Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation.

Abstract

Post-hoc subgroup analysis of the negative trial of interleukin-1β receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030.7 ηg/ml, ±SEM 7,411.1). In total 11 rare (minor allele frequency <5%) pathogenic or likely pathogenic variants causal for the monogenic disorders of Familial Hemophagocytic Lymphohistiocytosis, atypical Hemolytic Uremic Syndrome, Familial Mediterranean Fever, and Cryopyrin-associated Periodic Fever were identified. In these conditions, seven of the identified variants are currently targeted with IL1RA and four with anti-C5 antibody. Gene-targeted precision medicine may benefit this subgroup of patients with septic shock and pathogenic immune variation.

• Authors: Kate F Kernan, Lina Ghaloul-Gonzalez, Bita Shakoory, John A Kellum, Derek C Angus, Joseph A Carcillo
• Journal: Genes and immunity (Genes Immun) Vol. 20 Issue 6 Pg. 520-526 (07 2019) ISSN: 1476-5470 [Electronic] England
• PMID: 29977033 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)

Chemical References

• IL1RN protein, human
• Interleukin 1 Receptor Antagonist Protein
• Ferritins

Topics

• Adult
• Aged
• Cryopyrin-Associated Periodic Syndromes (genetics)
• Familial Mediterranean Fever (genetics)
• Female
• Ferritins (blood)
• Hemolytic-Uremic Syndrome (genetics)
• Humans
• Interleukin 1 Receptor Antagonist Protein (therapeutic use)
• Lymphohistiocytosis, Hemophagocytic (genetics)
• Macrophage Activation Syndrome (drug therapy, genetics, immunology, mortality)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Shock, Septic (drug therapy, genetics, immunology, mortality)
• Exome Sequencing