Prevention of invasive ventilation (PRiVENT)-a prospective, mixed-methods interventional, multicentre study with a parallel comparison group: study protocol.

BACKGROUND: Invasive mechanical ventilation (IMV) is a standard therapy for intensive care patients with respiratory failure. With increasing population age and multimorbidity, the number of patients who cannot be weaned from IMV increases, resulting in impaired quality of life and high costs. In addition, human resources are tied up in the care of these patients. METHODS: The PRiVENT intervention is a prospective, mixed-methods interventional, multicentre study with a parallel comparison group selected from insurance claims data of the health insurer Allgemeine Ortskrankenkasse Baden-Württemberg (AOK-BW) conducted in Baden-Württemberg, Germany, over 24 months. Four weaning centres supervise 40 intensive care units (ICUs), that are responsible for patient recruitment. The primary outcome, successful weaning from IMV, will be evaluated using a mixed logistic regression model. Secondary outcomes will be evaluated using mixed regression models. DISCUSSION: The overall objective of the PRiVENT project is the evaluation of strategies to prevent long-term IMV. Additional objectives aim to improve weaning expertise in and cooperation with the adjacent Intensive Care Units. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT05260853).

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients - indications for their potential involvement in the development of Long COVID?

Background: Recovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms. Objective: The objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVID. Design: A systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE (via Pubmed) and Web of Science. Results: The literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome's etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population. Conclusions: Persistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies.

First responder systems can stay operational under pandemic conditions: results of a European survey during the COVID-19 pandemic.

BACKGROUND: Dispatching first responders (FR) to out-of-hospital cardiac arrest in addition to the emergency medical service has shown to increase survival. The promising development of FR systems over the past years has been challenged by the outbreak of COVID-19. Whilst increased numbers and worse outcomes of cardiac arrests during the pandemic suggest a need for expansion of FR schemes, appropriate risk management is required to protect first responders and patients from contracting COVID-19. This study investigated how European FR schemes were affected by the pandemic and what measures were taken to protect patients and responders from COVID-19. METHODS: To identify FR schemes in Europe we conducted a literature search and a web search. The schemes were contacted and invited to answer an online questionnaire during the second wave of the pandemic (December 2020/ January 2021) in Europe. RESULTS: We have identified 135 FR schemes in 28 countries and included responses from 47 FR schemes in 16 countries. 25 schemes reported deactivation due to COVID-19 at some point, whilst 22 schemes continued to operate throughout the pandemic. 39 schemes communicated a pandemic-specific algorithm to their first responders. Before the COVID-19 outbreak 20 FR systems did not provide any personal protective equipment (PPE). After the outbreak 19 schemes still did not provide any PPE. The majority of schemes experienced falling numbers of accepted call outs and decreasing registrations of new volunteers. Six schemes reported of FR having contracted COVID-19 on a mission. CONCLUSIONS: European FR schemes were considerably affected by the pandemic and exhibited a range of responses to protect patients and responders. Overall, FR schemes saw a decrease in activity, which was in stark contrast to the high demand caused by the increased incidence and mortality of OHCA during the pandemic. Given the important role FR play in the chain of survival, a balanced approach upholding the safety of patients and responders should be sought to keep FR schemes operational.

Severe Dysbiosis and Specific Haemophilus and Neisseria Signatures as Hallmarks of the Oropharyngeal Microbiome in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients.

BACKGROUND: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders. METHODS: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). RESULTS: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. CONCLUSIONS: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.

Observational study on implications of the COVID-19-pandemic for cardiopulmonary resuscitation in out-of-hospital cardiac arrest: qualitative and quantitative insights from a model region in Germany.

BACKGROUND: The city of Freiburg has been among the most affected regions by the COVID-19 pandemic in Germany. In out of hospital cardiac arrest (OHCA) care, all parts of the rescue system were exposed to profound infrastructural changes. We aimed to provide a comprehensive overview of these changes in the resuscitation landscape in the Freiburg region. METHODS: Utstein-style quantitative data on OHCA with CPR initiated, occurring in the first pandemic wave between February 27th, 2020 and April 30th, 2020 were compared to the same time periods between 2016 and 2019. Additionally, qualitative changes in the entire rescue system were analyzed and described. RESULTS: Incidence of OHCA with attempted CPR did not significantly increase during the pandemic period (11.1/100.000 inhabitants/63 days vs 10.4/100.000 inhabitants/63 days, p = 1.000). In witnessed cases, bystander-CPR decreased significantly from 57.7% (30/52) to 25% (4/16) (p = 0.043). A severe pre-existing condition (PEC) was documented more often, 66.7% (16/24) vs 38.2% (39/102) there were longer emergency medical services (EMS) response times, more resuscitation attempts terminated on scene, 62.5% (15/24) vs. 34.3% (35/102) and less patients transported to hospital (p = 0.019). Public basic life support courses, an app-based first-responder alarm system, Kids Save Lives activities and a prehospital extracorporeal CPR (eCPR) service were paused during the peak of the pandemic. CONCLUSION: In our region, bystander CPR in witnessed OHCA cases as well as the number of patients transported to hospital significantly decreased during the first pandemic wave. Several important parts of the resuscitation landscape were paused. The COVID-19 pandemic impedes OHCA care, which leads to additional casualties. Countermeasures should be taken.

