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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335374

ABSTRACT

Background: Since development and approval of the world´s first mRNA vaccines, created under pressure of the global pandemic caused by SARS-CoV-2, potential side effects have naturally been a much-debated topic. Vaccination may be one, if not the only way out of the pandemic claiming more than 4 million deaths worldwide to date. Potential side effects from vaccination have long been controversial, and case reports of fatal side effects have been published. Therefore, data are needed to identify persons being at high risk for potential side effects. Until September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty © in young adults were registered by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty © or mRNA-1237 Moderna, Spikevax © ). Patients and Methods Eight patients between 13-56 years of age, vaccinated with mRNA vaccine either BNT162b2 or mRNA-1273 between January and August 2021 developed cardiac side effects shortly after either their first or second vaccination. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after onset of symptoms and investigated further in severe cases. Symptoms were defined as dyspnea, chest pain, cardiac arrhythmia as determined by electrocardiography. Results: Eight patients (five males and three females) developed cardiac symptoms compatible with myocarditis according to CDC criteria shortly after SARS-CoV-2 mRNA vaccination. Three patients (two males, one female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within seven days after symptom onset Conclusion: Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients.

2.
Rofo ; 2022 Feb 24.
Article in English | MEDLINE | ID: covidwho-1713251

ABSTRACT

PURPOSE: Classifications were created to facilitate radiological evaluation of the novel coronavirus disease 2019 (COVID-19) on computed tomography (CT) images. The categorical CT assessment scheme (CO-RADS) categorizes lung parenchymal changes according to their likelihood of being caused by SARS-CoV-2 infection. This study investigates the diagnostic accuracy of diagnosing COVID-19 with CO-RADS compared to the Thoracic Imaging Section of the German Radiological Society (DRG) classification and Radiological Society of North America (RSNA) classification in an anonymized patient cohort. To mimic advanced disease stages, follow-up examinations were included as well. METHOD: This study includes all patients undergoing chest CT in the case of a suspected SARS-CoV-2 infection or an already confirmed infection between March 13 and November 30, 2020. During the study period, two regional lockdowns occurred due to high incidence values, increasing the pre-test probability of COVID-19. Anonymized CT images were reviewed retrospectively and in consensus by two radiologists applying CO-RADS, DRG, and RSNA classification. Afterwards, CT findings were compared to results of sequential real-time reverse transcriptase polymerase chain reaction (qPCR) test performed during hospitalization to determine statistical analysis for diagnosing COVID-19. RESULTS: 536 CT examinations were included. CO-RADS, DRG and RSNA achieved an NPV of 96 %/94 %/95 % (CO-RADS/DRG/RSNA), PPV of 83 %/80 %/88 %, sensitivity of 86 %/76 %/80 %, and specificity of 96 %/95 %/97 %. The disease prevalence was 20 %. CONCLUSION: All applied classifications can reliably exclude a SARS-CoV-2 infection even in an anonymous setting. Nevertheless, pre-test probability was high in our study setting and has a great influence on the classifications. Therefore, the applicability of the individual classifications will become apparent in the future with lower prevalence and incidence of COVID-19. KEY POINTS: · CO-RADS, DRG, and RSNA classifications help to reliably detect infected patients in an anonymized setting. · Pre-test probability has a great influence on the individual classifications. · Difficulties in an anonymized study setting are severe pulmonary changes and residuals.. CITATION FORMAT: · Valentin B, Steuwe A, Wienemann T et al. Applicability of CO-RADS in an Anonymized Cohort Including Early and Advanced Stages of COVID-19 in Comparison to the Recommendations of the German Radiological Society and Radiological Society of North America. Fortschr Röntgenstr 2022; DOI: 10.1055/a-1740-4310.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-318089

ABSTRACT

The coronavirus disease 2019 (COVID‐19) is associated with a wide clinical spectrum of skin manifestations, including chilblain‐like, urticarial, vesicular and vasculitic lesions. Recently, delayed skin reactions following mRNA vaccination against SARS-CoV-2 have been reported. The exact pathomechanisms underlying these skin lesions remain unknown. Here, we describe eleven cases of delayed skin reactions after SARS-CoV-2 vaccination with the mRNA-1273 vaccine, discuss their transient and benign clinical courses and consider their potential pathomechanisms based on histopathological analyses. We conclude that further investigations to characterize the precise molecular and cellular mechanisms underlying this rare phenomenon are warranted.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310496

