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Background: Matrix Metalloproteinases (MMP) respond to tissue damage during sepsis. Higher plasma concentrations of MMPs and the tissue-inhibitor of matrix metalloproteinases (TIMP) have been reported in sepsis compared with healthy controls. The objective of this study was to examine if plasma levels of MMP-3, MMP-9, and TIMP-1 associate with mortality and organ dysfunction during sepsis. Methods: We conducted a prospective cohort study of critically ill patients with sepsis adjudicated per Sepsis-3 criteria at a tertiary academic medical center. We measured plasma concentrations of MMP-3, MMP-9, and TIMP-1 on intensive care unit admission. We phenotyped the subjects for shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality at 30 days. We used logistic regression to test the associations between the MMPs and TIMP-1 with shock, ARDS, AKI, and mortality. Results: Higher plasma TIMP-1 levels were associated with shock (odds ratio [OR] 1.51 per log increase [95% CI 1.25, 1.83]), ARDS (OR 1.24 [95% CI 1.05, 1.46]), AKI (OR 1.18 [95% CI 1.01, 1.38]), and mortality (OR 1.20 [95% CI 1.05, 1.46]. Higher plasma MMP-3 concentrations were associated with shock (OR 1.40 [95% CI 1.12, 1.75]) and mortality (OR 1.24 [95% CI 1.03, 1.48]) whereas MMP-9 levels were not associated with outcomes. Higher plasma TIMP-1 to MMP-3 ratios were associated with shock (OR 1.41 [95% CI 1.15, 1.72], P = 0.02). Conclusion: Elevated plasma concentrations of TIMP-1 associate with organ dysfunction and mortality in sepsis. Higher plasma levels of MMP-3 associate with shock and mortality. Plasma MMP and TIMP-1 may warrant further investigation as emerging sepsis theragnostic biomarkers.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses.

Rationale: To utilize high-dimensional proteomic data to identify dysregulated pathways that are associated with COVID-19 disease severity and suggest potential therapeutic targets. Methods: We enrolled 161 COVID-19 inpatients admitted at two tertiary care hospitals. Plasma samples collected within 48 hours of admission were analyzed with the Olink Proximity Extension Assay;713 unique proteins were assayed. The WHO COVID-19 ordinal severity scale at enrollment was dichotomized into moderate (levels 3-4) and severe (levels 5-7). Normalized protein expression (NPX) values were generated in relation to a common pooled control plasma on each plate. The association between NPX values and disease severity on admission was estimated with logistic regression (LR) after adjustment for age, sex, race, and select comorbidities. Ingenuity Pathway Analysis (IPA) was employed after application of the Benjamini-Hochberg procedure with a false discovery rate of 5% to all proteins for which the NPX difference was +/-0.8 between groups. Predictive models of disease severity on hospital day 7 using all proteins as potential features were fit using elastic net LR (ENLR) and gradient boosting (GBM). Performance was estimated on a held-out test set (40% of the data) with area under the receiveroperator characteristic curve (AUROC). Results: Of 161 subjects, 85 (53%) were classified as having severe COVID-19. A total of 552 proteins were differentially expressed (Figure 1), and 31 of these proteins met criteria for inclusion in pathway analysis. IPA identified the triggering receptor expressed on myeloid cells 1 (TREM-1) signaling pathway (4 members, p=3.8E-3), the tumor microenvironment (TME) pathway (5 members, p=4.1E-3), and the interleukin 17 (IL-17) signaling pathway (4 members, p=1.8E-2). Interleukin 1 receptor-like 1, a member of the TREM-1 pathway, was the protein most associated with disease severity (OR=3.18, p=1.82E-08). Tumor necrosis factor ligand superfamily member 11 (TNFSF11), a member of the IL-17 signaling pathway was the only factor whose enrichment was associated with less severe disease (OR=0.39, p=2.3E-05). ENLR and GBM predicted disease severity on day 7 with AUROC values of 0.908 (0.828, 0.968) and 0.882 (0.788, 0.957), respectively. Conclusion: We identified pathways differentially expressed between patients with severe and nonsevere COVID-19 associated with immune function and angiogenesis. Several agents currently being investigated to treat severe COVID-19 act on these dysregulated pathways, and future investigations could test whether these proteins act as enrichment markers or response indicators. Integrating protein expression with cellular immune phenotype may help explain COVID-19 pathophysiology.

Rationale: Respiratory viruses are commonly detected pathogens in pulmonary sepsis. Prior studies have demonstrated that patients with respiratory viral infections may have transient lymphocytopenia and thrombocytopenia. Leukocyte parameters including lymphocyte to monocyte ratio (LMR) and neutrophil to lymphocyte ratio (NLR) have been reported as screening tools for viral infections. Platelet counts and dynamics have been described as quantitative traits for ARDS risk and mortality. Therefore, we hypothesized that early hematologic parameters including lymphocyte count, monocyte count, platelet count, NLR, and LMR may distinguish viral from bacterial pulmonary sepsis. Methods: We enrolled 1,158 critically ill patients with pulmonary sepsis from 2009 to 2020 and measured lymphocyte count, monocyte count, platelet count, NLR, and LMR on ICU admission and at 24-hrs. Respiratory viruses were detected via PCR panel on nasopharyngeal swabs. Pulmonary sepsis was adjudicated by a physician panel. APACHE III scores were collected during the first 24-hrs. Shock was assessed by vasopressor use or mean arterial pressure

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation., Profound plasmablast expansion, innate cell modulation, and T cell activation are defining features of severe COVID-19.

Objective The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis. Research Design and Methods A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity. Results ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. Conclusions For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.