Higher SARS-CoV-2 Spike Binding Antibody Levels and Neutralization Capacity 6 Months after Heterologous Vaccination with AZD1222 and BNT162b2.

Within a year after the emergence of SARS-CoV-2, several vaccines had been developed, clinically evaluated, proven to be efficacious in preventing symptomatic disease, and licensed for global use. The remaining questions about the vaccines concern the duration of protection offered by vaccination and its efficacy against variants of concern. Therefore, we set out to analyze the humoral and cellular immune responses 6 months into homologous and heterologous prime-boost vaccinations. We recruited 190 health care workers and measured their anti-spike IgG levels, their neutralizing capacities against the Wuhan-Hu-1 strain and the Delta variant using a surrogate viral neutralization test, and their IFNγ-responses towards SARS-CoV-2-derived spike peptides. We here show that IFNγ secretion in response to peptide stimulation was significantly enhanced in all three vaccination groups and comparable in magnitude. In contrast, the heterologous prime-boost regimen using AZD1222 and BNT162b2 yielded the highest anti-spike IgG levels, which were 3-4.5 times more than the levels resulting from homologous AZD1222 and BNT162b2 vaccination, respectively. Likewise, the neutralizing capacity against both the wild type as well as the Delta receptor binding domains was significantly higher following the heterologous prime-boost regimen. In conclusion, our results suggest that mixing different SARS-CoV-2 vaccines might lead to more efficacious and longer-lasting humoral protection against breakthrough infections.

Distinguishing Incubation and Acute Disease Stages of Mild-to-Moderate COVID-19.

While numerous studies have already compared the immune responses against SARS-CoV-2 in severely and mild-to-moderately ill COVID-19 patients, longitudinal trajectories are still scarce. We therefore set out to analyze serial blood samples from mild-to-moderately ill patients in order to define the immune landscapes for differently progressed disease stages. Twenty-two COVID-19 patients were subjected to consecutive venipuncture within seven days after diagnosis or admittance to hospital. Flow cytometry was performed to analyze peripheral blood immune cell compositions and their activation as were plasma levels of cytokines and SARS-CoV-2 specific immunoglobulins. Healthy donors served as controls. Integrating the kinetics of plasmablasts and SARS-CoV-2 specific antibodies allowed for the definition of three disease stages of early COVID-19. The incubation phase was characterized by a sharp increase in pro-inflammatory monocytes and terminally differentiated cytotoxic T cells. The latter correlated significantly with elevated concentrations of IP-10. Early acute infection featured a peak in PD-1+ cytotoxic T cells, plasmablasts and increasing titers of virus specific antibodies. During late acute infection, immature neutrophils were enriched, whereas all other parameters returned to baseline. Our findings will help to define landmarks that are indispensable for the refinement of new anti-viral and anti-inflammatory therapeutics, and may also inform clinicians to optimize treatment and prevent fatal outcomes.

Single-dose SARS-CoV-2 vaccinations with either BNT162b2 or AZD1222 induce disparate Th1 responses and IgA production.

BACKGROUND: While vaccination programs against the severe acute respiratory syndrome virus 2 (SARS-CoV-2) are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness. METHODS: In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell, and antibody dynamics. RESULTS: AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein-specific effector T cells which were dominated by type 1 helper T cell responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA. CONCLUSIONS: Our results suggest that the strategy for spike protein delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.

Case Series: Convalescent Plasma Therapy for Patients with COVID-19 and Primary Antibody Deficiency.

Patients with primary antibody deficiency are at risk for severe and in many cases for prolonged COVID-19. Convalescent plasma treatment of immunocompromised individuals could be an option especially in countries with limited access to monoclonal antibody therapies. While studies in immunocompetent COVID19 patients have demonstrated only a limited benefit, evidence for the safety, timing, and effectiveness of this treatment in antibody-deficient patients is lacking. Here, we describe 16 cases with primary antibody deficiency treated with convalescent plasma in four medical centers. In our cohort, treatment was associated with a reduction in viral load and improvement of clinical symptoms, even when applied over a week after onset of infection. There were no relevant side effects besides a short-term fever reaction in one patient. Longitudinal full-genome sequencing revealed the emergence of mutations in the viral genome, potentially conferring an antibody escape in one patient with persistent viral RNA shedding upon plasma treatment. However, he resolved the infection after a second course of plasma treatment. Thus, our data suggest a therapeutic benefit of convalescent plasma treatment in patients with primary antibody deficiency even months after infection. While it appears to be safe, PCR follow-up for SARS-CoV-2 is advisable and early re-treatment might be considered in patients with persistent viral shedding.

Comparative sensitivity evaluation for 122 CE-marked rapid diagnostic tests for SARS-CoV-2 antigen, Germany, September 2020 to April 2021.

IntroductionNumerous CE-marked SARS-CoV-2 antigen rapid diagnostic tests (Ag RDT) are offered in Europe, several of them with unconfirmed quality claims.AimWe performed an independent head-to-head evaluation of the sensitivity of SARS-CoV-2 Ag RDT offered in Germany.MethodsWe addressed the sensitivity of 122 Ag RDT in direct comparison using a common evaluation panel comprised of 50 specimens. Minimum sensitivity of 75% for panel specimens with a PCR quantification cycle (Cq) ≤ 25 was used to identify Ag RDT eligible for reimbursement in the German healthcare system.ResultsThe sensitivity of different SARS-CoV-2 Ag RDT varied over a wide range. The sensitivity limit of 75% for panel members with Cq ≤ 25 was met by 96 of the 122 tests evaluated; 26 tests exhibited lower sensitivity, few of which failed completely. Some RDT exhibited high sensitivity, e.g. 97.5 % for Cq < 30.ConclusionsThis comparative evaluation succeeded in distinguishing less sensitive from better performing Ag RDT. Most of the evaluated Ag RDT appeared to be suitable for fast identification of acute infections associated with high viral loads. Market access of SARS-CoV-2 Ag RDT should be based on minimal requirements for sensitivity and specificity.

Establishment of a specimen panel for the decentralised technical evaluation of the sensitivity of 31 rapid diagnostic tests for SARS-CoV-2 antigen, Germany, September 2020 to April 2021.

IntroductionThe detection of SARS-CoV-2 with rapid diagnostic tests (RDT) has become an important tool to identify infected people and break infection chains. These RDT are usually based on antigen detection in a lateral flow approach.AimWe aimed to establish a comprehensive specimen panel for the decentralised technical evaluation of SARS-CoV-2 antigen rapid diagnostic tests.MethodsWhile for PCR diagnostics the validation of a PCR assay is well established, there is no common validation strategy for antigen tests, including RDT. In this proof-of-principle study we present the establishment of a panel of 50 pooled clinical specimens that cover a SARS-CoV-2 concentration range from 1.1 × 109 to 420 genome copies per mL of specimen. The panel was used to evaluate 31 RDT in up to six laboratories.ResultsOur results show that there is considerable variation in the detection limits and the clinical sensitivity of different RDT. We show that the best RDT can be applied to reliably identify infectious individuals who present with SARS-CoV-2 loads down to 106 genome copies per mL of specimen. For the identification of infected individuals with SARS-CoV-2 loads corresponding to less than 106 genome copies per mL, only three RDT showed a clinical sensitivity of more than 60%.ConclusionsSensitive RDT can be applied to identify infectious individuals with high viral loads but not to identify all infected individuals.

[Handling of COVID-19 Outbreak on a Non-invasive Ventilation Ward]. / Umgang mit COVID-19-Ausbruchssituation auf einer nicht invasiven Beatmungsstation.

COPD patients have a higher risk of experiencing severe COVID-19 illness. The outbreak of COVID-19 on an in-patient ward for non-invasive ventilation (NIV) furthermore demonstrated high mortality (32 %) for COPD patients with ongoing NIV and indicated enhanced contagiousness by used equipment.Prophylactic and therapeutic measures taken against COVID-19 are hereby displayed.

[Ophthalmological care of SARS-CoV-2 positive patients in intensive care units]. / Ophthalmologische Betreuung von stationären, intensivpflichtigen SARS-CoV-2-positiven Patienten.

