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Causes of death on antiretroviral therapy: a post-mortem study from South Africa.

Wong EB, Omar T, Setlhako GJ, Osih R, Feldman C, Murdoch DM, Martinson NA, Bangsberg DR, Venter WD - PLoS ONE (2012)

Bottom Line: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa.Needle biopsy was efficient and yielded excellent pathology.Complex, unrecognized co-morbidities pose an additional challenge.

View Article: PubMed Central - PubMed

Affiliation: Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa. emily.wong@k-rith.org

ABSTRACT

Background: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients.

Methods: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.

Results: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.

Conclusions: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

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Simultaneous C. neoformans pneumonia and paradoxical M. tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS).At the time of death, this patient (E33) had been on anti-tuberculosis therapy for pulmonary tuberculosis for 5 months (with good response to treatment) and antiretroviral therapy for 1 month. Histologic sections demonstrate (a) suppurative consolidation of the lungs with (b) cryptococcal organisms apparent on Grocott’s Methanamine Silver (GMS) stain. Kidney (c) and spleen (d) demonstrate well formed necrotizing granulomatous inflammation, with negative Ziehl-Neelsen and GMS stains for organisms; these were thought to represent an exuberant inflammatory response due to paradoxical TB IRIS.
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pone-0047542-g001: Simultaneous C. neoformans pneumonia and paradoxical M. tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS).At the time of death, this patient (E33) had been on anti-tuberculosis therapy for pulmonary tuberculosis for 5 months (with good response to treatment) and antiretroviral therapy for 1 month. Histologic sections demonstrate (a) suppurative consolidation of the lungs with (b) cryptococcal organisms apparent on Grocott’s Methanamine Silver (GMS) stain. Kidney (c) and spleen (d) demonstrate well formed necrotizing granulomatous inflammation, with negative Ziehl-Neelsen and GMS stains for organisms; these were thought to represent an exuberant inflammatory response due to paradoxical TB IRIS.

Mentions: Our finding that IRIS contributed to over 70% of early-ART deaths highlights the importance and deadly potential of severe IRIS; in cohort studies based at ART clinics the condition has been described as usually self-limited and infrequently fatal. [36], [37] In cohort studies from Uganda and South Africa that have determined cause of death through chart-review and verbal autopsy, IRIS has been implicated in 7% of early-ART deaths and 17% of all ART-deaths respectively. [8], [33] Fatal IRIS has been reported, especially in central nervous system infections.[38]–[40] Although our study setting at a tertiary referral hospital may have influenced our findings, our high rate is supported by detailed clinicopathological data. The fatal cases described here challenge certain characteristics that have been used to define IRIS. In the consensus definition, the presence of another infection excludes IRIS [30]; however case E26 in this study demonstrates convincing evidence of paradoxical central nervous system TB IRIS with a simultaneous nosocomial bacterial pneumonia. In case E33, exuberant necrotizing granulomatous inflammation of multiple organs convinced the clinico-pathologic committee to diagnose concomitant paradoxical TB IRIS and unmasking cryptococcal IRIS (Figure 1).


Causes of death on antiretroviral therapy: a post-mortem study from South Africa.

Wong EB, Omar T, Setlhako GJ, Osih R, Feldman C, Murdoch DM, Martinson NA, Bangsberg DR, Venter WD - PLoS ONE (2012)

Simultaneous C. neoformans pneumonia and paradoxical M. tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS).At the time of death, this patient (E33) had been on anti-tuberculosis therapy for pulmonary tuberculosis for 5 months (with good response to treatment) and antiretroviral therapy for 1 month. Histologic sections demonstrate (a) suppurative consolidation of the lungs with (b) cryptococcal organisms apparent on Grocott’s Methanamine Silver (GMS) stain. Kidney (c) and spleen (d) demonstrate well formed necrotizing granulomatous inflammation, with negative Ziehl-Neelsen and GMS stains for organisms; these were thought to represent an exuberant inflammatory response due to paradoxical TB IRIS.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3472995&req=5

pone-0047542-g001: Simultaneous C. neoformans pneumonia and paradoxical M. tuberculosis Immune Reconstitution Inflammatory Syndrome (IRIS).At the time of death, this patient (E33) had been on anti-tuberculosis therapy for pulmonary tuberculosis for 5 months (with good response to treatment) and antiretroviral therapy for 1 month. Histologic sections demonstrate (a) suppurative consolidation of the lungs with (b) cryptococcal organisms apparent on Grocott’s Methanamine Silver (GMS) stain. Kidney (c) and spleen (d) demonstrate well formed necrotizing granulomatous inflammation, with negative Ziehl-Neelsen and GMS stains for organisms; these were thought to represent an exuberant inflammatory response due to paradoxical TB IRIS.
Mentions: Our finding that IRIS contributed to over 70% of early-ART deaths highlights the importance and deadly potential of severe IRIS; in cohort studies based at ART clinics the condition has been described as usually self-limited and infrequently fatal. [36], [37] In cohort studies from Uganda and South Africa that have determined cause of death through chart-review and verbal autopsy, IRIS has been implicated in 7% of early-ART deaths and 17% of all ART-deaths respectively. [8], [33] Fatal IRIS has been reported, especially in central nervous system infections.[38]–[40] Although our study setting at a tertiary referral hospital may have influenced our findings, our high rate is supported by detailed clinicopathological data. The fatal cases described here challenge certain characteristics that have been used to define IRIS. In the consensus definition, the presence of another infection excludes IRIS [30]; however case E26 in this study demonstrates convincing evidence of paradoxical central nervous system TB IRIS with a simultaneous nosocomial bacterial pneumonia. In case E33, exuberant necrotizing granulomatous inflammation of multiple organs convinced the clinico-pathologic committee to diagnose concomitant paradoxical TB IRIS and unmasking cryptococcal IRIS (Figure 1).

Bottom Line: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa.Needle biopsy was efficient and yielded excellent pathology.Complex, unrecognized co-morbidities pose an additional challenge.

View Article: PubMed Central - PubMed

Affiliation: Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa. emily.wong@k-rith.org

ABSTRACT

Background: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients.

Methods: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.

Results: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.

Conclusions: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

Show MeSH
Related in: MedlinePlus