ABSTRACT
Importance: The benefit of routine screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of cancer patients diagnosed with Coronavirus Disease 2019 (COVID-19) by routine screening in comparison with those diagnosed based on clinical suspicion or exposure history (non-routine screening). Objective: To describe and compare the outcomes of cancer patients diagnosed with COVID-19 on routine screening vs. non-routine screening at a multi-site tertiary cancer center. To identify risk factors for COVID-19-related hospital admission. Design: A multi-site prospective observational study was conducted between March 18 and July 31, 2020. Setting: Three major and 5 satellite campuses of the Mayo Clinic Cancer Center. Participants: Adult patients diagnosed with active cancer within the past five years and confirmed SARS-CoV-2 infection were included. Primary Outcomes and Measures: Clinical and laboratory data were assessed as independent variables. The primary outcome was COVID-19- related hospital admission. Secondary outcomes included intensive care unit (ICU) admissions and all-cause mortality. Results: Between March 18 and July 31, 2020, 5452 patients underwent routine screening in the outpatient setting, 44 (0.81%) were diagnosed with COVID-19. Routine screening detected additional 19 patients from inpatient and pre-procedural settings;161 patients were diagnosed with COVID-19 based on non-routine screening. The median age of the entire cohort at diagnosis was 54 years, and 95 patients (42.2%) were female. COVID-19 related- hospitalization rate (17.5% vs. 26.7%, p=0.14), ICU admission (1.6% vs. 5.6%, p=0.19), and mortality (4.8% vs. 3.7%, p=0.72) were not significantly different between routine screening and non-routine screening groups. In the multivariable analysis, age ≥ 60 years (odds ratio: 4.4, p=0.023) and an absolute lymphocyte count ≤1.4 × 109 /L (odds ratio: 9.2, p=0.002) were independent predictors of COVID-19-related hospital admission. Conclusions and Relevance: The COVID-19 positivity rate was low based on routine screening. Comparing the outcome with the non-routine screening cohort, there was no significant difference. These results led to an important practice change at our cancer center. We currently follow a testing strategy based on symptoms, exposure, risk factors, and clinical judgment.
ABSTRACT
Background. Severe coronavirus disease 2019 (COVID-19) often results from the immune-mediated cytokine storm, triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), potentially leading to respiratory failure and death. Lenzilumab, a novel anti-human GM-CSF monoclonal antibody, neutralizes GM-CSF and demonstrated potential to improve clinical outcomes in a matched case-cohort study of patients with severe COVID-19 pneumonia. This Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to improve the likelihood of survival without invasive mechanical ventilation (SWOV), beyond available treatments. Methods. Hypoxic patients, hospitalized with COVID-19 (n=520), requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized on Day 0 to receive lenzilumab (1800mg, n=261) or placebo (n=259), and available treatments, including remdesivir and/or corticosteroids;and were followed through Day 28. Results. Baseline demographics were comparable between groups: male, 64.7%;mean age, 60.5 years;median CRP, 79.0 mg/L. Patients across both groups received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the primary endpoint, likelihood of SWOV in the mITT population, by 1.54-fold (HR: 1.54;95%CI: 1.02-2.32, p=0.0403). Lenzilumab improved SWOV by 1.91-fold (nominal p=0.0073) and 1.92-fold (nominal p=0.0067) in patients receiving remdesivir or remdesivir and corticosteroids, respectively. A key secondary endpoint of incidence of IMV, ECMO or death was also improved in patients receiving remdesivir (p=0.020) or remdesivir and corticosteroids (p=0.0180). Treatment-emergent serious adverse events were similar across both groups. Conclusion. Lenzilumab significantly improved SWOV in hypoxic COVID-19 patients upon hospitalization, with the greatest benefit observed in patients receiving treatment with remdesivir and corticosteroids. NCT04351152.
