COVID-19 disease, caused by SARS-CoV-2 infection, has resulted in more than 15.5 million infections and 634,000 deaths worldwide. A recent study of hospitals in New York City, at the initial epicenter of the COVID-19 pandemic in the United States, reported that, during March 2020, 21% of patients hospitalized with confirmed COVID-19 died 1 . These findings are aligned with outcomes observed in the Mount Sinai Health System 2,3 . There are currently no curative or preventive therapies for COVID-19, highlighting the need to enhance current understanding of SARS-CoV-2 pathogenesis for the rational development of therapeutics.Recent studies have suggested that, in addition to direct viral damage, uncontrolled inflammation contributes to disease severity in 5 ). Consistent with this hypothesis, high levels of inflammatory markers, including C-reactive protein (CRP), ferritin and D-dimer, high neutrophil-to-lymphocyte ratio [6][7][8][9] and increased levels of inflammatory cytokines and chemokines 6,8-11 have been observed in patients with severe diseases. Pathogenic inflammation, also referred to as cytokine storm, shares similarities with what was previously seen in patients infected with other severe coronaviruses, including SARS-CoV and Middle East respiratory syndrome coronavirus 12 , and bears similarities to cytokine release syndrome (CRS) observed in patients with cancer treated with chimeric antigen receptor-modified (CAR) T cells 13 . Tocilizumab, an IL-6 receptor inhibitor, is a US Food and Drug Administration (FDA)-approved treatment for CRS in patients receiving CAR T cells 14 . Several single-center studies have used IL-6 inhibitors to treat patients with COVID-19 with some clinical benefits 15 and reported failures 14 . Beyond IL-6, several cytokines have been shown to be elevated in CRS and to contribute to tissue damage. TNF-α is important in nearly all acute inflammatory reactions, acting as an amplifier of inflammation. TNF-α blockade has been used to treat more than ten different autoimmune inflammatory diseases, suggesting that this might be a potential therapeutic approach to reduce organ damage in patients with ). IL-1 is also a highly active pro-inflammatory cytokine, and monotherapy blocking

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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.

Background The COVID-19 pandemic, caused by SARS-CoV-2 virus, has resulted in over 100,000 deaths in the USA. Our institution has treated over 2000 COVID-19 patients during the pandemic in New York City. The pandemic directly impacted cancer patients and the organization of cancer care. Mount Sinai Hospital has a large and diverse multiple myeloma (MM) population. Herein, we report the characteristics of COVID-19 infection and serological response in MM patients in a large tertiary care institution in New York. Methods We performed a retrospective study on a cohort of 58 patients with a plasma-cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020, and April 30, 2020. We report epidemiological, clinical, and laboratory characteristics including the persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes. Results Of the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male and 63% were non-White. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (24%), and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (> 70 years), male sex, cardiovascular risk, and patients not in complete remission (CR) or stringent CR were significantly ( p < 0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant ( p < 0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-White race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. The median time to PCR negativity was 43 (range 19–68) days from initial positive PCR. Conclusions Drug exposure and MM disease status at the time of contracting COVID-19 had no bearing on mortality. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia was associated with higher mortality. The majority of patients mounted an antibody response to SARS-CoV-2. These findings pave a path to the identification of vulnerable MM patients who need early intervention to improve outcomes in future outbreaks of COVID-19.

Brief CommuniCation Nature MediciNeExtended Data Fig. 10 | immunohistochemistry showing BCMA protein expression in brain tissue of the patient and in a control brain. (a) BCMA immunohistochemistry of the caudate nucleus subependymal region (10x magnification, left, scale bar 200 µm). Inset (40x magnification, right, scale bar 50 µm) shows high magnification image of astrocytes (top) and a neuron (bottom) that stained positive for BCMA, whereas surrounding cells were negative. Images shown are representative slides from the caudate nucleus from the patient described in this case report (N = 1). For each region stained, at least 3 slides were available. (b) BCMA immunohistochemistry of selected brain regions as annotated in the patient of interest (left) versus a control brain (right) from a subject who died due to non-neurologic illness (10x magnification (top), scale bar 200 µm and 20x magnification (middle, bottom), scale bar 100 µm). Images shown are representative slides from the patient described in this case report (N = 1), as well as a single control brain (N = 1). For each region stained, at least 3 slides were available. The experiment was repeated in a second control brain with similar results.