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1.
Dtsch Med Wochenschr ; 146(23): 1538-1542, 2021 Nov.
Article in German | MEDLINE | ID: covidwho-1537357

ABSTRACT

The pathophysiological course of COVID-19 can be distinguished in a phase of viral replication and an inflammatory phase. Hyperinflammatory processes promote the development of severe COVID-19. Therefore, immunomodulating agents came into focus. Dexamethasone has already become standard of care for treatment of severe COVID-19. Two large randomized trials and a meta-analysis of collectively nine randomized trials showed a reduced mortality in patients with severe COVID-19 if Tocilizumab - an IL-6-rezeptor antagonist - was added to standard of care. Treatment with Baricitinib - a JAK 1/2 inhibitor - may also be beneficial for patients without or on low oxygen supplementation. National and international guidelines recommend Tocilizumab for treatment of severe COVID-19. Treatment with JAK inhibitors is an option for hospitalized patients with moderate COVID-19. It should be emphasized that comedication of JAK inhibitors and Tocilizumab is not recommended. Further high quality research is required for the widespread use of immunomodulating agents in COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , /therapeutic use , Azetidines/therapeutic use , Humans , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use
2.
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
3.
PLoS One ; 16(5): e0249760, 2021.
Article in English | MEDLINE | ID: covidwho-1223796

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is an independent risk factor for mortality, which affects about 5% of hospitalized coronavirus disease-2019 (COVID-19) patients and up to 25-29% of severely ill COVID-19 patients. Lopinavir/ritonavir and hydroxychloroquine show in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have been used for the treatment of COVID-19. Both, lopinavir and hydroxychloroquine are metabolized by cytochrome P450 (CYP) 3A4. The impact of a triple therapy with lopinavir/ritonavir and hydroxychloroquine (triple therapy) on kidney function in COVID-19 is currently not known. METHODS: We retrospectively analyzed both non-ICU and ICU patients with COVID-19 receiving triple therapy for the incidence of AKI. Patients receiving standard therapy served as a control group. All patients were hospitalized at the University Hospital of Freiburg, Germany, between March and April 2020. A matched-pair analysis for the National Early Warning Score (NEWS) 2 was performed to control for the severity of illness among non-intensive care unit (ICU) patients. RESULTS: In non-ICU patients, the incidence of AKI was markedly increased following triple therapy (78.6% vs. 21.4% in controls, p = 0.002), while a high incidence of AKI was observed in both groups of ICU patients (triple therapy: 80.0%, control group: 90.5%). ICU patients treated with triple therapy showed a trend towards more oliguric or anuric kidney injury. We also observed a linear correlation between the duration of the triple therapy and the maximum serum creatinine level (p = 0.004, R2 = 0.276, R = 0.597). CONCLUSION: Triple therapy is associated with an increase in the incidence of AKI in non-ICU COVID-19 patients. The underlying mechanisms may comprise a CYP3A4 enzyme interaction, and may be relevant for any future therapy combining hydroxychloroquine with antiviral agents.


Subject(s)
Acute Kidney Injury/etiology , Antiviral Agents/adverse effects , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Lopinavir/adverse effects , Acute Kidney Injury/epidemiology , Aged , Antiviral Agents/therapeutic use , COVID-19/virology , Creatinine/blood , Drug Therapy, Combination , Female , Germany/epidemiology , Humans , Hydroxychloroquine/therapeutic use , Incidence , Intensive Care Units , Lopinavir/therapeutic use , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/isolation & purification
4.
Dtsch Med Wochenschr ; 146(3): 162-166, 2021 Feb.
Article in German | MEDLINE | ID: covidwho-1054084

