Alveolar cytokines and interferon autoantibodies in COVID-19 ARDS.

Background: Type I interferon (IFN-I) and IFN autoantibodies play a crucial role in controlling SARS-CoV-2 infection. The levels of these mediators have only rarely been studied in the alveolar compartment in patients with COVID-19 acute respiratory distress syndrome (CARDS) but have not been compared across different ARDS etiologies, and the potential effect of dexamethasone (DXM) on these mediators is not known. Methods: We assessed the integrity of the alveolo-capillary membrane, interleukins, type I, II, and III IFNs, and IFN autoantibodies by studying the epithelial lining fluid (ELF) volumes, alveolar concentration of protein, and ELF-corrected concentrations of cytokines in two patient subgroups and controls. Results: A total of 16 patients with CARDS (four without and 12 with DXM treatment), eight with non-CARDS, and 15 healthy controls were included. The highest ELF volumes and protein levels were observed in CARDS. Systemic and ELF-corrected alveolar concentrations of interleukin (IL)-6 appeared to be particularly low in patients with CARDS receiving DXM, whereas alveolar levels of IL-8 were high regardless of DXM treatment. Alveolar levels of IFNs were similar between CARDS and non-CARDS patients, and IFNα and IFNω autoantibody levels were higher in patients with CARDS and non-CARDS than in healthy controls. Conclusions: Patients with CARDS exhibited greater alveolo-capillary barrier disruption with compartmentalization of IL-8, regardless of DXM treatment, whereas systemic and alveolar levels of IL-6 were lower in the DXM-treated subgroup. IFN-I autoantibodies were higher in the BALF of CARDS patients, independent of DXM, whereas IFN autoantibodies in plasma were similar to those in controls.

Thromboembolic and bleeding events in ICU patients with COVID-19: A nationwide, observational study.

BACKGROUND: Intensive care unit (ICU) patients with Coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications. We describe the occurrence of thromboembolic and bleeding events in all ICU patients with COVID-19 in Denmark during the first and second waves of the pandemic. METHODS: This was a sub-study of the Danish Intensive Care Covid database, in which all patients with SARS-CoV-2 admitted to Danish ICUs from 10th March 2020 to 30th June 2021 were included. We registered coagulation variables at admission, and all thromboembolic and bleeding events, and the use of heparins during ICU stay. Variables associated with thrombosis and bleeding and any association with 90-day mortality were estimated using Cox regression analyses. RESULTS: We included 1369 patients in this sub-study; 158 (12%, 95% confidence interval 10-13) had a thromboembolic event in ICU and 309 (23%, 20-25) had a bleeding event, among whom 81 patients (6%, 4.8-7.3) had major bleeding. We found that mechanical ventilation and increased D-dimer were associated with thrombosis and mechanical ventilation, low platelet count and presence of haematological malignancy were associated with bleeding. Most patients (76%) received increased doses of thromboprophylaxis during their ICU stay. Thromboembolic events were not associated with mortality in adjusted analysis (hazard ratio 1.35 [0.91-2.01, p = .14], whereas bleeding events were 1.55 [1.18-2.05, p = .002]). CONCLUSIONS: Both thromboembolic and bleeding events frequently occurred in ICU patients with COVID-19. Based on these data, it is not apparent that increased doses of thromboprophylaxis were beneficial.

Changes over time in characteristics, resource use and outcomes among ICU patients with COVID-19-A nationwide, observational study in Denmark.

BACKGROUND: Characteristics and care of intensive care unit (ICU) patients with COVID-19 may have changed during the pandemic, but longitudinal data assessing this are limited. We compared patients with COVID-19 admitted to Danish ICUs in the first wave with those admitted later. METHODS: Among all Danish ICU patients with COVID-19, we compared demographics, chronic comorbidities, use of organ support, length of stay and vital status of those admitted 10 March to 19 May 2020 (first wave) versus 20 May 2020 to 30 June 2021. We analysed risk factors for death by adjusted logistic regression analysis. RESULTS: Among all hospitalised patients with COVID-19, a lower proportion was admitted to ICU after the first wave (13% vs. 8%). Among all 1374 ICU patients with COVID-19, 326 were admitted during the first wave. There were no major differences in patient's characteristics or mortality between the two periods, but use of invasive mechanical ventilation (81% vs. 58% of patients), renal replacement therapy (26% vs. 13%) and ECMO (8% vs. 3%) and median length of stay in ICU (13 vs. 10 days) and in hospital (20 vs. 17 days) were all significantly lower after the first wave. Risk factors for death were higher age, larger burden of comorbidities (heart failure, pulmonary disease and kidney disease) and active cancer, but not admission during or after the first wave. CONCLUSIONS: After the first wave of COVID-19 in Denmark, a lower proportion of hospitalised patients with COVID-19 were admitted to ICU. Among ICU patients, use of organ support was lower and length of stay was reduced, but mortality rates remained at a relatively high level.

[Local immunopathology in COVID-19 associated lung injury].

Mechanisms of COVID-19-induced lung injury involve complex immunopathological events which are currently being elucidated. Studying immune mechanisms at the primary site of injury, i.e. the lower airways, are particularly informative. This review provides a brief introduction to the methods used to perform sampling from the lungs of critically ill patients with COVID-19, key immunopathological findings and a discussion on how immunosuppressants may exert their effects locally.

Therapeutic benefits of proning to improve pulmonary gas exchange in severe respiratory failure: focus on fundamentals of physiology.

NEW FINDINGS: What is the topic of this review? The use of proning for improving pulmonary gas exchange in critically ill patients. What advances does it highlight? Proning places the lung in its 'natural' posture, and thus optimises the ventilation-perfusion distribution, which enables lung protective ventilation and the alleviation of potentially life-threatening hypoxaemia in COVID-19 and other types of critical illness with respiratory failure. ABSTRACT: The survival benefit of proning patients with acute respiratory distress syndrome (ARDS) is well established and has recently been found to improve pulmonary gas exchange in patients with COVID-19-associated ARDS (CARDS). This review outlines the physiological implications of transitioning from supine to prone on alveolar ventilation-perfusion ( V ̇ A -- Q ̇ ${\dot V_{\rm{A}}}\hbox{--}\dot Q$ ) relationships during spontaneous breathing and during general anaesthesia in the healthy state, as well as during invasive mechanical ventilation in patients with ARDS and CARDS. Spontaneously breathing, awake healthy individuals maintain a small vertical (ventral-to-dorsal) V ̇ A / Q ̇ ${\dot V_{\rm{A}}}/\dot Q$ ratio gradient in the supine position, which is largely neutralised in the prone position, mainly through redistribution of perfusion. In anaesthetised and mechanically ventilated healthy individuals, a vertical V ̇ A / Q ̇ ${\dot V_{\rm{A}}}/\dot Q$ ratio gradient is present in both postures, but with better V ̇ A -- Q ̇ ${\dot V_{\rm{A}}}\hbox{--}\dot Q$ matching in the prone position. In ARDS and CARDS, the vertical V ̇ A / Q ̇ ${\dot V_{\rm{A}}}/\dot Q$ ratio gradient in the supine position becomes larger, with intrapulmonary shunting in gravitationally dependent lung regions due to compression atelectasis of the dorsal lung. This is counteracted by proning, mainly through a more homogeneous distribution of ventilation combined with a largely unaffected high perfusion dorsally, and a consequent substantial improvement in arterial oxygenation. The data regarding proning as a therapy in patients with CARDS is still limited and whether the associated improvement in arterial oxygenation translates to a survival benefit remains unknown. Proning is nonetheless an attractive and lung protective manoeuvre with the potential benefit of improving life-threatening hypoxaemia in patients with ARDS and CARDS.

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-A nationwide, observational study.

BACKGROUND: Most data on intensive care unit (ICU) patients with COVID-19 originate in selected populations from stressed healthcare systems with shorter term follow-up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID-19 in Denmark where the ICU capacity was not exceeded. METHODS: We identified all patients with SARS-CoV-2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis. RESULTS: There were 323 ICU patients with confirmed COVID-19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6-22) and hospital stay 19 days (11-30). Median follow-up was 79 days. At end of follow-up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co-morbidities. CONCLUSIONS: In this nationwide, population-based cohort of ICU patients with COVID-19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co-morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.

Lung Protection Strategies during Cardiopulmonary Bypass Affect the Composition of Bronchoalveolar Fluid and Lung Tissue in Cardiac Surgery Patients.

