Journal of Clinical Immunology (2023) 43:206–216 https://doi.org/10.1007/s10875-022-01345-y ORIGINAL ARTICLE Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA‑ERN Survey Muskan Israni1 · Bethany Nicholson1 · Nizar Mahlaoui2,3 · Laura Obici4 · Linda Rossi‑Semerano5 · Helen Lachmann6 · Georgia Hayward7 · Mojca Zajc Avramovič8 · Aurelien Guffroy9,10 · Virgil Dalm11,12 · Rachel Rimmer13,14 · Leire Solis15 · Carlotta Villar16 · Andrew R. Gennery17,18 · Stephanie Skeffington19 · Julia Nordin15 · Klaus Warnatz20,21 · Anne‑Sophie Korganow9,10 · Jordi Antón22 · Marco Cattalini23 · Tania Amin24 · Stephan Berg25,26 · Pere Soler‑Palacin27,28 · Siobhan O. Burns1,29 · Mari Campbell1,29 · RITA-ERN Transition Working Group Consortium Received: 7 March 2022 / Accepted: 7 August 2022 / Published online: 12 October 2022 © The Author(s) 2022 Abstract Background 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 cur- rently 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, encompass- ing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). Methods A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoim- mune 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 tran- sitioned 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 guide- lines to promote best practice. Keywords Transition · Primary immunodeficiencies · Autoinflammatory diseases · Network Introduction Highlights: Inborn errors of immunity (IEI) are a heterogeneous group 1. An effective transition from pediatric to adult services of rare disorders with increased, poor, or absent function process improves long-term outcomes for young people with in components of the innate and/or adaptive immune sys- chronic conditions 2. This is the first survey to understand transition practices in tems. Primary immunodeficiencies (PID) and autoinflam- Europe for young people with Inborn Errors of Immunity matory diseases (AID) represent the majority of known 3. The study highlights variation in practice and a need for IEI [1, 2] PID are characterized by infection susceptibil- national and international guidelines for transition of young people ity, often associated with autoimmune, inflammatory, and with Inborn Errors of Immunity malignant complications. In contrast, the dominant fea- Siobhan O. Burns and Mari Campbell contributed equally to this ture in AID is recurrent or chronic inflammatory episodes work. that are systemic, distinct from autoimmune diseases and associated with an increasingly wide clinical phenotype Extended author information available on the last page of the article 13 Journal of Clinical Immunology (2023) 43:206–216 207 [3, 4]. The majority of AID and more severe forms of PID Methods manifest in childhood although additional manifestations and new complications occur over life. Marked improve- A survey (Supplementary file2) asking about current tran- ments in the diagnosis and management of PID and AID sition numbers and practice was developed by the ERN- in the last decades have improved the outlook for many RITA steering group. The survey was circulated to clini- patients, but at the same time bring new challenges to cians working in European pediatric PID and AID services the care of these patients—many of whom have multi- in June 2018 through personal and professional networks. morbidity [5–7]. This modification of the natural history To enhance the response rate and capture additional cent- of the disease is associated with an increased survival of ers, the same questionnaire was sent or re-sent in Novem- pediatric patients with PID and AID, who now need trans- ber 2019 to centers who had not submitted responses to fer to adult services for life-long follow-up [8] Therefore, the first circulation. Clinicians were asked to complete a well-established interdisciplinary transition protocol is separate questionnaires for their cohorts of patients with considered a standard of care for these patients and their PID and AID and only one response per center for each families’ needs to be carefully planned and managed [9]. was permitted. Ethical approval was not required for col- Transition has been defined as “A purposeful, planned lection of this information. process that addresses the medical, psychosocial, and educational/vocational needs of adolescents and young adults with chronic physical and medical conditions as they move from child-centered