A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study

Background: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. Methods: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. Results: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. Conclusions: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.11 página

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study

Background The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis

Background: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior noninvasive respiratory support on outcomes. Methods: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICUs) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of ICU admission. Propensity score matching was used to achieve a balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different time-point (48 h from ICU admission) for early and delayed intubation. Results: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After propensity score matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%; p=0.01), ICU mortality (25.7% versus 36.1%; p=0.007) and 90-day mortality (30.9% versus 40.2%; p=0.02) compared with the early intubation group. Very similar findings were observed when we used a 48-h time-point for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth waves, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (HFNC) (n=294) who were intubated earlier. The subgroup of patients undergoing noninvasive ventilation (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. Conclusions: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received HFNC

ICU-Acquired Pneumonia Is Associated with Poor HealthPost-COVID-19 Syndrome

Background. Some patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients. Methods: This prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge. Results: A total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19. Conclusions: Persistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-1

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Abstract Background Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0–171.2] to 180.0 [135.4–227.9] mmHg and the ventilatory ratio from 1.73 [1.33–2.25] to 1.96 [1.61–2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01–1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01–1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93–1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Methodology of a Large Multicenter Observational Study of Patients with COVID-19 in Spanish Intensive Care Units.

The COVID-19 pandemic created tremendous challenges for health-care systems. Intensive care units (ICU) were hit with a large volume of patients requiring ICU admission, mechanical ventilation, and other organ support with very high mortality. The Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBERES), a network of Spanish researchers to investigate in respiratory disease, commissioned the current proposal in response to the Instituto de Salud Carlos III (ISCIII) call. CIBERESUCICOVID is a multicenter, observational, prospective/retrospective cohort study of patients with COVID-19 admitted to Spanish ICUs. Several work packages were created, including study population and ICU data collection, follow-up, biomarkers and miRNAs, data management and quality. This study included 6102 consecutive patients admitted to 55 ICUs homogeneously distributed throughout Spain and the collection of blood samples from more than 1000 patients. We enrolled a large population of COVID-19 ICU-admitted patients including baseline characteristics, ICU and MV data, treatments complications, and outcomes. The in-hospital mortality was 31%, and 76% of patients required invasive mechanical ventilation. A 3-6 month and 1 year follow-up was performed. Few deaths after 1 year discharge were registered. Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. These antibodies contribute to prevent systemic dissemination of SARS-CoV-2. The severity of COVID-19 impacts the circulating miRNA profile. Plasma miRNA profiling emerges as a useful tool for risk-based patient stratification in critically ill COVID-19 patients. We present the methodology used in a large multicenter study sponsored by ISCIII to determine the short- and long-term outcomes in patients with COVID-19 admitted to more than 50 Spanish ICUs

Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study.

Although there is evidence supporting the benefits of corticosteroids in patients affected with severe coronavirus disease 2019 (COVID-19), there is little information related to their potential benefits or harm in some subgroups of patients admitted to the intensive care unit (ICU) with COVID-19. We aim to investigate to find candidate variables to guide personalized treatment with steroids in critically ill patients with COVID-19. Multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish ICUs. The primary outcome was 90-day mortality. Subsequent analyses in clinically relevant subgroups by age, ICU baseline illness severity, organ damage, laboratory findings and mechanical ventilation were performed. High doses of corticosteroids (≥ 12 mg/day equivalent dexamethasone dose), early administration of corticosteroid treatment ( Between February 2020 and October 2021, 4226 patients were included. Of these, 3592 (85%) patients had received systemic corticosteroids during hospitalisation. In the propensity-adjusted multivariable analysis, the use of corticosteroids was protective for 90-day mortality in the overall population (HR 0.77 [0.65-0.92], p = 0.003) and in-hospital mortality (SHR 0.70 [0.58-0.84], p  Corticosteroid in ICU-admitted patients with COVID-19 may be administered based on age, severity, baseline inflammation, and invasive mechanical ventilation. Early administration since symptom onset may prove harmful

Procalcitonin and C-reactive protein to rule out early bacterial coinfection in COVID-19 critically ill patients

Although the prevalence of community-acquired respiratory bacterial coinfection upon hospital admission in patients with coronavirus disease 2019 (COVID-19) has been reported to be < 5%, almost three-quarters of patients received antibiotics. We aim to investigate whether procalcitonin (PCT) or C-reactive protein (CRP) upon admission could be helpful biomarkers to identify bacterial coinfection among patients with COVID-19 pneumonia. We carried out a multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish intensive care units (ICUs). The primary outcome was to explore whether PCT or CRP serum levels upon hospital admission could predict bacterial coinfection among patients with COVID-19 pneumonia. The secondary outcome was the evaluation of their association with mortality. We also conducted subgroups analyses in higher risk profile populations. Between 5 February 2020 and 21 December 2021, 4076 patients were included, 133 (3%) of whom presented bacterial coinfection. PCT and CRP had low area under curve (AUC) scores at the receiver operating characteristic (ROC) curve analysis [0.57 (95% confidence interval (CI) 0.51-0.61) and 0.6 (95% CI, 0.55-0.64), respectively], but high negative predictive values (NPV) [97.5% (95% CI 96.5-98.5) and 98.2% (95% CI 97.5-98.9) for PCT and CRP, respectively]. CRP alone was associated with bacterial coinfection (OR 2, 95% CI 1.25-3.19; p = 0.004). The overall 15, 30 and 90 days mortality had a higher trend in the bacterial coinfection group, but without significant difference. PCT ≥ 0.12 ng/mL was associated with higher 90 days mortality. Our study suggests that measurements of PCT and CRP, alone and at a single time point, are not useful for ruling in or out bacterial coinfection in viral pneumonia by COVID-19