An efficient diagnosis: A patient with X‐linked inhibitor of apoptosis protein (XIAP) deficiency in the setting of infantile hemophagocytic lymphohistiocytosis was diagnosed using high serum interleukin‐18 combined with common laboratory parameters

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To the Editor: In this letter, we report our experience with a 1-month-old male who presented with hemophagocytic lymphohistiocytosis (HLH) and markedly elevated serum interleukin-18 (IL-18). This high IL-18 level, combined with the results of common laboratory parameters, prompted us to perform target sequencing of candidate genes for HLH: X-linked inhibitor of apoptosis protein (XIAP), NLR family CARD domain containing 4 (NLRC4), and cell division cycle 42 (CDC42). We succeeded in rapidly diagnosing XIAP deficiency in this young patient. A 1-month-old male, the second child of healthy, nonconsanguineous Japanese parents, was admitted to our hospital with a persistent fever. Physical examination revealed mild hepatosplenomegaly, and laboratory analysis revealed a markedly elevated ferritin level and abnormal coagulation markers, as well as mild thrombocytopenia (Table 1). His symptoms improved rapidlywith a short trial of high-dose hydrocortisone but recurred shortly after discontinuation of the corticosteroid. The results of laboratory analysis onday12 fulfilled thediagnostic criteria for HLH (Table 1).1 The total lymphocyte percentage (46%) and the low soluble interleukin-2 receptor (sIL-2R):ferritin ratio indicated that a diagnosis of familial hemophagocytic lymphohistiocytosis (FHL) was less likely in our patient (Figure S1).2 However, the extremely high serum IL18 level (Table 1) narrowed the differential diagnosis to four conditions: XIAP deficiency,3 NLRC4-associated autoinflammatory disease,4 CDC42 carboxyl-terminal mutations,5,6 and systemic juvenile idiopathic arthritis.7,8 Targeted gene sequencing confirmed a known nonsense mutation causing p.E118X in the XIAP gene.9 A genetic panel revealed no additional pathogenic variants in the NLRC4 or CDC42 genes, or in other FHL-associated genes (Table 1). The patient was treated with dexamethasone (DEX), cyclosporin, etoposide, and immunoglobulin.1,10,11 He responded well and was discharged after 3 months in the hospital. He had a relapse of HLH at the age of 15 months; at that time, he was treated with tacrolimus and an increased dose of DEX. He is currently 27 months of age and asymptomatic on low-dose DEX and tacrolimus. Early distinction of FHL from other primary and secondary causes of HLH is crucial; patients with FHL require urgent hematopoietic cell transplantation (HCT), but the use of this procedure for other types of HLH remains controversial.12,13 Either flow cytometry analysis for perforin expression, or a CD107a degranulation assay, will provide a prompt diagnosis of FHL,14 while a similarly quick diagnosis of XIAP deficiency can be reached through flow cytometry protein screening and functional XIAP/nucleotide-binding oligomerization domain protein 2 (NOD2) screening using muramyl dipeptide stimulation and tumor necrosis factor-alpha (TNF-α) readout.15 However, these tests are only available in specialized laboratories. Gene panels are not suitable for rapid diagnosis.Wepreviously reported the usefulness of common laboratorymarkers for early detection of FHL: patientswith earlystage FHL have a high total lymphocyte percentage (>50%) on the hematology differential and a high sIL-2R (U/ml):ferritin (ng/ml) ratio (>103).2 Our patient, as well as those in other published reports of XIAP deficiency-associated HLH,16–19 had a relatively low total lymphocytepercentageanda lowsIL-2R:ferritin ratio at presentation, indicating that FHL was less likely. In addition, extremely high serum IL-18 levels (typically>104 pg/ml) at the time of HLH flare are only reported in patients with a few specific genetic disorders.3–8 Our experience suggests that the combination of IL-18 and common laboratory parameters facilitates the rapid assessment and appropriate treatment of patients with infantile HLH.