ABSTRACT

Corticosteroids have been found as useful adjunctive therapy in patients with various infections and hyperinflammation-associated disease. They are recommended in practice guidelines for patients with tuberculous and pneumococcal meningitis and patients with immune reconstitution syndrome associated with antiretroviral therapy. A new indication is severe COVID-19. Evidence from clinical trials is insufficient to allow the routine use of steroids among patients with septic shock, community-acquired pneumonia or tuberculous pericarditis.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , HIV Infections/complications , Immune Reconstitution Inflammatory Syndrome/drug therapy , Meningitis, Pneumococcal/drug therapy , Tuberculosis, Meningeal/drug therapy , Brain Abscess/drug therapy , Chemotherapy, Adjuvant , HIV Infections/drug therapy , Humans , Sepsis/drug therapy , Severity of Illness Index , Shock, Septic/drug therapy , Spirochaetales Infections/drug therapy , Tuberculosis/drug therapy
5.
JAMA Pediatr ; 175(6): 586-593, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1044436

ABSTRACT

Importance: School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance. Objective: To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample. Design, Setting, and Participants: This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany. Exposures: Potential exposure to SARS-CoV-2. Main Outcomes and Measures: The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription-polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay. Results: This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2-2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%). Conclusions and Relevance: In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.


Subject(s)
Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/epidemiology , SARS-CoV-2/isolation & purification , Adult , Age Distribution , Age Factors , Aged , COVID-19/blood , COVID-19 Serological Testing , Child , Child, Preschool , Cross-Sectional Studies , Germany/epidemiology , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , Parents , Prevalence , Seroepidemiologic Studies
6.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-5070

ABSTRACT

Background: School and day-care closures were enforced as measures to confine the COVID-19 pandemic based on the assumption that young children may play a key role in SARS-CoV-2 spreading. However, infection prevalence in children under 10 years of age is not very well analysed. Methods: The COVID-19 BaWü study is a large-scale multicentre cross-sectional investigation of children aged 1–10 years and one of their parents, both not diagnosed with COVID-19 before, in southwest Germany. We tested for SARS-CoV-2 RNA from nasopharyngeal swabs by RT-PCR and for SARS-CoV-2 specific IgG antibodies in serum by ELISA and immunofluorescence. Discordant results were clarified by ECLIA, a second ELISA or an in-house Luminex-based assay. We used mixed effects logistic regression to estimate the seroprevalence and to analyse the association between SARS-CoV-2 seropositivity and covariates. Findings: Between April 22nd and May 15th, 2020, we enrolled 4964 subjects, 2482 children and 2482 corresponding parents. 0•04% tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1•8%;95% CI, 1•2–2•4%) and 3-fold lower in children (0•6%;95% CI, 0•3–1•0%). We observed virus-neutralizing activity for 66 of 70 IgG-positive sera (94•3%). Interpretation: The spread of SARS-CoV-2 infection during a period of lock-down in southwest Germany was particularly low in children aged 1–10 years. Accordingly, it is unlikely that children have boosted the pandemic. This largest reported SARS-CoV-2 prevalence study focussing on children is instructive for how ad hoc mass testing provides the basis for rational political decision making in a pandemic setting. Funding: Grant from the Federal State of Baden-Württemberg, Germany Declaration of Interests: All authors state no conflict of interest. Ethics Approval Statement: The study protocol was approved by the independent Ethics committees of each centre. The study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all parents/guardians, with assent from children when appropriate for their age.

