Multisystem Inflammatory Syndrome in Children or Hemophagocytic Lymphohistiocytosis?: A Case Report

To the Editors: Hemophagocytic lymphohistiocytosis (HLH) represents a complex and potentially life-threatening disorder characterized by uncontrolled immune system activation. This rare condition typically manifests with persistent fever, hepatosplenomegaly, cytopenias and hyperferritinemia among its clinical hallmarks. Elevated ferritin levels, often exceeding 500 ng/mL, serve as a crucial biomarker in the diagnostic evaluation of HLH, reflecting intense macrophage activation and systemic inflammation.1–4 A 4-year-old girl presented with abdominal distension and persistent fever for 4 days. The patient, having previously experienced a severe acute respiratory syndrome coronavirus 2 infection 2 years ago, subsequently developed multisystem inflammatory syndrome in children (MIS-C), leading to her admission to the pediatric intensive care unit and receiving plasmapheresis treatment. On physical examination, her general condition was poor. She had a fever and exhibited an icteric appearance of the skin, mucosal pallor and ecchymosis on both thighs and the anterior tibia. She had dyspnea and tachypnea, and on auscultation, S3 and gallop rhythm were heard. Her abdomen was swollen due to splenomegaly, with the upper pole being palpable and the inferior border extending to the iliac crest, as well as hepatomegaly, with the liver edge palpable 3 cm below the right costal margin. The lab results are shown in Table 1. TABLE 1. - Laboratory Findings in Patients With Hemophagocytic Lymphohistiocytosis Parameter On Admission The Worst Levels On Discharge Day Normal Range Complete blood count Leukocytes 1420 990 2960 4300–13,500/μL Lymphocytes 800 200 2000 2–6 × 103/μL Neutrophils 570 240 750 1.5–6.13 × 103/μL Platelets 55,000 6000 244,000 150,000–450,000/μL Hemoglobin 7 6 10.2 11–14 g/dL Blood gas pH 7.37 7.20 7.42 7.35–7.45 pCO2 29 27 41.8 35–45 mm Hg HCO3 18,5 14 25.7 21–24 meq/L Inflammatory markers CRP 98.4 147.5 0.32 0–5 mg/L Procalcitonin 3.15 23.64 0.08 <0.5 ng/mL LDH 621 888 292 120–300 U/L Albumin 3.13 2.10 3.87 3.8–5.4 g/dL Ferritin 1634 10,192 321 4–67 μg/L Coagulation PT 21.6 25.5 12.7 11.3–15.6 s APTT 28.4 44 24.3 24–37 s INR 1.64 1.95 0.95 0.84–1.2 Fibrinogen 332 59 227 260–390 mg/dL d-dimers 2.18 4.48 2.53 0–0.5 μg/mL Liver function AST 1013 1013 39 2–48 U/L ALT 458 458 40 2–48 U/L Kidney function Creatinine 0.31 0.45 0.24 <0.47 mg/dL Urea 21 41 21 <39 mg/dL Triglycerides 200 344 181 <150 mg/dL ALT indicates alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CRP, C-reactive protein; INR, international normalized ratio; LDH, lactate dehydrogenase; PT, prothrombin time. Peripheral blood smear showed erythrocyte poikilocytosis, basophilic stippling, polychromatophilic macrocytes, no atypical leukocytes (<5%) and significant thrombocyte anisocytosis. Bone marrow aspiration indicated hypercellularity with increased erythroid series, consistent with hemophagocytosis. Systemic dexamethasone therapy was initiated at a dosage of 10 mg/m2/d for 7 days, followed by tapered doses for 10 days, along with intravenous immunoglobulin at 1 g/kg/d due to persistent fever, splenomegaly and cytopenias. Despite these intensive treatments, the patient's symptoms and abnormal laboratory findings persisted. Primary hemophagocytic lymphohistiocytosis (PHL) was considered due to the presence of prolonged fever, splenomegaly, pancytopenia, reduced fibrinogen levels, elevated triglycerides and high ferritin levels, meeting 6 of 8 diagnostic criteria. Genetic testing confirmed a homozygous c369_376delinsTGG frameshift variant in the STK11 gene. The patient was subsequently transferred to another facility for allogeneic bone marrow transplantation. Following the transplantation, the patient exhibited significant improvement. High ferritin levels (>5000 ng/mL) serve not only as a diagnostic marker but also as a prognostic indicator, correlating with disease severity and mortality risk in patients with HLH.1,2 A recent study examining children with MIS-C found that thrombocytopenia and hyperferritinemia were common, but no pathogenic variants were identified in HLH-related genes, suggesting that these features do not indicate a more severe disease phenotype but rather a distinct hyperinflammatory process.5 This underscores the need for careful genetic evaluation in patients with hyperferritinemia to differentiate between secondary causes and PHL. This case report highlights a 4-year-old patient diagnosed with PHL following a history of MIS-C post-severe acute respiratory syndrome coronavirus 2 infection. The patient exhibited classic clinical features, including prolonged fever, splenomegaly, pancytopenia and hyperferritinemia, prompting genetic testing that identified a homozygous STK11 mutation. In conclusion, the management of pediatric patients with markedly elevated ferritin levels should include a high index of suspicion for PHL.