ABSTRACT

COVID-19, the pandemic infection caused by SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients’ adaptive immune responses without progression to severe disease with patients’ Human Leukocyte Antigen (HLA) genetics, the presence or absence of near-loss-of-function delta 32 deletion mutant of C-C chemokine receptor type 5 (CCR5) and AB0 blood group antigens. We further analyzed the association of these immunogenetic background characteristics with patients’ humoral antiviral immune response patterns, assessed longitudinally. The study enrolled 157 convalescent adult patients followed up for up to 250 days. Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01) associated with reduced durations of disease and decreased (rather than increased) total anti-S IgG levels providing virus neutralizing capacity comparable to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:2 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A seeming association of a heterozygous CCR5 delta 32 mutation with prolonged disease duration suggested by univariate analyses was not confirmed by hierarchical multivariate testing.In conclusion, the current study shows that the presence of certain "protective" HLA alleles is of even stronger association with reduced duration of mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations assessing the impact of HLA genetics on the capacity of mounting protective vaccination responses may be warranted.

5.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1442406

ABSTRACT

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Base Sequence , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/blood , Pulmonary Fibrosis/pathology , RNA-Seq , Severity of Illness Index , Transcriptome/genetics , United Kingdom , United States
7.
Eur J Med Res ; 26(1): 107, 2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1412355

ABSTRACT

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/etiology , HLA Antigens/genetics , Receptors, CCR5/genetics , Adult , Aged , COVID-19/epidemiology , COVID-19/genetics , Female , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Histocompatibility Antigens Class I/genetics , Humans , Immunoglobulin G/blood , Male , Middle Aged , Morbidity , Mutation , Severity of Illness Index
8.
J Clin Med ; 10(17)2021 Aug 30.
Article in English | MEDLINE | ID: covidwho-1390662

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is the result of a hyper-inflammatory reaction to the severe acute respiratory syndrome coronavirus 2. The biomarkers of inflammation have been used to risk-stratify patients with COVID-19. Osteopontin (OPN) is an integrin-binding glyco-phosphoprotein involved in the modulation of leukocyte activation; its levels are associated with worse outcomes in patients with sepsis. Whether OPN levels predict outcomes in COVID-19 is unknown. METHODS: We measured OPN levels in serum of 341 hospitalized COVID-19 patients collected within 48 h from admission. We characterized the determinants of OPN levels and examined their association with in-hospital outcomes; notably death, need for mechanical ventilation, and need for renal replacement therapy (RRT) and as a composite outcome. The risk discrimination ability of OPN was compared with other inflammatory biomarkers. RESULTS: Patients with COVID-19 (mean age 60, 61.9% male, 27.0% blacks) had significantly higher levels of serum OPN compared to healthy volunteers (96.63 vs. 16.56 ng/mL, p < 0.001). Overall, 104 patients required mechanical ventilation, 35 needed dialysis, and 53 died during their hospitalization. In multivariable analyses, OPN levels ≥140.66 ng/mL (third tertile) were associated with a 3.5 × (95%CI 1.44-8.27) increase in the odds of death, and 4.9 × (95%CI 2.48-9.80) increase in the odds of requiring mechanical ventilation. There was no association between OPN and need for RRT. Finally, OPN levels in the upper tertile turned out as an independent prognostic factor of event-free survival with respect to the composite endpoint. CONCLUSION: Higher OPN levels are associated with increased odds of death and mechanical ventilation in patients with COVID-19, however, their utility in triage is questionable.

9.
Front Immunol ; 12: 645989, 2021.
Article in English | MEDLINE | ID: covidwho-1389177

ABSTRACT

We describe the unique disease course and cure of SARS-CoV-2 infection in a patient with SCID and graft failure. In absence of a humoral immune response, viral clearance was only achieved after transfusion of convalescent plasma. This observation underscores the necessity of the humoral immune response for SARS-CoV-2 clearance.


