Sepsis is an acute, life-threatening syndrome with millions of incidences each year (1). Up to 2020 the main pathogen inducing sepsis were bacteria (2, 3). However, similarly to bacterial pathogens, viruses are also capable of inducing critical conditions resulting in organ dysfunction and an increased Sequential Organ Failure Assessment (SOFA) Score (4) fulfilling the recent definition of sepsis [Sepsis-3 (5)]. During the COVID-19 pandemic up to 80% of sepsis cases were virally induced (6). In the post-pandemic era, the rate of virally sepsis has decreased; however, COVID-19 sepsis remains prevalent in ICUs worldwide, and it has guided the interest of clinicians towards virally induced sepsis, that was most likely underdiagnosed before (7).

In response to invasive bacterial pathogens, the human immune reaction initially involves the activation of the innate immunity. This consists of the complement-system as a non-cellular component as well as macrophages and neutrophile granulocytes and others as a cellular component, which opsonize, engulf and destroy bacteria. This is followed by the activation of a slower but more specific adaptive immune response. During the adaptive immune response, B-cells start the production of highly specific antibodies. Furthermore, T-cells that specifically target the invading bacteria are expanded.

In contrast, viral pathogens are intracellular and can partly evade from detection by the immune system. Thus, the immune response to viral infections involves the production of cytokines and specific interferons leading to

Therefore, a virus-specific cascade following an interferon-driven network with type 1 interferon (e.g. IFN-α) leading towards an inhibition of viral replication (9) is described. An inhibition of IL-10 and an upregulation of IL-16 (10) is observed but still incompletely understood and most probably not homogenous in different viral entities. During the pre-pandemic era, influenza was the predominant pathogen, associated to viral sepsis (2, 3).

The virus’ ability to evade the host’s immune defense and cause continuous inflammatory damage is accompanied by high levels of TNF-α and IL-6 as well as reduced IFN-γ expression (7). However, different viruses will most likely show different approaches to evading the immune defense (7).

In SARS-CoV-2-sepsis, the initially described cytokine storm turned out to be less pronounced, with moderate levels of IL-6 (11, 12) compared to bacterial sepsis.

Furthermore, an imbalance and predominance of non-type-1 cytokines (such as IL-4, or IL-17) is capable to draw the immune system towards an inappropriate response, leading to exhaustion of T-cells with ineffective clearance of viral-infected cells (7).

The immune response in COVID-19 sepsis is believed to differ significantly from bacterial immunity, characterized by a delayed and less severe response, as indicated by IL-6 serum concentrations (11, 12). When compared to Influenza, COVID-19-sepsis also develops with delayed symptoms and a prolonged inflammatory phase (12). The intricate immunological landscape involves a nuanced interplay of cytokines and key immunomodulatory elements, including Type 1 and Type 2 interferons, thereby demarcating a distinct divergence between bacterial and viral immune responses (12). Specifically, the interferon response in severe COVID-19 is released later and less pronounced than in Influenza-induced sepsis, leading to longer disease duration (12). In this multifaceted milieu, various host-related factors exert influence on immune defenses, encompassing age, genetic predisposition (13) and comorbidities such as pulmonary diseases (14), cardiovascular diseases (15, 16) and obesity (17). Notably, the identification of human cytomegalovirus (HCMV) serostatus as an independent predictor of survival in bacterial sepsis has added a significant layer to our understanding of sepsis risk factors (18).

HCMV is a herpes virus that, subsequent to the primary active infection, remains in the host’s body in a latent form detected by seropositivity. The virus re-activates frequently during life priming the immune system towards the anti-viral response. Reactivation of HCMV is mainly recognized during impaired immunity like transplant-related immunosuppression or during severe infection, often focused on sepsis. Here, reactivation is considered as a worsening factor regarding mortality, ICU-and hospital-duration and other secondary complication (19–23). Clear evidence for antiviral prophylaxis in these circumstances is still missing (24). A potential worsening effect of HCMV-reactivation on the clinical course of patients is also described in severe SARS-CoV-2, but this did not impact on patient’s mortality (25) except in the very elderly (26). As a mechanistic link between HCMV-reactivation and a propagated SARS-CoV-2 infection, an upregulation of the ACE2-receptor in lung epithelial cells driven by HCMV is discussed (27). Furthermore, a study by Choi et al. (28) describes CD8⁺ T-cell exhaustion following HCMV-reactivation.

Apart from HCMV-reactivation, HCMV in a controlled stage (latency) continuously concerns the human immunity and, in fact, HCMV seropositive patients have been reported to frequently have up to 20% of CD8⁺ T-cells specific for HCMV (29–31) a number that only increases with age.

The narrative, however, extends further. In the context of COVID-19, HCMV emerges as a consequential player, associated with heightened hospitalization (32) and ICU admission, particularly in individuals under the age of 60 (33). Despite the relatively modest cohort size in which the association regarding ICU-admission was observed, the findings suggest a complex interplay between SARS-CoV-2 and HCMV.

Moreover, HCMV has the ability to disrupt the antigen presentation process of T- and NK-cells and affect the surface maintenance of TLR4 and TLR5 on HCMV-infected cells, consequently altering immune system cascades (34). Therefore, HCMV-induced impairment of the immune system may have a significant impact on the host’s immunity during a subsequent COVID-19 infection and contribute to the development of secondary infections. Additionally, latent HCMV infection may alter the host’s response to SARS-CoV-2 vaccination, as has been observed with other viral vaccinations such as influenza (35).

