Herpes simplex virus enters the cardiometabolic risk conversation
A new systematic review and meta-analysis protocol in BMJ Open sets out to examine whether herpes simplex virus infection is linked to a broader cardiometabolic burden than has usually been considered in routine practice. The protocol focuses on HSV-1 and HSV-2 and their possible association with cardiovascular disease, type 2 diabetes mellitus, obesity, dyslipidaemia, hypertension and metabolic syndrome.
The question is biologically plausible. Herpes simplex virus establishes lifelong infection, and chronic viral persistence can keep innate and adaptive immune pathways activated for long periods. Persistent inflammation, endothelial dysfunction and immune dysregulation offer a credible route by which a common viral infection might influence vascular injury and metabolic deterioration over time. The clinical literature, however, has not settled the issue. Findings remain inconsistent, and that inconsistency is exactly what this review intends to organize.
A protocol built to sort inconsistent observational evidence
The review will be conducted under PRISMA-P guidance, with electronic searches planned across PubMed/MEDLINE, Web of Science, Scopus and the Cochrane Library. Only observational studies will be eligible, and the planned exposure is HSV infection in relation to cardiometabolic outcomes. The authors will consider studies addressing either HSV-1, HSV-2 or both, as long as the comparison to cardiometabolic disease is explicit.
The primary outcomes are broad but clinically coherent: myocardial infarction, stroke, coronary artery disease, type 2 diabetes mellitus, obesity, dyslipidaemia, hypertension and metabolic syndrome. Each of these outcomes sits on the same pathobiological terrain, where vascular inflammation, insulin resistance, lipid imbalance and abnormal blood pressure regulation often overlap. A viral exposure that nudges one node in that network could plausibly affect several others.
Two independent reviewers will handle screening, data extraction and risk of bias assessment. That design reduces the chance that one reviewer’s expectations will steer study selection or interpretation. When enough comparable studies are available, the team plans a random-effects meta-analysis, a model that is more appropriate than a fixed-effect approach when the included studies are expected to differ in populations, viral definitions, outcome ascertainment or confounding structure.
Why the question matters for vascular and metabolic medicine
HSV infection is common, chronic and often clinically silent. Because many infected individuals never present with dramatic acute symptoms, the infection can remain outside the frame when clinicians think about long-term cardiometabolic risk. If a consistent association emerges, it would raise practical questions about whether HSV status belongs in future risk stratification research, especially in populations already burdened by smoking, obesity, diabetes or established atherosclerotic disease.
The biologic rationale is not speculative in a casual sense; it is built on mechanisms already recognized in other chronic infectious states. Endothelial dysfunction can alter vascular tone and promote a pro-atherogenic surface. Sustained inflammatory signaling can accelerate plaque formation or destabilization. Immune dysregulation can also alter glucose metabolism and lipid handling, which creates a pathway into diabetes and dyslipidaemia rather than a purely vascular endpoint. A viral infection capable of maintaining low-grade immune activation over years deserves systematic scrutiny in that context.
One sentence captures the clinical tension: the association remains unresolved despite plausible biology.
What the review will measure and how strength of evidence will be judged
The protocol is explicit about effect measures. Pooled estimates will be reported as odds ratios, risk ratios or hazard ratios, each accompanied by 95% confidence intervals. That flexibility is necessary because observational studies in this field may use different analytic frameworks depending on whether the endpoint is prevalent disease, incident disease or time-to-event follow-up.
Heterogeneity will be assessed using the I² statistic. In a review of this kind, heterogeneity is not a nuisance variable to be minimized away; it is a central signal about how unstable the evidence base may be. Differences in age structure, baseline cardiometabolic risk, serologic versus clinical HSV definitions, and confounding control could all pull study estimates in different directions.
Publication bias will be explored using funnel plots and Egger’s test. Those tools will not fix a weak evidence base, but they can help identify whether small positive studies are overrepresented while null findings remain unpublished or harder to locate. In an area with mixed findings, that matters because a pooled estimate can look more convincing than the underlying evidence actually deserves.
The limits are built into the evidence base itself
This protocol does not promise definitive answers, and it does not pretend that an observational synthesis can establish causality. Confounding will remain a serious concern. HSV infection may cluster with behavioral, socioeconomic and comorbidity profiles that also influence cardiometabolic risk, and residual confounding can survive even careful adjustment. Serologic evidence of past infection can also differ from clinically diagnosed infection, creating another layer of uncertainty around exposure classification.
A protocol is a commitment to rigor, not a guarantee of a clean result.
Still, the review has practical value because the question spans several common diseases rather than one narrow endpoint. If the literature shows a consistent association, clinicians and researchers will have a stronger basis for studying HSV as part of broader inflammation-centered risk models. If the literature remains inconsistent after structured synthesis, that result will be equally useful, because it would argue against overinterpreting isolated positive studies.
The protocol is registered in PROSPERO under CRD420261390435. No ethical approval is required because only published data will be analyzed, and the findings are planned for peer-reviewed publication and scientific conference presentation. The eventual impact will depend on how coherent the observational literature turns out to be, how well confounding has been handled, and whether the pooled estimates hold across vascular and metabolic endpoints rather than drifting apart once the studies are grouped by outcome and design.