Subject(s)
COVID-19/therapy , SARS-CoV-2/physiology , Severe Combined Immunodeficiency/complications , Adult , Antibodies, Viral/blood , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Female , Graft Rejection/complications , Graft Rejection/immunology , Graft Rejection/virology , Humans , Immunization, Passive , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/virology , Sustained Virologic Response , Viral Load , Virus Replication
10.
Eur J Med Res ; 26(1): 98, 2021 Aug 25.
Article in English | MEDLINE | ID: covidwho-1371980

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) is associated with a wide clinical spectrum of skin manifestations, including urticarial, vesicular, vasculitic and chilblain-like lesions. Recently, delayed skin reactions have been reported in 1% individuals following mRNA vaccination against SARS-CoV-2. The exact pathophysiology and the risk factors still remain unclear. PATIENTS AND METHODS: 6821 employees and patients were vaccinated at our institutions between February and June 2021. Every patient received two doses of the mRNA-1273 vaccine in our hospitals, and reported back in case of any side effects which were collected in our hospital managed database. RESULTS: Eleven of 6821 vaccinated patients (0.16%) developed delayed skin reactions after either the first or second dose of the mRNA-1273 vaccine against SARS-CoV-2. Eight of 11 patients (73%) developed a rash after the first dose, while in 3/11 (27%), the rash occurred after the second dose. More females (9/11) were affected. Four of 11 patients required antihistamines, with two needing additional topical steroids. All the cutaneous manifestations resolved within 14 days. None of the skin reactions after the first dose of the vaccine prevented the administration of the second dose. There were no long-term cutaneous sequelae in any of the affected individuals. CONCLUSION: Our data suggests that skin reactions after the use of mRNA-1273 vaccine against SARS-CoV-2 are possible, but rare. Further studies need to be done to understand the pathophysiology of these lesions.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Dermatitis/etiology , Erythema/etiology , Adult , Aged , Dermatitis/drug therapy , Dermatitis/epidemiology , Erythema/drug therapy , Erythema/epidemiology , Female , Histamine Antagonists/therapeutic use , Humans , Male , Middle Aged , Steroids/therapeutic use , Vaccination/adverse effects
11.
Eur J Med Res ; 26(1): 87, 2021 Aug 06.
Article in English | MEDLINE | ID: covidwho-1344125

ABSTRACT

BACKGROUND: COVID-19 infection is a major threat to patients and health care providers around the world. One solution is the vaccination against SARS-CoV-2. METHODS: We performed a comprehensive query of the latest publications on the prevention of viral infections including the recent vaccination program and its side effects. RESULTS: The situation is evolving rapidly and there is no reasonable alternative to population-scale vaccination programs as currently enrolled. CONCLUSION: Therefore, regulatory authorities should consider supplementing their conventional mandate of post-approval pharmacovigilance, which is based on the collection, assessment, and regulatory response to emerging safety findings.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Informed Consent/standards , Pharmacovigilance , SARS-CoV-2/immunology , Vaccination/standards , COVID-19/immunology , COVID-19/virology , Disclosure , Humans
12.
Lancet Reg Health Eur ; 8: 100164, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1309324

ABSTRACT

BACKGROUND: Monoclonal antibodies (mAb) have been introduced as a promising new therapeutic approach against SARS-CoV-2. At present, there is little experience regarding their clinical effects in patient populations underrepresented in clinical trials, e.g. immunocompromised patients. Additionally, it is not well known to what extent SARS-CoV-2 treatment with monoclonal antibodies could trigger the selection of immune escape viral variants. METHODS: After identifying immunocompromised patients with viral rebound under treatment with bamlanivimab, we characterized the SARS-CoV-2-isolates by whole genome sequencing. Viral load measurements and sequence analysis were performed consecutively before and after bamlanivimab administration. FINDINGS: After initial decrease of viral load, viral clearance was not achieved in five of six immunocompromised patients treated with bamlanivimab. Instead, viral replication increased again over the course of the following one to two weeks. In these five patients, the E484K substitution - known to confer immune escape - was detected at the time of viral rebound but not before bamlanivimab treatment. INTERPRETATION: Treatment of SARS-CoV-2 with bamlanivimab in immunocompromised patients results in the rapid development of immune escape variants in a significant proportion of cases. Given that the E484K mutation can hamper natural immunity, the effectiveness of vaccination as well as antibody-based therapies, these findings may have important implications not only for individual treatment decisions but may also pose a risk to general prevention and treatment strategies. FUNDING: All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.

