Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

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.

Effect of High Altitude on the Survival of COVID-19 Patients in Intensive Care Unit: A Cohort Study.

Purpose: The effect of high altitude ( ≥ 1500 m) and its potential association with mortality by COVID-19 remains controversial. We assessed the effect of high altitude on the survival/discharge of COVID-19 patients requiring intensive care unit (ICU) admission for mechanical ventilation compared to individuals treated at sea level. Methods: A retrospective cohort multi-center study of consecutive adults patients with a positive RT-PCR test for COVID-19 who were mechanically ventilated between March and November 2020. Data were collected from two sea-level hospitals and four high-altitude hospitals in Ecuador. The primary outcome was ICU and hospital survival/discharge. Survival analysis was conducted using semi-parametric Cox proportional hazards models. Results: Of the study population (n = 670), 35.2% were female with a mean age of 58.3 ± 12.6 years. On admission, high-altitude patients were more likely to be younger (57.2 vs. 60.5 years old), presented with less comorbidities such as hypertension (25.9% vs. 54.9% with p-value <.001) and diabetes mellitus (20.5% vs. 37.2% with p-value <.001), less probability of having a capillary refill time > 3 sec (13.7% vs. 30.1%, p-value <.001), and less severity-of-illness condition (APACHE II score, 17.5 ± 8.1 vs. 20 ± 8.2, p < .01). After adjusting for key confounders high altitude is associated with significant higher probabilities of ICU survival/discharge (HR: 1.74 [95% CI: 1.46-2.08]) and hospital survival/discharge (HR: 1.35 [95% CI: 1.18-1.55]) than patients treated at sea level. Conclusions: Patients treated at high altitude at any time point during the study period were 74% more likely to experience ICU survival/discharge and 35% more likely to experience hospital survival/discharge than to the sea-level group. Possible reasons for these findings are genetic and physiological adaptations due to exposure to chronic hypoxia.

Analysis of Prior Aspirin Treatment on in-Hospital Outcome of Geriatric COVID-19 Infected Patients.

Background and Objectives: Aspirin (ASA) is a commonly used antithrombotic drug that has been demonstrated to reduce venous thromboembolism. The aim was to analyze if geriatric COVID-19 patients undergoing a 100 mg/day Aspirin (ASA) treatment prior to hospitalization differ in hospital outcome compared to patients without previous ASA therapy. Materials and Methods: An observational retrospective study was carried out using an anonymized database including geriatric COVID-19 patients (March to April 2020) admitted to Madrid Hospitals Group. A group of COVID-19 patients were treated with low ASA (100 mg/day) prior to COVID-19 infection. Results: Geriatric ASA-treated patients were older (mean age over 70 years; n = 41), had higher frequency of hypertension and hyperlipidemia, and upon admission had higher D-dimer levels than non-ASA-treated patients (mean age over 73 years; n = 160). However, patients under ASA treatment did not show more frequent pulmonary thromboembolism (PE) than non-ASA-treated patients. ASA-treated geriatric COVID-19-infected patients in-hospital < 30 days all-cause mortality was more frequent than in non-ASA-treated COVID-19 patients. In ASA-treated COVID-19-infected geriatric patients, anticoagulant therapy with low molecular weight heparin (LMWH) significantly reduced need of ICU care, but tended to increase in-hospital < 30 days all-cause mortality. Conclusions: Prior treatment with a low dose of ASA in COVID-19-infected geriatric patients increased frequency of in-hospital < 30 days all-cause mortality, although it seemed to not increase PE frequency despite D-dimer levels upon admission being higher than in non-ASA users. In ASA-treated geriatric COVID-19-infected patients, addition of LMWH therapy reduced frequency of ICU care, but tended to increase in-hospital < 30 days all-cause mortality.

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.

The Posterior Lumbar Epidural Space: Three-Dimensional Reconstruction of High-Resolution MRI: Real and Potential Epidural Spaces and Their Content In Vivo.

OBJECTIVE: Our aim was to study the posterior lumbar epidural space with 3D reconstructions of magnetic resonance images (MRIs) and to compare and validate the findings with targeted anatomic microdissections. DESIGN: We performed 3D reconstructions of high-resolution MRIs from seven patients and normal-resolution MRIs commonly used in clinical practice from 196 other random patients. We then dissected and photographed the lumbar spine areas of four fresh cadavers. RESULTS: From the 3D reconstructions of the MRIs, we verified that the distribution of the posterior fat pad had an irregular shape that resembled a truncated pyramid. It spanned between the superior margin of the lamina of the caudad vertebra and beyond the inferior margin to almost halfway underneath the cephalad lamina of the cranial vertebra, and it was not longitudinally or circumferentially continuous. The 3D reconstructions of the high-definition MRI also consistently revealed a prelaminar fibrous body that was not seen in most of the usually used low-definition MRI reconstructions. Targeted microdissections confirmed the 3D reconstruction findings and also showed the prelaminar tissue body to be fibrous, crossing from side to side anterior to the cephalad half of each lamina, and spanning from the dural sac to the laminae. CONCLUSIONS: Three-dimensional reconstructions and targeted microdissection revealed the unique appearance of posterior fat pads and a prelaminar fibrous body. The exact consistency, presence, prevalence with age, presence in other regions, and function of this body are unknown and require further research.