to adult-oriented health Results care systems”[10], while transition can often be used to refer to the physical move of care to adult services. It is Respondent demographics important to make a distinction between this “transfer” and “transition” which also includes the psychological shift The survey was sent to 154 clinicians, from 106 centers, whereby the young adult becomes responsible for their in 87 cities in 23 countries in Europe (Supplementary own care. To date, despite there already being well-estab- Fig. 1). In total, 76 responses were received from 52 cent- lished transition guidelines for patients with other life-long ers, in 45 cities across different 17 countries. Forty-four immune-mediated conditions that emerge in childhood, responses were received from PID centers based in 39 cit- such as rheumatic diseases [11], asthma, and allergy [12], ies in 15 countries, while the remaining 32 responses were transition pathways for PID and AID have been less clearly obtained from AID centers across 29 cities in 13 countries defined. Moreover, there are significant differences among in Europe. Of the 76 responding centers, 38 centers (50%) European countries regarding pediatric and adult specialist are members of the RITA-ERN network. healthcare provision for patients with PID and AID [13], PID services reported treating larger numbers of and to date there are no available data for dedicated transi- patients than AID services (Table 1), reflecting the rela- tion programs for these rare disorders. tive prevalence of the two conditions. Forty-one percent The European Reference Networks (ERN) are virtual (13/32) of AID services reported treating less than 50 networks involving healthcare providers across Europe pediatric patients compared with 19% (8/43) of PID ser- (https://​ec.​europa.​eu/​health/​ern_​en). ERNs aim to tackle vices. In contrast, 42% (18/43) of PID services follow complex or rare diseases and conditions that require highly more than 200 pediatric patients while only 6% (2/32) of specialized treatment and a concentration of knowledge AID centers follow cohorts of this size. and resources. To date, there are 24 ERNs involving 25 As guidance for other immune-mediated conditions rec- European countries, over 300 hospitals with over 900 ommend that the transition process is started in early ado- healthcare units and covering all major disease groups. lescence [11, 12] the centers were asked how many pediatric Among them, the European Reference Network on Rare patients with PID or AID they cared for between the ages Immunodeficiency, Autoinflammatory and Autoimmune of 12 and 18. The majority of centers follow fewer than 50 Disease (ERN-RITA) brings together leading European patients in this age group (71%, 22/31 of the AID services centers with expertise in diagnosis and treatment of rare and 50%, 22/44 of the PID services). None of the AID ser- immunological disorders including PID, AID and autoim- vices and only 18% (8/44) of the PID services cared for more mune diseases. than 100 patients in this transition age range (Table 1). The The ERN-RITA Transition Working Group aimed to vast majority of centers transfer only up to ten patients to define the current practices in transition for patients with adult care each year (91%, 29/32 AID services, and 73%, PID and AID diseases across European health centers as a 32/44 PID services) while a small proportion of PID cent- first step to creating global guidance for transition of these ers (5%, 2/44) transition 20–40 patients per year (Table 1). patients. 13 208 Journal of Clinical Immunology (2023) 43:206–216 Table 1  Demographics of responding centres of AID services). Delay in transfer to over 20 years of age Specialty PID AI was reported by a minority of centers (9%, 4/44 of PID cent- ers and 6%, 2/31 of AID centers). No. of Countries Responded 15 13 The majority of centers reported that patients were No. patients treated in service referred to an adult center a similar distance from the - < 50 8 13 patient’s home (75%, 33/44 pediatric PID services and -50–100 8 9 23/31, 74% pediatric AID services; Supplementary Fig. 2). -100–200 8 8 -200–500 13 2 Only one AID center reported that the adult center was fur- - > 500 5 0 ther from the patient’s home but 20%, 9/44 PID services and -Unknown 1 0 19%, 6/31 AID services responded that the distance between No. transition aged patients treated in service the patient’s home and adult center varied for each patient. - < 50 22 22 -50–100 13 9 -100–200 3 0 Transition partner and process - > 200 5 0 -Unknown 1 0 The majority of the response sites reported having formal No patients transferred to adult services each year transition partners in place (91%, 40/44 of PID services and -<5 17 17 94%, 29/31 AID services). Transfer was typically directly -5–10 15 12 to adult centers, with only 7% (3/44) PID services and 16% -10–20 8 2 (5/31) AID services transitioning to intermediate adolescent -20–40 2 0 -Unknown 2 1 services (Table 2). Few PID or AID respondents reported transferring their patients to adult care services with dedi- cated young adult clinics (11%, 5/44 PID and 29%, 9/31 Logistics of the transition process AID services). Joint appointments with healthcare profes- sionals from pediatric and adult services were common prior To determine whether patients continue to receive specialist to the transfer of care (75%, 33/44 PID and 68%, 21/31 AID care in adulthood, centers were asked where they transi- centers), involving physicians, nurses, psychologists, and tioned patients to. Fifteen respondents (20%) had more than specialists from other medical teams. The number of joint one option for transfer of care. The vast majority of cent- clinics held for each patient was determined by the severity ers that responded reported referring patients to specialist of illness. PID services described holding 1–5 joint clin- adult PID/AID centers (86%, 38/44 PID services and 77%, ics, with 4–5 appointments for patients with more complex 24/31 AID services: Fig. 1). In keeping with the fact that diseases. In contrast, the AID services reported holding 1–3 AID are often cared for within rheumatology services rather appointments for each patient. The vast majority of the ser- than immunology clinics, 32% (10/31) pediatric AID cent- vices examined described full integration of patient records ers referred to adult rheumatologists. No centers discharged with the adult care provider, with only 21% (9/43) PID cent- without hospital follow-up although a small number referred ers and 27% (8/30) AID services responding negatively to patients to non-specialist adult internal medicine physicians this item (Table 2). (16%, 7/44 PID services and 19%, 6/31 AID services). Just over three quarters of PID and AID services reported The transition process started at a median age of having a defined transition processes for transfer of care to 16–18 years for both PID and AID services (Fig. 2a). A adult services (34/44 and 24/31 respectively; Fig. 3a). How- higher proportion of AID than PID services started transi- ever, the majority of PID and AID services reported a lack tion before the age of 16 years (55%, 17/31 of AID centers of national disease-specific transition guidelines to refer to compared with 30%, 13/44 of PID centers). A significant (86%, 38/44 and 80%, 24/30 respectively; Fig. 3b). The PID minority of services reported initiating the transition pro- services describing the complete or partial use of national cess after patients turn 18 (23%, 10/44 of PID services and transition guidelines were located in Poland and the UK, 13%, 4/31 of AID services). The median age for the end of while the AID services were based in Italy, Finland, and the transition process was 18–20 years for both PID and the UK. Few centers reported transition-specific research AID (Fig. 2b) with a small proportion of centers reporting programs at their site (20%, 9/44 PID and 29%, 9/31 AID that the end of transition occurred after the age of 20 years centers; Table 2). (14%, 6/44 of PID centers and 10%, 3/31 of AID centers). In The majority of centers did not report specific difficulties in keeping with this, patients were most frequently transferred identifying adult care for their patients (Supplementary Fig. 3). to adult care between the ages of 18–20 years (Fig. 2c) with However, for those who did, the lack of specialist adult center a smaller proportion of centers transferring patients before (9%, 8/23 PID and 27%, 3/11 AID centers) was the biggest diffi- 18 years of age (32%, 14/44 of PID services and 32%, 10/31 culty. If reporting problems, the majority of clinicians identified 13 Journal of Clinical Immunology (2023) 43:206–216 209 Fig. 1  Site of referrals made for adult care Specialist adult PID or AID centre 24 38 Adult internal medicine physician 6 7 Place of referral General adult rheumatology clinic 10 3 Other adult clinic 1 AID 5 (N=31) General practitioner PID Discharge without specific follow-up (N=44) Unknown 0 10 20 30 40 Frequency a number of different weaknesses of the transition process in transferred less than 10 patients each year, but only 12 their services—with 54 respondents (71%) listing more than transferred more than 10. Services transitioning less than one difficulty. Lack of time to prepare the documents and/or ten patients each year treated fewer pediatric patients in funding and resource in adult services, fragmentation of adult total and within the 12–18 year age range (Supplemental services, lack of holistic care in both and adult pediatric ser- Fig. 4a and b). A higher percentage of centers transferring vices, lack of suitable centers to transition to, and patients not more than ten patients a year reported transferring patients wanting to engage were reported as the main weaknesses of the between the ages of 16 and 18, having a defined process for transition process (45%, 33%, 33%, 26%, 22%, 22%, and 18% of transition, having integrated medical files, and having joint services, respectively) (Supplementary Table 1). This survey did clinics with adult and pediatric centers (Table 3). A higher not capture specific problems with the suitability of adult ser- percentage of centers transferring less than ten patients a vices for transition. However, responders did note that it is often year reported initiating transition and/or transferring care the transfer of services for all the various comorbidities in the after the age of 18, transferring to services with a specialist adult sector, rather than transfer for PID itself that is problematic, young adult clinic, and having disease-specific guidelines and that different arrangements for transition may be required (Table 3). for different AID diagnoses. The lack of provision for patients with learning disability or mental health difficulties compared to pediatrics was also noted as a weakness of the process. Discussion Prior to transfer, services report discussing a number of different topics or concerns with their patients, with the Successful transition from pediatric to adult services is a majority of services discussing the patient’s understanding key component of clinical care for chronic conditions that of the disease (92% of services), and medication (88%), predicts treatment adherence and medical outcome [14–17]. genetics (86%), compliance with treatment (88%), and Transition for rare diseases (RD), such as PID and AID, pre- responsibility for own health care (82%), preference for tran- sent specific challenges, particularly for patients with mul- sition center (71%) and expectations of adult services (70%) tisystem disorders. In general, across Europe, pediatric PID (Supplementary Table 2). Around half of services discussed and AID care occurs mainly in specialist centers of varying mental health or wellbeing, vocational expectations, sexual sizes while dedicated adult services are less well defined. health, substance use, and/or life expectancy. Thus, provision for patients with PID and AID exhibits regional differences, creating variation in the patient care Challenges for smaller centers pathway as seen for other RD—a specific issue that ERNs seek to address [18]. This ERN-RITA study is the first report The data were reviewed to determine whether there were of transition practices for patients with PID and AID across differences between sites transferring more or less than European health centers and aimed to understand the current 10 patients to adult services each year. Sixty-one services processes and key barriers to transition for these RD. 13 210 Journal of Clinical Immunology (2023) 43:206–216 20 18 30 18 25 25 16 14 20 19 12 10 10 PID PID Frequency Frequency 10 8 8 (N=44) 15 (N=44) 8 7 AI 98 AI 6 5 10 4 (N=31) 6 (N=31) 4 3 11 5 3 3 2 0 00 00 00 11 0 00 0 0 Age range Age range 30 24 25 20 19 PID Frequency 15 13 (N=44) 9 AI 10 (N=31) 4 5 2 2 00 11 0 00 0 Age range Fig. 2  Median age at the start (a) and end (b) of the transition process and at transfer to an adult center (c) This survey was circulated to pediatric centers caring for leads to better knowledge and skills and