13.
Clin Case Rep ; 9(5): e04068, 2021 May.
Article in English | MEDLINE | ID: covidwho-1242709

ABSTRACT

This case of secondary sclerosing cholangitis (SSC-CIP) emphasizes the need to provide follow-up care for patients that have recovered from COVID-19 in order to understand the complexity of SARS-CoV-2 associated sequela.

14.
Trials ; 22(1): 343, 2021 May 17.
Article in English | MEDLINE | ID: covidwho-1232435

ABSTRACT

OBJECTIVES: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression. TRIAL DESIGN: This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested. PARTICIPANTS: The trial is conducted at 10-15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m2 Age > 65 years with at least one other risk factor (BMI > 35 kg/m2, coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m2 with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. Patients with organ or bone marrow transplant in the three months prior to screening visit INTERVENTION AND COMPARATOR: Participants will be randomized to the following 4 groups: 1) Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1-7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety. MAIN OUTCOMES: The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization. RANDOMIZATION: Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center. BLINDING (MASKING): The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate. TRIAL STATUS: The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021. TRIAL REGISTRATION: EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020). FULL PROTOCOL: The full protocol (V05F) 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. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
COVID-19 , Pharmaceutical Preparations , Pregnancy Complications, Infectious , Adolescent , Adult , Aged , Blood Component Transfusion , COVID-19/therapy , Child , Esters , Female , Germany , Guanidines , Humans , Immunization, Passive , Mesylates , Multicenter Studies as Topic , Plasma , Polymerase Chain Reaction , Pregnancy , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
15.
Eur J Clin Microbiol Infect Dis ; 40(5): 1063-1071, 2021 May.
Article in English | MEDLINE | ID: covidwho-1061091

ABSTRACT

Evaluation and power of seroprevalence studies depend on the performed serological assays. The aim of this study was to assess four commercial serological tests from EUROIMMUN, DiaSorin, Abbott, and Roche as well as an in-house immunofluorescence and neutralization test for their capability to identify SARS-CoV-2 seropositive individuals in a high-prevalence setting. Therefore, 42 social and working contacts of a German super-spreader were tested. Consistent with a high-prevalence setting, 26 of 42 were SARS-CoV-2 seropositive by neutralization test (NT), and immunofluorescence test (IFT) confirmed 23 of these 26 positive test results (NT 61.9% and IFT 54.8% seroprevalence). Four commercial assays detected anti-SARS-CoV-2 antibodies in 33.3-40.5% individuals. Besides an overall discrepancy between the NT and the commercial assays regarding their sensitivity, this study revealed that commercial SARS-CoV-2 spike-based assays are better to predict the neutralization titer than nucleoprotein-based assays are.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19/diagnosis , COVID-19/epidemiology , SARS-CoV-2/isolation & purification , Adolescent , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19 Serological Testing/standards , Contact Tracing , Female , Humans , Immunoassay , Male , Middle Aged , Neutralization Tests , Prevalence , SARS-CoV-2/immunology , Sensitivity and Specificity , Young Adult
16.
Genome Med ; 13(1): 7, 2021 01 13.
Article in English | MEDLINE | ID: covidwho-1027902

ABSTRACT

BACKGROUND: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. METHODS: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. RESULTS: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. CONCLUSIONS: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.


Subject(s)
COVID-19/pathology , Neutrophils/metabolism , Transcriptome , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Case-Control Studies , Down-Regulation , Drug Repositioning , Humans , Neutrophils/cytology , Neutrophils/immunology , Phenotype , Principal Component Analysis , RNA/blood , RNA/chemistry , RNA/metabolism , Sequence Analysis, RNA , Severity of Illness Index , Up-Regulation
17.
J Am Soc Nephrol ; 31(11): 2725-2735, 2020 11.
Article in English | MEDLINE | ID: covidwho-789004

ABSTRACT

BACKGROUND: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown. METHODS: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI. RESULTS: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups. CONCLUSIONS: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.


