Chemotherapy-Induced Severe Immunodeficiency Mimicking Primary Immunodeficiency: A Diagnostic Challenge

Introduction Chemotherapy regimens, particularly BEP (bleomycin, etoposide, cisplatin), commonly cause transient immune dysfunction; however, profound and persistent lymphopenia resembling primary immunodeficiency (PID) is exceedingly rare. Such severe immune impairment post-chemotherapy, especially without identified genetic causes, presents critical diagnostic and management challenges. Presentation of the Case A male patient previously treated for metastatic testicular cancer with surgery, radiotherapy, and six cycles of BEP chemotherapy developed profound and persistent lymphopenia (CD3: 123/µL; CD4: 62/µL; CD8: 39/µL) and hypogammaglobulinemia (IgG levels persistently between 189–310 mg/dL). Extensive genetic evaluations, including whole-genome sequencing and multi-gene panel analysis, revealed no mutations associated with PID. Clinically significant was the occurrence of cryptococcal meningitis, successfully treated with prolonged fluconazole therapy. Monthly intravenous immunoglobulin therapy (IVIG, 0.53 g/kg) effectively maintains immunoglobulin levels and prevents further infections. Comprehensive interdisciplinary follow-up, including positron emission tomography–computed tomography imaging, excluded malignancy recurrence. Discussion This case highlights a clinically significant but under-recognized phenomenon—severe, persistent chemotherapy-induced immunodeficiency closely mimicking PID. Such phenocopies complicate clinical diagnostics, particularly when standard genetic analyses yield negative results. Recognition of this entity is crucial for improving patient management, emphasizing the importance of prolonged immunological monitoring and tailored prophylactic strategies following intensive chemotherapy regimens. Future studies should evaluate the incidence, mechanisms, and optimal management strategies for chemotherapy-induced severe immunodeficiency phenocopies.