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BackgroundEarly 2020, short supply of hydroxychloroquine sulfate (HCQ) – then claimed as effective for treatment of COVID-19 in several countries - raised significant concerns for those who use HCQ for chronic diseases including SLE. In April 2020, Lupus Europe launched a survey to quantify the access gap, as well as the anxiety expressed by patients confronted with this outage. 2422 patients responded with an average level of anxiety about access to HcQ of 6.45 on a maximum of 10. After supply issues were resolved, a follow up survey (Aug-Sept 2020 – 1854 answers) showed a significantly reduced anxiety of 4.15. A second follow up survey (Nov 2021 -Feb 2022 - 2255 answers) showed a further reduction to 3.54. Importantly, a core group of 6.2-13.7% of patients remains extremely anxious (scoring 9 or 10) about supply of their medication, substantially more than in Portugal (3.5%) and Finland (0%), where supply remained fair at the heat of the crisis.ObjectivesTo provide consensus on how communication should be conducted to minimize the impact of medicine shortages on patient anxiety.MethodsThe Patient Advisory Network (PAN) of Lupus Europe established an extensive list of potential elements of a more effective communication on shortages, that could help reduce patient anxiety. 20 statements were derived from those elements and proposed to PAN members and Lupus Europe member organisations. 101 answers were collected from 17 countries. For each country, the individual ratings of all participants were averaged to assign an individual vote for each country on each statement. Consensus amongst the 17 countries was then considered as obtained if 14 or more of the 17 countries agreed or strongly agreed with statements.Results9 out of the 20 statements reached consensus:1. Lupus specialists should (a) clarify alternative medication existing and its difference versus current treatments, (b) clarify appropriate emergency procedures and (c) clarify to the patients how to handle a short supply.2. Specialists and Hospitals should establish alternative supply mechanisms to guarantee minimum availability.3. pharmaceutical industry should (a) provide all information to all stakeholders and (b) help create emergency supply routes to ensure that no patient is left without his/her medication for a sustained period of time.4. National authorities should help patients with demonstrated need have priority access to limited supply quantities through a simple process.5. Hospitals should communicate (by email or postal mail) information on the shortage, how to handle it and how to access emergency supply routes. The same number agreed with Health authorities performing that same communication.6. pharmaceutical industry should avoid diverting products from one country to another if that would reduce supply below normal consumption level.7. Patient organisations should stop the rumors that can quickly spread though social media.8. pharmacists should be better equipped in terms of data (on the reasons and clear timelines for resolution as well as alternatives or recommendations for patients facing shortages)9. GP's should clarify alternative medication and appropriate emergency procedures.ConclusionShortages of medicine create an anxiety that can be long lasting. Even when supply is re-established, the fear remains. For this reason, establishing an effective communication system is necessary to reassure patients when short term shortages are taking place, and is key to avoid fast spreading anxiety relating to this concern. In this process, patient associations, physicians, industries and all the stakeholders should be involved.Reference[1]Cornet A, Andersen J, Tani C, Mosca M. Hydroxychloroquine availability during COVID-19 crisis and its effect on patient anxiety. Lupus Sci Med. 2021 Apr;doi: 10.1136/lupus-2021-000496Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background: Blocking the C5a-C5aR axis in COVID-19 patients could improve outcomes by limiting myeloid cell infiltration in damaged organs and preventing excessive lung inflammation and endothelialitis. Aims and Objectives: Vilobelimab (VILO), an anti-C5a mAb that preserves the membrane attack complex (MAC), was tested in a Phase III adaptively designed multicenter, double-blind placebo (P)-controlled study for survival in critically ill COVID-19 patients. Method(s): COVID-19 pneumonia patients (N=369;VILO n=178, P n=191) within 48 hrs of intubation were randomly assigned to receive 6, 800 mg infusions of VILO or P on top of standard of care. Primary outcome was 28-day allcause mortality. Result(s): 28-day all-cause mortality was 31.7% VILO vs 41.6% P (Kaplan-Meier estimates;Cox regression site stratified, HR 0.73;95%CI:0.50-1.06;P=0.094) with a 22.7% relative mortality reduction to Day 60. In predefined primary outcome analysis without site stratification, VILO significantly reduced 28-day mortality (HR 0.67;95%CI:0.48-0.96;P=0.027);needed to treat number, 10 to save 1. VILO significantly reduced 28-day mortality in severe patients with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95%CI:0.40-0.95;P=0.028) or severe ARDS/PaO2/FiO2<=100 mmHg (n=98, HR 0.55;95%CI:0.30-0.98;P=0.044) or eGFR<60 mL/min/1.73m2 (n=108, HR 0.55;95%CI:0.31-0.96;P=0.036). Treatment emergent AEs were 90.9% VILO vs 91.0% P. Infections were comparable;VILO (62.9%), P (59.3%). Serious AEs were 58.9% VILO, 63.5% P. Conclusion(s): VILO reduced mortality at 28 to 60 days in severe COVID-19 pneumonia patients with no increase in infections suggesting the importance of targeting C5a while preserving MAC.