Pulmonary dysfunction is among the most frequent complications to cardiac surgeries. Exposure of blood to the cardiopulmonary bypass (CPB) circuit with subsequent lung ischemia-reperfusion leads to the production of inflammatory mediators and increases in microvascular permeability. The study aimed to elucidate histological, cellular, and metabolite changes following two lung protective regimens during CPB with Histidine-Tryptophan-Ketoglutarate (HTK) enriched or warm oxygenated blood pulmonary perfusion compared to standard regimen with no pulmonary perfusion. A total of 90 patients undergoing CPB were randomized to receiving HTK, oxygenated blood or standard regimen. Of these, bronchoalveolar lavage fluid (BALF) and lung tissue biopsies were obtained before and after CPB from 47 and 25 patients, respectively. Histopathological scores, BALF cell counts and metabolite screening were assessed. Multivariate and univariate analyses were performed. Profound histological, cellular, and metabolic changes were identified in all patients after CPB. Histological and cellular changes were similar in the three groups; however, some metabolite profiles were different in the HTK patients. While all patients presented an increase in inflammatory cells, metabolic acidosis, protease activity and oxidative stress, HTK patients seemed to be protected against severe acidosis, excessive fatty acid oxidation, and inflammation during ischemia-reperfusion. Additional studies are needed to confirm these findings.

Soluble ectodomain CD163 and extracellular vesicle-associated CD163 are two differently regulated forms of 'soluble CD163' in plasma.

CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammation-inducible TACE/ADAM17 enzyme. Accordingly, plasma 'soluble CD163' (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting 'soluble CD163' in plasma may therefore add to the diagnostic and prognostic value.

Inflammation-Induced Changes in Circulating T-Cell Subsets and Cytokine Production During Human Endotoxemia.

Observational clinical studies suggest the initial phase of sepsis may involve impaired cellular immunity. In the present study, we investigated temporal changes in T-cell subsets and T-cell cytokine production during human endotoxemia. Endotoxin (Escherichia coli lipopolysaccharide 4 ng/kg) was administered intravenously in 15 healthy volunteers. Peripheral blood and bronchoalveolar lavage fluid (BALF) were collected at baseline and after 2, 4, 6, 8, and 24 hours for flow cytometry. CD4+CD25+CD127lowFoxp3+ regulatory T cells (Tregs), CD4+CD161+ cells, and activated Human leukocyte antigen, HLA-DR+CD38+ T cells were determined. Ex vivo whole-blood cytokine production and Toll-like receptor (TLR)-4 expression on Tregs were measured. Absolute number of CD3+CD4+ (P = .026), CD3+CD8+ (P = .046), Tregs (P = .023), and CD4+CD161+ cells (P = .042) decreased after endotoxin administration. The frequency of anti-inflammatory Tregs increased (P = .033), whereas the frequency of proinflammatory CD4+CD161+ cells decreased (P = .034). Endotoxemia was associated with impaired whole-blood production of tumor necrosis factor-α, interleukin-10, IL-6, IL-17, IL-2, and interferon-γ in response to phytohaemagglutinin but did not affect TLR4 expression on Tregs. No changes in the absolute count or frequency of BALF T cells were observed. Systemic inflammation is associated with lymphopenia, a relative increase in the frequency of anti-inflammatory Tregs, and a functional impairment of T-cell cytokine production.

Changes in ventilatory capacity and pulmonary gas exchange during systemic and pulmonary inflammation in humans.

The exact mechanism linking the systemic inflammatory response associated with sepsis to changes in lung function remains to be determined. In a human experimental model of inflammation, we investigated how acute systemic and local pulmonary inflammation affects ventilatory capacity and pulmonary gas exchange. Fifteen volunteers received Escherichia coli lipopolysaccharide (LPS) intravenously or endobronchially on two different study days. Blood samples were obtained hourly (t = 0-8 h) and spirometry was performed at baseline and after 8 h. Both interventions decreased ventilatory capacity compared to baseline (p < 0.01), and this was more pronounced after intravenous (forced expiratory volume in 1-s, FEV1 ; 0.6 L/12% reduction) compared to endobronchial (FEV1 ; 0.32 L/7% reduction) administration (p < 0.05). Furthermore, the alveolar-arterial oxygen difference increased after intravenous but not after endobronchial endotoxin. These findings indicate that pulmonary gas exchange is impaired to a greater extent during endotoxin-induced systemic inflammation than during endotoxin-induced local pulmonary inflammation.

