Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA-ERN Survey

Autoinflammatory diseases; Primary immunodeficiencies; TransitionEnfermedades autoinflamatorias; Inmunodeficiencias primarias; TransiciónMalalties autoinflamatòries; Immunodeficiències primàries; TransicióBackground Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe. Objective To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). Methods A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI. Results Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16–18 years with transfer to the adult center occurring at a median age of 18–20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. Conclusions Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.This study was supported by the ERN-RITA

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients

Background: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. Methods: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients.

BACKGROUND: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. METHODS: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. RESULTS: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). CONCLUSION: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available

A step-wise approach for establishing a multidisciplinary team for the management of tuberous sclerosis complex: a Delphi consensus report.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. METHODS: To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. RESULTS: A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual's needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients' overall care. CONCLUSIONS: The results of our consensus provide guidance to support the initiation of an MDT in TSC

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts

Participation of civil society in European Union (EU) decision-making and agenda-setting: role of patient organisations on EU health policy

Civil society organisations (CSOs) play a prominent role in influencing national, regional and international policies. They are a key player in democratic societies, have shown to complement (and even replace) governments when it comes to health delivery and provision of services, and have gradually become global players as a result of globalisation. The focus of this study is the policy work of European CSOs representing (directly or indirectly) patients, and which normally act on behalf of national CSOs. The study aims to assess how successful civil society is in representing patients at the EU level and whether this representation has led to policy change. The dissertation explores factors that may influence the success of CSOs when advocating for EU health policies. A two-fold method has been adopted. The first element includes a review of scientific (28 articles were fully read and others consulted). The second element includes 14 semi-structured interviews conducted with high level stakeholders, 12 with representatives from CSOs working at the European policy level and two with officials working for institutions that develop and implement policies (i.e. policy-makers). Findings suggest that it is difficult to measure the influence of CSOs in EU health due to the abstract nature of policy work and the policy process, which is not linear. Moreover, the number of interactions and collaborations that exist are complex in nature hence difficult to map and analyse. Although there are challenges that both CSOs and policy-makers face in relation to patient participation in the development and implementation of policy, a number of success stories were provided showing that CSOs play an instrumental role in EU and national health policy. Although the complexity of EU advocacy makes generalisations difficult, patterns were found in interviews such as the way partnerships and coalitions are built, the way challenges are addressed and the way CSOs adapt to policy change. Future research is needed to explore in-depth formal and informal relationships and confounding factors to provide a clearer link between CSO advocacy work and policy outcomes.As Organizações da Sociedade Civil (OSC) desempenham um papel importante na sociedade e no contributo para a saúde global. A proliferação e os esforços das OSC na área das políticas de saúde europeias e globais são fenómenos recentes que se devem em grande parte à dimensão global da saúde e à necessidade de respostas internacionais coordenadas face a questões de políticas de saúde. A globalização aproximou as pessoas, mas as populações tornaram-se mais vulneráveis à propagação de doenças. Questões e decisões relacionadas com políticas de saúde tornaram-se rapidamente um assunto global, de onde emergiram, em grande número, novos atores e instituições. Sendo este um fenómeno recente, há necessidade de aprofundar o conhecimento nesta área. Este estudo tem como objetivo compreender se as OSC europeias que representam pacientes (direta ou indiretamente) contribuem e influenciam a formulação e implementação de políticas de saúde da União Europeia (UE). De forma a responder a esta questão tornou-se necessário analisar fatores que possam influenciar o sucesso das OSC no seu trabalho de advocacia junto das instituições da UE. Analisaram-se também as relações entre as OSC e as instituições Europeias e, mais especificamente, o funcionamento de mecanismos, muitas vezes coordenados por instituições da UE, que permitem o diálogo entre a sociedade civil e decisores políticos sobre políticas de saúde. Considerou-se também fundamental explorar como é que o envolvimento e participação da sociedade civil em questões de política europeia acontece na prática e quais as estratégias utilizadas para influenciar políticas de saúde europeias, tendo em conta o princípio da subsidiariedade e a competência dos Estados-Membros na área da saúde pública. A metodologia envolveu principalmente duas fases do trabalho. Na primeira, realizou-se uma revisão de literatura científica (28 referências) e na segunda efetuaram-se entrevistas semi-estruturadas a 12 representantes da sociedade civil que trabalham na área de advocacia e políticas de saúde junto das instituições europeias, bem como a dois decisores políticos, um que trabalha na Comissão Europeia e outro na Organização Mundial de Saúde. Foi então desenvolvida uma análise com base nos dados recolhidos durante a revisão bibliográfica e entrevistas. Num primeiro capítulo descreve-se o processo de tomada de decisão na UE e o papel das diferentes instituições