Autopsy Prevalence of Tuberculosis and Other Potentially Treatable Infections among Adults with Advanced HIV Enrolled in Out-Patient Care in South Africa

Abstract

Background: Early mortality among HIV-positive adults starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis (TB) the leading cause of death. However, current methods to estimate TB-related deaths are inadequate and most autopsy studies do not adequately represent those attending primary health clinics (PHCs). This study aimed to determine the autopsy prevalence of TB and other infections in adults enrolled at South African PHCs in the context of a pragmatic trial of empiric TB treatment ("TB Fast Track").

Methods and findings: Adults with CD4 ≤150 cells/μL, not on ART or TB treatment, were enrolled to TB Fast Track and followed up for at least six months. Minimally invasive autopsy (MIA) was conducted as soon as possible after death. Lungs, liver, and spleen were biopsied; blood, CSF, and urine aspirated; and bronchoalveolar lavage fluid obtained. Samples underwent mycobacterial, bacterial, and fungal culture; molecular testing (including Xpert® MTB/RIF); and histological examination. 34 MIAs were conducted: 18 (53%) decedents were female; median age was 39 (interquartile range 33-44) years; 25 (74%) deaths occurred in hospitals; median time from death to MIA was five (IQR 3-6) days. 16/34 (47%) had evidence of TB (14/16 [88%] with extrapulmonary disease; 6/16 [38%] not started on treatment antemortem); 23 (68%) had clinically important bacterial infections; four (12%) cryptococcal disease; three (9%) non-tuberculous mycobacterial disease; and two (6%) Pneumocystis pneumonia. Twenty decedents (59%) had evidence of two or more concurrent infections; 9/16 (56%) individuals with TB had evidence of bacterial disease and two (13%) cryptococcal disease.

Conclusions: TB, followed by bacterial infections, were the leading findings at autopsy among adults with advanced HIV enrolled from primary care clinics. To reduce mortality, strategies are needed to identify and direct those at highest risk into a structured pathway that includes expedited investigation and/or treatment of TB and other infections.

Fig 1. Six examples of histological changes observed in MIA tissue samples (n = 4).

Panels (A), (B), and (C) demonstrate mycobacterial and CMV disease in the lung and liver of decedent 08: (A) necrotising, intra-alveolar granuloma with superadded CMV nuclear inclusions (lung; H&E x40); (B) numerous acid-fast bacilli (lung; ZN x40); and (C) mycobacterial granuloma (liver; H&E x20). Panel (D) demonstrates polymorphous cryptococcal yeasts in alveolar spaces (decedent 19; lung; Grocott’s methenamine silver x40). Panel (E) illustrates the characteristic small, crescenteric, yeast-like fungi of Pneumocystis jirovecii pneumonia (decedent 11; lung; Grocott’s methenamine silver x40). Panel (F) shows active hepatitis B virus infection (decedent 34; liver; H&E x40). CMV: cytomegalovirus; H&E: haematoxylin and eosin; MIA: minimally invasive autopsy; ZN: Ziehl-Neelsen

Fig 2. Venn diagram illustrating overlap between diagnoses made at autopsy: any active TB; extrapulmonary TB; any bacterial infection; bacterial pneumonia; disease due to non-tuberculous mycobacteria; cryptococcal disease; and Pneumocystis pneumonia (n = 31*).

*Figure only includes decedents with autopsy evidence of disease due to specified pathogens