Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a dysregulated immune disorder [1]. It most often occurs in infants and children associated with Epstein–Barr virus (EBV) infection or malignancies [2, 3]. In its most severe form, HLH presents with signs and symptoms of hyperinflammation that progress to multiorgan failure with life-threatening consequences. The excessive inflammatory condition arises from dysregulation of critical pathways important in the resolution of the immunologic response to infection. In normal individuals, the response to infection promotes antigen-specific cytotoxic lymphocytes (CTL) to undergo clonal expansion to identify and undertake cell-mediated cytolysis of infected cells, including monocytes and histiocytes (macrophages and dendritic cells). Following pathogen clearance, this immune response is self-limiting and resolves in well-orchestrated pathways. Patients with impaired perforin and granzyme-dependent cytotoxic/apoptotic processes develop HLH due to inability to destroy infected and activated mononuclear phagocytic cells [1, 4]. This inability to control CTL and histiocyte activation often promotes an excessive and unrelenting inflammatory response cascading to a cytokine storm and multiorgan dysfunction. In severe cases, urgent use of proapoptotic chemotherapy (etoposide) and immunosuppressive drugs (corticosteroids) to reduce CTL and histiocyte activation have been found to be effective [1,2,3]. For unremitting cases, immunosuppressive therapy with emapalumab (anti-interferon ℽ antibody) or anakinra (interleukin-1 receptor inhibitor) is used [5, 6]. At times, however, the excessive systemic inflammatory process has progressed to such severe multiorgan injury that current approaches are too late to be effective.

In this regard, intervention with a develo** extracorporeal immunomodulatory treatment utilizing a selective cytopheretic device (SCD) could be considered. This approach has recently been shown to improve clinical outcomes in adult patients experiencing COVID-19-related cytokine storm [7]. The SCD with regional citrate anticoagulation has been shown to selectively bind the most highly activated circulating neutrophils and monocytes in blood and deactivate them before release back to systemic circulation [8]. This catch, deactivation, and release of these circulating cells of the innate immunologic system attenuates the final common pathway of excessive systemic inflammation resulting in multiorgan injury. Multiple clinical studies have demonstrated that this intervention results in attenuation of the hyperinflammation, resolution of ongoing tissue injury and progression to functional organ recovery [9, 10], including a recently published multi-center study in children [11]. The present case report describes the first use of the SCD to treat a child with EBV-related HLH with rapid resolution of cytokine storm and recovery from multiorgan failure.

Case synopsis

The patient was a previously healthy 14.1 kg child who presented with a week of fever, abdominal distension, organomegaly, pancytopenia, and signs of hyperinflammation. EBV PCR returned at > 25 million copies, cell separation and individual EBV PCR quantification revealed the disease burden was predominantly affecting T cells. The clinical and laboratory picture was consistent with systemic EBV-positive T cell lymphoma of childhood with symptoms secondary to HLH.

Emergency department (ED) course

On arrival to the ED, the patient was ill-appearing, grunting, with distended and tender abdomen, delayed capillary refill, and slightly jaundiced. Venous blood gas resulted with pH 7.30, pC02 28.3 mmHg, and pO2 34 mmHg. Initial kidney function panel resulted with a serum sodium 127 meq/L, potassium 4.3 meq/L, chloride 98 meq/L, total CO2 16 meq/L, blood urea nitrogen 25 mg/dL, and creatinine 0.63 mg/dL. Complete blood count revealed a hemoglobin of 8.7 g/dL, white blood cell count 3.3 × 103/microliter, absolute neutrophil count 890 cells/microliter and platelet count 26 × 103/microliter. Additional abnormal labs of interest at the time included serum uric acid 9.1 mg/dL, lactic acid 8.5 mmol/L, lactate dehydrogenase 1,783 units, total/direct bilirubin 4.0/2.7 mg/dL, D-dimer > 47,000, erythrocyte sedimentation rate 24 s, C-reactive protein 19 mg/dL, ferritin 18,000 ng/mL, and procalcitonin 43 ng/mL.

The patient received 60 mL/kg of lactated Ringer’s solution and intravenous cefepime and metronidazole. Computed tomography scan revealed hepatosplenomegaly, ascites, and pleural effusions. The patient was admitted to the pediatric intensive care unit (PICU) for further management with decreased heart rate, blood pressure of 75/32, and improved capillary refill.

