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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study.

BACKGROUND: The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. METHODS: We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (<1 N1 copies per mL), VIR-N1-Low (1-2747 N1 copies per mL), and VIR-N1-Storm (>2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. FINDINGS: 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16-0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26-0·57; p<0·0001, compared with the VIR-N1-Storm group). INTERPRETATION: The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood. FUNDING: Instituto de Salud Carlos III, Canadian Institutes of Health Research, Li Ka-Shing Foundation, Research Nova Scotia, and European Society of Clinical Microbiology and Infectious Diseases. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

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

PURPOSE: 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. METHODS: 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 (< 7 days since symptom onset) and long term of corticosteroids (≥ 10 days) were also investigated. RESULTS: 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 < 0.001). Significant effect modification was found after adjustment for covariates using propensity score for age (p = 0.001 interaction term), Sequential Organ Failure Assessment (SOFA) score (p = 0.014 interaction term), and mechanical ventilation (p = 0.001 interaction term). We observed a beneficial effect of corticosteroids on 90-day mortality in various patient subgroups, including those patients aged ≥ 60 years; those with higher baseline severity; and those receiving invasive mechanical ventilation at ICU admission. Early administration was associated with a higher risk of 90-day mortality in the overall population (HR 1.32 [1.14-1.53], p < 0.001). Long-term use was associated with a lower risk of 90-day mortality in the overall population (HR 0.71 [0.61-0.82], p < 0.001). No effect was found regarding the dosage of corticosteroids. Moreover, the use of corticosteroids was associated with an increased risk of nosocomial bacterial pneumonia and hyperglycaemia. CONCLUSION: 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.

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.

ICU-Acquired Pneumonia Is Associated with Poor Health Post-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-19.

Relationship between seasonal influenza rates and hospitalization and mortality rates due to acute cardiovascular diseases in a Spanish region. / Relación entre las tasas de gripe estacional y las tasas de hospitalización y mortalidad hospitalaria por enfermedades cardiovasculares agudas en una región española.

INTRODUCTION AND OBJECTIVE: Influenza virus infection can contribute to cardiovascular morbidity and mortality. The purpose of this study is to confirm if the increase in seasonal influenza rates is associated with a growth in hospitalisation and mortality rates for acute cardiovascular diseases (ACVD). METHODS: Retrospective cohort study of hospital discharges due to ACVD (myocardial infarction, unstable angina, heart failure and ischemic stroke) in the Castilla y León (Spain) hospital system between 2001 and 2015. Hospitalisation and hospital mortality rates due to ACVD, and influenza rates in Castilla y León between 2001 and 2015 were studied. To calculate hospitalisation and mortality rates, the hospital discharges database was used; for influenza rates, the weekly reports of the Sentinel System for the surveillance of influenza in Spain (Carlos III Health Institute) were used. A statistical analysis of linear and multivariate logistic regressions was performed. RESULTS: 239,586 ACVD (myocardial infarction: 55,004; unstable angina: 15,406; heart failure: 11,1647; ischemic stroke: 57,529) were studied. Increasing rates of influenza were associated with increased mortality due to ACVD and all the diseases studied, except unstable angina. A linear correlation was observed between influenza rates and hospitalisation (r2=0.03; p=0.02) and mortality (r2=0.14; p<0.001) rates by ACVD. Virtually all influenza rates were associated, as independent variables, to an increase in mortality due to ACVD, being higher in rates>139/100,000 inhabitants (OR: 1.25; p<0.001). CONCLUSIONS: The rates of hospitalisation and in-hospital mortality due to ACVD in the period 2001-2015 increased in relation to infection rates due to the influenza virus.

Trends in Hospitalization and Mortality Rates Due to Acute Cardiovascular Disease in Castile and León, 2001 to 2015.

