Steroid-sparing use of anakinra for secondary hemophagocytic lymphohistiocytosis in sickle cell disease with multiorgan failure – a case report Free

Background: Sickle cell disease (SCD) can cause life-threatening multiorgan failure syndrome (MOFS) in the setting of fat embolization syndrome (FES). There are reports of MOFS overlapping with hemophagocytic lymphohistiocytosis (HLH), a serious hyperinflammatory syndrome that can be fatal if untreated. Diagnostic criteria such as HLH-2024 or the H-Score for Reactive Hemophagocytic Syndrome have limitations in patients with sickle cell MOFS, as many findings are present in both conditions. Bone marrow biopsy, though helpful in diagnosis, may not be feasible in unstable patients, and natural killer cell activity assays have limited availability with a long turnaround time, rendering these impractical for making an urgent diagnosis.

CasePresentation: A 51-year-old lady with Hemoglobin-SC (HbSC) genotype presented with Vaso-occlusive crisis (VOC) involving femoral bones, ribs, and vertebrae preceded by triamcinolone injection. About 48 hours later, she developed altered mentation, respiratory distress, hypotension (blood pressure 69/31 mmHg), tachycardia (HR 133 bpm), and oxygen desaturation (SpO2 57% on room air). Laboratory findings were significant for leukocytosis (15 x10⁹/L), a drop in hemoglobin (from 8.9 to 5.3 g/dl), platelet count (from 691 to 105 x10⁹/L), and a rise in nucleated red cells (0.4% to 78%). She developed acute worsening of her renal and hepatic function as seen by blood urea nitrogen increase from 9 to 18 mg/dl, creatinine from 1 to 2.7 mg/dl, alkaline phosphatase from 73 to 191 U/L, alanine transaminase from 47 to 107 U/L, and aspartate transaminase from 41 to 221 U/L. ABG revealed severe acidosis with pH 7.09, PO₂ of 54 mmHg, PCO₂ of 49 mmHg, and lactate of 12.5 mmol/L. Coagulation studies revealed prothrombin time of 15.3 seconds, International Normalized Ratio of 1.4, and fibrinogen of 380 mg/dL. Computed tomography revealed small right pulmonary emboli and basal airspace opacities with small effusions and hepatomegaly. MRI head revealed frontal lobe microhemorrhages.

Management included intubation and ventilation, vasopressor support, and intravenous heparin. With rapidly developing respiratory failure, hepatic dysfunction, and acute kidney injury, a diagnosis of Sickle cell-related MOFS was made, likely triggered by fat embolization syndrome (FES). Patient received red cell exchange transfusion with resulting Hemoglobin S and C fractions being 6.1% and 5.9%, respectively.

Due to ongoing high temperatures (103 °F), marked hyperferritinemia (16,564 ng/mL), hypertriglyceridemia (958 mg/dL), elevated soluble CD25 (1329 pg/mL), and hepatomegaly, secondary HLH was suspected. Bone marrow biopsy was deferred due to bleeding risk from anticoagulation. Given the concern for steroids inducing VOC and cytotoxic agent-induced immunosuppression, anakinra (4 mg/kg/day) was given for five days. With anakinra, the patient had defervescence, down-trending ferritin and liver enzymes, and stable blood counts.

Discussion: This case underscores the difficulty in identifying concurrent secondary HLH in Patients with sickle MOFS. Identifying HLH in a critically ill patient with SCD can be difficult due to the commonalities in clinical and laboratory features such as fever, cytopenias, hyperferritinemia, organomegaly, and liver dysfunction. Published case reports describe similar cases where patients with HbSS or HbSC developed HLH-like syndromes during VOC or fat embolism, with clinical deterioration unresponsive to red cell exchange but rapid improvement following HLH-directed therapy. Presence of hemophagocytosis can help in the diagnosis, but may not reliably distinguish true HLH from reactive hemophagocytosis seen in SCD, and bone marrow biopsy may not be feasible in the presence of coagulopathy or anticoagulation. On the other hand, cytokine-mediated immune dysregulation seen in HLH needs to be addressed in addition to red cell exchange. In our patient, the decision to initiate anakinra reflected a pragmatic and individualized approach, aiming to suppress hyperinflammation while avoiding steroids due to their risk of VOC. This therapeutic choice is supported by emerging evidence favoring IL-1 blockade as a safer immunomodulatory strategy in selected ICU patients with features suggestive of HLH. Our case adds to the growing body of literature advocating for early identification of HLH in SCD patients with unremitting systemic inflammation and organ dysfunction.