Case Presentation: A 57 year-old woman without significant past medical history presented with fever, malaise, diffuse painful lymphadenopathy, and palpitations. Patient developed palpitations 4 weeks ago after receiving a second dose of the Pfizer-BioNTech COVID-19 vaccine. She later developed painful cervical lymphadenopathy and was treated with metoprolol, levofloxacin, and prednisone with minimal improvement. On admission, her exam was significant for diaphoresis, cervical and axillary lymphadenopathy, and tachycardia with heart rates in the 130s. Her labs were remarkable for leukocytosis, and elevated ferritin, CRP, and CD25. She had extensive infectious workup that revealed positive EBV in both PCR and axillary lymph node biopsy and negative for viral (including COVID-19), atypical organisms, parasitic, and fungal studies. Workup for lymphoma was negative. Imaging showed extensive thoracic, retroperitoneal, and bilateral inguinal lymphadenopathy, bilateral interstitial thickening, and mild splenomegaly. The patient was diagnosed with disseminated EBV infection with reactive lymphadenopathy secondary to immune reconstitution syndrome from the vaccine. She was started on broad-spectrum antibiotics with cefepime, vancomycin, and doxycycline which were later discontinued. The patient received high dose steroids with a week taper and subsequently had a near complete resolution of symptoms and normalization of the inflammatory markers.

Discussion: EBV is a DNA lymphotropic herpesvirus that affects more than 90% of the population worldwide and is a cause of infectious mononucleosis. EBV establishes life-long persistence in the memory B cells that may transform and permanently impair the immune response. Delayed infection, typically during adolescence, can result in AIM in 20-50% of the cases. It is a lymphoproliferative disease characterized by fever, lymphadenopathy, and fatigue that may continue for weeks or months. Most immunocompetent people have no clinical manifestations but it can be proliferated in immunocompromised individuals. In the context of an ongoing coronavirus pandemic, the association between concomitant reactivation of herpesvirus after severe covid infection has been observed, even in the absence of pre-existing immunodeficiency. Some studies have shown up to 82% of EBV coinfection in the COVID-19 patients. It’s hypothesized that an alteration of the NK and T-cell subpopulation, particularly CD8+, may correlate with COVID-19 severity and reactivation of EBV viraemia. While coinfection of COVID-19 and herpesvirus has been analyzed, the impact of COVID-19 vaccine side effects from infectious etiology, as shown in this case, remains unknown. Studies reported 18% of breakthrough COVID-19 infections in those who received at least one dose of the vaccine, but other infections were not included. With increasing vaccination rates, further investigation of the underlying mechanism of how the vaccine may lead to the reactivation of opportunistic infection may be warranted.

Conclusions: Pfizer-BioNTech COVID-19 Vaccine employs messenger RNA that triggers an immune response against spike protein found on the surface of the virus. While systemic and local side effects have been analyzed, there is limited data that identifies risk factors for reactivation of other infections. This case illustrates potential complications from the vaccine components that result in Epstein-Barr virus (EBV) reactivation and acute infectious mononucleosis (AIM).