A Case of Recurrent Hemophagocytic Lymphohistiocytosis-like Episodes in a Patient with XIAP Deficiency

A 14-year-old male with Crohn's disease since age 9, refractory to multiple treatments, was referred to immunology for evaluation of primary immunodeficiency. He had no history of recurrent infections and no family history of immunodeficiency, autoimmunity, or consanguinity. Evaluation demonstrated an absolute lymphocyte count of 900, normal lymphocyte subset percentages, but a low absolute CD3 count of 558, CD4 count of 373, and CD8 count of 130. Proliferation to mitogens and antigens showed decreased proliferation to concanavalin and phytohemagglutinin. Immunoglobulins and specific antibodies were normal. A neutrophil oxidative burst was normal. An inflammatory bowel disease (IBD) genetic panel demonstrated a hemizygous pathogenic variant in XIAP c.1141C>T (p.Arg381*), creating a premature translation stop signal resulting in an absent/disrupted protein product. X-linked proliferative disorder 2 (XLP2) was diagnosed. Further workup demonstrated mild anemia, no other cytopenia, normal ferritin, normal fibrinogen, and negative EBV serology. The possibility of hematopoietic stem cell transplant (HSCT) was discussed but deferred due to social considerations. A month after diagnosis, he was hospitalized for hypovolemic shock in the setting of norovirus colitis, with laboratory evidence of anemia and elevated inflammatory markers. He had elevated ferritin >10,000; elevated CD163; sIL2R 1,705; CXCL9 43,167; IL-18 57,094; normal NK cell function, and CD107a. CRP, ferritin, and liver function improved on broad-spectrum antibiotics, and he did not meet criteria or undergo treatment for HLH. Within the following 6 months he was hospitalized three times with fever, arthralgia, and HLH-like laboratory findings, without meeting HLH criteria. Considering these episodes and his poor IBD control, he was started on 150 mg canakinumab monthly for HLH-like episodes and chronic inflammation. He remained free of such episodes for a year but was then hospitalized again with severe arthralgia, fevers, and increased ostomy output despite IL-1 blockade, with CXCL9 7,388; IL-18 53,437; IL-1b 185.3; and sIL2R 1,387. All cultures were negative. Concerned he may have developed antibodies to canakinumab, he was trialed on anakinra, which resolved his fever and symptoms. He was discharged on rilonacept and has remained fever- and symptom-free since. Discussions regarding HSCT remain ongoing. This case highlights the importance of targeted pharmaceutical therapies, such as anti-IL-1, in managing complex inflammatory conditions like XLP2.