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Background/Introduction: Thromboinflammation in severe COVID-19 is associated with disease severity and outcome. The kallikrein pathway is suggested to mediate thromboinflammation in COVID-19 by activating inflammatory pathways and contactmediated coagulation. Purpose(s): The DAWn-antico study investigates if a multitarget modulation of the thromboinflammatory response improves outcomes in hospitalized patients with severe COVID-19. Method(s): In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID- 19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low-molecular-weight heparin (LMWH;SC 50 IU/kg twice daily at the ward, 75 IU/kg twice daily at intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1- receptor antagonist anakinra (100mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point WHO ordinal scale for clinical status, or discharge. The trial was funded by Life Sciences Research Partners, Research Foundation Flanders (G0G4720N), and KU Leuven COVID-19 fund. Result(s): Between 24 June 2020 and 01 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N=67 vs. SOC N=35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50;1.19], p=0.24) or mortality (intervention n=3 (4.6%) vs. SOC n=2 (5.7%), HR 0.82, [CI 0.14;4.94], p=0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleedings. Conclusion(s): In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19. (Disclosure: this RCT was presented at ISTH 2022 in London and will be published in Research and Practise in Thrombosis and Haemostasis).
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Background: Thromboinflammation in severe COVID-19 is associated with disease severity and inferior outcome. Evidence suggests that the kallikrein pathway potentially plays a vital role in COVID-19 associated thromboinflammation as it both activates downstream inflammatory pathways and contact-mediated coagulation. Aim(s): To investigate whether modulation of this pronounced thromboinflammatory response can improve outcomes in hospitalized patients with severe COVID-19. Method(s): This multicenter randomized clinical trial was approved by the ethics committee and supported by the KU Leuven COVID-19 fund and Research Foundation Flanders (FWO). After informed consent, eligible patients were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention (figure 1). The intervention consisted of off-label -kallikrein-inhibiting -aprotinin combined with low molecular weight heparin (LMWH). Additionally, patients with predefined hyperinflammation were treated with the interleukin-1 receptor antagonist anakinra. The primary endpoint was time to sustain a 2-point improvement in the WHO ordinal scale for clinical status. Result(s): Three hospitals in Belgium included 102 patients (35 SOC vs. 67 intervention). Twenty-five patients from the intervention group (37%) were treated with anakinra. Patients had elevated D-dimers (mean 1012.4 mug/L;SD 991.9 mug/L) and C-reactive protein (mean 81.4 mg/L;SD 59.6 mg/L) at admission confirming baseline activation of coagulation and inflammatory pathways. During hospitalization, 37% of patients were admitted to the ICU (29% SOC vs. 42% intervention), and 20% needed invasive ventilation (12% SOC vs. 25% intervention). The intervention did not affect the time to sustained clinical improvement or hospital discharge (figure 2), nor secondary clinical endpoints. Except for D-dimers at day 3, there was no significant C-reactive protein or D-dimer reductions. There were no differences in treatment-related adverse events. Conclusion(s): In hospitalized COVID-19 patients, additional modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra was feasible and safe but did not improve clinical nor biochemical outcomes.
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Background: A major concern across rheumatology in recent years is how contracting COVID-19 may impact the control of rheumatic diseases. Objectives: To quantify any difference in rheumatic disease control between those who did and did not contract COVID-19 between March and December 2020 and whether rheumatic disease control changed after COVID-19 was contracted. Methods: Adults with rheumatic diseases recruited to the COVID-19 European Patient Registry, a patient-led, online, self-referred prospective cohort recruiting participants from around the globe, were included if enrolled between March and December 2020. Rheumatic disease control was self-reported weekly on a scale of 0 (very poor) to 10 (very well). Dates of contracting COVID-19 were self-reported. Differences in rheumatic disease control trends between those who did and did not contract COVID-19 over the study period were tested via multilevel linear regression. Within those who contracted COVID-19, differences in rheumatic disease control trends were tested via segmented multilevel, multivariable linear regression, adjusting for month of COVID-19 contraction and with the interruption point set at the point of COVID-19 contraction. Results: Of 3646 adults with rheumatic diseases, the majority were female (89%), most commonly from the UK (82%) and the most common rheumatic disease diagnosis was RA (63%). Between March and December 2020, 3% of the cohort contracted COVID-19 (n=103). Over the study period, rheumatic disease control for adults who did not contract COVID-19 decreased weekly by 0.01 points (95% CI 0.01, 0.02, p<0.001). In those who contracted COVID-19, rheumatic disease control decreased weekly by 0.03 points (95% CI 0.2, 0.05, p<0.001), with a significant weekly difference of 0.86 points between groups (95% CI 0.28, 1.44, p=0.004) (Figure 1a). Within those that contracted COVID-19, there were signifcant differences in rheumatic disease control trends before and after contracting COVID-19 (p=0.001). In the run up to contracting COVID-19, rheumatic disease control signifcantly decreased weekly by 0.03 points (95% CI 0.02, 0.04, p<0.001), dropped signifcantly by 0.53 points (95% CI 0.23, 0.83, p=0.001) at the point of COVID contraction and then stabilised with no further reductions or improvement in rheumatic disease control for the remainder of follow-up (p=0.831) (Figure 1b). Conclusion: People who contracted COVID-19 had initial decreases in rheumatic disease control before contracting the virus, after which their disease control stabilised at a lower level. Those with disease flares should consider increased screening for COVID-19 and COVID-19 mitigation measures. The stabilising lower disease control post-COVID is concerning and should prompt further work into restoring disease control pre-COVID-19 levels.
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Introduction: By now, most of the children with COVID-19 infection have only mild symptoms. However, in the past year a small number of children have developed a serious inflammatory condition in temporal association with COVID-19 pandemic. This condition, named Multisystem Inflammatory Syndrome in Children (MIS-C), is characterized by a systemic inflammation with multiorgan failure;the clinical and laboratory features are similar to those usually observed in Kawasaki disease, cytokine storm syndrome and macrophage activation syndrome. While the SARS-CoV-2 PCR on nasal swab is positive only in a minority of patients, the serology is positive in most of them. Objectives: to create an International multicenter collection of patients with MIS-C involving the main pediatric networks committed in the care of patients with hyperinflammatory conditions. Primary endpoint of the project is to collect information on clinical presentation, laboratory parameters, clinical outcome and response to treatment of patients with MIS-C. Secondary endpoints of the project are: 1) to analyse different clusters in clinical phenotype in relation to age and geographical location, 2) to identify clinical and laboratory predictors of disease severity and outcome, 3) to evaluate the availability of samples of patients in the repositories linked to the different centers. Methods: a steering committee constituted by representatives of ERN-RITA, PRES, ESID and ISSAID and with the coordination of PRINTO developed a shared form to collect clinical manifestations, laboratory features, response to treatment and outcome of patients with MIS-C. The registry is available online on PRINTO website (www.printo.it). Results: a first survey between centers members of PRINTO network identified 365 patients from 51 centers (43 countries). Currently, 180 patients have been enrolled in the registry from 25 centers worldwide. Moreover, 11 additional centers have been activated and are ready to start enrollement. Ethical committee submission or activation procedures are ongoing in 36 more centers. 31 European countries and 12 extra-European countries are actively involved. Conclusion: After some interesting national initiatives, the HyperPEDCOVID registry will give the chance to analyze the impact of Multisystem Inflammatory Syndrome Children at the European and extra- European level, giving the possibility to analyze the distribution, clinical presentation and long-term outcome of this condition in different countries. The registry can also represent the basis for further biological and genetic studies in these patients.
