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

Abstract

In South Africa, the Coronavirus Disease 2019 (COVID-19) pandemic is occurring against the backdrop of high Human Immunodeficiency Virus (HIV), tuberculosis and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa during the period June–August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to COVID-19 severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included in this study. 61% were men and 39% women with a median age of 53 years (range 21–86). 29.8% (95% CI: 21.7–39.1%) of the cohort was HIV positive and 41.1% (95% CI: 31.6–51.1%) were KSHV seropositive. EBV VL was detectable in 84.4% (95% CI: 76.1–84.4%) of the cohort while KSHV DNA was detected in 20.6% (95% CI: 13.6–29.2%), with dual EBV/KSHV infection in 17.7% (95% CI: 11.1–26.2%). On enrollment, 48 [46.2% (95% CI: 36.8–55.7%)] COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements and 30 of these patients [28.8% (95% CI: 20.8–38.0%)] later died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV status and detectable EBV VL [p = 0.036, adjusted OR = 3.17 (95% CI: 1.08–9.32)]. Furthermore, in HIV negative COVID-19 patients, there was a trend indicating that KSHV VL may be related to COVID-19 disease severity [p = 0.054, unstandardized co-efficient 0.86 (95% CI: –0.015–1.74)] in addition to death [p = 0.008, adjusted OR = 7.34 (95% CI: 1.69–31.49)]. While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is indeed fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation.

SARS‐CoV‐2 infection and lytic reactivation of herpesviruses: A potential threat in the postpandemic era?

“…Finally, a study of 104 patients in South Africa, where there is a high prevalence of herpesviruses infections, reported that coinfection with KSHV but not EBV might be associated with the severity of clinical outcomes following COVID‐19. 26 …”

“…Finally, a study of 104 patients in South Africa, where there is a high prevalence of herpesviruses infections, reported that coinfection with KSHV but not EBV might be associated with the severity of clinical outcomes following COVID-19. 26 In addition to viral coinfection, anti-COVID-19 therapies, including azithromycin, nafamostat mesylate, and remdesivir are associated with activating different cellular signaling pathways leading to viral lytic reactivation. 23,27 Azithromycin, an antibiotic for treatment of bacterial infections, effectively upregulated mitogenactivated protein kinases (MAPKs) signaling activities to mediate lytic reactivation.…”

BUCCAL KAPOSI’S SARCOMA ASSOCIATED WITH HIV INFECTION AND COVID-19: A case report

“…Since covid 19, several studies have demonstrated the action of SARS Cov 2 on the reactivation of the HHV 8 virus hence the increased prevalence of Kaposi's sarcoma. They even found that the quality of life of patients with Kaposi's sarcoma infected with SARS Cov 2 without HIV infection is lower than those infected with HIV [1,6].…”

“…The severity lies in acute respiratory distress syndrome and multi-organ failure. In addition, several skin manifestations have also been widely documented including frostbite-like lesions, erythema multiforme and maculopapular lesions [1].…”

Epstein–Barr virus and COVID‐19

“…For instance, a previous study did not show increased disease severity in individuals with coinfection of EBV and SARS‐CoV‐2 and the results demonstrated no differences in terms of viral load and disease outcome. 15 On the other hand, EBV coinfection was associated with increased incidence of fever, higher aspartate aminotransferase and C‐reactive protein values, and corticosteroid use compared to SARS‐CoV‐2 infection alone in another study by Chen et al 6 EBV reactivation was also associated with a longer duration of Intensive care unit stay. 16 However, stringent care is advised in evaluating the evidence of the causal association of EBV with COVID‐19 severity or long COVID symptoms, considering the potential confounding effects of the high prevalence of EBV in the general population and the reactivation of other latent viruses in patients, such as herpes simplex virus, cytomegalovirus, Varicella zoster virus (VZV), human herpes virus‐6 (HHV‐6), and human herpes virus‐7 (HHV‐7).…”