COVID-19 (coronavirus disease 2019) is the current World Health Organization-approved term used to describe the clinical syndrome ^[1][2][1,2] associated with infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Initially, the most common signs and symptoms included fever, dry cough, and dyspnoea ^[1][2][1,2]. Clinical presentations have ranged from asymptomatic to life-threatening severe acute respiratory syndrome ^[3][4][3,4]. A global pandemic of COVID-19 was declared by the World Health Organization in March 2020 [5] and continues to the present day. Over this period of time, mutations of SARS-CoV-2 have resulted in waves of infection of several variants of the virus [6]. These variants have displayed differing capacities for spread and produced severe disease in both vaccinated and non-vaccinated populations ^[7][8][7,8], particularly as a consequence of new mutations in the SARS-CoV-2 spike receptor-binding domain, potentially enabling evasion of neutralizing antibody responses. SARS-CoV-2 vaccination is a fundamental strategy for reducing COVID-19 and, to date, several vaccines have been licensed for use, while others are in the late stages of development [9]. It is becoming increasingly realised that vaccination will be a long-term measure for controlling the COVID-19 pandemic and, similarly to influenza, regular boosting will be required [10].

Nine human herpesviruses have been described. According to recently updated nomenclature [11], these are Human alphaherpesvirus 1 (herpes simplex virus type 1), Human alphaherpesvirus 2 (herpes simplex virus type 2), Human alphaherpesvirus 3 (varicella-zoster virus), Human gammaherpesvirus 4 (Epstein–Barr virus), Human betaherpesvirus 5 (human cytomegalovirus), Human betaherpesvirus 6A (human herpesvirus 6A), Human betaherpesvirus 6B (human herpesvirus 6B), Human betaherpesvirus 7 (human herpesvirus 7), and Human gammaherpesvirus 8 (Kaposi’s sarcoma herpesvirus). Throughout this resviearchw, historical nomenclature/common names will be used for the human herpesviruses. A uniform characteristic of human herpesviruses is their capacity to establish long-term or life-long immunopathological relationships with their human hosts [12]. Following primary infection, human herpesviruses are not eradicated by the host’s immune response, and virus infection is maintained in various cell types in a mostly non-replicative state (latent infection). Should the host’s immune control of virus infection be diminished, for example, by immune senescence or iatrogenic events (e.g., induced immunosuppression for transplantation) or infection by other viruses (e.g., HIV), human herpesviruses can reactivate, potentially causing severe disease (Table 1).

SARS-CoV-2 infection or vaccination evokes an immune response; the interaction of the virus with the human host is complex and remains to be fully determined ^[22][23][22,23]. Several different pathologies have been identified following SARS-COV-2 infection, e.g., asymptomatic infection [24], acute respiratory distress syndrome with cytokine storm ^[3][4][3,4], and post-acute sequelae of COVID-19 [25], commonly described as “long COVID”.

2. COVID-19 and Human Herpesviruses Reactivations

There have been several reports of systemic or pulmonary reactivation of Herpes Simplex Virus (HSV-1) in critically ill COVID-19 patients (Table 2). This topic has recently been reviewed by Giacobbe et al. [26], who reviewed seven studies of HSV-1 reactivation in critically ill COVID-19 patients together with relevant immunology and clinical implications. These authors noted that the prevalence of HSV-1 reactivation may be as high as >50%, but with a large heterogeneity across studies that is potentially attributable to a lack of standardization. Specifically, some reports have noted the clinical significance of HSV-1 reactivations to be equivocal; for example, Luyt et al. [27] have reported a 50% rate of HSV lung reactivation in 145 patients with severe COVID-19 pneumonia requiring invasive mechanical ventilation but did not observe any impact on patient outcomes. In an attempt to clarify the association between HSV-1 reactivation and mortality, Meyer et al. [28] conducted an observational study of 153 critically ill COVID-19 patients using prospectively collected data and samples. In this study [28], 26.1% patients had confirmed HSV-1 reactivation, and day-60 mortality was higher in patients with HSV-1 reactivation (57.5%) versus without (33.6%). There is evidence [29] that herpes zoster due to varicella-zoster virus (VZV) reactivation has increased during the COVID-19 pandemic, which may possibly be related to the lymphopenia commonly associated with SARS-CoV-2 infection ^[30][31][30,31]. Salim Ali Algaadi [30] recently reviewed several case reports of herpes zoster associated with COVID-19, with the conclusion that there is a potential causal relationship between COVID-19 and subsequent herpes zoster. Unfortunately, most of the evidence for this phenomenon is derived from case reports, and there is a need for further epidemiological studies. Results from a large Italian observational study of COVID-19 patients with moderate to severe acute respiratory distress syndrome [32] have shown cytomegalovirus (CMV) viraemia/reactivation in 20.4% of patients studied (Table 2). There have been several reports describing CMV reactivation with gastrointestinal tract involvement [33]. It has been suggested by Alanio et al. [34] that latent CMV infection is associated with an increased risk of COVID-19-related hospitalisation. These authors [34] demonstrated that CMV seropositivity was associated with more than twice the risk of hospitalisation due to SARS-CoV-2 infection. Furthermore, a subset of patients was immune profiled, revealing altered T cell activation profiles potentially indicative of CMV-mediated immune phenomena influencing the outcome and severity of SARS-CoV-2 infection. Other studies—for example, Weber et al. [35]—have also identified CMV seropositivity as a potential novel risk factor for severe COVID-19 (Table 2