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Background: People with rheumatic diseases may be at increased risk of contracting COVID-19 due to their rheumatic disease or immunosuppressive treatments. It is currently unclear what the COVID-19 disease burden is for these people and whether any of their personal or disease characteristics are associated with contracting COVID-19. Objectives: To explore the proportion of, and characteristics associated with, contracting COVID-19 in children and young people (CYP) with rheumatic diseases and adults with rheumatic diseases from March 2020 to December 2020 during the COVID-19 pandemic. Methods: CYP and adults recruited to the international COVID-19 European Patient Registry, a parent-led, online, self-referred prospective cohort recruiting participants from around the globe, were included in current study if enrolled between 20th March 2020 and 30th December 2020. Demographic information was collected at enrolment and rheumatic disease, diagnoses of COVID-19 and lifestyle factors were collected at weekly intervals. The proportion of CYP and adults diagnosed with COVID-19 were assessed separately. Associations between contraction of COVID-19 at any point over follow-up and participant demographics, rheumatic disease and lifestyle factors at enrolment were assessed descriptively and via Mann-Whitney U-tests, Chisquared tests and Fisher's exact tests. Results: Within 642 CYP and 3646 adults, the majority were female (67%, 89%) and most commonly from the UK (43%, 82%), respectively. The most frequent diagnoses were polyarticular JIA (37%) in the CYP cohort and RA in the adults (63%). Comorbidities were common (45%, 61%) and the majority were taking one or more immunosuppressive therapies (88%, 92%), respectively. At the time of enrolment, 51% and 54% were practising social distancing, respectively. In both cohorts ∼3% contracted COVID-19 at some point during follow-up (n=18 (2.8%) in CYP and n=103 (2.8%) in the adult cohort). In CYP, those who contracted COVID-19 were older (no COVID, median: 10, IQR: 7, 13, vs COVID, median: 14, IQR: 12, 16, p<0.001) and less often had oligoarticular JIA (no COVID: 31%, COVID: 22%) or polyarticular JIA (No COVID: 38%, COVID: 11%). Systemic JIA (no COVID: 7%, COVID: 11%) and enthesitis-related JIA (no COVID: 5%, COVID: 22%) were more common in those who contracted COVID. No other differences between those with and without COVID-19 were observed with respect to country of residence (p=0.335), gender (p=0.624), control of rheumatic disease (p=0.459), comorbidities (p=0.752), immunosuppressive medication (p=0.713) or social distancing (p=0.729). In the adult cohort, those contracting COVID-19 were more commonly from Russia (no COVID: 2%, COVID: 14%) and less commonly from the UK (no COVID: 82%, COVID: 71%, p<0.001). There was greater female representation in those that contracted COVID-19 (no COVID: 88%, COVID: 93%, p=0.022). Although there were no differences in overall presence of comorbidity (p=0.923), kidney disease was overrepresented in those that had contracted COVID-19 (no COVID: 2%, COVID: 8%, p<0.001). Finally, there were lower levels of social distancing in those who contracted COVID (no COVID: 54%, COVID: 44%, p=0.047). There were no significant differences in age (p=0.203), BMI (p=0.617), smoking status (p=0.120), rheumatic disease (p=0.181) and its control (p=0.218) or immunosuppressive use (p=0.208) between those who did and did not contract COVID-19 in the adult cohort. Conclusion: A low proportion of CYP and adults with rheumatic diseases contracted COVID-19 in the 9 months since March 2020. However, given the self-reported nature of the survey and limited testing available across many countries, this study may underestimate the true burden of COVID-19 in the rheumatic disease community. Factors associated with COVID-19 differ between CYP and adults, with age and type of rheumatic disease associated in CYP and gender, kidney comorbidity and social distancing associated in adults.
