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BackgroundCOVID-19 has shaped the world over the last 3 years. Although the risk for severe COVID-19 progression in children is low it might be aggravated by chronic rheumatic disease or treatment with immunosuppressive drugs.ObjectivesWe analyzed clinical data of COVID-19 cases among paediatric patients with rheumatic diseases reported to BIKER between March 2020 and December 2022.MethodsThe main task of the German BIKER (Biologics in Pediatric Rheumatology) registry is safety monitoring of biologic therapies in JIA. After the onset of the COVID-19 pandemic, the survey was expanded with a standardized form to proactively interview all participating centers about occurrence, presentation and outcome of SARS-CoV-2 infections in children with rheumatic diseases.ResultsA total of 68 centres participated in the survey. Clinical data from 928 COVID infections in 885 patients with rheumatic diseases could be analyzed. JIA was the most common diagnosis with (717 infections), followed by genetic autoinflammation (103 infections), systemic autoimmune diseases (78 infections), idiopathic uveitis (n=25), vasculitis (n=5).In 374 reported COVID infections (40%), patients were receiving conventional DMARDs, in 331 (36%) biologics, mainly TNF inhibitors (TNFi, n=241 (26%)). In 567 reports (61%) patients used either a biologic or a DMARD, in 339 reports patients (37%) did not use any antirheumatic medication including steroid.Over the last 3 years, COVID-19 occurred in Germany in 5 distinguishable waves, calendar weeks (CW) 10-30 in 2020, CW 21/2020 – 8/2021(both predominantly wild-type variant), CW 9-27 in 2021 (Alpha variant in the majority of infections), CW 28-51 in 2021 (Delta variant), since CW 52/2021 (several Omikron variants;Robert-Koch Institute: VOC_VOI_Tabelle.xlsx;live.com))In our cohort, patients with SARS-CoV-2 infection were slightly older during the 1st and 2nd wave (mean age 12.7+/-3.5 and 12.8+/-4.3 years) compared to the 4th and 5th wave with 11.4+/-3.9 and 11.4+/-4.2 years;p=0.01.160 asymptomatic SARS-CoV-2 infections were reported, frequencies of symptoms associated with COVID-19 are shown in table 1.Five patients were hospitalized for 4-7 days. A 3½-year-old female patient succumbed during the first wave with encephalopathy and respiratory failure. The patient had been treated with MTX and steroids for systemic JIA. Genetic testing revealed a congenital immunodeficiency. No other patient needed ventilation or intensive care. One case of uncomplicated PIMS in an MTX treated JIA patient was reported.The duration of SARS-CoV-2 infection-associated symptoms was markably shorter during the 5th wave with 6.7+/-5.1 days, compared with reports from the other 4 waves (Table1).The duration of symptoms was higher in MTX treated patients (10.2+/-8.4 days) compared to patients without treatment (7.7+/-10.8;p=0.004) or patients treated with TNFi (8.2+/-4.8, p=0.002). Although patients treated with steroids also had a longer duration of symptoms (9.7+/-7.0), this was not significant.ConclusionExcept for one patient with congenital immunodeficiency who died, no case of severe COVID-19 was reported in our cohort. At the time of infection, over 60% of patients had been treated with conventional DMARDs and/or biologics. Although MTX treated patients had a slightly longer duration of symptoms, antirheumatic treatment did not appear to have a negative impact on severity or outcome of SARS-CoV-2 infection.Table 1.Characteristics and frequency of symptoms in SARS-CoV-2 infectionsN or mean (SD)1st wave N=202nd wave N=843rd wave N=384th wave N=1245th wave N=662female14532775432age at COVID-19, years12.7 (3.5)12.8 (4.3)11.8 (3.5)11.4 (3.9)11.4 (4.2)asymptomatic126132694duration of symptoms;days,11.9 (14.7)9.2 (7.0)14.1 (11.6)10.3 (7.6)6.7 (5.1)fever1218541306cough1015652245rhinitis5261344289headache4161227171sore throat61139132musculosceletal pain2751348loss of smell/taste71162113fatigue4882680dizziness122116gastrointestinal symptoms151864dyspnea1117pneumonia11bronchitis1REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Inter stsAriane Klein Speakers bureau: Novartis, Toni Hospach Speakers bureau: Speaking fee Novartis and SOBI., Frank Dressler Speakers bureau: Abbvie, Novartis, Pfizer, Advisory Boards Novartis and Mylan, Daniel Windschall Grant/research support from: research funds by Novartis, Roche, Pfizer, Abbvie, Markus Hufnagel: None declared, Wolfgang Emminger: None declared, Sonja Mrusek: None declared, Peggy Ruehmer: None declared, Alexander Kühn: None declared, Philipp Bismarck: None declared, Maria Haller: None declared, Gerd Horneff Speakers bureau: Pfizer, Roche, MSD, Sobi, GSK, Sanofi, AbbVie, Chugai, Bayer, Novartis, Grant/research support from: Pfizer, Roche, MSD, AbbVie, Chugai, Novartis.
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Airborne pathogen transmission mechanisms play a key role in the spread of infectious diseases such as COVID-19. In this work, we propose a computational fluid dynamics (CFD) approach to model and statistically characterize airborne pathogen transmission via pathogen-laden particles in turbulent channels from a molecular communication viewpoint. To this end, turbulent flows induced by coughing and the turbulent dispersion of droplets and aerosols are modeled by using the Reynolds-averaged Navier-Stokes equations coupled with the realizable k-model and the discrete random walk model, respectively. Via simulations realized by a CFD simulator, statistical data for the number of received particles are obtained. These data are post-processed to obtain the statistical characterization of the turbulent effect in the reception and to derive the probability of infection. Our results reveal that the turbulence has an irregular effect on the probability of infection, which shows itself by the multi-modal distribution as a weighted sum of normal and Weibull distributions. Furthermore, it is shown that the turbulent MC channel is characterized via multi-modal, i.e., sum of weighted normal distributions, or stable distributions, depending on the air velocity. Crown
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Airborne pathogen transmission mechanisms play a key role in the spread of infectious diseases such as COVID-19. In this work, we propose a computational fluid dynamics (CFD) approach to model and statistically characterize airborne pathogen transmission via pathogen-laden particles in turbulent channels from a molecular communication viewpoint. To this end, turbulent flows induced by coughing and the turbulent dispersion of droplets and aerosols are modeled by using Reynolds-averaged Navier-Stokes equations coupled with realizable k-epsilon model and the discrete random walk model, respectively. Via the simulations realized by a CFD simulator, statistical data for the number of received particles are obtained. These data are post-processed to obtain the statistical characterization of the turbulent effect in the reception and to derive the probability of infection. Our results reveal that the turbulence has an irregular effect on the probability of infection which shows itself by the multimodal distributions as a weighted sum of normal and Weibull distributions. © 2022 IEEE.
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Background: Autoinfammatory diseases (AID) are characterized by severe systemic and organ infammation as well as high burden of disease for patients and their families. Treatment with the monoclonal antibody canakinumab (CAN), an interleukin-1β inhibitor, has been proven to be safe and effective in clinical trials and real-life. Objectives: The present study explores the long-term efficacy and safety of CAN in routine clinical practice conditions in pediatric (age ≥2 years) and adult patients with CAPS (cryopyrin-associated periodic syndromes), FMF (familial Mediterranean fever), TRAPS (tumor necrosis factor receptor-associated periodic syndrome) and HIDS/MKD (hyperimmunoglobulinemia D syndrome/meva-lonate kinase defciency). Methods: RELIANCE is a prospective, non-interventional, observational study based in Germany. Patients with clinically confrmed diagnoses of AID routinely receiving CAN are enrolled. Besides efficacy parameters regarding disease activity and remission, safety parameters were recorded at baseline and assessed at 6-monthly intervals. Results: Here, we present the interim analysis of patients with AID (N=199) enrolled in the RELIANCE Registry between October 2017 and December 2021. Mean age in this cohort was 24.4 years (2-79 years) and the proportion of female patients was 53% (N=104). At baseline, median duration of prior CAN treatment was 2 years (0-12 years). A total of 123 patients (62%) experienced any AE (N=653) among which naso-pharyngitis, increase of infammatory markers and pyrexia were the most frequent AE with incidence rates per 100 patient years (IR) of 8.3, 6.2, and 6.2, respectively. 29 patients (15%) were affected by severe AE (SAE, total number N=90) including 11 patients (6%) with SAE suspected to be drug-related (SADR;total number N=30) with IR from 0.2 to 0.7 (Table 1). Overall, 16 AE comprised upper respiratory tract infections (URI). One death (COVID-19, not related) and one malignancy (skin papilloma, not related) were reported. No vertigo and no hyper-sensitivity reactions were observed. N=10 (IR 2.36) vaccination reactions were reported (no SAE). Conclusion: The interim data from the RELIANCE study, the longest running real-life canakinumab registry, confrm safety of long-term canakinumab treatment across the entire study population. A trend for dose-related increase of SAE/SADR requires continuous close monitoring and awareness in patient groups (children, severe phenotypes, certain genotypes) requiring greater than standard dose treatment regimens.