PICU course

The patient received invasive mechanical ventilation on PICU Day 1 for persistent metabolic acidosis without sufficient respiratory compensation. The patient started dexamethasone for presumed HLH on Day 1 and emapalumab-Izsg (anti- interferon ℽ antibody) on Day 2. Bone marrow biopsy on Day 2 showed hemophagocytosis, and the patient received one dose of anakinra (anti-interleukin-1 receptor antagonist). The patient received two doses of eculizumab for an initial sc5b-9 level of 1,208 ng/mL (normal < 244 ng/mL in our clinical laboratory) due to concerns for thrombotic microangiopathy (TMA). Flow cytometry and bone marrow biopsy were consistent with a T cell clonal expansion. The patient was given a final diagnosis of EBV-mediated T-cell lymphoproliferative disorder of childhood, with symptoms of secondary HLH and questionable TMA.

The patient developed Stage 3 acute kidney injury (AKI) with a peak serum creatinine level of 1.81 mg/dL on Day 2. Serum lactic acid level increased from 6.8 mmol/L to 18.2 mmol/L on Day 2. The patient was initiated on continuous kidney replacement therapy (CKRT) with a Prismaflex™ HF20™ filter (Baxter Healthcare, Deerfield, IL) for the indication of severe AKI and lactic acidosis refractory to medical management. The patient met inclusion criteria for an ongoing multicenter interventional single-arm study of SCD therapy in critically ill children weighing 10–20 kg, with AKI, more than one organ failure and receiving CKRT as part of the standard of clinical care (CCHMC IRB#2021–0170, NCT04869787). The patient’s parental guardians provided written informed consent prior to enrollment in the study. The consent form stipulates that data collected as part of this study may be used for peer-reviewed publication.

The CKRT-SCD configuration is depicted in Fig. 1. The relevant clinical course after CKRT-SCD therapy initiation is depicted in Table 1. The patient received only four total days of CKRT-SCD therapy (a maximum of 10 are allowed per study protocol), as the patient was extubated, off all vasoactive medications on Day 3 of CKRT therapy and had CKRT discontinued after Day 4. The circuit ionized calcium was within target range (< 0.4 mmol/L) 98.9% percent of the time (81.9/82.8 h on SCD). The patient received a 2-h intermittent hemodialysis treatment 2 days after CKRT-SCD discontinuation for a serum potassium of 5.1 meq/L. The patient has had normal kidney function since that single intermittent hemodialysis treatment. The patient underwent successful matched unrelated donor stem cell transplantation six weeks after presentation, demonstrated engraftment on Day 52 and has had multiple follow-up assessments showing 100% donor engraftment and normal kidney function (serum creatinine 0.25 mg/dL, cystatin C 0.824 mg/L (estimated cystatin C GFR 107 ml/min) eight months after presentation.

Fig. 1
figure 1

SCD CRRT circuit diagram (Created with BioRender.com)

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Table 1 Clinical and laboratory value course
Full size table

As displayed in Table 1, SCD treatment resulted with a progressive decline in plasma cytokine levels and in neutrophil activation markers, demonstrating resolution of cytokine storm and systemic neutrophil activation.

Discussion

This patient presented with clinical criteria for HLH disease, including fever, splenomegaly, neutropenia and thrombocytopenia, elevated serum ferritin levels and bone marrow evidence of hemophagocytosis [1]. The patient was rapidly deteriorating with 5 acute organ failures despite aggressive therapy with multiple immunosuppressant agents. The patient’s clinical picture was consistent with severe hyperinflammation with cytokine storm. This was confirmed with elevated plasma levels of multiple cytokines and neutrophil granule constituents (Table 1). Activation of neutrophils and organ microvasculature results in capillary sludging and tissue hypoxia. Migration of leukocytes into tissue and release of degradation enzymes promote toxic tissue injury. The concomitant hypoxic and toxic tissue injury leads to solid organ dysfunction and failure [12]. With this perspective, SCD treatment was undertaken to mitigate the excessive activation of the effector cells of the innate immunologic pathway. In the low ionized calcium (iCa) environment promoted with regional citrate anticoagulation and the low shear force approximating capillary shear, the SCD membranes selectively bind the most activated neutrophils and monocytes due to the calcium dependency of binding reactions of cell surface integrins on the leukocyte [13,

References

  1. Risma K, Jordan MB (2012) Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 24:9–15

    Article  CAS  Google Scholar 

  2. Marsh RA (2017) Epstein-Barr Virus and Hemophagocytic Lymphohistiocytosis. Front Immunol 8:1902

    Article  Google Scholar 

  3. Kim WY, Montes-Mojarro IA, Fend F, Quintanilla-Martinez L (2019) Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases. Front Pediatr 7:71

    Article  Google Scholar 

  4. de Saint BG, Menasche G, Fischer A (2010) Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 10:568–579

    Article  Google Scholar 

  5. Bami S, Vagrecha A, Soberman D, Badawi M, Cannone D, Lipton JM, Cron RQ, Levy CF (2020) The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 67:e28581

