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

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.

Figure 1. 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.