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Background: Although the risk for severe COVID-19 progression in children is low, this may be aggravated by the underlying disease and/or immunosuppres-sive drugs. Objectives: We analyzed clinical data of COVID-19 cases among paediatric patients with rheumatic diseases reported to the BIKER registry. Methods: The main task of the German BIKER (Biologics in Pediatric Rheumatology) registry is to monitor the safety of biologics therapies in JIA. After the onset of the COVID-19 pandemic, the survey was expanded with a standardized form to proactively interview all participating centers about the occurrence, presentation, and outcome of SARS-CoV-2-infections in children with rheumatic diseases. Interviews were conducted with 68 centers initially weekly and later biweekly. Results: A total of 68 centres participated in the survey. Clinical data from 194 COVID-19 cases reported to the BIKER registry from 41 German and 1 Austrian pediatric rheumatology institutions between February 2020 and December 2021 were analyzed. Juvenile idiopathic arthritis (JIA, n=144) was the most common diagnosis followed by genetic autoinflammation (n=18;i.e. FMF, TRAPS, CAPS, HIDS, DADA2), systemic autoimmune diseases (n=11;i.e. SLE, dermatomyositis, vasculitis) and 16 with other rheumatic diseases (i.e. CRMO, Uveitis). 5 patients with no rheumatic disease were excluded. 104 (54%) patients were receiving conventional DMARDs, 81 (43%) received biologics, mainly TNF inhibitors (n=66 (35%)). Of the 189 rheumatic patients with SARS-CoV2 infection, 123 (63%) were female. The mean age was 12.4+/-4.4 years in females and 13.2+/-4.1 in males. The duration of SARS-Co2 infection associated symptoms was 13.8+/-15.3 days (max. 113 days), in 35 (43%) patients they lasted for > 12 days. 46 (24%) were asymptomatic. Patients with autoinflammation and systemic autoimmunopathies reported more symptoms such as fever, head and throat ache. 4 patients only complained about dyspnea. Only 3 patients were hospitalized and received Oxygen-supplementation. The only patients admitted to ICU, received ventilation but succumbed. This 3/-year-old patient, initially diagnosed with systemic JIA, developed fatal disease with intracranial edema and respiratory failure, as well as typical pulmonary texture changes. Prior to her SARS-CoV-2 infection, the patient was treated with MTX and low-dose steroids. Genetic testing revealed a so far unrecognized congenital immunodeficiency. In the total JIA cohort, treatment with corticosteroids, conventional DMARDs, biologics or combinations did not influence the number of reported symptoms or the favorable outcome of the cohort. However, the duration of symptoms was lower in the TNF-treated cohort (10.4+/-6.4 days vs. 15.7 +/-19.7 days). In the cohort with autoinflammation, fever was observed in 11 (61%). Those 6 who received IL-1-inhibitors did not show a different outcome than those 12 who did not. No case of PIMS/MISC in children with rheumatic diseases was reported. Conclusion: Except for one patient with congenital immunodefciency who died from her COVID-19 infection, no case of severe COVID-19 was reported in our cohort. At the time of infection, over 80% of patients in our cohort had been treated with conventional DMARDs and/or biologics. This did not appear to have a negative impact on the severity or outcome of SARS-CoV2 infection. Interestingly, no case of PIMS/MISC was observed.
