Differentiating COVID-19 vaccine-related adverse events from long COVID: A comprehensive review of clinical manifestations, pathophysiology, and diagnostic approaches

The global deployment of COVID-19 vaccines has introduced diagnostic challenges due to overlapping symptoms with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), prompting a comprehensive review of vaccine safety profiles, long COVID manifestations, and evidence-based differentiation strategies. Through a literature search (PubMed, Scopus, Web of Science) from December 2020 to June 2025, including peer-reviewed studies, clinical trials, and cohort studies, the present review reports that COVID-19 vaccines maintain robust safety, with rare adverse events like myocarditis and thrombosis with thrombocytopenia syndrome, while long COVID affects 10–40 % of SARS-CoV-2 survivors, presenting symptoms such as fatigue, cognitive dysfunction, and dyspnea. Differentiation between these conditions relies on careful analysis of the timing of symptom onset, detailed symptom characterization, and the use of advanced diagnostic tools. Systematic clinical assessment is essential for accurate diagnosis, which is critical for appropriate patient management, maintaining public confidence in vaccination, and guiding future research. Further studies are needed to validate diagnostic biomarkers, develop targeted therapies, and monitor long-term outcomes, with standardized global registries and interdisciplinary collaboration identified as key priorities for improving care and advancing the field.