Subject(s)
Acute Kidney Injury/etiology , Betacoronavirus , Coronavirus Infections/complications , Pneumonia, Viral/complications , Receptors, Urokinase Plasminogen Activator/blood , Acute Kidney Injury/blood , Acute Kidney Injury/epidemiology , Adult , Aged , Aged, 80 and over , COVID-19 , Female , Humans , Incidence , Male , Middle Aged , Pandemics , SARS-CoV-2
18.
J Radiol Prot ; 40(3): 877-891, 2020 09.
Article in English | MEDLINE | ID: covidwho-723319

ABSTRACT

OBJECTIVES: The detection of Coronavirus Disease 2019 (COVID-19) by reverse transcription polymerase chain reaction (RT-PCR) has varying sensitivity. Computed tomography (CT) of the chest can verify infection in patients with clinical symptoms and a negative test result, accelerating treatment and actions to prevent further contagion. However, CT employs ionising radiation. The purpose of this study was to evaluate protocol settings, associated radiation exposure, image quality and diagnostic performance of a low-dose CT protocol in a university hospital setting. MATERIALS AND METHODS: Chest CT examinations were performed on a single scanner (Somatom Definition Edge, Siemens Healthineers, Germany) in 105 symptomatic patients (60 male, 45 female). Images were evaluated with regard to protocol parameters, image quality, radiation exposure and diagnostic accuracy. Serial RT-PCR served as the standard of reference. Based on this reference standard sensitivity, specificity, positive and negative predictive values of CT with 95% confidence interval were calculated. RESULTS: The mean effective dose was 1.3 ± 0.4 mSv (0.7-2.9 mSv) for the patient cohort (mean age 66.6 ± 16.7 years (19-94 years), mean body mass index (BMI) 26.6 ± 5.3 kg m-2 (16-46 kg/m2)). A sensitivity of 100 [95% CI: 82-100]%, a specificity of 78 [95% CI: 68-86]%, a positive predictive value of 50 [95% CI: 33-67]% and a negative predictive value of 100 [95% CI: 95-100]% were obtained. No COVID-19 diagnoses were missed by CT. Image noise did not strongly correlate with BMI or patient diameter and was rated as average. CONCLUSIONS: We presented a robust imaging procedure with a chest CT protocol for confident diagnosis of COVID-19. Even for an overweight patient cohort, an associated radiation exposure of only 1.3 ± 0.4 mSv was achieved with sufficient diagnostic quality to exclude COVID-19.


Subject(s)
Coronavirus Infections/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Radiation Dosage , Radiography, Thoracic/standards , Tomography, X-Ray Computed/standards , Adult , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Female , Hospitals, University , Humans , Male , Middle Aged , Pandemics , Predictive Value of Tests , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Sensitivity and Specificity
19.
Euro Surveill ; 25(22)2020 Jun.
Article in English | MEDLINE | ID: covidwho-525969

ABSTRACT

We whole-genome sequenced 55 SARS-CoV-2 isolates from Germany to investigate SARS-CoV-2 outbreaks in 2020 in the Heinsberg district and Düsseldorf. While the genetic structure of the Heinsberg outbreak indicates a clonal origin, reflecting superspreading dynamics from mid-February during the carnival season, distinct viral strains were circulating in Düsseldorf in March, reflecting the city's international links. Limited detection of Heinsberg strains in the Düsseldorf area despite geographical proximity may reflect efficient containment and contact-tracing efforts.


Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Genome, Viral/genetics , Pandemics , Pneumonia, Viral/diagnosis , Whole Genome Sequencing/methods , Betacoronavirus/isolation & purification , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Testing , Coronavirus Infections/epidemiology , Disease Outbreaks , Germany/epidemiology , Humans , Pneumonia, Viral/epidemiology , RNA-Directed DNA Polymerase , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2
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