In view of these intriguing observations, our study endeavors to elucidate the impact of HCMV serostatus on 30-day survival and immune response in COVID-19 sepsis, drawing parallels with the established association between HCMV and bacterial sepsis.

In our study, we observed no significant impact of HCMV serostatus on the 30-day mortality in COVID-19 sepsis. This finding contrasts starkly with bacterial sepsis, where HCMV serostatus was an independent risk factor for mortality (18). The intriguing divergence prompts contemplation on the nuanced interplay between HCMV, T-cell dynamics, and the heterogeneous landscape of COVID-19 sepsis.

The association of HCMV seropositivity with a specialized T-cell pool and diminished naïve T-cell reservoirs, known as T-cell inflation (36), has been postulated to render HCMV-seropositive patients more susceptible to heterologous infections, as their T-cell repertoire is significantly diminished (37). This might well be an explanation for the effects of HCMV on bacterial sepsis patients (18).

However, why does this not translate to COVID-19 sepsis? Interestingly, HCMV specific CD8⁺ T-cells have been shown to react to SARS-CoV-2 peptides (38) just as SARS-CoV-2 T-cell reacted to HCMV (33). This would grant HCMV seropositive patients a certain protection from COVID-19 induced death, as T-cell function is an important factor when it comes to SARS-CoV-2 immunity (39).

But how does this fit to the findings of others, that have reported that HCMV might be a risk factor for severe COVID-19 in non-geriatric patients (34)? This is especially interesting as we find the same effect of COVID-19 patients under the age of 60 more frequently being HCMV seropositive than post-surgical control patients of the same age group.

We assume, the explanation lies in the characteristic timeline of T-cell inflation, which unfolds over a longer lifetime due to recurrent HCMV reactivations (37). Consequently, any discernible effects on the immune system may be more pronounced in older patients, thereby explaining the association of HCMV with COVID-19 sepsis in younger adults.

Crucially, our study’s design deviates from previous works, such as Weber et al. (34), by contrasting severe COVID-19 cases with a pre-pandemic cohort of post-surgery patients devoid of infection or sepsis development. This approach enhances the generalizability of our findings beyond specific COVID-19 patient subsets, thereby augmenting the external validity of our results. This becomes particularly crucial when considering potential interventions or preventive measures based on our observations. What needs to be discussed at this point, is the main and obvious condition, distinguishing our post-surgery cohort from the COVID-19 patients under the age of 60 years: One main reason for surgery were malignant diseases. Thus, we cannot exclude that the known association between HCMV and malignancies (40) (41) plays further role. In this light the association does not contradict our interpretation, as we find even higher rates of HCMV-seropositivity in the COVID-19 patients than in the post-surgery cohort.

Future investigations should delve into the intricate interactions among HCMV, the immune system, and the pathogenesis of COVID-19-induced sepsis, with a specific focus on delineating the role of T-cell function and its implications for disease outcomes. By unraveling the underlying mechanisms, exploring associations in diverse patient populations, and scrutinizing potential interventions, we can deepen our understanding of HCMV’s impact on COVID-19 and potentially enhance patient management strategies.

Nevertheless, our study harbors limitations that warrant acknowledgment. Despite a relatively larger COVID-19 cohort compared to previous studies, the sample size remains modest, particularly when undertaking subgroup analyses. Thus, we advocate for retrospective assessments of HCMV serostatus in larger observational COVID-19 trials to validate our findings rigorously. The prevalence of HCMV seropositivity in the non-geriatric COVID-19 cohort introduces another constraint, diminishing the size of the seronegative cohort. As such, caution is warranted, and we refrain from definitively ruling out an effect of HCMV serostatus on the 30-day mortality in the non-geriatric cohort, given our limited statistical power.

In conclusion, our investigation unveils that HCMV seropositivity does not exert a discernible effect on the 30-day mortality in COVID-19 patients. However, a nuanced association surfaces, suggesting HCMV as a potential risk factor for severe disease, particularly in younger patients. This dichotomy underscores the complexity of viral-bacterial interactions within the immune landscape and underscores the need for further extensive studies to refine our comprehension.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of the Medical Faculty of Ruhr-University Bochum. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

DZ: Investigation, Writing – original draft, Writing – review & editing. AWo: Conceptualization, Data curation, Validation, Writing – original draft, Writing – review & editing. TR: Project administration, Writing – review & editing. HN: Software, Validation, Writing – review & editing. HH: Data curation, Writing – original draft. LB: Resources, Writing – review & editing. KR: Methodology, Resources, Writing – original draft. BD: Investigation, Writing – review & editing. LP: Data curation, Investigation, Writing – original draft. BM: Data curation, Writing – original draft. AWi: Data curation, Writing – review & editing. KW: Data curation, Writing – review & editing. SP: Supervision, Writing – review & editing. ME: Conceptualization, Investigation, Writing – review & editing. MoA: Conceptualization, Writing – review & editing. NB: Conceptualization, Writing – review & editing. TB: Conceptualization, Data curation, Methodology, Writing – review & editing. BS: Conceptualization, Methodology, Writing – review & editing. MB: Data curation, Writing – original draft. AZ: Conceptualization, Data curation, Writing – review & editing. TV: Data curation, Writing – review & editing. CP: Conceptualization, Writing – review & editing. SE: Data curation, Formal Analysis, Writing – original draft. CW: Data curation, Writing – review & editing. MiA: Conceptualization, Data curation, Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing. MU: Data curation, Investigation, Methodology, Resources, Visualization, Writing – original draft. BK: Conceptualization, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing.