Innate immune response in acute critical illness: a narrative review.

BACKGROUND: Activation of innate immunity is a first line of host defense during acute critical illness (ACI) that aims to contain injury and avoid tissue damages. Aberrant activation of innate immunity may also participate in the occurrence of organ failures during critical illness. This review aims to provide a narrative overview of recent advances in the field of innate immunity in critical illness, and to consider future potential therapeutic strategies. MAIN TEXT: Understanding the underlying biological concepts supporting therapeutic strategies modulating immune response is essential in decision-making. We will develop the multiple facets of innate immune response, especially its cellular aspects, and its interaction with other defense mechanisms. We will first describe the pathophysiological mechanisms of initiation of innate immune response and its implication during ACI. We will then develop the amplification of innate immunity mediated by multiple effectors. Our review will mainly focus on myeloid and lymphoid cellular effectors, the major actors involved in innate immune-mediated organ failure. We will third discuss the interaction and integration of innate immune response in a global view of host defense, thus considering interaction with non-immune cells through immunothrombosis, immunometabolism and long-term reprogramming via trained immunity. The last part of this review will focus on the specificities of the immune response in children and the older population. CONCLUSIONS: Recent understanding of the innate immune response integrates immunity in a highly dynamic global vision of host response. A better knowledge of the implicated mechanisms and their tissue-compartmentalization allows to characterize the individual immune profile, and one day eventually, to develop individualized bench-to-bedside immunomodulation approaches as an adjuvant resuscitation strategy.

Endocan as a biomarker for acute respiratory distress syndrome: A systematic review and meta-analysis.

Background and Aims: Endocan is a marker of endothelial damage. Data regarding the association of this proteoglycan and acute respiratory distress syndrome (ARDS) is discrepant. Hence, this study sought to investigate the possible correlation between serum/plasma endocan concentration and ARDS. Methods: A systematic review and meta-analysis of international online databases was conducted following PRISMA guidelines. PubMed, SCOPUS, Embase, and Web of Science were searched in March 2023, with the leading search terms being "ARDS" OR "respiratory distress" AND "endocan" and other associated terms. Studies that measured endocan levels in patients with ARDS and compared it with non-ARDS controls or within different severities of ARDS were included. We performed a random-effect meta-analysis for pooling the differences using standardized mean difference (SMD) and 95% confidence interval (CI). Results: We included 14 studies involving 1,058 patients. Those developing ARDS had significantly higher levels of endocan compared to those without ARDS (SMD: 0.47, 95% CI: 0.10-0.84, p = 0.01). Our meta-analysis of three studies found that endocan levels in ARDS nonsurvivors were significantly higher than in survivors (SMD: 0.31, 95% CI: 0.02-0.60, p = 0.03). Three studies investigated endocan levels in different severities of ARDS. Only one of these studies reported significantly higher endocan levels in patients with worsening acute respiratory failure at Day 15. The other two reported no significant association between ARDS severity and circulating endocan levels. Conclusion: Blood endocan levels were significantly higher in patients with ARDS than those without. Additionally, among patients with ARDS, blood endocan values were significantly elevated in nonsurvivors compared to survivors. These findings could help researchers design future studies and solidify these findings and finally, clinicians to take advantage of measuring endocan in clinical settings for assessment of patients with ARDS.

Accuracy of the Infectious Diseases Society of America and British Thoracic Society Criteria for Acute Pneumonia in Differentiating Chemical and Bacterial Complications of Aspiration in Comatose Ventilated Patients Following Drug Poisoning.

Drug poisoning frequently leads to admission to intensive care units, often resulting in aspiration, a potentially life-threatening condition if not properly managed. Aspiration can manifest as either bacterial aspiration pneumonia (BAP) or aspiration pneumonitis (AP), which are challenging to distinguish potentially leading to overprescription of antibiotics and the emergence of multidrug-resistant bacteria. This study aims to assess the accuracy of the Infectious Diseases Society of America (IDSA) and British Thoracic Society (BTS) criteria in differentiating BAP from AP in comatose ventilated patients following drug poisoning. This cross-sectional study included 95 patients admitted for drug poisoning at the Lille University Hospital intensive care department, between 2013 and 2017, requiring mechanical ventilation and receiving antibiotics for aspiration. Patients were categorized as having bacterial complications if tracheal sampling yielded positive culture results, and if they were otherwise considered to have chemical complications. The sensitivity, specificity, positive predictive value, and negative predictive value of IDSA and BTS criteria in identifying patients with bacterial complications were evaluated. Among the patients, 34 (36%) experienced BAP. The IDSA criteria demonstrated a sensitivity of 62% and specificity of 33%, while the BTS criteria showed a sensitivity of 50% and specificity of 38%. Both the IDSA and BTS criteria exhibited poor sensitivity and specificity in identifying microbiologically confirmed pneumonia in comatose ventilated patients following drug poisoning.

Esm-1 mediates transcriptional polarization associated with diabetic kidney disease.

Esm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a secreted proteoglycan, with notable expression in kidney, which attenuates inflammation and albuminuria. However, little is known about Esm1 expression in mature tissues in the presence or absence of diabetes. We utilized publicly available single-cell RNA sequencing data to characterize Esm1 expression in 27,786 renal endothelial cells (RECs) obtained from three mouse and four human databases. We validated our findings using bulk transcriptome data from 20 healthy subjects and 41 patients with DKD and using RNAscope. In both mice and humans, Esm1 is expressed in a subset of all REC types and represents a minority of glomerular RECs. In patients, Esm1(+) cells exhibit conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and shift expression toward chemotaxis pathways. Esm1 correlates with a majority of genes within these pathways, delineating a glomerular transcriptional polarization reflected by the magnitude of Esm1 deficiency. Diabetes correlates with lower Esm1 expression and with changes in the functional characterization of Esm1(+) cells. Thus, Esm1 appears to be a marker for glomerular transcriptional polarization in DKD.NEW & NOTEWORTHY Esm-1 is primarily expressed in glomerular endothelium in humans. Cells expressing Esm1 exhibit a high degree of conservation in the enrichment of genes related to blood vessel development. In the context of diabetes, these cells are reduced in number and show a significant transcriptional shift toward the chemotaxis pathway. In diabetes, there is a transcriptional polarization in the glomerulus that is reflected by the degree of Esm1 deficiency.

ICU-Acquired Colonization and Infection Related to Multidrug-Resistant Bacteria in COVID-19 Patients: A Narrative Review.

A large proportion of ICU-acquired infections are related to multidrug-resistant bacteria (MDR). Infections caused by these bacteria are associated with increased mortality, and prolonged duration of mechanical ventilation and ICU stay. The aim of this narrative review is to report on the association between COVID-19 and ICU-acquired colonization or infection related to MDR bacteria. Although a huge amount of literature is available on COVID-19 and MDR bacteria, only a few clinical trials have properly evaluated the association between them using a non-COVID-19 control group and accurate design and statistical methods. The results of these studies suggest that COVID-19 patients are at a similar risk of ICU-acquired MDR colonization compared to non-COVID-19 controls. However, a higher risk of ICU-acquired infection related to MDR bacteria has been reported in several studies, mainly ventilator-associated pneumonia and bloodstream infection. Several potential explanations could be provided for the high incidence of ICU-acquired infections related to MDR. Immunomodulatory treatments, such as corticosteroids, JAK2 inhibitors, and IL-6 receptor antagonist, might play a role in the pathogenesis of these infections. Additionally, a longer stay in the ICU was reported in COVID-19 patients, resulting in higher exposure to well-known risk factors for ICU-acquired MDR infections, such as invasive procedures and antimicrobial treatment. Another possible explanation is the surge during successive COVID-19 waves, with excessive workload and low compliance with preventive measures. Further studies should evaluate the evolution of the incidence of ICU-acquired infections related to MDR bacteria, given the change in COVID-19 patient profiles. A better understanding of the immune status of critically ill COVID-19 patients is required to move to personalized treatment and reduce the risk of ICU-acquired infections. The role of specific preventive measures, such as targeted immunomodulation, should be investigated.

Development of a Decision Support Tool for Anticoagulation in Critically Ill Patients Admitted for SARS-CoV-2 Infection: The CALT Protocol.

Severe COVID-19 infections are at high risk of causing thromboembolic events (TEEs). However, the usual exams may be unavailable or unreliable in predicting the risk of TEEs at admission or during hospitalization. We performed a retrospective analysis of two centers (n = 124 patients) including severe COVID-19 patients to determine the specific risk factors of TEEs in SARS-CoV-2 infection at admission and during stays at the intensive care unit (ICU). We used stepwise regression to create two composite scores in order to predict TEEs in the first 48 h (H0-H48) and during the first 15 days (D1-D15) in ICU. We then evaluated the performance of our scores in our cohort. During the period H0-H48, patients with a TEE diagnosis had higher D-Dimers and ferritin values at day 1 (D1) and day 3 (D3) and a greater drop in fibrinogen between D1 and D3 compared with patients without TEEs. Over the period D1-D15, patients with a diagnosis of a TEE showed a more marked drop in fibrinogen and had higher D-Dimers and lactate dehydrogenase (LDH) values at D1 and D3. Based on ROC analysis, the COVID-related acute lung and deep vein thrombosis (CALT) 1 score, calculated at D1, had a diagnostic performance for TEEs at H0-H48, estimated using an area under the curve (AUC) of 0.85 (CI95%: 0.76-0.93, p < 10-3). The CALT 2 score, calculated at D3, predicted the occurrence of TEEs over the period D1-D15 with an estimated AUC of 0.85 (CI95%: 0.77-0.93, p < 10-3). These two scores were used as the basis for the development of the CALT protocol, a tool to assist in the decision to use anticoagulation during severe SARS-CoV-2 infections. The CALT scores showed good performances in predicting the risk of TEEs in severe COVID-19 patients at admission and during ICU stays. They could, therefore, be used as a decision support protocol on whether or not to initiate therapeutic anticoagulation.

Esm-1 mediates transcriptional polarization associated with diabetic kidney disease.

Background: Esm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a cytokine- and glucose-regulated, secreted proteoglycan, that is notably expressed in kidney and attenuates inflammation and albuminuria. Esm1 has restricted expression at the vascular tip during development but little is known about its expression pattern in mature tissues, and its precise effects in diabetes. Methods: We utilized publicly available single-cell RNA sequencing data to explore the characteristics of Esm1 expression in 27,786 renal endothelial cells obtained from four adult human and three mouse databases. We validated our findings using bulk transcriptome data from an additional 20 healthy subjects and 41 patients with DKD and using RNAscope. Using correlation matrices, we relate Esm1 expression to the glomerular transcriptome and evaluated these matrices with systemic over-expression of Esm-1. Results: In both mice and humans, Esm1 is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients, Esm1 (+) cells exhibit a highly conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and profoundly shift expression to reflect chemotaxis pathways. Analysis of these gene sets highlight candidate genes such as Igfbp5 for cross talk between cell types. We also find that diabetes induces correlations in the expression of large clusters of genes, within cell type-enriched transcripts. Esm1 significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude of Esm1 deficiency. In diabetic mice, these gene clusters link Esm1 expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes. Conclusions: A comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lower Esm1 expression and with changes in the functional characterization of Esm1 (+) cells. Esm1 is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.

Ventilator-Associated Pneumonia in Immunosuppressed Patients.

Immunocompromised patients-including patients with cancer, hematological malignancies, solid organ transplants and individuals receiving immunosuppressive therapies for autoimmune diseases-account for an increasing proportion of critically-ill patients. While their prognosis has improved markedly in the last decades, they remain at increased risk of healthcare- and intensive care unit (ICU)-acquired infections. The most frequent of these are ventilator-associated lower respiratory tract infections (VA-LTRI), which include ventilator-associated pneumonia (VAP) and tracheobronchitis (VAT). Recent studies have shed light on some of the specific features of VAP and VAT in immunocompromised patients, which is the subject of this narrative review. Contrary to previous belief, the incidence of VAP and VAT might actually be lower in immunocompromised than non-immunocompromised patients. Further, the relationship between immunosuppression and the incidence of VAP and VAT related to multidrug-resistant (MDR) bacteria has also been challenged recently. Etiological diagnosis is essential to select the most appropriate treatment, and the role of invasive sampling, specifically bronchoscopy with bronchoalveolar lavage, as well as new molecular syndromic diagnostic tools will be discussed. While bacteria-especially gram negative bacteria-are the most commonly isolated pathogens in VAP and VAT, several opportunistic pathogens are a special concern among immunocompromised patients, and must be included in the diagnostic workup. Finally, the impact of immunosuppression on VAP and VAT outcomes will be examined in view of recent papers using improved statistical methodologies and treatment options-more specifically empirical antibiotic regimens-will be discussed in light of recent findings on the epidemiology of MDR bacteria in this population.

Evaluation of Endocan as a Treatment for Acute Inflammatory Respiratory Failure.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition resulting from acute pulmonary inflammation. However, no specific treatment for ARDS has yet been developed. Previous findings suggest that lung injuries related to ARDS could be regulated by endocan (Esm-1). The aim of this study was to evaluate the potential efficiency of endocan in the treatment of ARDS. METHODS: We first compared the features of acute pulmonary inflammation and the severity of hypoxemia in a tracheal LPS-induced acute lung injury (ALI) model performed in knockout (Esm1-/-) and wild type (WT) littermate C57Bl/6 mice. Next, we assessed the effects of a continuous infusion of glycosylated murine endocan in our ALI model in Esm1-/- mice. RESULTS: In our ALI model, we report higher alveolar leukocytes (p < 0.001), neutrophils (p < 0.001), and MPO (p < 0.001), and lower blood oxygenation (p < 0.001) in Esm1-/- mice compared to WT mice. Continuous delivery of glycosylated murine endocan after LPS-induced ALI resulted in decreased alveolar leukocytes (p = 0.012) and neutrophils (p = 0.012), higher blood oxygenation levels (p < 0.001), and reduced histological lung injury (p = 0.04), compared to mice treated with PBS. CONCLUSIONS: Endocan appears to be an effective treatment in an ARDS-like model in C57Bl/6 mice.

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Are Cirrhotic Patients Receiving Invasive Mechanical Ventilation at Risk of Abundant Microaspiration.

Previous studies have identified cirrhosis as a risk factor for ventilator-associated pneumonia (VAP). The aim of our study was to determine the relationship between cirrhosis and abundant gastric-content microaspiration in intubated critically ill patients. We performed a matched cohort study using data from three randomized controlled trials on abundant microaspiration in patients under mechanical ventilation. Each cirrhotic patient was matched with three to four controls for gender, age ± 5 years and simplified acute physiology score II (SAPS II) ± 5 points. Abundant microaspiration was defined by significant levels of pepsin and alpha-amylase in >30% of tracheal aspirates. All tracheal aspirates were collected for the first 48 h of the study period. The percentage of patients with abundant gastric-content microaspiration was the primary outcome. The abundant microaspiration of oropharyngeal secretions, VAP incidence, the duration of mechanical ventilation, length of intensive care unit (ICU) stay and mortality were the secondary outcomes. A. total of 39 cirrhotic patients were matched to 138 controls. The percentage of patients with abundant gastric-content microaspiration did not differ between the two groups (relative risk: 0.91 (95% CI: 0.75 to 1.10)). There was no significant difference between the two groups in terms of the abundant microaspiration of oropharyngeal secretions, VAP, the duration of mechanical ventilation, the length of ICU stay and mortality. Our results suggest that cirrhosis is not associated with abundant gastric-content microaspiration.

Accuracy and trending ability of finger plethysmographic cardiac output monitoring in late pregnancy.

PURPOSE: Individuals in late pregnancy are at risk of significant hemodynamic variations, especially during Cesarean delivery. Although non-invasive monitoring might enable the early detection of variations in cardiac output (CO), clinical validation is lacking. METHODS: In a prospective, single-center study, we measured CO simultaneously with finger plethysmography and transthoracic echocardiography in 100 third-trimester pregnant individuals in the supine and left lateral decubitus (LLD) positions. RESULTS: A Bland-Altman analysis revealed a mean (standard deviation) bias of 1.36 (1.04) L·min-1 in the supine position (95% limits of agreement, -0.68 to 3.4 L·min-1; percent error, 26.6%), indicating overestimation by finger plethysmography. The intra-class correlation coefficient was 0.43 (95% confidence interval [CI], 0.33 to 0.51). Regarding the changes in CO induced by the supine-to-LLD transition, the concordance rate in a four-quadrant plot was 98.3% (95% CI, 91.1 to 99.9%). CONCLUSION: Our study showed a poor reliability of finger plethysmography for static measurement of CO. Nevertheless, finger plethysmography had a reasonably high concordance rate for the detection of CO changes secondary to positional changes in late-pregnant individuals. STUDY REGISTRATION DATE: www. CLINICALTRIALS: gov (NCT03735043); registered 8 November 2018.