INTRODUCTION AND OBJECTIVES: To analyze hospitalization and mortality rates due to acute cardiovascular disease (ACVD). METHODS: We conducted a cross-sectional study of the hospital discharge database of Castile and León from 2001 to 2015, selecting patients with a principal discharge diagnosis of acute myocardial infarction (AMI), unstable angina, heart failure, or acute ischemic stroke (AIS). Trends in the rates of hospitalization/100 000 inhabitants/y and hospital mortality/1000 hospitalizations/y, overall and by sex, were studied by joinpoint regression analysis. RESULTS: A total of 239 586 ACVD cases (AMI 55 004; unstable angina 15 406; heart failure 111 647; AIS 57 529) were studied. The following statistically significant trends were observed: hospitalization: ACVD, upward from 2001 to 2007 (5.14; 95%CI, 3.5-6.8; P < .005), downward from 2011 to 2015 (3.7; 95%CI, 1.0-6.4; P < .05); unstable angina, downward from 2001 to 2010 (-12.73; 95%CI, -14.8 to -10.6; P < .05); AMI, upward from 2001 to 2003 (15.6; 95%CI, 3.8-28.9; P < .05), downward from 2003 to 2015 (-1.20; 95%CI, -1.8 to -0.6; P < .05); heart failure, upward from 2001 to 2007 (10.70; 95%CI, 8.7-12.8; P < .05), upward from 2007 to 2015 (1.10; 95%CI, 0.1-2.1; P < .05); AIS, upward from 2001 to 2007 (4.44; 95%CI, 2.9-6.0; P < .05). Mortality rates: downward from 2001 to 2015 in ACVD (-1.16; 95%CI, -2.1 to -0.2; P < .05), AMI (-3.37, 95%CI, -4.4 to -2, 3, P < .05), heart failure (-1.25; 95%CI, -2.3 to -0.1; P < .05) and AIS (-1.78; 95%CI, -2.9 to -0.6; P < .05); unstable angina, upward from 2001 to 2007 (24.73; 95%CI, 14.2-36.2; P < .05). CONCLUSIONS: The ACVD analyzed showed a rising trend in hospitalization rates from 2001 to 2015, which was especially marked for heart failure, and a decreasing trend in hospital mortality rates, which were similar in men and women. These data point to a stabilization and a decline in hospital mortality, attributable to established prevention measures.

Out-of-hospital cardiac arrest (OHCA) attended by mobile emergency teams with a physician on board. Results of the Spanish OHCA Registry (OSHCAR).

Most survival outcomes in out-of-hospital cardiac arrest (OHCA) are provided by emergency medical services (EMS) without a doctor on board. Our objective was to determine such outcomes in a whole country with public physician-led EMS. METHODS: We analyzed data from a nationwide prospective registry of OHCA cases attended by 19 public EMS in Spain, covering the period from 1-October 2013 to 30-October 2014. RESULTS: Advanced life support (ALS) was initiated in 9347 cases (incidence 18.6 cases/105 inhabitants per year). Resuscitation was considered futile in 558 cases (5.9%), and ALS was continued in 8789 cases (94.1%); mean age 63.5±17 years, 72.1% men. Initial rhythm was shockable in 22.1% of cases. Basic life support (BLS) was provided by bystanders in 1602 (24%) cases (635 of them with telephone assistance from the dispatch center). Of 8789 patients receiving ALS, 72.1% men, 2669 (30.4%) patients had return of spontaneous circulation on hospital arrival, 50.6% when the initial rhythm was shockable. Hospital discharge with good neurological status (CPC1-2) was found in 11.1% of the study population and in 27.6% when considering the Utstein comparator group of patients. A total of 216 (2.5%) patients arrived at the hospital with ongoing resuscitation, of whom only one survived with CPC1-2, and 165 (1.9%) patients were included in non-heart-beating donation programs. CONCLUSIONS: In Spain with physician-led EMS, OHCA survival with CPC1-2 reached a reasonable percentage despite only a modest contribution of bystander BLS. Ongoing resuscitation strategy seems to be futile except when considering non-heart beating donation programs.

Survival and Neurologic Outcome After Out-of-hospital Cardiac Arrest. Results of the Andalusian Out-of-hospital Cardiopulmonary Arrest Registry.

INTRODUCTION AND OBJECTIVES: There is a paucity of data on prehospital cardiac arrest in Spain. Our aim was to describe the incidence, patient characteristics, and outcomes of out-of-hospital emergency care for this event. METHODS: We conducted a retrospective analysis of a prospective registry of cardiopulmonary arrest handled by an out-of-hospital emergency service between January 2008 and December 2012. The registry included all patients considered to have a cardiac etiology as the cause of arrest, with a descriptive analysis performed of general patient characteristics and factors associated with good neurologic outcome at hospital discharge. RESULTS: A total of 4072 patients were included, with an estimated incidence of 14.6 events per 100000 inhabitants and year; 72.6% were men. The mean age was 62.0 ± 15.8 years, 58.6% of cases occurred in the home, 25% of patients had initial defibrillable rhythm, 28.8% of patients arrived with a pulse at the hospital (58.3% of the group with defibrillable rhythm), and 10.2% were discharged with good neurologic outcome. The variables associated with this recovery were: witnessed arrest (P=.04), arrest witnessed by emergency team (P=.005), previous life support (P=.04), initial defibrillable rhythm (P=.0001), and performance of a coronary interventional procedure (P=.0001). CONCLUSIONS: More than half the cases of sudden cardiac arrest occur at home, and the population was found to be relatively young. Although recovery was satisfactory in 1 out of every 10 patients, there is a need for improvement in the phase prior to emergency team arrival. Coronary interventional procedures had an impact on patient prognosis.

