Revisiting the Diagnostic Approach to Epstein–Barr Virus-associated Severe Aplastic Anemia in Children

To the Editors: We read with great interest the report by Arcos Viscarra et al1 describing a case of severe aplastic anemia (SAA) following Epstein–Barr virus (EBV) reactivation in a previously healthy adolescent, along with a comprehensive review of pediatric cases reported in the literature. The authors should be commended for highlighting this rare but potentially fatal complication of EBV infection in children. However, we would like to raise several points for critical discussion that may have important diagnostic and clinical implications.2 First, the diagnosis of EBV reactivation in the reported case, as well as in the majority of cases included in the literature review, relied predominantly on serological testing. While EBV serology is useful for epidemiological classification, it has well-recognized limitations in distinguishing viral reactivation from past infection, especially in severe or atypical presentations. The absence of systematic EBV DNA quantification by polymerase chain reaction, particularly in blood and bone marrow samples, limits diagnostic certainty and hampers assessment of viral burden and disease activity. Current evidence supports molecular testing as a more reliable tool in severe EBV-associated complications, including bone marrow failure syndromes.2 Second, although the patient was described as “previously healthy,” the occurrence of EBV-associated SAA should prompt a more extensive evaluation for underlying primary immunodeficiency disorders. Increasing data demonstrate that severe EBV disease, including marrow aplasia, hemophagocytic syndromes and lymphoproliferative disorders, may represent the first clinical manifestation of inborn errors of immunity affecting T-cell cytotoxicity, natural killer cells function or immune regulation. Conditions such as X-linked lymphoproliferative disease, cytidine triphosphate synthase 1 deficiency, GATA binding protein 2 deficiency and other combined immunodeficiencies are now well recognized in this context.3 In this regard, we believe that immunological workup—including lymphocyte subsets,natural killer cells function, immunoglobulin levels and assessment of EBV-specific T-cell responses—should be systematically addressed in such cases. Furthermore, early genetic testing using targeted primary immunodeficiency disorders panels or whole-exome sequencing may be crucial, not only for etiological clarification but also for prognostic stratification and therapeutic decision-making, particularly when hematopoietic stem cell transplantation is considered.4–6 Finally, given the high mortality observed in EBV reactivation-associated SAA reported by the authors, a standardized diagnostic approach incorporating molecular virology and immunogenetic evaluation could contribute to earlier recognition of high-risk patients and potentially improve outcomes. We present a proposed diagnostic approach for SAA associated with EBV in children (Fig. 1).FIGURE 1.: Proposed diagnostic approach to severe aplastic anemia associated with Epstein–Barr virus in children.We appreciate the authors’ valuable contribution and hope these considerations may stimulate further discussion and refinement of diagnostic strategies for severe EBV-associated hematologic complications in children.