Viral Co-infection in COVID-19: Prevalence and Clinical Associations of Human Pegivirus

ObjectiveThis study investigates the prevalence of human pegivirus (HPgV) in SARS-CoV-2-positive patients within the context of viral co-infections that may modulate COVID-19 outcomes and assesses whether HPgV co-infection is associated with COVID-19 severity. HPgV is a widely circulating but rarely monitored human virus with documented immunomodulatory effects in other viral infections, including HIV and Ebola. While HPgV prevalence is low in the general U.S. population (1-2%), it rises markedly in the setting of chronic viral co-infections, particularly HIV (15-40%). Given its immunologic effects and persistence, HPgV represents a biologically plausible but unexplored viral co-factor SARS-CoV-2 infection. MethodsWe analyzed four cohorts: SARS-CoV-2-positive individuals, ICU patients with respiratory symptoms but SARS-CoV-2-negative, HIV-positive individuals as a positive control for HPgV detection, and uninfected controls. ResultsHPgV prevalence in COVID-19 patients was low (2.1%) and comparable to population estimates. As expected, HPgV prevalence was substantially higher in the HIV cohort (34%), validating assay performance and cohort stratification. Among HPgV-positive COVID-19 cases, most experienced mild disease, with directional trends toward reduced severity despite high baseline risk factors. Healthcare workers in the control group showed unexpectedly elevated HPgV prevalence (9.6%). ConclusionsHPgV is an unmonitored but widely circulating viral co-infection in humans that may influence host responses to SARS-CoV-2. Although limited by small numbers, our findings support further investigation of HPgV and other immunomodulatory viral co-infections in COVID-19. This study suggests that HPgV co-infection may influence COVID-19 outcomes, warranting further investigation. HighlightsO_LISystematic screening of human pegivirus (HPgV), an unmonitored viral co-infection, in COVID-19 (n = 634). C_LIO_LIHPgV prevalence in COVID-19 mirrored population estimates but was markedly enriched in HIV (positive control). C_LIO_LIHPgV-positive COVID-19 cases showed trends toward milder clinical outcomes. C_LIO_LIFindings highlight the potential relevance of immunomodulatory viral co-infections in SARS-CoV-2 infection. C_LI Executive SummaryThis study evaluated the prevalence of human pegivirus (HPgV) co-infection among SARS-CoV-2-positive patients as part of a broader effort to understand how concurrent viral infections may influence COVID-19 severity. HPgV is a largely unmonitored, persistent human virus with well-described immunomodulatory effects in other viral infections, yet it has not been systematically evaluated in COVID-19. We therefore screened HPgV prevalence across COVID-19 cases, comparator cohorts, and an HIV-positive cohort as a positive control due to the well-established high prevalence of HPgV in HIV infection. Our findings indicate that HPgV prevalence in SARS-CoV-2-positive and -negative hospitalized individuals are consistent with the general U.S. population range (approximately 1-5%). Healthcare professionals exhibited a higher HPgV prevalence ([~]10%), suggesting that repeated occupational viral exposures may influence infection rates. While limited by small numbers, HPgV co-infection in COVID-19 cases was associated with directional trends toward reduced disease severity, warranting further longitudinal and mechanistic investigation. Editors summaryThis study identifies human pegivirus as a widely circulating, unmonitored viral co-infection in COVID-19 with potential relevance to disease severity.