D-Dimer in Viral Respiratory Infections: Established Evidence in COVID-19 and Emerging Evidence in Other Respiratory Viruses

Viral respiratory infections remain a major cause of global morbidity and mortality, with severe disease increasingly recognized to involve profound interactions between inflammation, endothelial dysfunction, coagulation activation, and immunothrombosis. D-dimer, a fibrin degradation product and established biomarker of fibrin turnover, has gained considerable attention because of its strong association with adverse outcomes in coronavirus disease 2019 (COVID-19). This narrative review compares the evidence for D-dimer in COVID-19 with that available for other respiratory viruses and deliberately separates three questions that are frequently conflated: whether D-dimer predicts severity or death (prognostic), whether it identifies or excludes venous thromboembolism (diagnostic), and whether it identifies patients who benefit from anticoagulation (treatment-predictive). In COVID-19, elevated D-dimer is reproducibly associated with disease severity, thromboembolic complications, intensive care unit admission, and mortality, and the association persists after adjustment; however, discrimination is only moderate, incremental value over routine clinical variables has rarely been tested, and randomized trials have not established D-dimer as a treatment-selection biomarker. Outside of COVID-19, the evidence is substantially weaker and uneven: influenza is supported mainly by comparative cohorts, adenovirus by a single unvalidated paediatric prediction model, and the only direct study of D-dimer and clinical severity in bronchiolitis was negative, while for MERS-CoV, parainfluenza, and human metapneumovirus, we identified no study relating D-dimer to a clinical outcome. Moreover, substantial heterogeneity in assay methodology, sampling strategies, and proposed cut-off values restricts standardization and cross-study comparisons. We therefore present COVID-19 as a mechanistic and methodological reference rather than a validated universal rule, and summarize the evidence in a structured table and a visual evidence map. Overall, D-dimer appears to represent an integrated biomarker of coagulation activation, endothelial injury, and systemic inflammation rather than thrombosis alone, supporting its role in risk stratification while underscoring the need for context-specific interpretation. The cross-viral propositions advanced here should be regarded as hypothesis-generating. Future prospective multicentre studies using standardized assays, serial biomarker assessment, and multimarker prediction models are required to establish pathogen-specific prognostic frameworks and define the role of D-dimer in precision medicine for viral respiratory infections.