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Background:Familial Mediterranean Fever (FMF) is characterized by recurrent attacks of fever and serositis as well as elevated inflammatory markers. FMF treatment goals according to EULAR are to control acute attacks and subclinical inflammation and to improve patients´ quality of life1. In a phase 3 pivotal study (CLUSTER study), FMF patients treated with the interleukin-1β inhibitor canakinumab met all these goals2.Objectives:The present study explores the long-term efficacy and safety of canakinumab (CAN) in routine clinical practice in pediatric (age ≥2 years) and adult FMF patients.Methods:RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a three-year follow-up period. Patients with clinically confirmed diagnosis of FMF who routinely receive CAN were enrolled in order to evaluate effectiveness and safety of CAN under standard clinical practice conditions. Disease activity and remission by physicians´ assessment, disease activity, fatigue and impact on social life by patients’ assessment, inflammatory markers and AIDAI (Auto-Inflammatory Diseases Activity Index) score were recorded at baseline and were assessed at 6-monthly intervals within the three-year observation period of the study.Results:This interim analysis of FMF patients (N=54) enrolled by December 2020 includes baseline as well as 6-, 12- and 18-month data. Mean age in this cohort was 25 years (4−56 years) and the proportion of female patients was 46 % (N=25). At baseline, median duration of prior CAN treatment was 2.0 years (0−6 years).While physician ratings report around 62% of patients in disease remission, 52% with absent and 34% with mild-moderate disease activity, patient-reported disease activity decreased from moderate (PPA 3.0) to low (PPA 2.0) during the observation period. A decrease was observed regarding disease activity parameters, in particular in patients without prior CAN therapy (Table 1, Figure 1). A total of 11 serious adverse events was reported, of which one case of tonsillectomy was classified as drug-related.Conclusion:Interim data of FMF patients from the RELIANCE study, the longest running real-life CAN registry, confirm efficacy and safety of long-term CAN treatment.References:[1]Ozen S, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644–651. doi:10.1136/annrheumdis-2015-208690[2]De Benedetti F, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908–19.Table 1.Baseline characteristics and third interim analysis data of patients with FMFBaseline6 months12 months18 monthsAll patients ;patients without prior CAN therapyNumber of patients, N5411357275163Number (%*) of patients in disease remission (physician assessment)18 (48.6)1 (20.0)19 (73.1)3 (75.0)13 (65.0)1 (50.0)8 (61.5)1 (100.0)Physician Global Assessment, percentage* of absent/mild-moderate/severe rating43/38/110/40/6065/27/050/50/055/35/00/50/046/46/00/100/0Patient assessment of current disease activity;0–10, median (min;max)3.0 (0;10)7.0 (0;10)2.5 (0;7)2.0 (0;5)2.0 (0;7)2.0 (0;2)2.0 (0;6)0.5 (0;1)Patient assessment of current fatigue;0–10, median (min;max)5.0 (0;10)5.0 (0;9)3.5 (0;10)3.0 (1;6)3.0 (0;10)0.0 (0;4)3.0 (0;7)0.5 (0;1)Number (%*) of patients without impairment of social life by the disease19 (46.3)3 (37.5)18 (66.7)3 (75.0)14 (66.7)4 (80.0)5 (55.6)2 (66.7)CRP, median (mg/dl)0.21.10.20.10.20.00.10.5SAA, median (mg/dl)0.76.80.80.40.80.60.60.7ESR, median (mm/h)9.018.56.05.05.54.08.05.0SAENumber of eventsIncidence rate per 100 patient yearsTotal1116.23Arthritis57.38SARS-CoV-2 infection22.95Familial Mediterranean Fever11.48Intestinal Hemorrhage11.48Pyrexia11.48Tonsillectomy (SADR)11.48*not reported for all patientsCRP, c-reactive protein;ESR, erythrocyte sedimentation rate;n. a., not annotated;SAA, serum amyloid A;SADR, serious adverse drug reaction;SAE, serious adverse eventDisclosure of Interests:Jörg Henes Consultant of: Novartis, AbbVie, Sobi, Roche Janssen, Boehringer-Ingelheim, Grant/research support from: Novartis, Roche, J. B. Kuemmerle-Deschner Consultant of: Novartis, AbbVie, Sobi, Grant/research support from: Novartis, AbbVie, Sobi, Tilmann Kallinich Consultant of: Sobi, Novartis, Roche, Grant/research support from: Novartis, Frank Dressler Consultant of: Abbvie, Mylan, Novartis, Pfizer, Grant/research support from: Novartis, Frank Weller-Heinemann: None declared, Birgit Kortus-Goetze Consultant of: Novartis, Ivan Foeldvari Consultant of: Novartis, Gerd Horneff Speakers bureau: bbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Grant/research support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Markus Hufnagel Grant/research support from: Novartis, Florian Meier Speakers bureau: Novartis, Julia Weber-Arden Employee of: Novartis, Norbert Blank Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, Grant/research support from: Novartis, Sobi
