Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis

Wohlfarth, Philipp; Agis, Hermine; Gualdoni, Guido A.; Weber, Johannes; Staudinger, Thomas; Schellongowski, Peter; Robak, Oliver

doi:10.1177/0885066617711386

Cited by 103 publications

(103 citation statements)

References 40 publications

(81 reference statements)

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“…4A) were also unable to confer protection. These data are consistent with the poor efficacy of cytokine blockade in patients with sHLH (34,35). Given the glycolytic phenotype of IC:LPS-treated macrophages, we next asked if inhibition of glycolysis with the 2-DG can reduce inflammation and improve survival in our HLH model.…”

Section: Influenza Infection Potentiates Mortality Of Nonpathogenic Esupporting

confidence: 70%

Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice

Wang

Pope

Weinstein

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Secondary hemophagocytic lymphohistiocytosis (sHLH) is a highly mortal complication associated with sepsis. In adults, it is often seen in the setting of infections, especially viral infections, but the mechanisms that underlie pathogenesis are unknown. sHLH is characterized by a hyperinflammatory state and the presence hemophagocytosis. We found that sequential challenging of mice with a nonlethal dose of viral toll-like receptor (TLR) agonist followed by a nonlethal dose of TLR4 agonist, but not other permutations, produced a highly lethal state that recapitulates many aspects of human HLH. We found that this hyperinflammatory response could be recapitulated in vitro in bone marrow-derived macrophages. RNA sequencing analyses revealed dramatic up-regulation of the red-pulp macrophage lineage-defining transcription factor SpiC and its associated transcriptional program, which was also present in bone marrow macrophages sorted from patients with sHLH. Transcriptional profiling also revealed a unique metabolic transcriptional profile in these macrophages, and immunometabolic phenotyping revealed impaired mitochondrial function and oxidative metabolism and a reliance on glycolytic metabolism. Subsequently, we show that therapeutic administration of the glycolysis inhibitor 2-deoxyglucose was sufficient to rescue animals from HLH. Together, these data identify a potential mechanism for the pathogenesis of sHLH and a potentially useful therapeutic strategy for its treatment.

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Section: Influenza Infection Potentiates Mortality Of Nonpathogenic Esupporting

confidence: 70%

Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice

Wang

Pope

Weinstein

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite its FDA designation, anakinra is used off label to treat a variety of autoinflammatory diseases. Although limited, there are now case reports and series showing both sIJA‐related MAS (19‐22) and other HLH secondary subtypes (22‐27) responding favorably to anakinra. As such, it appears that anakinra may be viewed as an emerging and effective therapy in the treatment of MAS.…”

Section: Introductionmentioning

confidence: 99%

Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome

Monteagudo

Boothby

Gertner

2020

ACR Open Rheumatology

166

149

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Objective The objective of this study was to report the benefit of a therapeutic approach consisting of intravenous (IV) continuous anakinra (recombinant human interleukin‐1 receptor antagonist) infusions in treating severely ill adult patients with secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome (MAS). Methods A retrospective chart review of five patients treated at Regions Hospital from 2016 to 2019 was conducted. Demographic, clinical, and laboratory characteristics and outcomes were recorded. Results Continuous IV anakinra infusions up to 2400 mg/d resulted in rapid serologic, then clinical response in 4 of 5 severely ill patients who were refractory to all other therapies, including subcutaneous anakinra. Subsequently, 3 of 5 patients have been maintained on anakinra or canakinumab, with no recurrence of MAS. Conclusion Continuous infusion of IV anakinra may result in rapid serologic and subsequent clinical improvement in adult patients with MAS. This method for treating cytokine storm should be considered in the current COVID‐19 pandemic in the subgroup of patients with severe disease who have a cytokine storm presentation.

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“…A trial of salvage therapy of doxorubicin-etoposidemethylprednisolone in adults with mostly non-familial refractory HLH, demonstrated an overall response rate of 75%, with 29 of 48 patients surviving to undergo disease specific therapy [31]. A recent case series reported the use of the interleukin 1 antagonist, anakinra, with steroids and IVIG in eight critically ill patients with HLH and demonstrated a hospital survival rate of 50% [32]. Additional research on nonetoposide based treatment regimens may therefore be warranted for critically ill patients with multiple organ failure.…”

Section: Treatmentmentioning

confidence: 99%

Hemophagocytic Lymphohistiocytosis and Other Culture Negative Sepsis-Like Syndromes in the ICU

Denstaedt

Singer

2020

Evidence-Based Critical Care

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A 57 year old man with history of idiopathic panniculitis on long-term steroid treatment presented to the hospital with a 1 month history of dyspnea, malaise, nausea and vomiting. He was hypotensive and tachycardic with an acute kidney injury. Prior to this presentation, he had been hospitalized for 2 weeks at a nearby hospital with similar symptoms and had been found to have multifocal ground glass opacities on CT of the chest. His condition after admission improved with fluid resuscitation, stress-dose steroids, and treatment for presumed sepsis. Infectious and rheumatologic workups were negative. He was noted to have bilateral pulmonary infiltrates ( Fig. 79.1a, b). One week after discharge, however, he presented again with systemic inflammatory response syndrome (SIRS). A bronchoscopy revealed only acute and chronic organizing pneumonia, with no evidence of infection. A bone marrow biopsy was performed, which demonstrated a hypercellular marrow. Pulse dose steroids were initiated for organizing pneumonia and he improved significantly over the next week with continuation of empiric antimicrobials and tapering of steroids. After 1 week of this regimen, however, he again decompensated with hypoxia and hypotension. Worsening infiltrates were noted on his chest radiograph ( Fig. 79.1c). Ferritin was elevated at 7652 ng/mL, and sIL-2R was elevated at 3432 U/ mL. Trigylcerides were normal and fibrinogen was elevated. Given his unremarkable bone marrow biopsy 7 days before and elevated fibrinogen, the possibility of hemophagocytic lymphohistiocytosis (HLH) was dismissed as his hyperferritinemia and elevated sIL-2R were attributed to history of blood transfusion and occult infection. He continued to improve with empiric antimicrobials and steroids, and was discharged from the hospital 5 days after admission to the ICU to complete a course of levofloxacin on 40 mg of prednisone daily.He presented to the hospital for the third time 2 days after discharge with hypotension and hypoxia requiring endotracheal intubation and vasopressors, and antibiotics and steroids were restarted. He was admitted to the ICU and his pulmonary status rapidly improved. After 3 days, however, he again decompensated with hypotension and an elevated lactate. He received intravenous fluids and intravenous steroids. Given the unclear association between changes in his antimicrobial regimen, steroid dosing, and clinical condition, his steroid dose was decreased from 40 mg prednisone daily by 10 mg each day. A repeat bone marrow biopsy was performed, which showed rare hemophagocytic macrophages but no evidence of malignancy. The next day, in the setting of reducing his steroid dose, he again had an episode of hypoxia and hypotension. Ferritin was measured at that time and was 9148 ng/mL, increased from 4074 ng/mL the day before ( Fig. 79.2). sIL2-R was measured and was elevated at 3494 U/mL. A diagnosis of HLH was made, and he was started on chemotherapy with etoposide and high dose dexamethasone. Eight weeks had elapsed since his initial presentati...

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Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis

Cited by 103 publications

References 40 publications

Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice

Specific sequences of infectious challenge lead to secondary hemophagocytic lymphohistiocytosis-like disease in mice

Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome

Hemophagocytic Lymphohistiocytosis and Other Culture Negative Sepsis-Like Syndromes in the ICU

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