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Introduction: Obesity is a major risk factor for severe coronavirus disease, and clinical evidence now supports the GI tract, in addition to the respiratory system, as a potential route for SARS-CoV-2 infection. Expression of viral entry factors ACE2, TMPRSS2, and CTSL have been detected along the human GI tract including gastric, ileal and colonic mucosa. It is unclear whether obesity confers increased susceptibility to initial SARS-CoV-2 infection, or what gut mechanisms in obesity predispose to vulnerability to SARS-CoV-2. Thus, we aimed to investigate, by single cell RNA-sequencing (scRNA-Seq) of human colonic mucosa, whether patients with obesity may be more susceptible to SARS-CoV-2 infection, by virtue of enhanced expression of SARS-CoV2 entry cofactors followed protein assessment in colon biopsies. Methods: We studied 19 patients: 10 lean (age 33±3y, BMI 23±1kg/m2, 90% female), and 9 with obesity (age 43±3y, BMI 36±1kg/m2, 89% female). Human colonic biopsies from lean (n=4 scRNA-Seq;n=6 validation) and obesity (n=6 scRNASeq;n=3 validation) participants were obtained by sigmoidoscopy. Biopsies were dissociated, and viable cells were FACS-isolated. Chromium-10X Genomics was used for scRNA-Seq library prep, followed by Illumina HiSeq4000 sequencing. COVID-19 entry factors displaying significant differential expression between lean and obesity were then validated for gene, and protein expression in the validation cohort using Illumina TruSeq, and quantitative immunofluorescence confocal microscopy, respectively. Results: The initial dataset analysis revealed sequencing of 59,653 cells, 705 million reads, at 127,000 reads per cell. The human colonic mucosa partitioned into 20 cell subsets (Fig1A,B), and 15 of the 20 clusters displayed detectable expression of at least one of the COVID-19 entry factors: TMPRSS2, CTSL, or ACE2 (Fig1C,D,E). Goblet cell expression of TMPRSS2 was increased 4.6-fold (p<0.05), stromal cell expression of CTSL was increased 1.2-fold (p<0.0001), and ACE2 expression was increased 1.27-fold (p<0.001) in crypt-top (CT) colonocytes of obesity compared to lean controls (Fig2A). Colonic overexpression of TMPRSS2 mRNA (p<0.05) and protein (p<0.05), and CTSL (p<0.05) mRNA, but not ACE2 mRNA, in obesity was further validated in a second validation cohort (Fig2B-F). Conclusions: scRNA-Seq analysis of human colonic epithelium in obesity compared to healthy controls revealed multiple epithelial cell subsets (goblet cell, stromal, and colonocytes) with overexpression of COVID-19 entry factors TMPRSS2, CTSL, and ACE2, confirming the digestive system as a portal for infection by SARS-CoV-2.Furthermore goblet, stromal, and colonocyte-specific overexpression of TMPRSS2, CTSL, and ACE2 in obesity may play a significant role in increased initial susceptibility to COVID-19, and worse disease outcomes in human obesity.(Figure Presented) Single-Cell RNA-Seq Profiling of Human Colonic Epithelium in Obesity. A) t-SNE plot of single-cell RNA-seq profiles of native human colonic epithelial cells, colored by cluster number and identity, listed by largest to smallest population, and annotated by cluster identity, determined by highest ranking gene marker for the colonic cells clustered and profiled between lean and obesity, where dotted blue, red, and green circles represents goblet cells, stromal cells, and CT colonocytes, respectively. B) Proposed cluster identities based on conserved expression of known markers for annotated cell types. Clusters identified displayed expression of at least one of the COVID-19 entry factors: TMPRSS2, CTSL, or ACE2. The average proportion of cells in annotated clusters expressing, C) TMPRSS2, D) CTSL, and E) ACE2 among all studied participants.
ABSTRACT
BackgroundThe hyperinflammatory cytokine storm (CS) of COVID-19 is mediated by GM-CSF leading to release of downstream inflammatory chemokines, cytokines, and markers of systemic inflammation (C-reactive protein, CRP). The LIVE-AIR study demonstrated that lenzilumab, an anti-GM-CSF monoclonal antibody in patients hospitalized with COVID-19, safely improved the likelihood of achieving the primary endpoint, survival without ventilation (SWOV) by 1.54-fold (HR: 1.54;95%CI: 1.02–2.32, p=0.0403) compared with placebo. An exploratory analysis in patients with CRP<150 mg/L and age<85 years was conducted to determine lenzilumab efficacy when administered prior to advanced inflammation.MethodsLIVE-AIR was a phase 3 randomized, double-blind, placebo-controlled trial. Patients with COVID-19 (n=520), >18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation (IMV), were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Participants were followed through Day 28 following treatment.ResultsOverall, baseline demographics were comparable between treatment groups: male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;median CRP, 79 mg/L;CRP was <150 mg/L in 78% of participants. Participants received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab (n=159) improved the likelihood