ABSTRACT
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.
ABSTRACT
Introduction: Individuals with clonal hematopoiesis (CH) have a higher risk of malignant and cardiovascular diseases. The latter has been linked to a higher inflammatory tonus in clonal myeloid and T cells driving pro-inflammatory circuits. As 'hyperinflammation' is one hallmark associated with fatal outcome of COVID-19, our study aimed to characterize the prevalence and clinical impact of CH in COVID-19. Methods: 160 individuals, which were either hospitalized or came for follow-up evaluation with COVID-19 were analyzed for somatic mutations indicative of CH (≥2% variant allele frequency). Trial protocols were approved by the institutional review board at Innsbruck Medical University (EK-Nb: 1091/2020 and 1103/2020). Detection of CH variants was performed by next generation sequencing on MiSeq devices using the TrueSight Myeloid sequencing panel from Illumina. For data analysis, the SeqNext software of JSI Medical Systems was utilized. Only coding variants not frequent in the general population with a variant allele frequency (VAF) between 2% and 45% were included in the dataset. Results: CH was detected in 31 of 160 (19.4%) evaluable individuals, with an age and gene distribution comparable to published data. To characterize the interplay between CH, inflammation and COVID-19 course, we divided our patient cohort into 'Severe COVID-19' and 'Non-severe COVID-19' based on the following criteria: Patients, requiring ≥2 liters/ minute of supplemental oxygen support at any given time point were classified as 'Severe COVID-19'. Of the study cohort, 99 patients (61.9%) had non-severe COVID-19 while 61 (38.1%) had severe COVID-19 according to our criteria. Of the latter, 37 patients (23.1%) had to be admitted to an intensive care unit due to respiratory insufficiency. However, the presence of CH and COVID-19 disease severity revealed no association between CH and 'severe COVID-19' (p-value: 0.678). Moreover, as COVID-19 does not spare individuals with active hematologic diseases, it is important to understand the dynamics of the clonal composition during active viral disease and upon its resolution. Analysis of 15 variants of eight individuals at different timepoints (up to six months follow-up) revealed that the clonal size is stable during the course of SARS-CoV2 infection. Conclusion: In summary, we demonstrate that CH is not indicative for an aggravated course of COVID-19 and that the clone size is not significantly modulated during the course of COVID-19.