatr Pathol Lab Med 1997; 17:569–576.
    1. Jeena PM, Coovadia HM, Chrystal V. Pneumocystis carinii and cytomegalovirus infections in severely ill, HIV-infected African infants. Ann Trop Paediatr 1996; 16:361–368.
    1. Lucas SB, Peacock CS, Hounnou A, Brattegaard K, Koffi K, Honde M, et al. Disease in children infected with HIV in Abidjan, Cote d’Ivoire. BMJ 1996; 312:335–338.
    1. Nathoo KJ, Gondo M, Gwanzura L, Mhlanga BR, Mavetera T, Mason PR, et al. Fatal Pneumocystis carinii pneumonia in HIV-seropositive infants in Harare, Zimbabwe. Trans R Soc Trop Med Hyg 2001; 95:37–39.
    1. Rennert WP, Kilner D, Hale M, Stevens G, Stevens W, Crewe-Brown H. Tuberculosis in children dying with HIV-related lung disease: clinical-pathological correlations. Int J Tuberc Lung Dis 2002; 6:806–813.
    1. Ayisi NK, Wiredu EK, Sata T, Nyadedzor C, Tsiagbe VK, Newman M, et al. T-lymphocytopaenia, opportunistic infections and pathological findings in Ghanaian AIDS patients and their sexual partners. East Afr Med J 1997; 74:784–791.
    1. Carrilho C, Monteiro E, Ussene E, Macie A, Fernandes F, Lorenzoni C, et al. Causes of death in HIV/AIDS patients in Maputo Central Hospital: a retrospective study from 2011. Histopathology 2012; 61:1–2.
    1. Deshmukh SD, Jadhav MV, Gogate BP, Kakarani AL, Bulakh PM, Labhsetwar AS, et al. Profile of lesions in patients of HIV/AIDS with tuberculosis: an autopsy study [Abstract 896]. Program and abstracts of the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2003, Paris, France. Geneva, Switzerland: Interntional AIDS Society.
    1. Garcia-Jardon M, Bhat VG, Blanco-Blanco E, Stepian A. Postmortem findings in HIV/AIDS patients in a tertiary care hospital in rural South Africa. Trop Doct 2010; 40:81–84.
    1. Liu D, Lin CS. Clinicopathological study of 34 autopsy cases of mycobacteriosis in patients with acquired immunodeficiency syndrome. Zhonghua Jie He He Hu Xi Za Zhi 1996; 19:136–139.
    1. Satyanarayana S, Kalghatgi AT, Malaviya AK, Bhardwaj JR, Muralidhar A, Jawed KZ, et al. Needle necropsy in AIDS. Indian J Pathol Microbiol 2003; 46:416–419.
    1. Soeiro AdeM, Hovnanian ALD, Parra ER, Canzian M, Capelozzi VL. Postmortem histological pulmonary analysis in patients with HIV/AIDS. Clinics (Sao Paulo) 2008; 63:497–502.
    1. Souza SL, Feitoza PV, Araújo JR, Andrade RV, Ferreira LC. Causes of death among patients with acquired immunodeficiency syndrome autopsied at the Tropical Medicine Foundation of Amazonas. Rev Soc Bras Med Trop 2008; 41:247–251.
    1. Viriyavejakul P, Rojanasunan P, Viriyavejakul A, Tangwanicharoen T, Punyarit P, Punpoowong B, et al. Necropsy in HIV-infected patients. Southeast Asian J Trop Med Public Health 2002; 33:85–91.
    1. Gupta A, Wood R, Kaplan R, Bekker L-G, Lawn SD. Prevalent and incident tuberculosis are independent risk factors for mortality among patients accessing antiretroviral therapy in South Africa. PLoS One 2013; 8:e55824.
    1. Bates M, Mudenda V, Shibemba A, Kaluwaji J, Tembo J, Kabwe M, et al. Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study. Lancet Infect Dis 2015; 15:544–551.
    1. World Health Organization. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents: Recommendations for HIV-prevalent and resource-constrained settings. Geneva, Switzerland: 2007. [Accessed 28 January 2015]
    1. Lawn SD, Ayles H, Egwaga S, Williams B, Mukadi YD, Santos Filho ED, et al. Potential utility of empirical tuberculosis treatment for HIV-infected patients with advanced immunodeficiency in high TB-HIV burden settings. Int J Tuberc Lung Dis 2011; 15:287–295.
    1. Lawn SD, Mwaba P, Bates M, Piatek A, Alexander H, Marais BJ, et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis 2013; 13:349–361.
    1. World Health Organization. Automated Real-time Nucleic Acid Amplification Technology for Rapid and Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB /RIF System Policy Statement. Geneva, Switzerland. 2011. [Accessed 28 January 2015]
    1. Maynard-Smith L, Larke N, Peters JA, Lawn SD. Diagnostic accuracy of the Xpert MTB/RIF assay for extrapulmonary and pulmonary tuberculosis when testing nonrespiratory samples: a systematic review. BMC Infect Dis 2014; 14:709.
    1. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J 2014; 44:435–446.
    1. World Health Organization. Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. 2014. [Accessed 28 January 2015]
    1. Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, et al. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med 2011; 8:e1001067.
    1. Lawn SD, Kerkhoff AD, Vogt M, Wood R. High diagnostic yield of tuberculosis from screening urine samples from HIV-infected patients with advanced immunodeficiency using the Xpert MTB/RIF assay. J Acquir Immune Defic Syndr 2012; 60:289–294.
    1. Lawn SD. Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV-associated tuberculosis: a state of the art review. BMC Infect Dis 2012; 12:103.
    1. Lawn SD, Kerkhoff AD, Vogt M, Wood R. Clinical significance of lipoarabinomannan (LAM) detection in urine using a low-cost point-of-care diagnostic assay for HIV-associated tuberculosis. AIDS 2012; 26:1635–1643.
    1. Lawn S, Kerkhoff A, Burton R, Vogt M, Pahlana P, Nicol M, et al. Systematic investigation for tuberculosis in HIV-infected patients on the first day of admission to a South African hospital: incremental diagnostic yield, accuracy and prognostic value of a urine LAM lateral-flow assay. Abstr 45th Union World Conf Lung Heal Int Union Against Tuberc Lung Dis (IUATLD) Barcelona, Spain 2014; HIV Late Breaker Oral Presentation (HIV_LB04).
    1. Peter JG, Theron G, Muchinga TE, Govender U, Dheda K. The diagnostic accuracy of urine-based Xpert MTB/RIF in HIV-infected hospitalized patients who are smear-negative or sputum scarce. PLoS One 2012; 7:e39966.
    1. UNAIDS. Fast-track: ending the AIDS epidemic by 2030. UNAIDS, Geneva, 2014. [Accessed 28 January 2015]
    1. Suthar AB, Lawn SD, del Amo J, Getahun H, Dye C, Sculier D, et al. Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and meta-analysis. PLoS Med 2012; 9:e1001270.
    1. Lawn SD. Preventing HIV-associated tuberculosis with antiretroviral therapy: shut the stable door early!. Int J Tuberc Lung Dis 2015; 19:3–4.
    1. Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G, et al. Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. Lancet 2014; 384:682–690.
    1. 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.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe