Effectiveness of mid-regional pro-adrenomedullin, compared to other biomarkers (including lymphocyte subpopulations and immunoglobulins), as a prognostic biomarker in COVID-19 critically ill patients: New evidence from a 15-month observational prospective study.

Background: Mid-regional pro-adrenomedullin (MR-proADM), an endothelium-related peptide, is a predictor of death and multi-organ failure in respiratory infections and sepsis and seems to be effective in identifying COVID-19 severe forms. The study aims to evaluate the effectiveness of MR-proADM in comparison to routine inflammatory biomarkers, lymphocyte subpopulations, and immunoglobulin (Ig) at an intensive care unit (ICU) admission and over time in predicting mortality in patients with severe COVID-19. Methods: All adult patients with COVID-19 pneumonia admitted between March 2020 and June 2021 in the ICUs of a university hospital in Italy were enrolled. MR-proADM, lymphocyte subpopulations, Ig, and routine laboratory tests were measured within 48 h and on days 3 and 7. The log-rank test was used to compare survival curves with MR-proADM cutoff value of >1.5 nmol/L. Predictive ability was compared using the area under the curve (AUC) and 95% confidence interval (CI) of different receiver-operating characteristic curves. Results: A total of 209 patients, with high clinical severity [SOFA 7, IQR 4-9; SAPS II 52, IQR 41-59; median viral pneumonia mortality score (MuLBSTA)-11, IQR 9-13] were enrolled. ICU and overall mortality were 55.5 and 60.8%, respectively. Procalcitonin, lactate dehydrogenase, D-dimer, the N-terminal prohormone of brain natriuretic peptide, myoglobin, troponin, neutrophil count, lymphocyte count, and natural killer lymphocyte count were significantly different between survivors and non-survivors, while lymphocyte subpopulations and Ig were not different in the two groups. MR-proADM was significantly higher in non-survivors (1.17 ± 0.73 vs. 2.31 ± 2.63, p < 0.0001). A value of >1.5 nmol/L was an independent risk factor for mortality at day 28 [odds ratio of 1.9 (95% CI: 1.220-3.060)] after adjusting for age, lactate at admission, SOFA, MuLBSTA, superinfections, cardiovascular disease, and respiratory disease. On days 3 and 7 of the ICU stay, the MR-proADM trend evaluated within 48 h of admission maintained a correlation with mortality (p < 0.0001). Compared to all other biomarkers considered, the MR-proADM value within 48 h had the best accuracy in predicting mortality at day 28 [AUC = 0.695 (95% CI: 0.624-0.759)]. Conclusion: MR-proADM seems to be the best biomarker for the stratification of mortality risk in critically ill patients with COVID-19. The Ig levels and lymphocyte subpopulations (except for natural killers) seem not to be correlated with mortality. Larger, multicentric studies are needed to confirm these findings.

First Cases of Candida auris in a Referral Intensive Care Unit in Piedmont Region, Italy.

Candida auris is an emerging healthcare-associated infection that can easily cause dissemination in hospitals through colonizing the skin and contaminating environmental surfaces, especially in Intensive Care Units (ICU). Difficulties with identification of this organism, uncertainty about routes of transmission and antifungals resistance have impacted significantly outbreak detection and management. Here, we describe our experience with colonization/infection of C. auris among critically ill patients, admitted to a referral ICU of a University Hospital, in a transitional period (July 2021-March 2022) between management of non-COVID-19 and COVID-19 patients due to the reconversion of the ICU between two waves. A total of 8 patients presented colonization from C. auris, and two of them developed invasive infection from C. auris. The fungal pathogen was cultured from different sites: the skin (7 isolates), urine (2), respiratory tract (1), blood (1). The median time from admission to first detection is 24 days with 100% of patients requiring mechanical ventilation. All 8 patients received broad-spectrum antibiotic therapy for bacterial infections before identification of C. auris; 62.5% of the patients had prior antifungal exposure; 87.5% received steroids; 37.5% patients used immunomodulatory; and 75% had severe COVID-19 illness prior to C. auris identification. Only two cases (25%) were treated with antifungals as C. auris infections (1 patient for suspected UTI; 1 patient with candidemia). Infection control measures, including rapid microbiological identification, contact isolation, screening of contacts, antisepsis of colonized patients, dedicated equipment, cleaning and disinfection of the environment and subsequent follow-up sampling, remain essential in critically ill patients. Our experience highlights the importance of establishing a multidisciplinary model and bundling of practices for preventing C. auris' spread.