    Article  CAS  Google Scholar 

  6. Lounder DT, Bin Q, de Min C, Jordan MB (2019) Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections. Blood Adv 3:47–50

    Article  CAS  Google Scholar 

  7. Yessayan L, Szamosfalvi B, Napolitano L, Singer B, Kurabayashi K, Song Y, Westover A, Humes HD (2020) Treatment of Cytokine Storm in COVID-19 Patients With Immunomodulatory Therapy. ASAIO J 66:1079–1083

    Article  CAS  Google Scholar 

  8. Ding F, Song JH, Jung JY, Lou L, Wang M, Charles L, Westover A, Smith PL, Pino CJ, Buffington DA, Humes HD (2011) A biomimetic membrane device that modulates the excessive inflammatory response to sepsis. PLoS One 6:e18584

  9. Pino CJ, Westover AJ, Johnston KA, Buffington DA, Humes HD (2018) Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung. Kidney Int Rep 3:771–783

    Article  Google Scholar 

  10. Yessayan LT, Neyra JA, Westover AJ, Szamosfalvi B, Humes HD (2022) Extracorporeal Immunomodulation Treatment and Clinical Outcomes in ICU COVID-19 Patients. Crit Care Explor 4:e0694

    Article  Google Scholar 

  11. Goldstein SL, Askenazi DJ, Basu RK, Selewski DT, Paden ML, Krallman KA, Kirby CL, Mottes TA, Terrell T, Humes HD (2021) Use of the Selective Cytopheretic Device in Critically Ill Children. Kidney Int Rep 6:775–784

    Article  Google Scholar 

  12. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF (2006) Neutrophils in development of multiple organ failure in sepsis. Lancet 368:157–169

    Article  CAS  Google Scholar 

  13. Ivetic A (2013) Signals regulating L-selectin-dependent leucocyte adhesion and transmigration. Int J Biochem Cell Biol 45:550–555

    Article  CAS  Google Scholar 

  14. Li R, Haruta I, Rieu P, Sugimori T, **ong JP, Arnaout MA (2002) Characterization of a conformationally sensitive murine monoclonal antibody directed to the metal ion-dependent adhesion site face of integrin CD11b. J Immunol 168:1219–1225

    Article  CAS  Google Scholar 

  15. Whyte MK, Hardwick SJ, Meagher LC, Savill JS, Haslett C (1993) Transient elevations of cytosolic free calcium retard subsequent apoptosis in neutrophils in vitro. J Clin Invest 92:446–455

    Article  CAS  Google Scholar 

  16. Szamosfalvi B, Westover A, Buffington D, Yevzlin A, Humes HD (2016) Immunomodulatory Device Promotes a Shift of Circulating Monocytes to a Less Inflammatory Phenotype in Chronic Hemodialysis Patients. ASAIO J 62:623–630

    Article  CAS  Google Scholar 

  17. Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, Degar B, Garrington TP, Sevilla J, Putti MC, Fagioli F, Ahlmann M, Dapena Diaz JL, Henry M, De Benedetti F, Grom A, Lapeyre G, Jacqmin P, Ballabio M, de Min C (2020) Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med 382:1811–1822

    Article  Google Scholar 

  18. Mehta P, Cron RQ, Hartwell J, Manson JJ, Tattersall RS (2020) Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol 2:e358–e367

    Article  Google Scholar 

  19. Gloude NJ, Dandoy CE, Davies SM, Myers KC, Jordan MB, Marsh RA, Kumar A, Bleesing J, Teusink-Cross A, Jodele S (2020) Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy. J Clin Immunol 40:699–707

    Article  Google Scholar 

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Authors and Affiliations

  1. Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7022, Cincinnati, Ohio, 45229, USA

    Stuart L. Goldstein, Kelli A. Krallman & Michaela Collins

  2. University of Michigan Medical Center, University of Michigan Hospital, Ann Arbor, MI, USA

    Lenar T. Yessayan, Angela Westover & H. David Humes

  3. Cincinnati Children’s Hospital Medical Center Burnet Campus, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

    Stefanie Benoit

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  1. Stuart L. Goldstein
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Correspondence to Stuart L. Goldstein.

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SLG consults for SeaStar Medical, Inc. HDH and AW report a financial interest in SeaStar Medical, Inc.

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Goldstein, S.L., Yessayan, L.T., Krallman, K.A. et al. Use of extracorporeal immunomodulation in a toddler with hemophagocytic lymphohistiocytosis and multisystem organ failure. Pediatr Nephrol 38, 927–931 (2023). https://doi.org/10.1007/s00467-022-05692-1

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