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Background: In 2017, Adalimumab Biosimilars became approved. Comparative studies to the originator have been performed in adult patients with rheumatoid arthritis, ankylosing spondylitis and psoriasis and extrapolation led to approval for juvenile idiopathic arthritis (JIA). Objectives: So far there is limited experience with biosimilars in JIA: The large national data base of the BIKER-registry was used to describe experience with Adalimumab biosimilars in clinical practice Methods: This retrospective analysis used data of the German BIKER-registry. The data basis war screened for patients exposed to Adalimumab. Subcohorts with initiation of treatment after 2017, use of the originator and of biosimilars were built. The course of JADAS10, Physician global assessment VAS 0-100-mm, Parent/patient global assessment VAS 0-100-cm, Active joint count 0-71, truncated at 10, ESR and CHAQ-DI was analyzed. Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESI). Results: Until 31.10.2020, 1173 JIA patients were reported to have received Adalimumab. 352 treatments have been started after January 1, 2017. A biosimilar was used first line in 44 patients. Further 55 patients switched for the originator to a biosimilar. 2 patient switched from a biosimilar to the originator. 3 patients switched to a second biosimilar while 5 patients who switched from the originator to a biosimilar reswitched back to the originator. After 2017, 33 pediatric rheumatology centres reported initiation of Adalimumab treatment. 17 have used a biosimilar. 15 centres have swichted at least 1 patient from the originator to a biosimilar and 14 have used first line a biosimilar in at least 1 patient. In a single centre, initiation of a biosimilar was used more frequently (8 versus 7). The patients' characteristics and disease activity parameters were brightly comparable. The JIA category rheumatoid factor (RF) negative polyarthritis was less frequent in the biosimilar first cohort while RF positive polyarthritis and psoriatic arthritis was more frequent. In patients with idiopathic uveitis the originator was used more often. In the switching cohort, more patients had RF negative polyarthritis, persistent oligoarthritis but less had psoriatic arthritis and no had RF positive polyarthritis. No difference in disease activity parameters between patients receiving the originator or biosimilars were noted, neither at baseline, during the course of treatment nor at last observation upon treatment (Figure 1). At the time of switching, 46 (92%) had JADAS minimal disease activity (MDA) and 30 (69%) were in JASDAS remission. At last observation, those numbers were comparable with 42 (86%) with JADAS MDA and 28 (57%) with JADAS remission. In total, 45 adverse events (AE) were reported in 45 patients upon biosimilar treatment. 26 patients had 1, 12 patients had 2 and 6 patients reported 3 and 1 reported 4 events. Adverse event of special interest were Infection associated leukopenia (n=1), COVID 19 infection (n=1), Uveitis flare (n=8), other disease deterioration (arthritis flare) (n=20), injection site reaction n=2. A single serious AE was reported. A 16 year old female adolescent was admitted for unexpected CK elevation. In 10 patients, Adalimumab was discontinued, in 2 it was temporarily paused. Conclusion: This article is the first attempt to present a large sample of data on JIA patients exposed to Adalimumab biosimilars. Since approval of Adalimumab-Biosimilars, limited experience from clinical practice is available. Biosimilars are used in a minority of patients and by a minority of centers although no difference in efficacy or safety was noted from our analysis.
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Molecular communication is not only able to mimic biological and chemical communication mechanisms, but also provides a theoretical framework for viral infection processes. In this tutorial, aerosol and droplet transmission is modeled as a multiuser scenario with mobile nodes, related to broadcasting and relaying. In contrast to data communication systems, in the application of pathogen-laden aerosol transmission, mutual information between nodes should be minimized. Toward this goal, several countermeasures are reasoned. The findings are supported by experimental results and by an advanced particle simulation tool. This work is inspired by the recent outbreak of the coronavirus (COVID-19) pandemic, but also applicable to other airborne infectious diseases like influenza.