Extracorporeal membrane oxygenation for COVID-19 and influenza H1N1 associated acute respiratory distress syndrome: a multicenter retrospective cohort study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become an established rescue therapy for severe acute respiratory distress syndrome (ARDS) in several etiologies including influenza A H1N1 pneumonia. The benefit of receiving ECMO in coronavirus disease 2019 (COVID-19) is still uncertain. The aim of this analysis was to compare the outcome of patients who received veno-venous ECMO for COVID-19 and Influenza A H1N1 associated ARDS. METHODS: This was a multicenter retrospective cohort study including adults with ARDS, receiving ECMO for COVID-19 and influenza A H1N1 pneumonia between 2009 and 2021 in seven Italian ICU. The primary outcome was any-cause mortality at 60 days after ECMO initiation. We used a multivariable Cox model to estimate the difference in mortality accounting for patients' characteristics and treatment factors before ECMO was started. Secondary outcomes were mortality at 90 days, ICU and hospital length of stay and ECMO associated complications. RESULTS: Data from 308 patients with COVID-19 (N = 146) and H1N1 (N = 162) associated ARDS who had received ECMO support were included. The estimated cumulative mortality at 60 days after initiating ECMO was higher in COVID-19 (46%) than H1N1 (27%) patients (hazard ratio 1.76, 95% CI 1.17-2.46). When adjusting for confounders, specifically age and hospital length of stay before ECMO support, the hazard ratio decreased to 1.39, 95% CI 0.78-2.47. ICU and hospital length of stay, duration of ECMO and invasive mechanical ventilation and ECMO-associated hemorrhagic complications were higher in COVID-19 than H1N1 patients. CONCLUSION: In patients with ARDS who received ECMO, the observed unadjusted 60-day mortality was higher in cases of COVID-19 than H1N1 pneumonia. This difference in mortality was not significant after multivariable adjustment; older age and longer hospital length of stay before ECMO emerged as important covariates that could explain the observed difference. TRIAL REGISTRATION NUMBER: NCT05080933 , retrospectively registered.

Effects of Steroids and Tocilizumab on the Immune Response Profile of Patients with COVID-19-Associated ARDS Requiring or Not Veno-Venous Extracorporeal Membrane Oxygenation.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving rescue therapy in patients with Acute Respiratory Distress Syndrome (ARDS). ECMO has been associated with development of lymphocytopenia that is also common in COVID-19. Hyperinflammation may complicate SARS-CoV-2 pneumonia, prompting therapy with steroids and immunomodulatory drugs. We aimed to evaluate the association of therapies such as steroids and Tocilizumab with trajectories of the total leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers in COVID-19-related ARDS, requiring or not VV-ECMO support. The association of the trajectories of the leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers with treatment with steroids (Steroids), Tocilizumab (Tocilizumab), both drugs (Steroids + Tocilizumab), and absence of treatment (No Treatment) were analyzed using mixed effects regression models, where ECMO was considered as a potential effect modifier. One hundred and thirty-nine leukocyte and eighty-one lymphocyte subpopulation counts were obtained from thirty-one patients who required (VV-ECMO, N = 13) or not (no VV-ECMO, N = 18) extracorporeal support. In both groups, treatment with Steroids + Tocilizumab was independently associated with a significant reduction of 46% and 67% in total lymphocytes, 22% and 60% in CD3+, and 61% and 91% in CD19+ (B lymphocytes) compared to those obtained without treatment, respectively. In the no VV-ECMO group, Tocilizumab was associated with a 79% increase in total lymphocytes and with a reduction in procalcitonin compared to no treatment. CD45+, CD3+CD4+ (Th cell), CD3+CD8+, CD4+/CD8+, the NK cell subpopulation, neutrophils, monocytes, and basophils were significantly reduced by Steroids + Tocilizumab without an effect modification by VV-ECMO support. In critically ill COVID-19 patients with ARDS, concomitant therapies with steroids and Tocilizumab, beside mitigating the inflammation and fibrinolysis, could reduce the total leukocyte, lymphocyte, and subpopulation count. Moreover, the effect of Tocilizumab in increasing the total lymphocytes and reducing procalcitonin might be blunted by VV-ECMO.

Tracheostomy Timing and Outcome in Severe COVID-19: The WeanTrach Multicenter Study.

BACKGROUND: Tracheostomy can be performed safely in patients with coronavirus disease 2019 (COVID-19). However, little is known about the optimal timing, effects on outcome, and complications. METHODS: A multicenter, retrospective, observational study. This study included 153 tracheostomized COVID-19 patients from 11 intensive care units (ICUs). The primary endpoint was the median time to tracheostomy in critically ill COVID-19 patients. Secondary endpoints were survival rate, length of ICU stay, and post-tracheostomy complications, stratified by tracheostomy timing (early versus late) and technique (surgical versus percutaneous). RESULTS: The median time to tracheostomy was 15 (1-64) days. There was no significant difference in survival between critically ill COVID-19 patients who received tracheostomy before versus after day 15, nor between surgical and percutaneous techniques. ICU length of stay was shorter with early compared to late tracheostomy (p < 0.001) and percutaneous compared to surgical tracheostomy (p = 0.050). The rate of lower respiratory tract infections was higher with surgical versus percutaneous technique (p = 0.007). CONCLUSIONS: Among critically ill patients with COVID-19, neither early nor percutaneous tracheostomy improved outcomes, but did shorten ICU stay. Infectious complications were less frequent with percutaneous than surgical tracheostomy.

ECMO Support and Operator Safety in the Context of COVID-19 Outbreak: A Regional Center Experience.