Dynamic Cerebral Autoregulation after Cardiopulmonary Bypass.

Background Cerebral hemodynamic disturbances in the peri- or postoperative period may contribute to postoperative cognitive dysfunction (POCD) in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). We therefore examined dynamic cerebral autoregulation (dCA) post-CPB and changes in neurocognitive function in patients that had undergone CABG. Materials and Methods We assessed dCA by transfer function analysis of spontaneous oscillations between arterial blood pressure and middle cerebral artery blood flow velocity measured by transcranial Doppler ultrasound in eight patients 6 hours after the cessation of CPB; 10 healthy volunteers served as controls. Neurocognitive function was assessed by four specific tests 1 day prior to and 3 days after CPB. Results Even though patients exhibited systemic inflammation and anemic hypoxemia, dCA was similar to healthy volunteers (gain: 1.24 [0.94-1.49] vs. 1.22 [1.06-1.34] cm mm Hg-1 s-1, p = 0.97; phase: 0.33 [0.15-0.56] vs. 0.69 [0.50-0.77] rad, p = 0.09). Neurocognitive testing showed a perioperative decline in the Letter Digit Coding Score (p = 0.04), while weaker dCA was associated with a lower Stroop Color Word Test (rho = - 0.90; p = 0.01). Discussion and Conclusion We found no changes in dCA 6 hours after CPB. However, based on the data at hand, it cannot be ruled out that changes in dCA predispose to POCD, which calls for larger studies that assess the potential impact of dCA in the early postoperative period on POCD.

Progressive intracranial hypertension and cerebral hypoperfusion in a fatal case of cerebral aspergilloma.

We report a case of cerebral aspergilloma in a 25-year-old immunoincompetent man admitted to a general intensive care unit. Monitoring of intracranial pressure was instigated and revealed hour-long epochs of severe intracranial hypertension, despite a normal opening pressure, with decreases in cerebral perfusion pressure. We documented that this was associated with cerebral hypoperfusion by transcranial Doppler ultrasound. The present case illustrates that severe intracranial hypertension may evolve despite a normal opening pressure; it furthermore shows that continuous monitoring of intracranial pressure may be used to predict changes in cerebral haemodynamics in critically ill patients with neuroinfection.

Transcompartmental inflammatory responses in humans: IV versus endobronchial administration of endotoxin*.

OBJECTIVES: Transcompartmental signaling during early inflammation may lead to propagation of disease to other organs. The time course and the mechanisms involved are still poorly understood. We aimed at comparing acute transcompartmental inflammatory responses in humans following lipopolysaccharide-induced pulmonary and systemic inflammation. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING ICU SUBJECTS: Healthy male volunteers. INTERVENTIONS: Fifteen volunteers (mean age, 23; SD, 2 yr) received Escherichia coli endotoxin (lipopolysaccharide, 4 ng/kg) IV or endobronchially on two different study days. Groups were evaluated by bronchoalveolar lavage at baseline (0 hr) and 2, 4, 6, 8, or 24 hours postchallenge. Cardiorespiratory variables were continuously recorded throughout the study day, and plasma and bronchoalveolar lavage fluid markers of inflammation were measured. MEASUREMENTS AND MAIN RESULTS: IV endotoxin elicited a systemic inflammatory response with a time-dependent increase and peak in tumor necrosis factor-α, interleukin-6, and leukocyte counts (all p < 0.001). Furthermore, a delayed (6-8 hr) increase in bronchoalveolar lavage fluid interleukin-6 concentration (p < 0.001) and alveolar leukocyte count (p = 0.03) and a minor increase in bronchoalveolar lavage fluid tumor necrosis factor-α were observed (p = 0.06). Endobronchial endotoxin was followed by progressive alveolar neutrocytosis and increased bronchoalveolar lavage fluid tumor necrosis factor-α, interleukin-6, and albumin (all p < 0.001); a systemic inflammatory response was observed after 2-4 hours, with no change in plasma tumor necrosis factor-α. CONCLUSIONS: Acute lung or systemic inflammation in humans is followed by a transcompartmental proinflammatory response, the degree and differential kinetics of which suggests that the propagation of inflammation may depend on the primary site of injury.