Impact of a training program on adherence to recommendations for care of venous lines in internal medicine departments in Spain.

A high percentage of venous lines (VLs) are placed in non-ICU patients, particularly those treated in the internal medicine department (IMD). We assessed adherence to VL care after a training program aimed at nurses and clinicians attending patients admitted to Spanish IMDs. We performed a multicenter prospective observational point prevalence study in 14 Spanish IMDs in 2013 and 2016. We included all adult patients (> 18 years) admitted to IMDs on the study day and reviewed nursing records for patients with VL in place before and after a 1-year training program during 2015. Answers from an interview with head nurses of the IMDs regarding commonly used practices in the daily management of VLs were also compared. A total of 638 and 693 patients were seen during each period, respectively, and 530 and 598 patients had ≥ 1 VL implanted (83.1 vs. 86.3%). Catheters were considered unnecessary in 12.8 and 15.0% of cases (p = 0.28). Daily recording of the need for catheter use increased from 43.8 to 71.8% (p < 0.001). Furthermore, daily monitoring of the insertion site remained very frequent (94.4 vs. 92.2%; p = 0.16). The date of insertion was recorded in 86.3 and 85.5% of cases (p = 0.73), and no combination of closed connectors with open caps increased from 74.8 to 90.3% (p < 0.001). Overall, head nurses' knowledge improved in 4 out of 14 recommendations assessed (28.6%). A simple and easy program for training on management of VLs in Spanish IMDs was associated with improved quality of care.

Development of Aspergillosis in a cohort of non-neutropenic, non-transplant patients colonised by Aspergillus spp.

BACKGROUND: A previous study explored factors discriminating colonization and true infection among non-transplant, non-neutropenic patients with repeated Aspergillus spp. isolation from lower respiratory samples. The present study explored the evolution of patients with Aspergillus colonization in that study to determine the percentage of cases progressing to aspergillosis and time to development. METHODS: Clinical records were retrospectively reviewed (for each patient from his end date in the past study) and data from all respiratory processes suffered by patients up to April 2015 were recorded. Comparisons of variables were performed between colonized patients that developed aspergillosis and those that did not. A Kaplan-Meier curve was used to describe time to development of aspergillosis in chronic obstructive pulmonary disease (COPD) patients for II-IV stages of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. RESULTS: Sixty seven colonized patients were followed, 12 of them (17.9%) developed aspergillosis. Diagnoses included six tracheobronchitis (4 invasive, 2 simple tracheobronchitis), four pulmonary disease (2 invasive pulmonary aspergillosis, 2 chronic pulmonary aspergillosis), one allergic bronchopulmonary aspergillosis and one pulmonary aspergilloma. Up to 47 (70.4%) of the study patients presented COPD. Among patients developing aspergillosis COPD was more frequent (100%) than among those that did not develop aspergillosis (35 out of 55; 63.6%) (p = 0.012), as well as GOLD IV patients were more frequent among COPD patients developing aspergillosis than among COPD patients that did not (50.0 vs. 26.1%, p = 0.046). Mean time to development of aspergillosis was 18.4 months (median: 8.5) with a wide range (1-58). Overtime, the percentage of patients developing aspergillosis was significantly higher among GOLD IV patients than among GOLD II-III patients (p = 0.032). CONCLUSIONS: The high percentage of cases progressing to aspergillosis among colonized patients, especially among those with COPD (25.5%), stresses the importance of colonization as risk factor, and creates awareness of the possible change from colonization to invasive disease in GOLD IV patients.

[Potential indications of dalbavancin in clinical practice]. / Potenciales indicaciones de dalbavancina en la práctica clínica.

Dalbavancin is a semisynthetic lipoglycopeptide with two properties that distinguish it from other members of the antibiotic family from which it is derived: a greater intrinsic activity and a very prolonged mean half-life that allows weekly or twice-weekly dosing with a single 1000mg or 1500mg dose, respectively. Because of this half-life, dalbavancin is a unique antibiotic. This drug allows the design of new treatment strategies that facilitate early hospital discharge without the need for vascular access and with guaranteed treatment adherence. Dalbavancin could be used to resolve some of the problems that commonly occur in the management of infections in daily clinical practice, particularly in consolidation therapy in acute processes, infections requiring prolonged treatment and in the prophylaxis of some recurrent processes caused by Gram-positive cocci.

[Role of ceftaroline in skin and soft tissue infections]. / Papel de ceftarolina en infecciones de piel y partes blandas.

Skin and soft tissue infections (SSTI) are relatively common. Although most of these infections are mild, a few are severe, requiring hospital admission for intravenous antimicrobial therapy and, fairly frequently, surgery. These infections can be produced by any microorganism, but the most frequent is Staphylococcus aureus. Traditionally, the bacteria causing community-acquired SSTI have been sensitive to antimicrobial agents but this situation has changed with the dissemination of community-acquired microbial resistance, as has occurred in many countries with the increase in methicillin-resistant S. aureus (MRSA). These changes complicate empirical therapy and increase the risk of monotherapy being insufficient to cover all the diagnostic possibilities of SSTI. Within this epidemiological framework, ceftaroline, because of its activity against MRSA, can be used as empirical monotherapy for SSTI.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients.

