Herpesvirus reactivation in critical illness: Pathogenesis, clinical consequences, and diagnostic challenges

Human herpesviruses (HHV) remain latent after primary infection and may reactivate during critical illness. HHV reactivation has been associated with adverse clinical outcomes, yet its pathogenic significance and optimal management remain unclear. This review summarizes the dysregulated immune mechanisms and risk factors for HHV reactivation in critical illness, treatment options, outcomes, current diagnostic challenges, and emerging precision medicine approaches. Critical illness induces profound immune dysregulation characterized by an initial hyperinflammatory response followed by immunosuppression, T-cell exhaustion, impaired natural killer cell function, and disrupted antiviral surveillance. These changes facilitate reactivation of latent HHV, including herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6). HSV and CMV reactivation in mechanically ventilated and septic patients have been associated with prolonged mechanical ventilation, longer intensive care unit (ICU) stay, secondary infections, and increased mortality. However, the distinction between clinically significant disease from asymptomatic reactivation remains challenging. Current evidence does not support routine antiviral prophylaxis in immunocompetent ICU patients. Emerging approaches including metagenomic next-generation sequencing, host transcriptomics, immune phenotyping, and multi-omics integration may improve risk stratification and identify patient subgroups that are most likely to benefit from targeted intervention. HHV reactivation may serve as a biomarker and potential mediator of adverse outcomes. Improved understanding of host-virus interactions, coupled with precision medicine that integrates virological and immunological data, is required to differentiate clinically relevant reactivation from epiphenomena and to guide individualized therapeutic strategies.