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Background/AimsIn March 2020, the WHO characterised COVID-19 as a pandemic.Whilst many people with COVID-19 infection appeared to have mild orno symptoms, a significant proportion became seriously ill. At the time, little was known about how patients with rheumatic or autoimmuneconditions, many of whom use immunosuppressive medications, areaffected by the virus. The aim of the patient-led longitudinal survey (theCOVID-19 European Patient Registry, EPR) is to better understand theimpact of COVID-19 on these patients. This specific analysis aims tounderstand how the number of confirmed COVID-19 cases affects theself-reported level of worry experienced by participants.MethodsThe EPR comprises an online health questionnaire. Each weekparticipants are sent a short follow-up survey concerning exposureto COVID-19, symptoms, diagnosis, how worried they feel (scale, 0-10), and a range of behaviours. The weekly mean worry score fromparticipants was calculated by country, and compared to the weeklytotal number of cases of COVID-19 reported within each country. Theassociation between worry score and a range of behaviours was alsocalculated.ResultsTo 27 September 2020, a total of 3, 619 adults and 639 children wereincluded in the EPR. There is a correlation between the total number ofweekly cases and the mean worry score amongst UK-based adultparticipants in the EPR (linear regression, R2=0.779, P<0.001).Interestingly, there is no such correlation in any other country withparticipants in the EPR, nor amongst parents of children withrheumatic conditions. Additionally, the level of worry is associatedwith specific behaviours that affect exposure to the coronavirus for alladult participants. ConclusionThe number of confirmed cases of COVID-19 is associated with thelevel of worry, and consequent behaviour change, amongst UK adultswith rheumatic conditions. This suggests that the number of cases, government response, and media portrayal affect how worriedparticipants feel. This in turn drives behavioural change towardsCOVID-avoiding behaviours. This phenomenon appears exclusive toUK-based adults, suggesting differences in the perception of thethreat posed by COVID varies between countries.
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Background/AimsYounger and older people with rheumatic diseases may experienceincreased anxiety during the COVID-19 pandemic, due to theuncertainty regarding their likelihood of contracting the virus, itscomplications alongside their existing condition and whether theirimmunosuppressive treatments pose additional risks. This studyexplored trajectories of anxiety in parents of children and youngpeople (CYP) with rheumatic diseases and adults with rheumaticdiseases in the six months following March 2020 during the COVID-19pandemic.MethodsCYP and adults recruited to the international COVID-19 EuropeanPatient Registry, a parent-led, online, self-referred prospective cohortrecruiting participants globally, were selected if enrolled within 20thMarch to 17th April 2020. Anxiety scores (0-10, 10=Highest anxiety)were collected weekly for up to 28 weeks and denoted parent anxietyin the CYP cohort and self-reported anxiety in the adult cohort.Group-based trajectory models explored anxiety clusters usingcensored-normal models in the CYP and adult populations, separately.Linear, quadratic and cubic polynomials were tested within 1 to 10clusters and optimal models selected based on a combination ofmodel fit (BIC), parsimony and clinical plausibility. Demographic(country, age, gender) and clinical (diagnosis, disease control, respiratory comorbidity, immunosuppressive therapy) informationand COVID-19 mitigation behaviours (isolation, distancing, none)were collected at initial enrolment and compared between clustersusing Chi-squared, Fisher's exact and Kruskal-Wallis tests.ResultsAmong 498 CYP and 2640 adults, most were female (65%, 89%) andfrom the UK (50%, 84%), respectively. The most common diagnoseswere polyarticular JIA (37%) and oligoarticular JIA (29%) among CYPand RA among the adults (63%). Respiratory comorbidities wereuncommon in the CYP (10%) and adult (17%) cohorts, and most weretaking any immunosuppressive therapies (85%, 87%), respectively. Asof March 2020, 88% and 79% were self-isolating, respectively. In boththe parents of CYP and adult cohorts, four trajectory clusters wereidentified with similar patterns: Persistent extremely high anxiety (32%, 17%), persistent high anxiety (43%, 41%), high anxiety that marginallyimproved (25%, 32%) and moderate anxiety that improved (11%, 10%). Among CYP, few characteristics distinguished the clusters.However, in the adult cohort, clusters with greater and more persistentanxiety were associated with higher levels of respiratory comorbidities, higher use of immunosuppressive therapies, higher initial levels of selfisolation and slightly older age than those with lower or improvinganxiety over time.ConclusionThis study reports four trajectories of anxiety during the COVID-19pandemic that are consistent across parents of CYP with rheumaticdiseases and among adults with these conditions. Despite relativelylower risks for CYP, parental anxiety regarding COVID-19 was highand not associated with characteristics of their child or of their child'sdisease. Among adults with rheumatic diseases, greater anxiety wasassociated with risk factors potentially associated with COVID-19morbidity and mortality.
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BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.