The Contribution of Kaposi’s Sarcoma–Associated Herpesvirus to Mortality in Hospitalized Human Immunodeficiency Virus–Infected Patients Being Investigated for Tuberculosis in South Africa

Abstract

Background Despite increasing numbers of human immunodeficiency virus (HIV)–infected South Africans receiving antiretroviral therapy (ART), tuberculosis (TB) remains the leading cause of mortality. Approximately 25% of patients treated for TB have microbiologically unconfirmed diagnoses. We assessed whether elevated Kaposi’s sarcoma–associated herpesvirus (KSHV) viral load (VL) contributes to mortality in hospitalized HIV-infected patients investigated for TB. Methods Six hundred eighty-two HIV-infected patients admitted to Khayelitsha Hospital, South Africa, were recruited, investigated for TB, and followed for 12 weeks. KSHV serostatus, peripheral blood KSHV-VL, and KSHV-associated clinical correlates were evaluated. Results Median CD4 count was 62 (range, 0–526) cells/μL; KSHV seropositivity was 30.7% (95% confidence interval [CI], 27%–34%); 5.8% had detectable KSHV-VL (median, 199.1 [range, 13.4–2.2 × 106] copies/106 cells); 22% died. Elevated KSHV-VL was associated with mortality (adjusted odds ratio, 6.5 [95% CI, 1.3–32.4]) in patients without TB or other microbiologically confirmed coinfections (n = 159). Six patients had “possible KSHV-inflammatory cytokine syndrome” (KICS): 5 died, representing significantly worse survival (P < .0001), and 1 patient was diagnosed with KSHV-associated multicentric Castleman disease at autopsy. Conclusions Given the association of mortality with elevated KSHV-VL in critically ill HIV-infected patients with suspected but not microbiologically confirmed TB, KSHV-VL and KICS criteria may guide diagnostic and therapeutic evaluation.

Kaposi’s Sarcoma-Associated Herpesvirus, but Not Epstein-Barr Virus, Co-infection Associates With Coronavirus Disease 2019 Severity and Outcome in South African Patients

“…KSHV DNA was detected in 20.6% (95% CI: 13.6-29.2%) with a median VL of 1.0 copies/10 6 cells (range 1.0-38,784 copies/10 6 cells). This percentage positive is significantly higher than that reported in our previous study (Blumenthal et al, 2019) [6.4% (95% CI: 4.7-8.4%); p < 0.0001]. Both EBV and KSHV DNA was detectable in 17.7% (95% CI: 11.1-26.2%) of the cohort.…”

“…KSHV infection is generally considered to be obtained in childhood in sub-Saharan Africa, with KSHV seroprevalence peaking before adulthood (Bourboulia et al, 1998) therefore it is unlikely these cases represent new infections. Indeed, while KSHV detection is greater in this cohort than what we have seen in pre-pandemic cohorts (Blumenthal et al, 2019), viral loads are significantly lower and it is plausible that the antibody levels in these cases fall below the detection limit of our assay. In severely ill patients, lytic KSHV infection can culminate in generalized inflammation and an IL-6 induced cytokine storm (described as KICS) (Uldrick et al, 2010;Polizzotto et al, 2012;Blumenthal et al, 2019).…”

“…While this was not evident in our cohort, possibly due to almost ubiquitous EBV detection in the South African population even before the COVID-19 pandemic, it is tempting to speculate that similar mechanisms play a role for the related herpesvirus, KSHV, in our cohort, causing some disease synergy. Indeed, we found a higher than usual detection of lytic KSHV compared to previous pre-pandemic HIV-1-infected patient cohorts from the same geographic area (Blumenthal et al, 2019), and in vitro studies have also suggested that SARS-CoV-2 and drugs used in COVID-19 treatment, namely Azithromycin and Nafamostat mesylate, can induce KSHV lytic reactivation . This suggests that SARS-CoV-2 infection may cause reactivation of KSHV in latently infected individuals.…”

Epidemiology of Kaposi’s Sarcoma

“…It reaches 50% in Uganda [11,12], where the prevalence is already high in early childhood, with little increase thereafter, whereas the prevalence in South Africa and Zimbabwe in early adulthood is lower (<15%) and then increases with age [12]. In a recent study investigating patients with tuberculosis symptoms, the authors reported a seroprevalence of 30.7% in Cape Town South Africa [13].…”

The Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) gH/gL Complex Is the Predominant Neutralizing Antigenic Determinant in KSHV-Infected Individuals

“…The distribution of KSHV varies globally. In some areas such as sub-Saharan Africa (SSA), KSHV seroprevalence can be as high as 80%, whereas in the US and Europe, the prevalence is 3%-20% [3,4]. The prevalence of KS increases significantly with HIV-1 infection, making it one of the leading cancers among people living with HIV/AIDS in SSA [5,6].…”