The proteolytic airway environment associated with pneumonia acts as a barrier for treatment with anti-infective antibodies.

Like pneumonia, coronavirus disease 2019 (COVID-19) is characterized by a massive infiltration of innate immune cells (such as polymorphonuclear leukocytes) into the airways and alveolar spaces. These cells release proteases that may degrade therapeutic antibodies and thus limit their effectiveness. Here, we investigated the in vitro and ex vivo impact on anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) IgG1s and other IgG subclasses (IgG2 and IgG4) of the neutrophil elastase, proteinase 3 and cathepsin G (the three main neutrophil serine proteases) found in endotracheal aspirates from patients with severe COVID-19. Although the IgGs were sensitive to neutrophil serine proteases, IgG2 was most resistant to proteolytic degradation. The two anti-SARS CoV2 antibodies (casirivimab and imdevimab) were sensitive to the lung's proteolytic environment, although neutrophil serine protease inhibitors only partly limited the degradation. Overall, our results show that the pneumonia-associated imbalance between proteases and their inhibitors in the airways contributes to degradation of antiviral antibodies.

The positive impact of COVID-19 on critical care: from unprecedented challenges to transformative changes, from the perspective of young intensivists.

Over the past 2 years, SARS-CoV-2 infection has resulted in numerous hospitalizations and deaths worldwide. As young intensivists, we have been at the forefront of the fight against the COVID-19 pandemic and it has been an intense learning experience affecting all aspects of our specialty. Critical care was put forward as a priority and managed to adapt to the influx of patients and the growing demand for beds, financial and material resources, thereby highlighting its flexibility and central role in the healthcare system. Intensivists assumed an essential and unprecedented role in public life, which was important when claiming for indispensable material and human investments. Physicians and researchers around the world worked hand-in-hand to advance research and better manage this disease by integrating a rapidly growing body of evidence into guidelines. Our daily ethical practices and communication with families were challenged by the massive influx of patients and restricted visitation policies, forcing us to improve our collaboration with other specialties and innovate with new communication channels. However, the picture was not all bright, and some of these achievements are already fading over time despite the ongoing pandemic and hospital crisis. In addition, the pandemic has demonstrated the need to improve the working conditions and well-being of critical care workers to cope with the current shortage of human resources. Despite the gloomy atmosphere, we remain optimistic. In this ten-key points review, we outline our vision on how to capitalize on the lasting impact of the pandemic to face future challenges and foster transformative changes of critical care for the better.

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.

Energetic dysfunction in sepsis: a narrative review.

BACKGROUND: Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. MAIN TEXT: Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. CONCLUSIONS: Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.

Inhaled bacteriophage therapy in a porcine model of pneumonia caused by Pseudomonas aeruginosa during mechanical ventilation.

BACKGROUND AND PURPOSE 255: Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of pneumonia caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy. EXPERIMENTAL APPROACH: (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anaesthetized, mechanically ventilated and infected with P. aeruginosa. KEY RESULTS: By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5-log reduction, p < .001). No infective phage was detected in the sera and urines throughout the experiment. CONCLUSION AND IMPLICATIONS: Our findings demonstrated (i) the feasibility of delivering large amounts of active phages by nebulization during mechanical ventilation and (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of P. aeruginosa pneumonia with high translational value.

Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.

High Dimensional Single-Cell Analysis Reveals iNKT Cell Developmental Trajectories and Effector Fate Decision.

CD1d-restricted invariant Natural Killer T (iNKT) cells represent a unique class of T lymphocytes endowed with potent regulatory and effector immune functions. Although these functions are acquired during thymic ontogeny, the sequence of events that gives rise to discrete effector subsets remains unclear. Using an unbiased single-cell transcriptomic analysis combined with functional assays, we reveal an unappreciated diversity among thymic iNKT cells, especially among iNKT1 cells. Mathematical modeling and biological methods unravel a developmental map whereby iNKT2 cells constitute a transient branching point toward the generation of iNKT1 and iNKT17 cells, which reconciles the two previously proposed models. In addition, we identify the transcription co-factor Four-and-a-half LIM domains protein 2 (FHL2) as a critical cell-intrinsic regulator of iNKT1 specification. Thus, these data illustrate the changing transcriptional network that guides iNKT cell effector fate.

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option. Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure. Design, Setting, and Participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board. Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73). Main Outcomes and Measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay. Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions and Relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT02517489.

Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients.

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.

Long-term survival of elderly patients after intensive care unit admission for acute respiratory infection: a population-based, propensity score-matched cohort study.

BACKGROUND: Intensive care unit (ICU) hospitalisations of elderly patients with acute respiratory infection have increased, yet the long-term effects of ICU admission among elderly individuals remain unknown. We examined differences over the 2 years after discharge in mortality, healthcare utilisation and frailty score between elderly survivors of ARI in the ICU and an elderly control population. METHODS: We used 2009-2017 data from 39 hospital discharge databases. Patients ≥ 80 years old discharged alive from ICU hospitalisation for acute respiratory infection were propensity score-matched with controls (cataract surgery) discharged from the hospital at the same time and adjusted for age, sex and comorbidities present before hospitalisation. We reported 2-year mortality and compared healthcare utilisation and frailty scores in the 2-year periods before and after ICU hospitalisation. RESULTS: One thousand two hundred and twenty elderly survivors of acute respiratory infection in the ICU were discharged, and 988 were successfully matched with controls. After discharge, patients had a 10.1-fold [95% CI, 6.1-17.3] higher risk of death at 6 months and 3.6-fold [95% CI, 2.9-4.6] higher risk of death at 2 years compared with controls. They also had a 2-fold increase in both healthcare utilisation and frailty score in the 2 years after hospital discharge, whereas healthcare utilisation and frailty scores among controls were stable before and after hospitalisation. CONCLUSIONS: We observed a substantially increased rate of death in the years following ICU hospitalisation for elderly patients along with elevated healthcare resource use and accelerated age-associated decline as assessed by frailty score. These findings provide data for better informed goals-of-care discussions and may help target post-ICU discharge services.

Preoperative Chemerin Level Is Predictive of Inflammatory Status 1 Year After Bariatric Surgery.

BACKGROUND: Obesity is associated with chronic low-grade inflammation, which has been linked to increased morbidity. However, inflammation variably and unpredictably improves after bariatric surgery. This study aimed at (1) evaluating the relationship between amplitude of weight loss and variation of inflammatory parameters after bariatric surgery, and (2) identifying, among clinical and biological baseline parameters, predictive factors of variation in inflammatory parameters. METHODS: In a prospective cohort of patients who underwent bariatric surgery, serum concentrations of interleukin (IL)-6, IL-10, resistin, leptin, adiponectin chemerin, and C-reactive protein (CRP) were measured preoperatively and 1 year after surgery, and routine clinical and biochemical parameters were retrieved. Univariate and multivariate analyses (partial least square method) were performed to assess how parameters were associated with weight loss and to predict improvement of inflammatory parameters. RESULTS: Eighty-seven patients were included (mean weight ± SD 136.3 ± 3.2 kg, 35 gastric bypasses, 52 sleeve gastrectomies). In parallel with weight loss (39.5 ± 13.8 kg), pro-inflammatory markers (IL-6, CRP, leptin, resistin) significantly decreased, and anti-inflammatory markers (IL-10, adiponectin) increased. Multivariate analysis revealed a significant association between weight loss and improvement in inflammatory parameters. Among all the clinical and biological preoperative parameters, baseline chemerin level was the only parameter that was significantly associated with global improvement of the inflammatory status after surgery. CONCLUSION: The amplitude of weight loss 1 year after bariatric surgery was strongly correlated with improvement of inflammatory profile, which could be predicted by baseline plasma level of chemerin. This suggests a key role of chemerin in obesity-driven inflammation, and a potential use as a biomarker.

Interleukin-7 protects against bacterial respiratory infection by promoting IL-17A-producing innate T-cell response.

Interleukin-7 (IL-7) is a critical cytokine in B- and T-lymphocyte development and maturation. Recent evidence suggests that IL-7 is a preferential homeostatic and survival factor for RORγt+ innate T cells such as natural killer T (NKT) cells, γδT cells, and mucosal-associated invariant T (MAIT) cells in the periphery. Given the important contribution of these populations in antibacterial immunity at barrier sites, we questioned whether IL-7 could be instrumental in boosting the local host immune response against respiratory bacterial infection. By using a cytokine-monoclonal antibody approach, we illustrated a role for topical IL-7 delivery in increasing the pool of RORγt+ IL-17A-producing innate T cells. Prophylactic IL-7 treatment prior to Streptococcus pneumoniae infection led to better bacterial containment, a process associated with increased neutrophilia and that depended on γδT cells and IL-17A. Last, combined delivery of IL-7 and α-galactosylceramide (α-GalCer), a potent agonist for invariant NKT (iNKT) cells, conferred an almost total protection in terms of survival, an effect associated with enhanced IL-17 production by innate T cells and neutrophilia. Collectively, we provide a proof of concept that IL-7 enables fine-tuning of innate T- cell functions. This might pave the way for considering IL-7 as an innovative biotherapeutic against bacterial infection.

Healthcare trajectories before and after critical illness: population-based insight on diverse patients clusters.

BACKGROUND: The post intensive care syndrome (PICS) gathers various disabilities, associated with a substantial healthcare use. However, patients' comorbidities and active medical conditions prior to intensive care unit (ICU) admission may partly drive healthcare use after ICU discharge. To better understand retative contribution of critical illness and PICS-compared to pre-existing comorbidities-as potential determinant of post-critical illness healthcare use, we conducted a population-based evaluation of patients' healthcare use trajectories. RESULTS: Using discharge databases in a 2.5-million-people region in France, we retrieved, over 3 years, all adult patients admitted in ICU for septic shock or acute respiratory distress syndrome (ARDS), intubated at least 5 days and discharged alive from hospital: 882 patients were included. Median duration of mechanical ventilation was 11 days (interquartile ranges [IQR] 8;20), mean SAPS2 was 49, and median hospital length of stay was 42 days (IQR 29;64). Healthcare use (days spent in healthcare facilities) was analyzed 2 years before and 2 years after ICU admission. Prior to ICU admission, we observed, at the scale of the whole study population, a progressive increase in healthcare use. Healthcare trajectories were then explored at individual level, and patients were assembled according to their individual pre-ICU healthcare use trajectory by clusterization with the K-Means method. Interestingly, this revealed diverse trajectories, identifying patients with elevated and increasing healthcare use (n = 126), and two main groups with low (n = 476) or no (n = 251) pre-ICU healthcare use. In ICU, however, SAPS2, duration of mechanical ventilation and length of stay were not different across the groups. Analysis of post-ICU healthcare trajectories for each group revealed that patients with low or no pre-ICU healthcare (which represented 83% of the population) switched to a persistent and elevated healthcare use during the 2 years post-ICU. CONCLUSION: For 83% of ARDS/septic shock survivors, critical illness appears to have a pivotal role in healthcare trajectories, with a switch from a low and stable healthcare use prior to ICU to a sustained higher healthcare recourse 2 years after ICU discharge. This underpins the hypothesis of long-term critical illness and PICS-related quantifiable consequences in healthcare use, measurable at a population level.

Effects of mean arterial pressure on arousal in sedated ventilated patients with septic shock: a SEPSISPAM post hoc exploratory study.

BACKGROUND: It is unknown whether the recommended mean arterial pressure (MAP) target of 65 mmHg during initial resuscitation of septic shock is sufficient to maintain cerebral perfusion. Thus, we tested the hypothesis that a higher MAP target in patients with septic shock may improve level of arousal. METHODS: We performed a post hoc exploratory analysis of the SEPSISPAM trial, which assessed the effect of a "high-target" level of MAP (80-85 mmHg) versus the recommended "low-target" MAP (65-70 mm Hg) on mortality in patients with septic shock. Among the 776 patients originally recruited in SEPSISPAM trial, we selected those who were mechanically ventilated and sedated and with available evaluation of arousal level assessed by the Richmond Agitation and Sedation Scale (RASS). RESULTS: We restricted our analysis to the period in which patients were treated with vasoactive drugs. Cumulative sedative drugs were assessed daily. A total of 532 patients were included in this study: 253 (47.6%) in the low-target group and 279 (52.4%) in the high-target group. Daily cumulative sedative drugs were similar in both groups. Compared to the low-target group, minimal and maximal RASS were significantly higher in the high-target group at day 2, 4 and 5. Furthermore, in order to consider the fact that multiple measures were done for each patient and to consider the global effect of time on these measures, we used a mixed linear regression and multivariate models: we confirmed that maximal RASS values were significantly higher in the high-target group. CONCLUSION: In patients with septic shock who were mechanically ventilated and sedated, resuscitation with MAP target between 80 and 85 mmHg was associated with higher arousal level as compared to a MAP target between 65 and 70 mmHg.

Rapid detection of bacterial meningitis using a point-of-care glucometer.

BACKGROUND: In case of acute bacterial meningitis, a decision on the need for intensive care admission should be made within the first hour. The aim of this study was to assess the ability of a point-of-care glucometer to determine abnormal cerebrospinal fluid (CSF) glucose concentration at the bedside that contributes toward bacterial meningitis diagnosis. METHODS: We carried out a prospective study and simultaneously measured the glucose concentrations in CSF and blood using a central laboratory and a point-of-care glucometer. We compared CSF/blood glucose ratios obtained at the bedside with a glucometer versus those obtained by the central laboratory. We determined the performance characteristics of the CSF/blood glucose ratio provided by a glucometer to detect bacterial infection in the CSF immediately after CSF sampling. RESULTS: We screened 201 CSF collection procedures during the study period and included 172 samples for analysis. Acute bacterial meningitis was diagnosed in 17/172 (9.9%) of CSF samples. The median turnaround time for a point-of-care glucometer analysis was 5 (interquartile range 2-10) min versus 112 (interquartile range 86-154) min for the central laboratory (P<0.0001). The optimal cut-off of the CSF/blood glucose ratio calculated from a bedside glucometer was 0.46, with a sensitivity of 94.1% (95% confidence interval: 71.3-99.9%), a specificity of 91% (95% confidence interval: 85.3-95%), and a positive likelihood ratio of 10. CONCLUSION: A glucometer accurately detects an abnormal CSF/blood glucose ratio immediately after the lumbar puncture. This cheap point-of-care method has the potential to speed up the diagnostic process of patients with bacterial meningitis.