Elastase and exacerbation of neutrophil innate immunity are involved in multi-visceral manifestations of COVID-19.

BACKGROUND: Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19. METHODS: We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls. RESULTS: Blood neutrophil elastase, histone-DNA, myeloperoxidase-DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10-fold, compared with controls. Neutrophil elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin-6 (IL-6), IL-8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL-8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity. CONCLUSION: Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19.

Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France.

BACKGROUND: In patients with severe coronavirus disease 2019 (COVID-19), data are scarce and conflicting regarding whether chronic use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) influences disease outcomes. In patients with severe COVID-19, we assessed the association between chronic ACEI/ARB use and the occurrence of kidney, lung, heart, and liver dysfunctions and the severity of the inflammatory reaction as evaluated by biomarkers kinetics, and their association with disease outcomes. METHODS: We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. Independent predictors were assessed through receiver operating characteristic analysis, time-series analysis, logistic regression analysis, and multilevel modeling for repeated measures. RESULTS: On the 149 patients included in the study 30% (44/149) were treated with ACEI/ARB. ACEI/ARB use was independently associated with the following biochemical variations: phosphorus >40 mg/L (odds ratio [OR], 3.35, 95% confidence interval [CI], 1.83-6.14), creatinine >10.1 mg/L (OR, 3.22, 2.28-4.54), and urea nitrogen (UN) >0.52 g/L (OR, 2.65, 95% CI, 1.89-3.73). ACEI/ARB use was independently associated with acute kidney injury stage ≥1 (OR, 3.28, 95% CI, 2.17-4.94). The daily dose of ACEI/ARB was independently associated with altered kidney markers with an increased risk of +25 to +31% per each 10 mg increment of lisinopril-dose equivalent. In multivariable multilevel modeling, UN >0.52 g/L was independently associated with the risk of acute respiratory failure (OR, 3.54, 95% CI, 1.05-11.96). CONCLUSIONS: Patients chronically treated with ACEI/ARB who have severe COVID-19 are at increased risk of acute kidney injury. In these patients, the increase in UN associated with ACEI/ARB use could predict the development of acute respiratory failure.

Usefulness of procalcitonin at admission as a risk-stratifying biomarker for 50-day in-hospital mortality among patients with community-acquired bloodstream infection: an observational cohort study.

PURPOSE: To assess the association between plasma procalcitonin concentration at hospital admission and the risk of 50-day in-hospital mortality among patients with community-acquired bloodstream infections. METHODS: We carried out a retrospective, observational cohort study with all consecutive patients with bacteriologically confirmed community-acquired bloodstream infections hospitalized between 2006 and 2012. We aimed to assess the association between plasma procalcitonin at admission and 50-day in-hospital mortality. Patients were included in the analysis if they had undergone a blood culture test within 48 hours of hospitalization with a concomitant procalcitonin assay (time < 12 hours between the two tests). Inclusion in the study began on the day of hospital admission, and each patient was followed until death, discharge from the hospital, or last known follow-up in the 50 days following hospital admission. The endpoint was the occurrence of all-cause in-hospital mortality during the 50 days following hospital admission. RESULTS: During the 7-year study period, 1593 patients were admitted to one of the healthcare facilities of the University Hospital of Nancy from home or through the emergency department and had positive blood cultures and concomitant procalcitonin assays. Among the patients, 452 met the selection criteria and were analyzed. In ROC analysis, procalcitonin at baseline was significantly associated with 50-day in-hospital mortality, with an optimal threshold > 4.24 ng/mL. A baseline procalcitonin > 4.24 ng/mL was independently associated with an increased risk of in-hospital mortality (multivariable logistic regression: odds ratio, 2.58; 95% CI, 1.57-4.25; P = 0.0002; Cox proportional hazard regression: hazard ratio, 2.01; 95% CI, 1.30-3.11; P = 0.002). In sensitivity analyses, baseline procalcitonin quartiles were independently associated with 50-day in-hospital mortality (multivariable logistic regression: odds ratio, 1.47; 95% CI, 1.17-1.85; P = 0.001; Cox proportional hazard regression: hazard ratio, 1.31; 95% CI, 1.07-1.60; P = 0.008). The independent associations between baseline procalcitonin and the risk of 50-day in-hospital mortality were maintained after adjusting for C-reactive protein and sepsis status at admission. CONCLUSION: Our data provide the first evidence of the usefulness of plasma procalcitonin at admission as a risk-stratifying biomarker for predicting 50-day in-hospital mortality among patients with community-acquired bloodstream infections.

[Use of the multiparametric panel CD3/CD4/CD8/CD7/CD26/CD158k in the detection and use of flow cytometry of Sezary cells]. / Apport du panel multiparamétrique CD3 CD4 CD8 CD7 CD26 CD158k dans la détection et le suivi par cytométrie en flux des cellules de Sézary.

The Sezary syndrome has been defined by a triad combining erythrodermia, generalized lymphadenopathy, and the presence of circulating Sezary cells > 1 × 109/L characterized by a CD4+/CD8- phenotype with loss of one or more T antigens (mainly CD7 and/or CD26). We retrospectively reviewed the immunophenotypic profiles of 10 SS patients followed in our institution (University Hospital at Nancy, France). The application of the WHO criteria resulted in a diagnostic confirmation for 9 out of 10 cases. Since 2008, new diagnostic and staging criteria have been proposed, including the CD158k/KIR3DL2 receptor detection. The application of these new criteria to our cohort led us to notice a phenotypic heterogeneity of our cases but allowed to achieve a relevant diagnosis of Sezary syndrome in all cases, especially for patients with lymphopenia. The use of such a panel of monoclonal antibodies also optimized the follow-up of the patients.