INTRODUCTION: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. METHODS: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. RESULTS: The median [p25-p75] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions. CONCLUSION: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities.

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.

Repeated Aspergillus isolation in respiratory samples from non-immunocompromised patients not selected based on clinical diagnoses: colonisation or infection?

BACKGROUND: Isolation of Aspergillus from lower respiratory samples is associated with colonisation in high percentage of cases, making it of unclear significance. This study explored factors associated with diagnosis (infection vs. colonisation), treatment (administration or not of antifungals) and prognosis (mortality) in non-transplant/non-neutropenic patients showing repeated isolation of Aspergillus from lower respiratory samples. METHODS: Records of adult patients (29 Spanish hospitals) presenting ≥ 2 respiratory cultures yielding Aspergillus were retrospectively reviewed and categorised as proven (histopathological confirmation) or probable aspergillosis (new respiratory signs/symptoms with suggestive chest imaging) or colonisation (symptoms not attributable to Aspergillus without dyspnoea exacerbation, bronchospasm or new infiltrates). Logistic regression models (step-wise) were performed using Aspergillosis (probable + proven), antifungal treatment and mortality as dependent variables. Significant (p < 0.001) models showing the highest R2 were considered. RESULTS: A total of 245 patients were identified, 139 (56.7%) with Aspergillosis. Aspergillosis was associated (R2 = 0.291) with ICU admission (OR = 2.82), congestive heart failure (OR = 2.39) and steroids pre-admission (OR = 2.19) as well as with cavitations in X-ray/CT scan (OR = 10.68), radiological worsening (OR = 5.22) and COPD exacerbations/need for O2 interaction (OR = 3.52). Antifungals were administered to 79.1% patients with Aspergillosis (100% proven, 76.8% probable) and 29.2% colonised, with 69.5% patients receiving voriconazole alone or in combination. In colonised patients, administration of antifungals was associated with ICU admission at hospitalisation (OR = 12.38). In Aspergillosis patients its administration was positively associated (R(2) = 0.312) with bronchospasm (OR = 9.21) and days in ICU (OR = 1.82) and negatively with Gold III + IV (OR = 0.26), stroke (OR = 0.024) and quinolone treatment (OR = 0.29). Mortality was 78.6% in proven, 41.6% in probable and 12.3% in colonised patients, and was positively associated in Aspergillosis patients (R2 = 0.290) with radiological worsening (OR = 3.04), APACHE-II (OR = 1.09) and number of antibiotics for treatment (OR = 1.51) and negatively with species other than A. fumigatus (OR = 0.14) and aspergillar tracheobronchitis (OR = 0.27). CONCLUSIONS: Administration of antifungals was not always closely linked to the diagnostic categorisation (colonisation vs. Aspergillosis), being negatively associated with severe COPD (GOLD III + IV) and concomitant treatment with quinolones in patients with Aspergillosis, probably due to the similarity of signs/symptoms between this entity and pulmonary bacterial infections.

[Daptomycin in complicated skin and soft tissue infections]. / Tratamiento con daptomicina en las infecciones complicadas de piel y partes blandas.

In recent years, Staphylococcus aureus, the most commonly identified infectious agent causing skin and soft tissue infections (SSTIs), has shown an increase in methicillin resistance and decreased susceptibility to vancomycin. Because of its spectrum, microbiological activity, pharmacokinetics, and safety, as well as clinical experience in its use, daptomycin seems to be a highly appropriate antibiotic in the treatment of SSTIs, especially those produced by methicillin-resistant S. aureus.

Immunomodulatory therapy for the management of critically ill patients with COVID-19: A narrative review.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. AIM: To describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of hyperinflammation and abnormal immune responses to disease progression together with a complete narrative review of the different immunoadjuvant treatments used so far in COVID-19 and their indication in severe and life-threatening subsets. METHODS: A comprehensive literature search was developed. Authors reviewed the selected manuscripts following the PRISMA recommendations for systematic review and meta-analysis documents and selected the most appropriate. Finally, a recommendation of the use of each treatment was established based on the level of evidence of the articles and documents reviewed. This recommendation was made based on the consensus of all the authors. RESULTS: A brief rationale on the SARS-CoV-2 pathogenesis, immune response, and inflammation was developed. The usefulness of 10 different families of treatments related to inflammation and immunopathogenesis of COVID-19 was reviewed and discussed. Finally, based on the level of scientific evidence, a recommendation was established for each of them. CONCLUSION: Although several promising therapies exist, only the use of corticosteroids and tocilizumab (or sarilumab in absence of this) have demonstrated evidence enough to recommend its use in critically ill patients with COVID-19. Endotypes including both, clinical and biological characteristics can constitute specific targets for better select certain therapies based on an individualized approach to treatment.

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. Funding: ISCIII, UNESPA, CIBERES, FEDER, ESF.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19.

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.