of SWOV by 3.04-fold in participants with CRP<150 mg/L and age<85 years (3.04;1.68–5.51, nominal p=0.0003) compared with placebo (n=178). Response to lenzilumab was observed in the first through third quartiles of baseline CRP (<41 mg/L, HR:8.33;41<79 mg/L, HR:1.60;79<137 mg/L, HR: 2.12;>137 mg/L, HR: 1.17). The incidence of IMV, ECMO, or death was reduced (OR: 0.31;95%CI: 0.15–0.63, p=0.002) and mortality was improved by 2.22-fold (OR: 2.22;95%CI: 1.07–4.67, p=0.034). In these participants, lenzilumab decreased CRP as early as Day 2 following treatment, compared with placebo which was further decreased by 38% on Day 28 compared with placebo (24.4±3.4 mg/L vs 39.1±4.9 mg/L).ConclusionLenzilumab significantly improved SWOV in hospitalized, hypoxic participants with COVID-19 pneumonia with the greatest benefits in SWOV and survival in patients with CRP<150 mg/L and age <85 years. Inhibition of GM-CSF, an orchestrator of CS, early in the hyperinflammatory response improved outcomes in COVID-19. NCT04351152
ABSTRACT
Background: In the setting of SARS-CoV-2 infection and COVID-19 illness, a subset of symptomatic patients has been reported to experience severe leukopenia. Viral proteins have been described to have the capacity to induce cell death in peripheral blood cells in infections such as HIV. Given the expression of the cognate receptor, ACE-2, on the surface of Peripheral blood mononuclear cells (PBMCs), we hypothesized that SARS-CoV-2 may induce leukopenia via spike protein ligand-receptor interaction. Methods: PBMCs were isolated from the fresh blood of normal donors and were treated with 1ug/ml of recombinant spike protein, and analyzed for cell death via the Incucyte Live/Cell imaging system. To measure subset specific cell death, PBMCs treated with recombinant spike protein for 48 hours were analyzed by flow cytometry for the expression of cell specific surface receptors and concomitant active caspase 3 expression. Culture supernatant was analyzed by multiplex cytokine analysis to evaluate the presence of pro-inflammatory cytokines. Similar assays were carried out in the presence of a spike- binding domain-antagonistic antibody in order to determine the specific role of spike- ACE2 interaction in causing cell death. Finally, cells from COVID positive patients were analyzed to determine if similar results were observable in-vivo. Results: The treatment of PBMCs with recombinant SARS-CoV-2 spike resulted in significant cell death over time in 2 out of three donors tested (p<0.05) by IncuCyte live imaging analysis. When analyzed for subset specific cell death, a significant increase in cell death (p<0.01), as measured by Caspase 3, was observed in CD14+CD3- cells, correlating with the monocyte population. Supernatants from these cultures demonstrated markedly increased IL-8 production (p=0.0536). Cultures carried out in the presence of a spike antagonistic antibody abrogated the effects of spike protein, indicating a direct relationship between spike-ACE2 interaction and cell death in this sub-population. Similar flow cytometric analysis from 5 febrile patients with COVID-19 demonstrated significantly increased monocyte apoptosis (p<0.05), compared to CD3+ lymphocytes from the same donors;whereas significantly increased monocyte apoptosis was not observed in 5 afebrile COVID-19 patients. Conclusion: These results indicate that SARS-CoV-2 spike protein may induce apoptosis specifically in Monocytes, in an ACE2 dependent manner, in some but not all patients.
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Objective: To determine the association between chronic statin use and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19). Patients and Methods: We identified a retrospective cohort of patients requiring admission at the Mayo Clinic using our enterprise-wide COVID-19 registry from March 1, 2020, through September 30, 2020. Available information included age, sex, use of statins, medical comorbidities, and 30-day mortality. We estimated the association of statins with 30-day mortality using odds ratios and 95% CIs from logistic regression modeling. Results: Patients (N=1295) between the ages of 30 and 80 years tested positive for COVID-19 and required admission during the study period, of whom 500 (38.6%) were taking statins at admission. Patients taking statins were older and more likely to have diabetes mellitus or congestive heart failure. Within 30 days of diagnosis, 59 (4.6%) died. In multivariable analysis, statin users did not have statistically different odds of death within 30 days with an odds ratio of 1.14 (95% CI, 0.64 to 2.03;P=.67) compared to nonusers. Conclusion: Patients with COVID-19 taking statins had similar 30-day mortality to those not taking statins after adjusting for relevant covariates. Although this is partly influenced by a higher prevalence of risk factors for more severe COVID-19 presentation not entirely adjusted for by the Charlson comorbidity index, these data would not support statins as a likely therapeutic intervention for COVID-19 in the hospital setting.