Comparison of Different Bone Marrow-Derived Stem Cell Approaches in Reperfused STEMI. A Multicenter, Prospective, Randomized, Open-Labeled TECAM Trial.

BACKGROUND: Stem cell-based therapy has emerged as a potential therapy in acute myocardial infarction (AMI). Although various approaches have been studied, intracoronary injection of bone marrow autologous mononuclear cells (BMMC) and the ability of granulocyte colony-stimulating factor (G-CSF) to mobilize endogenous cells have attracted the most attention. OBJECTIVES: This study compares, for the first time, the efficacy of BMMC injection, G-CSF mobilization, and the combination of both with standard treatment. METHODS: On Day 1 after primary percutaneous coronary intervention, 120 patients were randomized to a 1) intracoronary BMMC injection; 2) mobilization with G-CSF; 3) both (BMMC injection plus G-CSF); or 4) conventional treatment (control group). G-CSF, 10 µg/kg/day subcutaneously, was started Day 1 and maintained for 5 days. BMMC injection was performed on Days 3 to 5. Our primary endpoint was absolute change in 12-month left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume (LVESV) relative to baseline measured by cardiac magnetic resonance. RESULTS: The mean change in LVEF between baseline and follow-up for all patients was 4 ± 6% (p = 0.006). Change in LVEF and LVESV over time did not differ significantly among the 4 groups. Patients actively treated with any stem cell approach showed similar changes in LVEF and LVESV versus control subjects, with a small but significant reduction in infarct area (p = 0.038). CONCLUSIONS: In our study, 3 different bone marrow-derived stem cell approaches in AMI did not result in improvement of LVEF or volumes compared with standard AMI care (Trial of Hematopoietic Stem Cells in Acute Myocardial Infarction [TECAM]; NCT00984178).

Role of the paclitaxel-eluting stent and tirofiban in patients with ST-elevation myocardial infarction undergoing postfibrinolysis angioplasty: the GRACIA-3 randomized clinical trial.

BACKGROUND: A catheter-based approach after fibrinolysis is recommended if fibrinolysis is likely to be successful in patients with acute ST-elevation myocardial infarction. We designed a 2x2 randomized, open-label, multicenter trial to evaluate the efficacy and safety of the paclitaxel-eluting stent and tirofiban administered after fibrinolysis but before catheterization to optimize the results of this reperfusion strategy. METHODS AND RESULTS: We randomly assigned 436 patients with acute ST-elevation myocardial infarction to (1) bare-metal stent without tirofiban, (2) bare-metal stent with tirofiban, (3) paclitaxel-eluting stent without tirofiban, and (4) paclitaxel-eluting stent with tirofiban. All patients were initially treated with tenecteplase and enoxaparin. Tirofiban was started 120 minutes after tenecteplase in those patients randomly assigned to tirofiban. Cardiac catheterization was performed within the first 3 to 12 hours after inclusion, and stenting (randomized paclitaxel or bare stent) was applied to the culprit artery. The primary objectives were the rate of in-segment binary restenosis of paclitaxel-eluting stent compared with that of bare-metal stent and the effect of tirofiban on epicardial and myocardial flow before and after mechanical revascularization. At 12 months, in-segment binary restenosis was similar between paclitaxel-eluting stent and bare-metal stent (10.1% versus 11.3%; relative risk, 1.06; 95% confidence interval, 0.74 to 1.52; P=0.89). However, late lumen loss (0.04+/-0.055 mm versus 0.27+/-0.057 mm, P=0.003) was reduced in the paclitaxel-eluting stent group. No evidence was found of any association between the use of tirofiban and any improvement in the epicardial and myocardial perfusion. Major bleeding was observed in 6.1% of patients receiving tirofiban and in 2.7% of patients not receiving it (relative risk, 2.22; 95% confidence interval, 0.86 to 5.73; P=0.14). CONCLUSIONS: This trial does not provide evidence to support the use of tirofiban after fibrinolysis to improve epicardial and myocardial perfusion. Compared with bare-metal stent, paclitaxel-eluting stent significantly reduced late loss but appeared not to reduce in-segment binary restenosis. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00306228.