An inflammatory cytokine signature helps predict COVID-19 severity and death

Abstract

The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-α, and IL-1β in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to evaluate the independent predictive value of baseline cytokines. We found that high serum IL-6, IL-8, and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival. Importantly, when adjusting for disease severity score, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. We also propose that patients with high IL-6 and TNF-α levels should be assessed for combinatorial blockade of pathogenic inflammation in this disease.

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

“…These different effector functions of antibodies are modulated by antibody-intrinsic characteristics, such as isotype, subclass, allotype, and glycosylation (24). In severely ill COVID-19 patients the glycosylation of anti-Spike IgG is changed, which we here show amplifies the IgG effector function to promote pro-inflammatory cytokine production, of which COVID-19-associated cytokines such as IL-1β, IL-6, and TNF (5,32) are most pronounced. Decreased IgG fucosylation, as observed in severe cases of COVID-19, has so far only been observed in patients infected with HIV and Dengue virus (33,34), but may actually be a general phenomenon in a response to enveloped viruses (26).…”

In-depth blood proteome profiling analysis revealed distinct functional characteristics of plasma proteins between severe and non-severe COVID-19 patients

“…One of the most significant regulators is IL-6, and the immune response triggered by it is activated in severe COVID-19 patients, as reported in previous publications [5,6,23,24]. In addition to IL-6, IL-1B and tumor necrosis factor (TNF) are the major components of the cytokine storm commonly observed in severe COVID-19 patients [25].…”

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

“…In the course of a severe SARS-CoV-2 viral infection, acute pulmonary damage has been observed concomitantly with elevated cytokine levels in serum and infiltration of macrophages and lymphocytes into multiple organs, indicative of both local and systemic immunological responses [11,15]. To better understand these dynamics, we leveraged scRNA-seq data from BALF and blood to compare severityspecific shifts in cellular composition at the local and systemic levels.…”

“…A hallmark of severe and critical COVID-19 cases is a rampant dysregulation of the immune system concomitant with the development of a hypoxemic respiratory condition widely characterized as acute respiratory distress syndrome (ARDS) [1,7,8,9,10]. The serological profile of severe COVID-19 patients largely resembles the cytokine profile of ARDS [9] and has been characterized by high levels of many cytokines including IL-2, IL-6, IL-7, IL-8, IL-18, CCL2, CCL8, TNF-α, and IFN-γ [9,11,12,13,14].…”

“…Previous investigations of peripheral blood responses have shown various compositional shifts between severe and mild disease including cytopenias of monocytes, natural killer (NK) cells, dendritic cells (DCs), and T cells, [28,29,30,31,32] accompanied by increases in plasmablasts, B cells, and neutrophils [33,34,35,36]. Serum cytokine levels are reportedly altered between severe and mild patients, including increased IL-6, IL-8, and TNF-ɑ [11,35] and deficient IFN-α and IFN-γ [33], while blood single-cell transcriptional analyses have shown alteration of the TNF-α/NF-κB pathway, interferon signatures, and HLA class II expression [33,34,36,32].…”