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.

Development and external validation of a prediction risk model for short-term mortality among hospitalized U.S. COVID-19 patients: A proposal for the COVID-AID risk tool

“…In addition, given our focus on short-term mortality as an outcome, we found that lower MAP at presentation was linked with early death and remained a consistent, early adverse predictor among patients in our cohort. We hypothesize that this is due to the fact that these patients were more likely to be suffering from systemic vasodilatory states, such as sepsis [ 23 ] or the inflammatory cytokine storm syndrome, which has been associated with severe COVID-19 and ARDS [ 24 – 26 ]. Interestingly, we also found that kidney dysfunction at presentation (defined as serum creatinine ≥2 mg/dL), regardless of chronicity, was the most significant extra-thoracic organ system to impact short-term mortality among hospitalized patients afflicted with COVID-19.…”

SARS-CoV-2-Encoded Proteome and Human Genetics: From Interaction-Based to Ribosomal Biology Impact on Disease and Risk Processes

“…Hyperferritinemia has been suggested to have genetic associations through pathogenic variants in genes targetable by IL1RAP and anti-C5 antibodies. 140 Type-1 interferonopathies, like heterozygous null variants in IRF7, have been shown to result in severe manifestations of seasonal influenza virus. 141 Similar monogenetic variants likely exist that lead to the individual risk of severe disease onset from SARS-CoV-2 in previously healthy patients.…”

Understanding Disseminated Intravascular Coagulation and Hepatobiliary Dysfunction Multiple Organ Failure in Hyperferritinemic Critical Illness*

“…18,19 We recently described the pathophysiologic basis for these observations as well as putative therapies to be considered. 20–23 According to our reviews, the MOF pattern of DIC and hepatobiliary dysfunction requires 1) plasma exchange therapy to reverse coagulopathy/DIC, and to remove ferritin and free hemoglobin which together are important mediators of feed forward inflammation, 2) IVIG to neutralize DNA viremia which stimulates TLR9 activation and induces liver injury, and 3) anakinra to stop cytokine induced liver injury.…”