Early ophthalmological care of patients in intensive care with SARS-CoV­2 (Severe-Acute-Respiratory-Syndrom-Corona-Virus-2) infections is very time-consuming; however, this approach might prevent other ophthalmological diseases, such as lagophthalmos. There is no difference in ophthalmological treatment between SARS-CoV­2 positive and other intensive care patients. Due to the small number of cases in our observational study, a specific ophthalmological clinical pattern related to SARS-CoV­2 infections cannot currently be identified; however, the increased occurrence of subconjunctival hemorrhage in intensive care SARS-CoV­2 patients is remarkable. It remains unclear how ocular symptoms in SARS-CoV­2 infections are related or how they occur in different stages of the disease. Therefore, further studies are necessary for representative statements.

[Coronavirus disease 2019-Lessons learned für die Mikrobiologie und Labormedizin]. / "Coronavirus disease 2019" ­ "lessons learned" für die Mikrobiologie und Labormedizin.

Resources for the rapid and comprehensive availability of reliable diagnostic tests were an important prerequisite for the detection and management of the pandemic triggered by the coronavirus disease 2019 (COVID-19). The capacity for the diagnostic tests had to be rapidly planned and established in early 2020 and had to be constantly expanded. The German healthcare system with dedicated and experienced specialists for laboratory medicine, clinical microbiology, virology and infection epidemiology was well prepared to meet these challenges, both professionally and organizationally. The experiences with the challenges in the first year of the pandemic are presented in this article.

Smartphone based alerting of first responders during the corona virus disease-19 pandemic: An observational study.

ABSTRACT: Smartphone alerting systems (SAS) for first responders potentially shorten the resuscitation-free interval of patients with acute cardiac arrest. During the corona virus disease-19 (COVID-19) pandemic, many systems are suspended due to potential risks for the responders.Objective of the study was to establish a concept for SAS during the COVID-19 pandemic and to evaluate whether a SAS can safely be operated in pandemic conditions.A SAS had been implemented in Freiburg (Germany) in 2018 alerting nearby registered first responders in case of emergencies with suspected cardiac arrest. Due to the pandemic, SAS was stopped in March 2020. A concept for a safe restart was elaborated with provision of a set with ventilation bag/mask, airway filter, and personal protective equipment (PPE) for every volunteer. A standard operating procedure was elaborated following the COVID-19 guidelines of the European Resuscitation Council.Willingness of the participants to respond alarms during the pandemic was investigated using an online survey. The response rates of first responders were monitored before and after deactivation, and during the second wave of the pandemic.The system was restarted in May 2020. The willingness to respond to alarms was lower during the pandemic without PPE. It remained lower than before the pandemic when the volunteers had been equipped with PPE, but the alarm response rate remained at approximately 50% during the second wave of the pandemic.When volunteers are equipped with PPE, the operation of a SAS does not need to be paused, and the willingness to respond remains high among first responders.

[Coronavirus disease 2019-Lessons learned für die Mikrobiologie und Labormedizin]. / "Coronavirus disease 2019" ­ "lessons learned" für die Mikrobiologie und Labormedizin.

Resources for the rapid and comprehensive availability of reliable diagnostic tests were an important prerequisite for the detection and management of the pandemic triggered by the coronavirus disease 2019 (COVID-19). The capacity for the diagnostic tests had to be rapidly planned and established in early 2020 and had to be constantly expanded. The German healthcare system with dedicated and experienced specialists for laboratory medicine, clinical microbiology, virology and infection epidemiology was well prepared to meet these challenges, both professionally and organizationally. The experiences with the challenges in the first year of the pandemic are presented in this article.

Impact of the COVID-19 Pandemic on Surgical Oncology in Europe: Results of a European Survey.

BACKGROUND: The first COVID-19 pandemic wave hit most of the health-care systems worldwide. The present survey aimed to provide a European overview on the COVID-19 impact on surgical oncology. METHODS: This anonymous online survey was accessible from April 24 to May 11, 2020, for surgeons (n = 298) who were contacted by the surgical society European Digestive Surgery. The survey was completed by 88 surgeons (29.2%) from 69 different departments. The responses per department were evaluated. RESULTS: Of the departments, 88.4% (n = 61/69) reported a lower volume of patients in the outpatient clinic; 69.1% (n = 47/68) and 75.0% (n = 51/68) reported a reduction in hospital bed and the operating room capacity, respectively. As a result, the participants reported an average reduction of 29.3% for all types of oncological resections surveyed in this questionnaire. The strongest reduction was observed for oncological resections of hepato-pancreatico-biliary (HPB) cancers. Of the interviewed surgeons, 68.7% (n = 46/67) agreed that survival outcomes will be negatively impacted by the pandemic. CONCLUSION: The first COVID-19 pandemic wave had a significant impact on surgical oncology in Europe. The surveyed surgeons expect an increase in the number of unresectable cancers as well as poorer survival outcomes due to cancellations of follow-ups and postponements of surgeries.