A previously healthy 9-year-old female presented with fever and sore throat; respiratory pathogen testing detected human metapneumovirus. Initial laboratory evaluation showed elevated creatinine (1.68 mg/dL), hyponatremia (Na 133 mEq/L), thrombocytopenia (platelets 69 × 10^3/µL), and leukopenia (WBC 2.09 × 10^3/µL). Inflammatory markers at presentation included ferritin 301.7 ng/mL, C-reactive protein (CRP) 11.7 mg/dL, and markedly elevated procalcitonin (>100 ng/mL).
Within hours the patient progressed to fulminant shock with mixed acidosis (pH 7.06, pCO2 57.5 mmHg, base deficit −14), poor perfusion, and cyanotic distal extremities. She was intubated, obtained central and arterial access, and required substantial fluid resuscitation (120 mL/kg of crystalloid/colloid over 6 hours) for persistent low central venous pressures consistent with profound capillary leak.
Despite high-dose inotropic support (epinephrine 0.2 µg/kg/min and dobutamine 10 µg/kg/min), perfusion and blood pressure did not improve and the patient was cannulated for venoarterial ECLS for refractory shock. Her calculated PRISM III score was 36, corresponding to an estimated 67% mortality risk on admission.
The institutional Dysregulated Immune Response Team (DIRT) evaluated the patient and, given the clinical picture of sepsis with suspected cytokine storm, empirically initiated the IL-1 receptor antagonist anakinra at 100 mg every 12 hours (8 mg/kg/day) early in the course for 8 days. Because of disseminated intravascular coagulation features and severe thrombocytopenia (nadir 20 × 10^3/µL) with schistocytes on smear, the team diagnosed thrombocytopenia-associated multiple organ failure (TAMOF) and commenced therapeutic plasma exchange (TPE).
Clinical course included an INR peak of 2.8 on hospital day (HD) 1 that normalized to 1.0 by HD 4, and platelet recovery from the 20 × 10^3/µL nadir on HD 2 to >80 × 10^3/µL by HD 4. The patient was decannulated from ECLS on HD 5, remained mechanically ventilated until HD 9, was downgraded from pediatric intensive care on HD 12, and discharged to inpatient rehabilitation on HD 20. At approximately 6 weeks she was reported fully functional.
As part of an IRB-approved observational study (Systemic Immune Profiles of Sepsis, SIPS), remnant plasma samples were collected and stored for post hoc cytokine measurement using the Ella automated immunoassay. Selected biomarkers measured included CXCL9, sIL-2RA, IL-6, IL-8, IL-18, and sTNFR1. After the initiation of anakinra and ECLS, IL-6 and IL-8 concentrations showed dramatic decreases—IL-8 decreased roughly 100-fold and IL-6 decreased approximately 1,000-fold from their peaks just prior to ECLS and anakinra. Other markers such as sIL-2RA and sTNFR1 declined more gradually, and CXCL9 peaked after ECLS initiation then fell. Measured IL-1 receptor antagonist levels reflected both endogenous and exogenous (anakinra) contributions.
Daily pediatric SOFA (pSOFA) scores peaked on HD 2 and fell to zero by HD 9.
TPE was administered given the diagnosis of TAMOF. The patient received a 1.5× plasma volume exchange with fresh frozen plasma on HD 2, followed by 1× volume exchanges on HD 3 and HD 4. The authors note that ASFA guidelines list TPE for sepsis-induced MODS as a Category III, Grade 2A indication recommending individualized decisions regarding potential benefit.
To explore mechanisms linking IL-1 signaling and IL-6 expression, the investigators recreated published pairwise cytokine models in adult C57BL/6 mice. Recombinant cytokines (TNF, IL-1β, IL-18, IFN-γ) were administered intravenously via retro-orbital injection under isoflurane anesthesia. Serial tail vein blood sampling at 3, 6, 24, and 48 hours allowed measurement of mouse IL-1β, TNF, IL-6, IFN-γ, and CXCL9 using automated microfluidic immunoassays and ELISA.
In agreement with prior reports, combinations of TNF + IL-1β and TNF + IFNγ were universally fatal in these models, while TNF and TNF + IL-18 produced weight loss without mortality. Because of rapid mortality with TNF + IL-1β and TNF + IFNγ, early time points (3 and 6 hours) provided the most informative biomarker data.
Across preclinical experiments, IL-6 levels increased after TNF administration. Crucially, mice receiving both TNF and IL-1β had significantly higher IL-6 concentrations than mice given TNF or IL-1β alone. Using sublethal lower doses (1 µg) of TNF and IL-1β, the combination induced more weight loss than either cytokine alone; TNF and IL-1β levels themselves followed expected pharmacokinetics with rapid decline after administration. These findings suggest a synergistic effect of IL-1 and TNF on IL-6 induction in this model.
The clinical case documents early anakinra administration in a child with sepsis-induced MODS managed with concurrent ECLS and TPE. Post hoc cytokine measurement showed sharp decreases in IL-6 and IL-8 temporally associated with anakinra administration. Preclinical pairwise cytokine models demonstrated that IL-6 production is amplified when IL-1 and TNF are present together, supporting a biologic mechanism by which IL-1 blockade could reduce IL-6 levels during cytokine storm.
The authors emphasize that a single causal attribution cannot be made: ECLS provided hemodynamic support and maintained organ perfusion, TPE addressed TAMOF, and anakinra was given early. They reference prior preclinical and clinical data suggesting IL-1 antagonism benefits in septic shock, and note ongoing clinical trials examining anakinra in pediatric MODS, with differences in timing (for example, some trials start anakinra on MODS day 2).
The case also highlights diagnostic complexity: cultures were negative except for a post-intubation tracheal aspirate that grew MSSA, but the patient did not meet clinical criteria for pneumonia. The authors discuss possible viral priming with subsequent exaggerated responses to bacterial products and note that the patient met criteria for MAS by Ravelli criteria but not for HLH by HLH-2004 or H-score assessments.
Limitations reported by the authors include the concurrent use of multiple interventions that preclude attribution of outcome to anakinra alone, post hoc timing and availability of remnant samples for cytokine analysis, and translational differences between acute cytokine administration in mice and human sepsis pathophysiology. The authors call for further research to define appropriate patient selection, optimal timing, and dosing strategies for IL-1 blockade with anakinra in cytokine storm–induced MODS.
In this single pediatric case, early empirical anakinra use occurred alongside ECLS and TPE and was temporally associated with marked reductions in IL-6 and IL-8 and clinical recovery. Preclinical pairwise cytokine models support a biologic interaction in which IL-1 and TNF synergize to amplify IL-6 production, providing mechanistic plausibility for IL-1 blockade reducing downstream IL-6 in cytokine storm. Controlled studies are needed to determine causality, optimal timing, dosing, and which patient populations may benefit from IL-1 receptor antagonism during sepsis-induced MODS.