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Background. SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized doubleblind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods. COVID-19 pneumonia pts (N=368;Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results. Pts enrolled in the study were on corticosteroids (97%) and anticoagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates;Cox regression site-stratified, HR 0.73;95% CI:0.50-1.06;P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67;95% CI:0.48-0.96;P=0.027) and 60 days (HR 0.67;95% CI:0.48-0.92;P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62;95% CI:0.40-0.95;P=0.028), severe ARDS/PaO2/FiO2 <= 100 mmHg (n=98, HR 0.55;95% CI:0.30-0.98;P=0.044) and eGFR < 60 mL/min/1.73m2 (n=108, HR 0.55;95% CI:0.31-0.96;P=0.036). Treatment-emergent AEs were 90.9% Vilo vs 91.0% P. Infections were comparable: Vilo 62.9%, P 59.3%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion. Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. (Figure Presented).
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Background: Vaccine-induced immune thrombosis and thrombocytopenia (VITT) has been recognized as a rare thrombotic complication of adenovirus-based vaccines against COVID-19. While VITT presents some common features with heparin-induced thrombocytopenia (HIT), VITT antibodies differ from typical HIT antibodies by their ability to induce spontaneous platelet aggregation in the absence of heparin. In this context, reliable functional tests are of crucial importance to confirm VITT diagnosis. Aim(s): To compare the performances of Heparin-Induced Multiple Aggregometry (HIMEA) and Heparin-Induced Platelet Activation assay (HIPA) for VITT diagnosis. Method(s): From April to October 2021, 7 patients meeting the 5 following criteriae of definite VITT were included: Onset of symptoms 5-42 days after vaccination, thrombosis, thrombocytopenia, D-dimers >4000 ng/mL and positive anti-PF4 IgG (Zymutest HIA IgG and/or Lifecodes PF4 IgG). HIMEA was performed on whole blood from healthy donors in the hematology laboratory of Alexandra General Hospital. HIPA was performed on washed platelets from healthy donors in the hematology laboratory of Bichat Hospital. Result(s): 4 patients showed a characteristic pattern that was concordant between the two methods. HIMEA showed a sigmoid curve with elevated area under the curve (mean AUC 189+/-78 AU) in saline, that was lower (mean 148+/-51 AU) in the presence of heparin 1 IU/mL and further decreased (mean 34+/-28 AU) in the presence of heparin 100 IU/mL. HIPA showed positive aggregation in the presence of saline and heparin 0,2 IU/mL but no aggregation with heparin 50 IU/mL. 2 patients who showed lower AUC in HIMEA saline (109 and 60 AU) had weakly positive or negative results with HIPA. In these 2 cases, blood was drawn after intravenous immunogloblulin (IVIG) initiation. 1 patient showed discrepant results with typical positive HIMEA but negative HIPA patterns. Conclusion(s): VITT antibodies show heterogenous reactivity patterns that can be highlighted only by using different functional assays such as HIMEA and HIPA. IVIG treatment can be reponsible for lower antibody reactivity.
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Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.
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In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients. It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.