B366 - Hemophagocytic Lymphohistiocytosis Secondary to Cytomegalovirus in a Kidney Transplant Recipient with DiGeorge Syndrome

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Author Block: K. S. Wei, W. S. Asch, Internal Medicine / Nephrology, Yale University, New Haven, CT
*Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by excessive immune activation. In solid organ transplant recipients, secondary HLH is most often triggered by viral infections such as cytomegalovirus (CMV). Patients with underlying primary immunodeficiencies, including DiGeorge syndrome, are particularly vulnerable due to impaired immune response. We describe a unique case of CMV-associated HLH in a young adult with DiGeorge syndrome following en-bloc deceased-donor kidney transplantation (DDKT).
*Methods: A 32-year-old woman with DiGeorge syndrome, seizure disorder, and end-stage renal disease underwent en-bloc DDKT in March 2025. Induction immunosuppression included alemtuzumab, followed by maintenance therapy with Belatacept, mycophenolate mofetil (MMF), and prednisone. Tacrolimus was avoided due to seizure risk, and Everolimus was deferred because of wound-healing concerns. The patient was CMV seropositive (R+) with a CMV seronegative donor (D−) and received 3 months of valganciclovir prophylaxis.
*Results: Six months post-transplant, she was admitted with fever, cough, headache, and malaise. Laboratory evaluation showed pancytopenia (WBC 1.6 × 10⁹/L, Hgb 8.6 g/dL, platelets 120 × 10⁹/L) and elevated CMV PCR (5.35 log IU/mL) raising concern for HLH. Additional studies showed markedly elevated Ferritin (4039 ng/mL) and increased soluble IL-2 receptor (CD25) (3148 U/mL), hypertriglyceridemia and hypofibrinogenemia (<50 mg/dL), supporting HLH. Bone marrow biopsy was deferred, given clear evidence of cytokine-storm physiology and hemophagocytosis can be patchy. She was initially treated with intravenous Ganciclovir, later transitioned to oral Valganciclovir, and subsequently maintained on Letermovir for prophylaxis. Due to persistent fevers, cytopenias, and rising ferritin, she received intravenous immunoglobulin (IVIG) 1 g/kg for two doses. MMF was held, prednisone (5 mg daily) was continued, and Belatacept was delayed for one week. Following IVIG, fever defervesced, blood counts improved, and CMV PCR declined to <1.54 log IU/mL.
*Conclusions: This case illustrates the diagnostic and therapeutic challenges of HLH in immunocompromised transplant recipients with underlying immune deficiency. Profound T-cell depletion from alemtuzumab, superimposed on the congenital T-cell dysfunction of DiGeorge syndrome, likely predisposed to severe CMV reactivation and secondary HLH. Importantly, our patient achieved clinical resolution with targeted antiviral therapy and IVIG alone, without the need for cytotoxic or high-dose corticosteroid therapy. This case highlights the need for heightened vigilance for HLH in transplant recipients presenting with infection and pancytopenia and raises caution regarding the use of alemtuzumab induction might best be avoided in patients with congenital immunodeficiencies like DiGeorge Syndrome.