Since the beginning of the COVID-19 emergency, the referral Intensive Care Unit for the Extracorporeal Membrane Oxygenation (ECMO) support of Piedmont Region (Italy), in cooperation with infectious disease specialists, perfusionists and cardiac surgeons, developed a protocol to guarantee operator safety during invasive procedures, among which the ECMO positioning or inter-hospital transport. The use of powered air-purifying respirators, filtering facepiece particles (FFP) 2-3 masks, protective suits, disposable sterile surgical gowns, and two pairs of sterile gloves as a part of a protocol seemed effective and feasible for trained healthcare workers and allow all the complex activities connected with the positioning of the ECMO support to be completed effectively. The simulation training on donning and doffing procedures and the presence of a dedicated team member to verify the compliance with the safety procedure effectively reassured operators and likely reduced the risk of self-contamination. From 1 March to 31 December 2020, we used the procedure in 35 severe acute respiratory distress syndrome (ARDS) patients and one acute respiratory failure caused by neoplastic total tracheal obstruction, all positive to COVID-19, to be connected to veno-venous ECMO in peripheral hospitals and centralized for ECMO management. This preliminary experience seems to confirm that the use of ECMO during COVID-19 outbreaks is feasible and the risks associated with its positioning and management are sustainable for the health-care workers and safe for patients.

Extracorporeal Membrane Oxygenation for COVID-19 Respiratory Distress Syndrome: An Italian Society for Cardiac Surgery Report.

An increased need of extracorporeal membrane oxygenation (ECMO) support is going to become evident as treatment of SARS-CoV-2 respiratory distress syndrome. This is the first report of the Italian Society for Cardiac Surgery (SICCH) on preliminary experience with COVID-19 patients receiving ECMO support. Data from 12 Italian hospitals participating in SICCH were retrospectively analyzed. Between March 1 and September 15, 2020, a veno-venous (VV) ECMO system was installed in 67 patients (94%) and a veno-arterio-venous ECMO in four (6%). Five patients required VA ECMO after initial weaning from VV ECMO. Thirty (42.2%) patients were weaned from ECMO, while 39 (54.9%) died on ECMO, and six (8.5%) died after ECMO removal. Overall hospital survival was 36.6% (n = 26). Main causes of death were multiple organ failure (n = 14, 31.1%) and sepsis (n = 11, 24.4%). On multivariable analysis, predictors of death while on ECMO support were older age (p = 0.048), elevated pre-ECMO C-reactive protein level (p = 0.048), higher positive end-expiratory pressure on ventilator (p = 0.036) and lower lung compliance (p = 0.032). If the conservative treatment is not effective, ECMO support might be considered as life-saving rescue therapy for COVID-19 refractory respiratory failure. However warm caution and thoughtful approaches for timely detection and treatment should be taken for such a delicate patients population.

Effectiveness of mid-regional pro-adrenomedullin (MR-proADM) as prognostic marker in COVID-19 critically ill patients: An observational prospective study.

OBJECTIVE: To test the effectiveness of mid-regional pro-adrenomedullin (MR-proADM) in comparison to C-reactive protein (CRP), procalcitonin (PCT), D-dimer, lactate dehydrogenase (LDH) in predicting mortality in COVID-19-ICU-patients. METHODS: All consecutive COVID-19 adult patients admitted between March and June 2020 to the ICU of a referral, university hospital in Northern-Italy were enrolled. MR-proADM and routine laboratory test were measured within 48 hours from ICU admission, on day 3, 7 and 14. Survival curves difference with MR-proADM cut-off set to 1.8 nmol/L were tested using log-rank test. Predictive ability was compared using area under the curve and 95% confidence interval of different receiver-operating characteristics curves. RESULTS: 57 patients were enrolled. ICU and overall mortality were 54.4%. At admission, lymphocytopenia was present in 86% of patients; increased D-dimer and CRP levels were found in 84.2% and 87.7% of patients respectively, while PCT values > 0.5 µg/L were observed in 47.4% of patients. MR-proADM, CRP and LDH were significantly different between surviving and non-surviving patients and over time, while PCT, D-dimer and NT-pro-BNP did not show any difference between the groups and over time; lymphocytes were different between surviving and non-surviving patients only. MR-proADM was higher in dying patients (2.65±2.33vs1.18±0.47, p<0.001) and a higher mortality characterized patients with MR-proADM >1.8 nmol/L (p = 0.016). The logistic regression model adjusted for age, gender, cardiovascular disease, diabetes mellitus and PCT values confirmed an odds ratio = 10.3 [95%CI:1.9-53.6] (p = 0.006) for MR-proADM >1.8 nmol/L and = 22.2 [95%CI:1.6-316.9] (p = 0.022) for cardiovascular disease. Overall, MR-proADM had the best predictive ability (AUC = 0.85 [95%CI:0.78-0.90]). CONCLUSIONS: In COVID-19 ICU-patients, MR-proADM seems to have constantly higher values in non-survivor patients and predict mortality more precisely than other biomarkers. Repeated MR-proADM measurement may support a rapid and effective decision-making. Further studies are needed to better explain the mechanisms responsible of the increase in MR-proADM in COVID-19 patients.