MIF is a Common Genetic Determinant of COVID-19 Symptomatic Infection and Severity.

BACKGROUND: Genetic predisposition to COVID-19 may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. AIM: To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. METHODS: This retrospective case control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the United States, Hungary, and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. RESULTS: In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls (11% vs. 19%, OR: 0.54 [0.41, 0.72], p < 0.0001). Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR: 2.87 [1.42, 5.78], p = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, p < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, p = 0.01) and maximum CRP (r = 0.16, p = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. CONCLUSIONS: In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7  MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of host genetics in different stages of COVID-19 infection.

A distinct association of inflammatory molecules with outcomes of COVID-19 in younger versus older adults.

Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.

Diagnosis of SARS-CoV-2 infection in the setting of the cytokine release syndrome.

INTRODUCTION: Coronavirus disease (COVID-19) can trigger a cytokine response storm (CRS) that is associated with high mortality but for which the underlying pathophysiology and diagnostics are not yet well characterized. This review provides an overview of the underlying immune profile of COVID-19-related CRS as well as laboratory markers for acute diagnosis and chronic follow-up of patients with SARS-CoV-2 and CRS. AREAS COVERED: Innate and acquired immune profiles in COVID-19-CRS, RNA-detection methods for SARS-CoV-2 in the setting of CRS including factors that affect assay performance, serology for SARS-CoV-2 in the setting of CRS, and other biomarkers for COVID-19 will be discussed. EXPERT OPINION: Studies support the implication of CRS in the pathogenesis, clinical severity and outcome of COVID-19 through the production of multiple inflammatory cytokines and chemokines from activated innate and adaptive immune cells. Although these inflammatory molecules, including IL-6, IL-2 R, IL-10, IP-10 and MCP-1, often correlate with disease severity as possible biomarkers, the pathogenic contributions of individual molecules and the therapeutic benefits of targeting them are yet to be demonstrated. Detection of SARS-CoV-2 RNA is the gold standard method for diagnosis of COVID-19 in the context of CRS but assay performance varies and is susceptible to false-negative results even as patients clinically deteriorate due to decreased viral shedding in the setting of CRS. Biomarkers including CRP, ferritin, D-dimer and procalcitonin may provide early clues about progression to CRS and help identify thrombotic and infectious complications of COVID-19.