7.
PLoS One ; 15(11): e0242127, 2020.
Article in English | MEDLINE | ID: covidwho-922708

ABSTRACT

BACKGROUND: Reported mortality of hospitalised Coronavirus Disease-2019 (COVID-19) patients varies substantially, particularly in critically ill patients. So far COVID-19 in-hospital mortality and modes of death under state of the art care have not been systematically studied. METHODS: This retrospective observational monocenter cohort study was performed after implementation of a non-restricted, dynamic tertiary care model at the University Medical Center Freiburg, an experienced acute respiratory distress syndrome (ARDS) and extracorporeal membrane-oxygenation (ECMO) referral center. All hospitalised patients with PCR-confirmed SARS-CoV-2 infection were included. The primary endpoint was in-hospital mortality, secondary endpoints included major complications and modes of death. A multistate analysis and a Cox regression analysis for competing risk models were performed. Modes of death were determined by two independent reviewers. RESULTS: Between February 25, and May 8, 213 patients were included in the analysis. The median age was 65 years, 129 patients (61%) were male. 70 patients (33%) were admitted to the intensive care unit (ICU), of which 57 patients (81%) received mechanical ventilation and 23 patients (33%) ECMO support. Using multistate methodology, the estimated probability to die within 90 days after COVID-19 onset was 24% in the whole cohort. If the levels of care at time of study entry were accounted for, the probabilities to die were 16% if the patient was initially on a regular ward, 47% if in the intensive care unit (ICU) and 57% if mechanical ventilation was required at study entry. Age ≥65 years and male sex were predictors for in-hospital death. Predominant complications-as judged by two independent reviewers-determining modes of death were multi-organ failure, septic shock and thromboembolic and hemorrhagic complications. CONCLUSION: In a dynamic care model COVID-19-related in-hospital mortality remained very high. In the absence of potent antiviral agents, strategies to alleviate or prevent the identified complications should be investigated. In this context, multistate analyses enable comparison of models-of-care and treatment strategies and allow estimation and allocation of health care resources.


Subject(s)
Coronavirus Infections/mortality , Hospital Mortality , Pneumonia, Viral/mortality , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Extracorporeal Membrane Oxygenation , Female , Germany/epidemiology , Humans , Intensive Care Units , Male , Middle Aged , Models, Statistical , Pandemics , Respiration, Artificial , Retrospective Studies , SARS-CoV-2 , Tertiary Healthcare
8.
Front Immunol ; 11: 2086, 2020.
Article in English | MEDLINE | ID: covidwho-771524

ABSTRACT

Immunosuppressive therapies increase the susceptibility of patients to infections. The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA).


Subject(s)
Betacoronavirus/genetics , Churg-Strauss Syndrome/complications , Churg-Strauss Syndrome/drug therapy , Coronavirus Infections/complications , Cyclophosphamide/therapeutic use , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/drug therapy , Immunosuppressive Agents/therapeutic use , Pneumonia, Viral/complications , Adult , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Therapy, Combination , Glucocorticoids/therapeutic use , Humans , Immunocompromised Host , Male , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Prednisolone/therapeutic use , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Rituximab/therapeutic use , SARS-CoV-2 , Treatment Outcome
9.
Infect Control Hosp Epidemiol ; 42(6): 653-658, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-765932

ABSTRACT

BACKGROUND: The pressures exerted by the coronavirus disease 2019 (COVID-19) pandemic pose an unprecedented demand on healthcare services. Hospitals become rapidly overwhelmed when patients requiring life-saving support outpace available capacities. OBJECTIVE: We describe methods used by a university hospital to forecast case loads and time to peak incidence. METHODS: We developed a set of models to forecast incidence among the hospital catchment population and to describe the COVID-19 patient hospital-care pathway. The first forecast utilized data from antecedent allopatric epidemics and parameterized the care-pathway model according to expert opinion (ie, the static model). Once sufficient local data were available, trends for the time-dependent effective reproduction number were fitted, and the care pathway was reparameterized using hazards for real patient admission, referrals, and discharge (ie, the dynamic model). RESULTS: The static model, deployed before the epidemic, exaggerated the bed occupancy for general wards (116 forecasted vs 66 observed), ICUs (47 forecasted vs 34 observed), and predicted the peak too late: general ward forecast April 9 and observed April 8 and ICU forecast April 19 and observed April 8. After April 5, the dynamic model could be run daily, and its precision improved with increasing availability of empirical local data. CONCLUSIONS: The models provided data-based guidance for the preparation and allocation of critical resources of a university hospital well in advance of the epidemic surge, despite overestimating the service demand. Overestimates should resolve when the population contact pattern before and during restrictions can be taken into account, but for now they may provide an acceptable safety margin for preparing during times of uncertainty.


Subject(s)
COVID-19/epidemiology , Hospital Bed Capacity , Hospitals, University/organization & administration , COVID-19/prevention & control , Cross Infection/prevention & control , Forecasting , Germany/epidemiology , Hospitals, University/statistics & numerical data , Humans , Incidence , Models, Statistical , Patient Safety
10.
Cancer Med ; 9(22): 8412-8422, 2020 11.
Article in English | MEDLINE | ID: covidwho-757780

ABSTRACT

BACKGROUND: Patients with cancer are considered a high-risk group for viral pneumonia, with an increased probability of fatal outcome. Here, we investigated the clinical characteristics and outcome of patients with solid and hematological cancers and concomitant Covid-19 at a Comprehensive Cancer Center in a Covid-19 hotspot area in Germany. METHODS: We performed a retrospective single center cohort study of 39 patients with hematological and solid cancers who were hospitalized at the University Hospital Freiburg for Covid-19. Using univariate and multivariate Cox regression models we compared time to severe events and overall survival to an age-matched control cohort of 39 patients with confirmed Covid-19 without a cancer diagnosis. RESULTS: In the cancer cohort 29 patients had a diagnosis of a solid tumor, and 10 had a hematological malignancy. In total, eight patients (21%) in the cancer and 14 patients (36%) from the noncancer cohort died during the observation period. Presence of a malignancy was not significantly associated with survival or time to occurrence of severe events. Major influences on mortality were high IL-6 levels at Covid-19 diagnosis (HR = 6.95, P = .0121) and age ≥ 65 years (HR = 6.22, P = .0156). CONCLUSIONS: Compared to an age-matched noncancer cohort, we did not observe an association between a cancer diagnosis and a more severe disease course or higher fatality rate in patients with Covid-19. Patients with a hematological malignancy showed a trend towards a longer duration until clinical improvement and longer hospitalization time compared to patients with a solid cancer. Cancer per se does not seem to be a confounder for dismal outcome in Covid-19.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/complications , Hematologic Neoplasms/epidemiology , Hospitalization/statistics & numerical data , Neoplasms/epidemiology , Oncology Service, Hospital/trends , Pneumonia, Viral/complications , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/transmission , Coronavirus Infections/virology , Female , Germany/epidemiology , Hematologic Neoplasms/virology , Humans , Male , Middle Aged , Neoplasms/virology , Pandemics , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Prognosis , Retrospective Studies , Risk Factors , SARS-CoV-2 , Survival Rate
11.
Dtsch Med Wochenschr ; 145(11): 740-746, 2020 Jun.
Article in German | MEDLINE | ID: covidwho-535976

ABSTRACT

- Case numbers in China are clearly declining, case numbers in many European regions are no longer increasing exponentially.- Data on mortality from SARS-CoV-2 infection are contradictory; mortality is certainly lower than for SARS and MERS, but probably higher than for most seasonal flu outbreaks in recent years- The main complication of SARS-CoV-2 infection is pneumonia with development of acute respiratory distress syndrome (ARDS)- Asymptomatic and oligosymptomatic courses with virus shedding are not uncommon; they may be more frequent in children than in adults. Virus excretion in asymptomatic people and in the pre-symptomatic phase of an infection is relevant for transmission- An effective antiviral therapy has not yet been established. Steroids for anti-inflammatory therapy are not recommended- It is very important to prepare all actors in the health care system for a longer-term burden of inpatients and complications and to create the necessary capacities. Low-threshold diagnostic testing and rapid detection of infection chains remain essential for better control of the pandemic. An effective vaccine is urgent.


Subject(s)
Coronavirus Infections/epidemiology , Pandemics/classification , Pneumonia, Viral/classification , COVID-19 , Coronavirus Infections/classification , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Coronavirus Infections/virology , Global Health/statistics & numerical data , Humans
12.
Trials ; 21(1): 470, 2020 Jun 03.
Article in English | MEDLINE | ID: covidwho-505925

ABSTRACT

OBJECTIVES: SARS-CoV2 infection leads to a concomitant pulmonary inflammation. This inflammation is supposed to be the main driver in the pathogenesis of lung failure (Acute Respiratory Distress Syndrome) in COVID-19. Objective of this study is to evaluate the efficacy and safety of a single dose treatment with Tocilizumab in patients with severe COVID-19. We hypothesize that Tocilizumab slows down the progression of SARS-CoV-2 induced pneumonia and inflammation. We expect an improvement in pulmonary function compared to placebo-treated patients. Desirable outcomes would be that tocilizumab reduces the number of days that patients are dependent on mechanical ventilation and reduces the invasiveness of breathing assistance. Furthermore, this treatment might result in fewer admissions to intensive care units. Next to these efficacy parameters, safety of a therapy with Tocilizumab in COVID-19 patients has to be monitored closely, since immunosuppression could lead to an increased rate of bacterial infections, which could negatively influence the patient's outcome. TRIAL DESIGN: Multicentre, prospective, 2-arm randomised (ratio 1:1), double blind, placebo-controlled trial with parallel group design. PARTICIPANTS: Inclusion criteria 1.Proof of SARS-CoV2 (Symptoms and positive polymerase chain reaction (PCR))2.Severe respiratory failure: a.Ambient air SpO2 ≤ 92% orb.Need of ≥ 6l O2/min orc.NIV (non-invasive ventilation) ord.IMV (invasive mechanical ventilation)3.Age ≥ 18 years Exclusion criteria 1.Non-invasive or invasive mechanical ventilation ≥ 48 hours2.Pregnancy or breast feeding3.Liver injury or failure (AST/ALT ≥ 5x ULN)4.Leukocytes < 2 × 103/µl5.Thrombocytes < 50 × 103/µl6.Severe bacterial infection (PCT > 3ng/ml)7.Acute or chronic diverticulitis8.Immunosuppressive therapy (e.g. mycophenolate, azathioprine, methotrexate, biologicals, prednisolone >10mg/d; exceptions are: prednisolone ≤ 10mg/d, sulfasalazine or hydroxychloroquine)9.Known active or chronic tuberculosis10.Known active or chronic viral hepatitis11.Known allergic reactions to tocilizumab or its ingredients12.Life expectation of less than 1 year (independent of COVID-19)13.Participation in any other interventional clinical trial within the last 30 days before the start of this trial14.Simultaneous participation in other interventional trials (except for participation in COVID-19 trials) which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed15.Failure to use one of the following safe methods of contraception: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception. The data collection of the primary follow up (28 days after randomisation) takes place during the hospital stay. Subsequently, a telephone interview on the quality of life is conducted after 6 and 12 months. Participants will be recruited from inpatients at ten medical centres in Germany. INTERVENTION AND COMPARATOR: Intervention arm: Application of 8mg/kg body weight (BW) Tocilizumab i.v. once immediately after randomisation (12 mg/kg for patients with <30kg BW; total dose should not exceed 800 mg) AND conventional treatment. Control arm: Placebo (NaCl) i.v. once immediately after randomisation AND conventional treatment. MAIN OUTCOMES: Primary endpoint is the number of ventilator free days (d) (VFD) in the first 28 days after randomisation. Non-invasive ventilation (NIV), Invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) are defined as ventilator days. VFD's are counted as zero if the patient dies within the first 28 days. RANDOMISATION: The randomisation code will be generated by the CTU (Clinical Trials Unit, ZKS Freiburg) using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. Randomisation will be stratified by centre and will be performed in blocks of variable length in a ratio of 1:1 within each centre. The block lengths will be documented separately and will not be disclosed to the investigators. The randomisation code will be produced by validated programs based on the Statistical Analysis System (SAS). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 100 participants will be randomised to each group (thus 200 participants in total). TRIAL STATUS: Protocol Version: V 1.2, 16.04.2020. Recruitment began 27th April 2020 and is anticipated to be completed by December 2020. TRIAL REGISTRATION: The trial was registered before trial start in trial registries (EudraCT: No. 2020-001408-41, registered 21st April 2020, and DRKS: No. DRKS00021238, registered 22nd April 2020). 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)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Lung/drug effects , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Double-Blind Method , Germany , Host-Pathogen Interactions , Humans , Lung/physiopathology , Lung/virology , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Prospective Studies , Randomized Controlled Trials as Topic , Recovery of Function , Respiration, Artificial , Risk Assessment , SARS-CoV-2 , Severity of Illness Index , Time Factors , Treatment Outcome
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