Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331621

ABSTRACT

Post-acute lung sequelae of COVID-19 are challenging many survivors across the world, yet the mechanisms behind are poorly understood. Our results delineate an inflammatory cascade of events occurring along disease progression within fibrovascular niches. It is initiated by endothelial dysfunction, followed by heme scavenging of CD163+ macrophages and production of CCL18. This chemokine synergizes with local CCL21 upregulation to influence the stromal composition favoring endothelial to mesenchymal transition. The local immune response is further modulated via recruitment of CCR7+ T cells into the expanding fibrovascular niche and imprinting an exhausted, T follicular helper like phenotype in these cells. Eventually, this culminates in the formation of tertiary lymphoid structures, further perpetuating chronic inflammation. Thus, our work presents misdirected immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and leads to profound tissue repurposing and chronic inflammation.

2.
Crit Care Med ; 2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1684855

ABSTRACT

OBJECTIVES: To investigate the effect of extracorporeal cytokine reduction by CytoSorb (CytoSorbents, Monmouth Junction, NJ) on COVID-19-associated vasoplegic shock. DESIGN: Prospective, randomized controlled pilot study. SETTING: Eight ICUs at three sites of the tertiary-care university hospital Charité-Universitätsmedizin Berlin. PATIENTS: COVID-19 patients with vasoplegic shock requiring norepinephrine greater than 0.2 µg/kg/min, C-reactive protein greater than 100 mg/L, and indication for hemodialysis. INTERVENTIONS: Randomization of 1:1 to receive CytoSorb for 3-7 days or standard therapy. To account for inadvertent removal of antibiotics, patients in the treatment group received an additional dose at each adsorber change. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time until resolution of vasoplegic shock, estimated by Cox-regression. Secondary endpoints included mortality, interleukin-6 concentrations, and catecholamine requirements. The study was registered in the German Registry of Clinical Trials (DRKS00021447). From November 2020 to March 2021, 50 patients were enrolled. Twenty-three patients were randomized to receive CytoSorb and 26 patients to receive standard of care. One patient randomized to cytokine adsorption was excluded due to withdrawal of informed consent. Resolution of vasoplegic shock was observed in 13 of 23 patients (56.5%) in the CytoSorb and 12 of 26 patients (46.2%) in the control group after a median of 5 days (interquartile range [IQR], 4-5 d) and 4 days (IQR, 3-5 d). The hazard ratio (HR) for the primary endpoint, adjusted for the predefined variables age, gender, extracorporeal membrane oxygenation-therapy, or time from shock onset to study inclusion was HR, 1.23 (95% CI, 0.54-2.79); p = 0.63. The mortality rate was 78% in the CytoSorb and 73% in the control group (unadjusted HR, 1.17 [95% CI, 0.61-2.23]; p = 0.64). The effects on inflammatory markers, catecholamine requirements, and the type and rates of adverse events were similar between the groups. CONCLUSIONS: In severely ill COVID-19 patients, CytoSorb did not improve resolution of vasoplegic shock or predefined secondary endpoints.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296076