Europeias no processo de formulação e implementação de políticas de saúde. Um exemplo de como um ato legislativo da União Europeia em matéria de saúde é debatido e aprovado demonstra as várias fases do processo político, nas quais a sociedade civil participa de diversas formas, nem sempre documentadas. Neste capítulo também se problematiza a estratégia da UE ‘Juntos para a saúde’ que se apoia na estratégia de crescimento ‘Europa 2020’, e se apresenta os principais programas europeus de saúde de modo a demonstrar a forma como a UE apoia projetos focados na saúde e o papel da sociedade civil. O segundo capítulo analisa conceitos essenciais de saúde pública, nomeadamente as desigualdades na saúde e os seus determinantes sociais, um dos maiores focos de políticas de saúde Europeias, e como tal um importante indicador da coerência de políticas de saúde. A revisão bibliográfica demonstrou que a compreensão da participação pública na área da saúde aparece cada vez mais em discussões teóricas, onde se defende a participação como elemento fundamental da sociedade democrática, e o acesso à saúde e a redução de desigualdades como um direito de cidadania. Apesar de se terem encontrado definições de sociedade civil diversas, parece existir consenso de que a sociedade civil é diferente do Estado e da economia, e de que se relaciona com princípios de democracia e liberdade. Em linhas gerais, a revisão bibliográfica mostra que a investigação nesta área debruça-se sobre: os diferentes papéis e mandatos das OSC; diferenças entre as OSC nacionais, europeias, internacionais e globais; diferenças entre países desenvolvidos e países em desenvolvimento; a importância de recursos que permitam uma advocacia eficaz e planeada da parte das OSC; e a necessidade de indicadores de avaliação que permitam avaliar a influência política das OSC. A noção de ‘governança global para a saúde’ foi também encontrada na literatura. Processos políticos ocorrem normalmente num ambiente onde existem regras (Estado), mas quando se trata de governança global as ‘regras do jogo’ não são fáceis de definir, e surgem, portanto, questões relacionadas com legitimidade, transparência ou responsabilização. Representantes de OSC entrevistados destacaram assuntos relacionados, e muitas das vezes semelhantes, aos principais temas de investigação que se encontraram durante a revisão bibliográfica. Os temas mais salientes relevaram a importância de parcerias entre OSC; de recursos que permitam o desenvolvimento de capacidades, o acesso a competências, o acesso a decisores políticos; e a necessidade de mecanismos que assegurem a transparência do processo político. Obstáculos para a participação da sociedade civil foram também encontrados e são apresentados em quatro grupos: 1) obstáculos relacionados com a falta de recursos humanos e financeiros, onde se inclui a necessidade de desenvolvimento de capacidades, a barreira da língua, a falta de recursos financeiros que possibilitem representação perto das instituições Europeias (em Bruxelas) e a impossibilidade de participação devido aos sintomas da doença; 2) obstáculos relacionados com questões de legitimidade e responsabilidade, incluindo a necessidade de boa governança e de uma representação de interesses mais transparente, incluindo no seio das OSC, assim como o problema da dependência financeira e das relações com a indústria farmacêutica; 3) obstáculos relacionados com a falta de coordenação e alinhamento, e a importância de desenvolvimento de estratégias conjuntas; 4) obstáculos relacionados com mudanças nas agendas e interesses políticos que requerem uma rápida adaptação por parte das OSC. Demonstrou-se, através das entrevistas, que ultrapassar os obstáculos requer o recurso a parcerias e a proatividade da parte da sociedade civil, e que a adaptação de estratégias de advocacia é necessária face a mudanças políticas, o que pode resultar em novas oportunidades para as OSC. A noção de ‘participação significativa’ também foi destacada, e estudos de caso e histórias de sucesso foram partilhadas pelos representantes das OSC e das instituições Europeias e internacionais. A maior parte das OSC consideram desempenhar um papel fundamental, não apenas na adoção de políticas e iniciativas de saúde da UE, mas na avaliação da implementação de políticas nos Estados-membros, mesmo que seja quase impossível estabelecer uma relação entre ações específicas por parte das OSC e resultados políticos

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Background: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl− cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE):a prospective, multicentre, observational cohort study

INTRODUCTION: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures.METHODS: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025.FINDINGS: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5-5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4-10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32-4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23-11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation.INTERPRETATION: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification.FUNDING: UK Research and Innovation and National Institute for Health Research.</p

Patient and public involvement toolkit for antimicrobial medicines development research

PPI is a rapidly growing and important global movement. PPI specifically in antimicrobial medicines development research, however, is new and unfamiliar. There is currently a lack of literature and clear practical guidance focusing on PPI in this area (Evans et al., 2017). Given the short-term nature of many microbial infections, there are few established patient support groups or voluntary organisations in the field of infection sciences. In view of the increasing costs of medicines development and the financial consequences of market failure, early incorporation of PPI in research may reduce waste of resources (Geissler et al., 2017). COMBACTE-MAGNET is a consortium funded by the Innovative Medicines Initiative (www.imi.europa.eu) Joint Undertaking and EFPIA (European Federation of Pharmaceutical Industries and Association) companies seeking new ways of treating multi-resistant bacterial infections. As part of its clinical coordinating work package, WP6i, we have developed this toolkit to provide systematic and evidence-based guidance on how and when to involve the public in medicines development research, in particular antimicrobials