Severe Aplastic Anemia Following Epstein-Barr Virus Reactivation in a Previously Healthy Adolescent

To the Editors: Epstein-Barr virus (EBV) is a ubiquitous lymphotropic herpesvirus that establishes latency in memory B cells.1 Although typically asymptomatic in childhood, EBV reactivation may lead to severe hematologic complications, including, rarely, aplastic anemia.2 We report a case of EBV-associated severe aplastic anemia (SAA) in a previously healthy adolescent and summarize findings from a pediatric literature review. A 12-year-old previously healthy girl from northeastern Mexico presented with a 2-week history of fatigue, intermittent fever and gingival bleeding. One week before admission, she developed purpuric lesions on the lower extremities, worsening asthenia and recurrent epistaxis (Fig. 1A). On admission, she was febrile and had pancytopenia (Hb 10.3 g/dL, WBC 1.28 × 10⁹/L, Neu 0.02 × 10⁹/L and Plt 18.2 × 10⁹/L) with laboratory evidence of hemolysis. Despite empiric antibiotic therapy, she remained febrile, meeting criteria for fever of unknown origin. Bone marrow aspiration excluded malignancy. On hospital day 5, she developed odynophagia, cervical lymphadenopathy and exudative tonsillitis (Fig. 1B). EBV serology revealed viral capsid antigen IgM+, viral capsid antigen IgG+ and Epstein–Barr nuclear antigen IgG+, indicating viral reactivation. Serologic tests for cytomegalovirus, HIV, hepatitis B and C viruses, and Brucella (Rose Bengal test) were all negative. Bone marrow biopsy confirmed SAA. She was enrolled in a hematopoietic stem cell transplantation (HSCT) protocol with an human leukocyte antigen-identical sibling donor.FIGURE 1.: A: Diffuse petechial rash on the lower extremities at presentation. B: Pharyngeal erythema and tonsillar exudate observed during physical examination.To characterize pediatric EBV-associated aplastic anemia, we reviewed literature from 1978 to June 2025. Databases searched included PubMed, SciELO, LILACS, Embase, Scopus and Europe PMC. Inclusion required confirmed EBV infection and bone marrow-diagnosed aplastic anemia in patients 0–18 years old. We identified 20 pediatric cases worldwide (Table 1). Median age was 11 years (range: 1–17); 65% were female, and 90% had no comorbidities. Ten cases (50%) involved EBV reactivation, 9 (45%) primary infection and 1 unclassified. Overall mortality was 45% (9/20), higher in reactivation cases (50%) than in primary infection (33%). Treatments varied: 30% received supportive care only, 55% immunosuppressive therapy and 10% underwent HSCT. TABLE 1. - Clinical Characteristics and Outcomes of Pediatric Patients With Aplastic Anemia Associated With Epstein-Barr Virus Infection Total (N = 20) Clinical Outcome P-value Survive (n = 11) Death (n = 9) Age (years) 11.5 (1–17) 9.5 (1–17) 9.3 (1–15) Sex Female 13 (65%) 8 (72.7%) 5 (55.6%) 0.3 Male 7 (35%) 3 (27.3%) 4 (44.4%) Infection Primoinfection 9 (45%) 6 (54.5%) 3 (33.3%) 0.6 Reactivation 10 (50%) 5 (45.5%) 5 (55.6%) Unknown 1 (5%) - 1 (11.1%) Comorbidities Non-Hodgkin Lymphoma 1 (5%) - 1 (11.1%) Spherocytosis 1 (5%) 1 (9.1%) - No 18 (90%) 10 (90.9%) 8 (88.9%) Diagnosis Serology 17 (85%) - - PCR-based detection 3 (15%) - - Coinfection Parvovirus B-19 1 (5%) 1 (9.1%) - No 19 (95%) 10 (90.9%) 9 (100%) Treatment Supportive care only 6 (30%) 1 (9.1%) 5 (55.5%) 0.4 ATG + CsA + corticosteroids 11 (55%) 9 (81.8%) 2 (22.2%) IVIG + G-CSF 1 (5%) 1 (11.1%) HSCT 2 (10%) 1 (9.1%) 1 (11.1%) ATG indicates antithymocyte globulin; CsA, cyclosporine A; IVIG, intravenous immunoglobulin; G-CSF, granulocyte colony-stimulating factor; HSCT, hematopoietic stem cell transplant; PCR, polymerase chain reaction. No statistically significant associations were observed between outcome and type of infection, sex, comorbidities or treatment, though mortality was highest among those with EBV reactivation. Most diagnoses were based on serology (85%), with 15% confirmed by polymerase chain reaction. One patient had coinfection with parvovirus B-19. This case illustrates that EBV-associated SAA may present during reactivation, even in immunocompetent children, and may mimic malignancy or systemic inflammatory syndromes.3 The literature suggests poor prognosis in a substantial proportion of cases, especially in reactivation cases with pancytopenia, for which there are no established treatment guidelines, leading to delayed or variable management approaches.4,5 Clinicians should maintain a high index of suspicion for EBV-induced marrow failure in patients with febrile pancytopenia. Early bone marrow evaluation and EBV testing are critical to guide timely interventions, including HSCT when available. Acknowledgments The authors thank the patient and her mother for their support in the publication of this report.