ABSTRACT

Background: Several observations indicate a hyperinflammatory state in severely ill COVID-19 patients. The aim of this study was to investigate the effect of extracorporeal cytokine elimination by CytoSorb® on COVID-19 associated vasoplegic shock.<br><br>Methods: In this prospective randomised pilot study COVID-19 patients with vasoplegic shock requiring norepinephrine >0·2 µg/kg/min, CRP >100 mg/L and indication for hemodialysis were randomised 1:1 to receive CytoSorb® treatment for 3-7 days or standard of care. The primary endpoint was time until resolution of vasoplegic shock, estimated by a Cox-regression model. Secondary endpoints included mortality, serum interleukin-6 concentrations, and catecholamine requirements. The study was registered in the German Registry of Clinical Trials (DRKS00021447).<br><br>Findings: From November 2020 to March 2021, 50 patients were enrolled of which 23 patients were randomised to receive CytoSorb® treatment and 26 patients to receive standard of care. One patient randomised to cytokine adsorption was excluded due to withdrawal of informed consent. Resolution of vasoplegic shock was observed in 13 (56·5%) of 23 patients in the CytoSorb® and 12 (46·2%) of 26 patients in the control group after a median of 5 (IQR 4-5) and 4 (IQR 3-5) days, respectively. The hazard ratio (HR) for the primary endpoint, adjusted for the predefined variables age, gender, ECMO-therapy, or time from shock onset to study inclusion was HR 1·23 (95%CI: 0·54-2·79), p=0·63). The mortality rate was 78% in the CytoSorb® and 73% in the control group (unadjusted HR 1·17 (95%CI: 0·61-2.23), p=0·64). The effects on inflammatory markers and catecholamine requirements and the type and rates of adverse events were similar in the two groups.<br><br>Interpretation: In this pilot trial in severely ill COVID-19 patients CytoSorb® treatment did not improve resolution of vasoplegic shock as compared to standard treatment. Mortality rates, catecholamine requirements, inflammatory markers and adverse events did not differ between the two groups.<br><br>Trial Registration: The study was registered in the German Registry of Clinical Trials (DRKS00021447<br><br>Funding: Internal university funds<br><br>Declaration of Interest: HS, LJL, MP, TK, PT, FS, KUE, SK, JVK, MO, AKrü, A Kra, KB declare no conflicts of interest. PE received honoraria from GSK and AstraZeneca and filed two patents for novel urinary biomarkers outside the submitted work. ST received research funding and honoraria for workshops and lectures from Orionpharma. He additionally received honoraria for workshops and lectures from Edwards and honoraria for lectures from Amomed and Smith&Nephews. CS received grants from: Drägerwerk AG& Co.KGaA;German Reseach Society;German Aerospace Center;Einstein Foundation Berlin;Federal Joint Committee (G-BA);Inner University grants;Project Management Agency;Non-Profit Promoting Science and Education;European Society of Anesthesiology and Intensive Care;Baxter Deutschland GmbH;Cytosorbents Europe GmbH;Edwards Lifsciences Germany GmbH;Fresenius Medical Care;Grünenthal GmbH;Massimo Europe Ltd.;Pfizer Pharma PFE GmbH;Georg Thieme Verlag, Dr. F Köhler Chemie GmbH;Sintetica GmbH;Stifterverband für die deutsche Wissenschaft e.V./Philips;Stiftung Charié;AGUETTANT Deutschland GmbH;AbbVie Deutschland GmbH & Co.KG;Amomed Pharma GmbH;InTouch Health;Copra System GmbH;Correvio GmbH;Max Plank Gesellschaft zur Förderung der Wissenschaften e.V.;Deutsche Gesellschaft für Anästhesiologie & Intensivmedizin (DGAI);Stifterverband für die Deutsche Wissenschaft e.V./Medtronic;Philipps ElectronicsNederland BV;BMG, BMBF, German Research Society all outside the submitted work. In addition, CS has different patents. DK received fees for speaking at a symposia organized on behalf of Fresenius Medical Care AG, Germany.<br><br>Ethical Approval: The original protocol and the changes were approved by the local ethics<br>committee (EA1/069/20).

5.
Kidney Int Rep ; 6(4): 905-915, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1169160

ABSTRACT

INTRODUCTION: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development. METHODS: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI. RESULTS: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings. CONCLUSION: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.

7.
Journal of Clinical Investigation ; 130(12):6477-6489, 2020.
Article in English | ProQuest Central | ID: covidwho-1021205

ABSTRACT

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4· T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2specific CD4· T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-y-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-y· T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.

8.
J Clin Invest ; 130(12): 6477-6489, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1021209

ABSTRACT

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.


Subject(s)
COVID-19/immunology , Interferon-gamma/immunology , Interleukin-2/immunology , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/pathology , Disease Susceptibility , Female , Humans , Male , Middle Aged , Severity of Illness Index , Th1 Cells/pathology
9.
Nephrologe ; : 1-5, 2020 Dec 22.
Article in German | MEDLINE | ID: covidwho-986661

ABSTRACT

Acute kidney injury (AKI) is a frequent and severe complication in coronavirus disease 2019 (COVID-19) patients in the intensive care unit. The development of COVID-19 associated AKI is closely linked to the severity of the disease course. The main risk factor for kidney failure requiring kidney replacement therapy is the necessity for invasive ventilation, whereby the onset of renal failure is often closely associated with the timing of intubation. Additionally, the risk factors for a severe course of COVID-19 have been shown to also be risk factors for renal failure. AKI in COVID-19 shows a high mortality and in some patients leads to chronic kidney disease; however, full recovery of kidney function in survivors who need dialysis is not uncommon. With respect to prevention and treatment of renal failure associated with COVID-19, the same recommendations as for AKI from other causes are valid (Kidney Disease: Improving Global Outcomes, KDIGO bundles). Due to the large numbers of patients in the setting of overwhelmed resources, the availability of extracorporeal renal replacement procedures can become critical, especially since hypercoagulation is frequent in COVID­19. In order to avoid triage situations, in some centers acute peritoneal dialysis was used as an alternative to extracorporeal procedures.

10.
Trials ; 21(1): 577, 2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-613556

ABSTRACT

OBJECTIVES: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb". PARTICIPANTS: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 µg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. INTERVENTION AND COMPARATOR: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment. MAIN OUTCOMES: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury. RANDOMIZATION: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. BLINDING (MASKING): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. TRIAL STATUS: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. TRIAL REGISTRATION: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Cytokines/blood , Hemadsorption , Pneumonia, Viral/immunology , Randomized Controlled Trials as Topic , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Critical Illness , Cytokines/isolation & purification , Humans , Middle Aged , Pandemics , Prospective Studies , SARS-CoV-2 , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL