Adjuvante Therapien für Beatmungsassoziierten Lungenschaden und akutes Lungenversagen

Die Mortalität des akuten Lungenversagens ist auch nach vielen Dekaden experimenteller und klinischer Forschung weiterhin hoch. Die Beatmungsassoziierte Lungenschädigung (VILI; ventilator-induced lung injury) ist ein integraler Bestandteil des ARDS mit relevanten Einfluss auf Morbidität und Mortalität. Sowohl die Mechanismen des ARDS als auch des VILI sind mittlerweile sehr gut charakterisiert und die bekannten molekularen Mechanismen legen nahe, dass pharmakologische adjuvante Therapien im ARDS/VILI wirksam sein können. In dieser Arbeit wurden exemplarisch drei pharmakologische Therapiestrategien für das akute Lungenversagen untersucht in komplexen Tiermodellen vorgestellt von denen zwei in diesem Kontext effektiv waren: Adrenomedullin und die Neutralisation von C5a. Sowohl Adrenomedullin, als auch die C5a Neutralisation werden derzeit in klinischen Studien bei ARDS und Sepsis untersucht. Neben adjuvanten pharmakologischen Interventionen könnten auch subtile Veränderungen von Beatmungsparametern Einfluss auf den Krankheitsverlauf von ARDS Patient:innen haben. Hier wurde diesbezüglich eine Arbeit vorgestellt, in der die Verlängerung der Inspirationszeit bei gleicher Atemfrequenz, Plateaudrücken, PEEP und Tidalvolumen zur Aggravierung von VILI führt. In der Zukunft könnten sowohl adjuvante pharmakologische Therapien als auch ein besseres Verständnis der Mechanismen von VILI dazu beitragen, das Überleben von Patienten im ARDS zu verbessern

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

Background: Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILIassociated lung permeability in vivo. Methodology/Principal Findings: Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxi

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study.

Funder: Humboldt-Universität zu Berlin (1034)PURPOSE: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. METHODS: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. RESULTS: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. CONCLUSIONS: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

IMD improved endothelial barrier function in endothelial cells.

<p>HPMVECs grown to confluence on gold microelectrodes to measure transcellular electrical resistance (TER) were stimulated with 0.01 or 0.1 µM IMD or with solvent. IMD dose dependently improved endothelial barrier function as displayed by TER increase. (n = 6).</p

IMD had no impact on oxygenation in VILI.

<p>Mice were ventilated with a tidal volume of 12 ml/kg for 6 h and treated with IMD 0.025 mg/kg*h (6<b> </b>h vent.+IMD) or solvent (6<b> </b>h vent). A) Peripheral SpO₂ was monitored. B) At the end of the 6<b> </b>h ventilation period, SpO₂ was not relevantly different between groups. C) After 6<b> </b>h of MV, the P/F ratio was not different between groups. (***p<0.001, n = 15)</p

Regulation of IMD and its receptor complexes in VILI.

<p>Mice were ventilated with a tidal volume of 12 ml/kg for 6 h (6<b> </b>h vent.). Non ventilated individuals (NV) served as controls. A) Regulation of IMD, CGRP and RAMP1-3 was quantified by qRT-PCR in the lungs of ventilated (6<b> </b>h vent.) and non ventilated mice (NV). (** p<0.01, n = 5). B) Immunofluorescence analysis of subpleural peripheral lung. IMD-immunolabelling was slightly enhanced in ventilated (6<b> </b>h vent.) compared to non-ventilated mice (NV) while CRLR-immunolabelling did not differ between groups. Tissue sections depicting NV and 6<b> </b>h vent groups were processed simultaneously and images were taken at the same exposure time (30 ms for IMD and 150 ms for CRLR).</p

Pulmonary distribution of IMD and CRLR was not altered in VILI.

<p>In non ventilated mice (A) and individuals ventilated with a tidal volume of 12 ml/kg for 6 h (6<b> </b>h vent.) (B) IMD- and CRLR-immunolabelling colocalized with CD31-immunoreactivity (<i>arrows</i>), a marker for endothelial cells. In addition, alveolar macrophages were IMD- and CRLR-positive (<i>arrowheads</i>). (n = 5, representative images shown).</p

VILI-induced cytokine production was not altered by IMD.

<p>Mice were ventilated with a tidal volume of 12 ml/kg for 6 h and treated with IMD 0.025 mg/kg*h (6<b> </b>h vent.+IMD) or solvent (6<b> </b>h vent). NV = non-ventilated mice. A) IL-1β, IL-18, IL-6, KC, MIP-1α, MIP-2, MCP-1, IL12p40 were detemined in lung homogenate by multiplex assay technique. (*p<0.05 vs. NV, **p<0.01 vs. NV n = 8) B) IL-1β, IL-18, IL-6, KC, MIP-1α, MIP-2, MCP-1, IL12p40 were determined in plasma by multiplex assay technique. (*p<0.05 vs. NV, **p<0.01 vs. NV n = 8).</p