RéSUMé: OBJECTIF: Les personnes en fin de grossesse sont à risque de variations hémodynamiques importantes, en particulier pendant un accouchement par césarienne. Bien que le monitorage non invasif puisse permettre la détection précoce des variations du débit cardiaque (DC), la validation clinique de ce type de monitorage fait défaut. MéTHODE: Dans une étude prospective monocentrique, nous avons mesuré le DC simultanément avec la pléthysmographie au doigt et l'échocardiographie transthoracique chez 100 femmes au troisième trimestre de leur grossesse en décubitus dorsal et en décubitus latéral gauche (DLG). RéSULTATS: Une analyse de Bland-Altman a révélé un biais moyen (écart type) de 1,36 (1,04) L·min­1 en décubitus dorsal (limites d'agrément à 95 %, -0,68 à 3,4 L·min­1; pourcentage d'erreur, 26,6 %), indiquant une surestimation lorsque mesuré par pléthysmographie au doigt. Le coefficient de corrélation intraclasse était de 0,43 (intervalle de confiance [IC] à 95 %, 0,33 à 0,51). En ce qui concerne les changements de DC induits par la transition du décubitus dorsal au décubitus latéral gauche, le taux de concordance dans un diagramme à quatre quadrants était de 98,3 % (IC 95 %, 91,1 à 99,9 %). CONCLUSION: Notre étude a montré une faible fiabilité de la pléthysmographie au doigt pour la mesure statique du DC. Néanmoins, la pléthysmographie au doigt avait un taux de concordance raisonnablement élevé pour la détection des changements de DC secondaires aux changements de position chez les patientes en fin de grossesse. www.clinicaltrials.gov (NCT03735043); enregistrée le 8 novembre 2018.

Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges.

BACKGROUND: Post-intensive care syndrome (PICS) encompasses physical, cognition, and mental impairments persisting after intensive care unit (ICU) discharge. Ultimately it significantly impacts the long-term prognosis, both in functional outcomes and survival. Thus, survivors often develop permanent disabilities, consume a lot of healthcare resources, and may experience prolonged suffering. This review aims to present the multiple facets of the PICS, decipher its underlying mechanisms, and highlight future research directions. MAIN TEXT: This review abridges the translational data underlying the multiple facets of chronic critical illness (CCI) and PICS. We focus first on ICU-acquired weakness, a syndrome characterized by impaired contractility, muscle wasting, and persisting muscle atrophy during the recovery phase, which involves anabolic resistance, impaired capacity of regeneration, mitochondrial dysfunction, and abnormalities in calcium homeostasis. Second, we discuss the clinical relevance of post-ICU cognitive impairment and neuropsychological disability, its association with delirium during the ICU stay, and the putative role of low-grade long-lasting inflammation. Third, we describe the profound and persistent qualitative and quantitative alteration of the innate and adaptive response. Fourth, we discuss the biological mechanisms of the progression from acute to chronic kidney injury, opening the field for renoprotective strategies. Fifth, we report long-lasting pulmonary consequences of ARDS and prolonged mechanical ventilation. Finally, we discuss several specificities in children, including the influence of the child's pre-ICU condition, development, and maturation. CONCLUSIONS: Recent understandings of the biological substratum of the PICS' distinct features highlight the need to rethink our patient trajectories in the long term. A better knowledge of this syndrome and precipitating factors is necessary to develop protocols and strategies to alleviate the CCI and PICS and ultimately improve patient recovery.

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Derivation and Validation of a Predictive Score for Respiratory Failure Worsening Leading to Secondary Intubation in COVID-19: The CERES Score.

Predictive scores assessing the risk of respiratory failure in COVID-19 mostly focused on the prediction of early intubation. A combined assessment of clinical parameters and biomarkers of endotheliopathy could allow to predict late worsening of acute respiratory failure (ARF), subsequently warranting intubation in COVID-19. Retrospective single-center derivation (n = 92 subjects) and validation cohorts (n = 59 subjects), including severe COVID-19 patients with non-invasive respiratory support, were assessed for at least 48 h following intensive care unit (ICU) admission. We used stepwise regression to construct the COVID endothelial and respiratory failure (CERES) score in a derivation cohort, and secondly assessed its accuracy for the prediction of late ARF worsening, requiring intubation within 15 days following ICU admission in an independent validation cohort. Platelet count, fraction of inspired oxygen, and endocan measured on ICU admission were identified as the top three predictive variables for late ARF worsening and subsequently included in the CERES score. The area under the ROC curve of the CERES score to predict late ARF worsening was calculated in the derivation and validation cohorts at 0.834 and 0.780, respectively. The CERES score is a simple tool with good performances to predict respiratory failure worsening, leading to secondary intubation, in COVID-19 patients.

The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies.

SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.

Invasive pulmonary aspergillosis among intubated patients with SARS-CoV-2 or influenza pneumonia: a European multicenter comparative cohort study.

BACKGROUND: Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients. OBJECTIVES: To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients. METHODS: This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event. RESULTS: A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53-7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88-5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization. CONCLUSIONS: Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 .