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1.
Mycoses ; : 1, 2022.
Article in English | Academic Search Complete | ID: covidwho-1807220

ABSTRACT

Background Methods Results Conclusions Candida aurisis a frequently multidrug‐resistant yeast species that poses a global health threat due to its high potential for hospital outbreaks. While C. auris has become endemic in parts of Asia and Africa, transmissions have so far rarely been reported in Western Europe except for Great Britain and Spain. We describe the first documented patient‐to‐patient transmission of C. auris in Germany in a COVID‐19 intensive care unit (ICU) and infection control measures implemented to prevent further spread of the pathogen.Identification of C. auris was performed by MALDI‐TOF and confirmed by internal transcribed spacer (ITS) sequencing. Antifungal susceptibility testing was carried out. We conducted repeated cross‐sectional examinations for the presence of C. auris in the patients of the affected ICU and investigated possible routes of transmission.The index patient had been transferred to Germany from a hospital in Northern Africa and was found to be colonised with C. auris. The contact patient developed C. auris sepsis. Infection prevention and control (IPC) measures included strict isolation of the two C. auris patients and regular screening of non‐affected patients. No further case occurred during the subsequent weeks. Reusable blades used in video laryngoscope‐guided intubation were considered as the most likely vehicle of transmission.In view of its high risk of transmission, vigilance regarding C. auris colonisation in patients referred from endemic countries is crucial. Strict and immediate IPC measures may have the potential to prevent C. auris outbreaks. [ FROM AUTHOR] Copyright of Mycoses is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

2.
Mycoses ; 2022 Apr 14.
Article in English | MEDLINE | ID: covidwho-1788892

ABSTRACT

BACKGROUND: Candida auris is a frequently multi-drug resistant yeast species that poses a global health threat due to its high potential for hospital outbreaks. While C. auris has become endemic in parts of Asia and Africa, transmissions have so far rarely been reported in Western Europe except for Great Britain and Spain. We describe the first documented patient-to-patient transmission of C. auris in Germany in a COVID-19 intensive care unit (ICU) and infection control measures implemented to prevent further spread of the pathogen. METHODS: Identification of C. auris was performed by MALDI-TOF and confirmed by internal transcribed spacer (ITS) sequencing. Antifungal susceptibility testing was carried out. We conducted repeated cross-sectional examinations for the presence of C. auris in the patients of the affected ICU and investigated possible routes of transmission. RESULTS: The index patient had been transferred to Germany from a hospital in Northern Africa and was found to be colonised with C. auris. The contact patient developed C. auris sepsis. Infection prevention and control (IPC) measures included strict isolation of the two C. auris patients and regular screening of non-affected patients. No further case occurred during the subsequent weeks. Reusable blades used in video laryngoscope-guided intubation were considered as the most likely vehicle of transmission. CONCLUSIONS: In view of its high risk of transmission, vigilance regarding C. auris colonisation in patients referred from endemic countries is crucial. Strict and immediate IPC measures may have the potential to prevent C. auris outbreaks.

3.
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.

4.
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.

5.
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).

6.
Mycoses ; 65(1): 103-109, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1470452

ABSTRACT

BACKGROUND: Most COVID-19-associated mucormycosis (CAM) cases are reported from India and neighbouring countries. Anecdotally cases from Europe have been presented. OBJECTIVE: To estimate the disease burden and describe the clinical presentation of CAM in Germany. METHODS: We identified cases through German mycology networks and scientific societies, and collected anonymised clinical information via FungiScope®. RESULTS: We identified 13 CAM cases from six tertiary referral hospitals diagnosed between March 2020 and June 2021. Twelve patients had severe or critical COVID-19, eleven were mechanically ventilated for a median of 8 days (range 1-27 days) before diagnosis of CAM. Eleven patients received systemic corticosteroids. Additional underlying medical conditions were reported for all but one patient, five were immunocompromised because of malignancy or organ transplantation, three were diabetic. Eleven patients developed pneumonia. Mortality was 53.8% with a median time from diagnosis of mucormycosis to death of 9 days (range 0-214 days) despite treatment with liposomal amphotericin B and/or isavuconazole in 10 of 13 cases. CAM prevalence amongst hospitalised COVID-19 patients overall (0.67% and 0.58% in two centres) and those admitted to the intensive care unit (ICU) (1.47%, 1.78% and 0.15% in three centres) was significantly higher compared to non-COVID-19 patients (P < .001 for respective comparisons). CONCLUSION: COVID-19-associated mucormycosis is rare in Germany, mostly reported in patients with comorbidities and impaired immune system and severe COVID-19 treated in the ICU with high mortality compared to mainly rhino-orbito-cerebral CAM in patients with mild COVID-19 in India. Risk for CAM is higher in hospitalised COVID-19 patients than in other patients.


Subject(s)
COVID-19 , Mucormycosis , Antifungal Agents/therapeutic use , COVID-19/complications , Germany/epidemiology , Humans , Mucormycosis/diagnosis , Mucormycosis/drug therapy , Mucormycosis/epidemiology , Tertiary Care Centers
7.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Article in English | MEDLINE | ID: covidwho-1267622

ABSTRACT

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Subject(s)
Biomarkers/analysis , COVID-19/pathology , Disease Progression , Proteome/physiology , Age Factors , Blood Cell Count , Blood Gas Analysis , Enzyme Activation , Humans , Inflammation/pathology , Machine Learning , Prognosis , Proteomics , SARS-CoV-2/immunology
8.
Sci Rep ; 11(1): 10678, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1238016

ABSTRACT

With an urgent need for bedside imaging of coronavirus disease 2019 (COVID-19), this study's main goal was to assess inter- and intraobserver agreement in lung ultrasound (LUS) of COVID-19 patients. In this single-center study we prospectively acquired and evaluated 100 recorded ten-second cine-loops in confirmed COVID-19 intensive care unit (ICU) patients. All loops were rated by ten observers with different subspeciality backgrounds for four times by each observer (400 loops overall) in a random sequence using a web-based rating tool. We analyzed inter- and intraobserver variability for specific pathologies and a semiquantitative LUS score. Interobserver agreement for both, identification of specific pathologies and assignment of LUS scores was fair to moderate (e.g., LUS score 1 Fleiss' κ = 0.27; subpleural consolidations Fleiss' κ = 0.59). Intraobserver agreement was mostly moderate to substantial with generally higher agreement for more distinct findings (e.g., lowest LUS score 0 vs. highest LUS score 3 (median Fleiss' κ = 0.71 vs. 0.79) or air bronchograms (median Fleiss' κ = 0.72)). Intraobserver consistency was relatively low for intermediate LUS scores (e.g. LUS Score 1 median Fleiss' κ = 0.52). We therefore conclude that more distinct LUS findings (e.g., air bronchograms, subpleural consolidations) may be more suitable for disease monitoring, especially with more than one investigator and that training material used for LUS in point-of-care ultrasound (POCUS) should pay refined attention to areas such as B-line quantification and differentiation of intermediate LUS scores.


Subject(s)
COVID-19/diagnostic imaging , Lung/diagnostic imaging , Point-of-Care Systems , SARS-CoV-2 , COVID-19/therapy , Female , Humans , Male , Middle Aged , Monitoring, Physiologic , Observer Variation , Prospective Studies , Ultrasonography
10.
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.

12.
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
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