long-term outcome patients with PID and AID and therefore the results reflect [19]. As the majority of the pediatric PID and AID services the pediatric heath care professional (HCP) perspective. begin the transition process when the patient is between the Our results report that the majority of pediatric centers ages of 16 and 18, the processes of transition and trans- have transition processes in place although only a minor- fer to adult services often occur closely together, reducing ity start early in adolescence, which is recommended as it time for adjustment for patients and their families. The most Table 2  Access to and Use of PID AI Transition Resources Patients transitioned to adolescent services prior to moving to adult care 3/44 (7%) 5/31 (16%) Transfer to adult services with designated young adult clinics 5/44 (11%) 9/31 (29%) Joint transition clinics with paediatric and adult services 33/44 (75%) 21/31 (68%) Full integration of records across paediatric and adult services 34/43 (79%) 22/30 (73%) Transition-specific research programs in the paediatric service 9/44 (20%) 9/31 (29%) 13 Journal of Clinical Immunology (2023) 43:206–216 211 Fig. 3  Use of defined transi- 38 40 40 tion processes (a) and access to national disease-specific 35 35 guidelines for transition (b) 30 30 Frequency 25 24 Frequency 25 20 20 15 Yes Yes 15 10 No No 10 6 6 5 0 5 PID AI (N=31) 0 (N=44) PID (N=44) AI (N=30) Condition Condition frequently reported factor influencing age of transfer was young people living with long-term conditions [23]. This “patient considered ready for transition,” but data were not occurred in the majority of, but not all, centers transition- gathered on whether readiness for transition is evaluated by ing young adults with PID or AID through the provision patients themselves or by medical teams. This is especially of joint in-person or virtual clinics attended by HCPs from important because 18% of the total respondents reported both pediatric and adult centers prior to the transfer of care. patient unwillingness to engage as one of the main weak- Although special care services for young people are recom- nesses of their transition program. Furthermore, patient mended by the International Patient Organisation for Pri- readiness has been observed to influence optimal transition mary immunodeficiencies (IPOPI) [24], only a small propor- in terms of health-related outcomes and the development of tion of PID and AID clinics surveyed reported transferring self-management skills by patients [20, 21]. Generic transi- their patients to adult services with designated young adult tion guidelines suggest that the process of transition should clinics, with even fewer transferring their patient cohort to start when the patient is 13 or 14 at the latest [22], in order adolescent immunology clinics prior to adult services. These to enhance patient familiarity with the adult unit and staff practices may reduce the confidence of young adults to man- prior to transfer and augment patient readiness for transfer. age their health, as only 60% or less of all the services in It may be advisable for centers to administer questionnaires this sample discuss broader psychosocial and occupational measuring the patient’s readiness to transition and tailor concerns like fertility, sexual health, substance use, men- transition plans accordingly to address the unique concerns tal health and wellbeing, vocational and life expectations, of each patient. and health insurance with their patients prior to transfer Meeting the adult team prior to transfer has been identi- (see Supplementary Table 3). Transition to adolescent cent- fied as a significant factor in predicting better outcomes for ers or dedicated young adult clinics may thus allow for the Table 3  Differences between < 10 > 10 services transferring more and less than 10 patients a year Initiate transition before 16 years 25/60 (42%) 4/12 (33%) Initiate transition between 16–18 years 22/60 (37%) 6/12 (50%) Initiate transition after 18 years 12/60 (20%) 1/12 (8%) Transfer between 14–16 years 2/60 (3%) 0/12 (0%) Transfer between 16–18 years 16/60 (27%) 5/12 (42%) Transfer between 18–20 years 36/60 (60%) 6/12 (50%) Have formal transition partner 57/60 (95%) 11/12 (92%) Defined process of transition 47/60 (78%) 11/12 (92%) Disease specific transition guidelines 10/59 (17%) 1/12 (8%) Integration of medical files 45/59 (76%) 10/11 (91%) Joint transition clinics with paediatric and adult services 44/60 (73%) 10/12 (83%) Patients transitioned to adolescent services prior to moving to adult care 6/60 (10%) 2/12 (17%) Transfer to adult services with designated young adult clinics 12/60 (20%) 1/12 (8%) Transition-specific research programs in the paediatric service 14/60 (23%) 3/12 (25%) 13 212 Journal of Clinical Immunology (2023) 43:206–216 provision of holistic care to young patients by addressing translating guidelines to practice. In addition, most infor- health and wellbeing concerns specific to this developmental mation came from countries with established Adult Immu- stage alongside those stemming from their IEI. nology Services. This study did not examine a patient and While a minority of services reported difficulties in trans- family/carer perspective, which may be different to a pro- ferring patients to adult services, there were shared difficul- fessional overview. Hence, it will be important for future ties in the process of transition where these were reported, research to explore patient and family/carer experiences of particularly the lack of engaged specialist adult services, transition and their reported difficulties with the process. which may be a contributing factor to delayed transition Finally, it is possible that findings from this study were in some centers. Fragmentation of healthcare teams across affected by selection bias—with centers already invested different services also may present challenges in identi- in transition practices being more likely to respond to the fying suitable adult centers equipped to offer all required survey. Hence, results from this survey may not reflect tran- aspects of interdisciplinary care for young patients with sition policies in centers with less-established transition multimorbidity. In addition, many services identified lack programs. of time to prepare documentation as the main weakness of Further work is needed to develop comprehensive their transition program, and/or incomplete integration of national and international illness-specific transition guide- medical records across pediatric and adult services. It is our lines for PID and AI. These should establish practices to opinion that each pediatric service, and adult services who enable young people to develop independence with respect receive transfer should have a nominated transition lead and to their healthcare and address aspects of life and wellbeing dedicated administrative staff to oversee documentation and impacted by specific health conditions. Future work should allow for more seamless transition. also consider factors conducive to successful and unsuccess- At present, while the majority of the pediatric PID and ful transition, for example, avoiding transfer of care during AID clinics across Europe reported using a defined tran- active disease phase, and any guidelines should highlight sition process to transfer patients to adult services, few the need to understand the proportion of young patients who reported having access to national disease-specific guide- are lost to follow-up or show a decline in treatment adher- lines for transition. In the interest of optimizing health- ence subsequent to the transfer of care. Accordingly, the next related outcomes for adolescents undertaking increased step for the RITA–ERN transition group is to develop good responsibility of their health, it may be advantageous to practice recommendations for transition in these populations develop disease-specific guidelines that outline gold-stand- and identify the outcome measures that can be used in future ard transition practices and outcomes based on consensus studies to assess the impact of transition guidance on the from multidisciplinary healthcare professionals. Since the long-term health of adults living with childhood-onset IEI. completion of this study, the French Network for Autoim- mune and Autoinflammatory Diseases and Italian Primary Supplementary Information The online version contains supplemen- tary material available at https://d​ oi.o​ rg/​10.1​ 007/s​ 10875-​022-​01345-y. Immunodeficiency Network have published their consen- sus statements on management of transition from pediatric RITA-ERN Transition Working Group Consortium Collaborators to adult care in patients affected with childhood-onset IEI Wouters, C. MD ­PhD30,31, Meyts, I. MD ­PhD30,31, van der Werff ten aimed at improving clinical practice in this area, with a Bosch, J. E. MD, P ­ hD32, Goffin, L. M ­ D33, Ogunjimi, B. MD P ­ hD34-36, helpful focus on different requirements for specific types Gilliaux, O. ­MD37,38, Kelecic, J. ­MD39, Jelusic, M. MD ­PhD40, Fin- gerhutová, Š. ­MUDr41, Sediva, A. MD ­PhD42, Herlin, T. MD ­PhD43, of IEI [25, 26]. Future work could also focus on guide- Seppänen Mikko R. J. MD ­PhD44, Aalto, K. MD ­PhD45, Ritterbusch, lines to support the clinical management of IEI patients H. ­RN19, Insalaco, A. M ­ D46, Moschese, V. MD P ­ hD47, Plebani, A. with certain comorbidities (such as learning disabilities) Professor of Pediatrics MD ­PhD23, Cimaz. R. ­MD48, Canessa, C. ­MD49, and those requiring long-term follow-up after corrective or Dellepiane, R. M. ­MD50, Carrabba, M. MD ­PhD51, Barzaghi, F. ­MD52, Tommasini, A. MD ­PhD53, van Laar, J.A.M. MD ­PhD11, Wulffraat, N. novel treatments (such as stem cell therapies). M. Prof MD ­PhD54, Marques L. ­MD55, Carreras, C. ­MD56, Sánchez- This study was the first large-scale survey of transition Manubens J. MD P ­ hD57, Alsina, L. MD P­ hD58,59, Seoane Reula, M. E. practices for primary immunodeficiency and autoinflam- MD ­PhD60, Mendez-Echevarria, A. MD P ­ hD61,62, Gonzales-Granado, matory conditions in Europe. However, it is important to ­ D63-65, Santamaria M. MD P L. I. M ­ hD66, Neth, O. MD P ­ hD67, Ekwall, O. MD ­PhD25,68, Brodszki, N. MD ­PhD69, Hague, R. ­MD70, Devlin, recognize that there may be a bias in reporting related to L. A. MB BChBAO MRCPCH MD ­FRCPath71, Brogan, P. MBChB the geography of the responding centers. The majority ­PhD72, Arkwright, P.D. MB P ­ hD73, Riordan, A. M ­ D74, McCann, L. of the response sites in this study were based in the UK, MRCPCH ­MMedSc74, McDermott, E. FRCP, FRCPath, ­DM75, Faust, Belgium, Italy, and Spain, and these findings may not be S. N. ­PhD76,77, Carne, E. ­MSc78 30 Department of Microbiology and Immunology, Pediatric Immu- representative of transition programs and patient cohorts in nology, KU Leuven - University of Leuven, B-3000, Leuven, Belgium regions with fewer response sites, like Central and Eastern 31 Department of Pediatrics, Division Pediatric Rheumatology, Uni- Europe and Scandinavia. The challenges are likely to be versity Hospitals Leuven, B-3000, Leuven, Belgium 32 different in different regions which may have an impact for Department of Pediatrics UZ Brussel, Brussels, Belgium 13 Journal of Clinical Immunology (2023) 43:206–216 213 33 59 Pediatric Rheumatology Department, Hôpital Universitaire des Functional Unit of Immunology, Sant Joan de Déu Hospital, Insti- Enfants Reine Fabiola (HUDERF) – Université Libre de Bruxelles, tut de Recerca Sant Joan de Déu, University of Barcelona, Barcelona, Brussels, Belgium Spain 34 60 Division of Paediatric Rheumatology, Department of Paediatrics, Multidisciplinary Immunodeficiencies Unit of adults and chil- Antwerp University Hospital, Antwerp, Belgium dren, Gregorio Marañon Hospital, Complutense University of Madrid, 35 Division of Paediatric Rheumatology, Department of Rheumatol- Madrid, Spain 61 ogy, Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium Department of Pediatric Infectious Diseases, La Paz University 35 Division of Paediatric Rheumatology, Department of Paediatrics, Hospital, 28046 Madrid, Spain 62 Universitair Ziekenhuis Brussel, Jette, Belgium Translational Research Network in Pediatric Infectious Diseases, 36 Centre for Health Economics Research and Modeling Infectious 28009 Madrid, Spain 63 Diseases, University of Antwerp, Antwerp, Belgium Primary Immunodeficiencies Unit, Pediatrics Hospital 12 octubre, 37 Pediatric department, CHU of Charleroi (Hôpital civil Marie Madrid, Spain 64 Curie), Charleroi, Belgium Instituto de Investigación, Hospital 12 octubre (imas12), Madrid, 38 Laboratory of experimental medicine (ULB222), Medicine fac- Spain 65 ulty, Université libre de Bruxelles, ISPPC, CHU of Charleroi, Charleroi School of Medicine, Complutense University, Madrid, Spain 66 (Lodelinsart), Belgium. Prof Immunology, H.U. Reina Sofia, Faculty of Medicine, Uni- 39 University Hospital Center Zagreb, Department of Pediatrics, versity of Cordoba, Cordoba, Spain 67 Division of Clinical Immunology, Allergology, Respiratory Diseases Pediatric Infectious Diseases, Rheumatology and Immunology and Rheumatology, Kišpatićeva 12, 10000 Zagreb, Croatia Unit, Hospital Universitario Virgen del Rocío, Institute of Biomedicine 40 Professor of Paediatrics, University of Zagreb, School of Medi- of Seville (IBIS)/ Universidad de Sevilla/CSIC, Red de Investigación cine, Croatia Translacional en Infectología Pediátrica RITIP, Seville, Spain 41 68 Centre for Paediatric Rheumatology and Autoinflammatory Dis- The Department of Rheumatology and Inflammation Research, eases, Department of Paediatrics and Inherited Metabolic Disorders, The Sahlgrenska Academy at University of Gothenburg, Sweden 69 1st Faculty of Medicine, Charles University, General University Hos- Department of Pediatric Oncology and Immunology, Children’s pital in Prague, Ke Karlovu 2, 128 08 Prague 2, Czech Republic Hospital, Skåne University Hospital, Lund, Sweden 42 70 Department of Immunology, Motol University Hospital, 2nd Fac- Royal Hospital for Children, Glasgow, Scotland 71 ulty of Medicine, Charles University, Prague, Czech Republic Regional Immunology Service, Royal Victoria Hospital, Belfast, 43 Department of Pediatrics, Aarhus University Hospital, Aarhus, BT126BA 72 Denmark UCL GOS Institute of Child Health, London UK 44 73 Rare Disease and Pediatric Research Centers, University of Hel- Department of Paediatric Allergy & Immunology, Royal Man- sinki and Helsinki University Central Hospital, Finland chester Children’s Hospital, Manchester, UK 45 74 Pediatric Rheumatologist, Pediatric Rheumatology, New Chil- Alder Hey Children’s Foundation Trust, Liverpool, UK 75 dren’s Hospital, University of Helsinki and Helsinki University Hos- Clinical Immunology and Allergy Department, Nottingham Uni- pital, Helsinki, Finland versity Hospitals NHS Trust 46 76 Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, NIHR Southampton Clinical Research Facility and Biomedical 00146 Roma, Italy Research Centre, University Hospital Southampton NHS Foundation 47 Pediatric Immunopathology and Allergology Unit, University of Trust, Southampton, SO16 6YD, UK 77 Rome Tor Vergata, Policlinico Tor Vergata, Rome, Italy, Saint Camillus Faculty of Medicine and Institute for Life Sciences, University of International University of Health and Medical Sciences, Italy Southampton, Southampton, SO17 1BJ, UK 48 78 Department of Clinical Sciences and Community Health, Uni- Immunodeficiency Centre for Wales, Cardiff, UK versity of Milano, Italy 49 Division of Pediatric Immunology, Department of Health Sci- Author contribution MI, BN, NM, LO, LR-S, HL, GH, MZA, AG, ences, University of Florence and Meyer Children’s Hospital, Flor- VD, RR, LS, CV, ARG, SS, JN, KW, ASK, JA, MC, TA, SB, PS-P, ence, Italy SOB, and MC contributed to the study conception, design, and material 50 Department of Pediatrics Fondazione IRCCS Ca’ Granda preparation. Data collection was performed the RITA-ERN Transition Ospedale Maggiore Policlinico Milano, Italy Working Group Consortium. Data analysis was performed by MI, BN, 51 Immunodeficiency and Autoinflammatory Disorders Centre, Inter- SOB, and MC. The first draft of the manuscript was written by MI, nal Medicine Department. Fondazione IRCCS Ca’ Granda Ospedale SOB, and MC, and all authors commented on previous versions of the Maggiore Policlinico of Milan, Italy manuscript. All authors read and approved the final manuscript. 52 San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto Funding This study was supported by the ERN-RITA. di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Insti- tute, Milan, Italy 53 Institute for Maternal and Child Health IRCCS Burlo Garofolo Data availability The datasets generated during and/or analyzed dur- and University of Trieste, Trieste, Italy ing the current study are available from the corresponding author on 54 Department of Pediatric Rheumatology, Pediatrics Division, Uni- reasonable request. versity Medical Center Utrecht, University Utrecht, the Netherlands 55 Paediatric Immunodefciencies and Infectious Diseases Unit, Pae- Declarations diatric Department, Department Centro Materno-Infantil do Norte, CHUPorto, Porto, Portugal 56 Consent for publication All authors agreed to this publication. Hospital Universitario y Politécnico La Fe, Valencia 57 Pediatric Rheumatology Unit, Department of Pediatrics, Hospital Consent to participate Consent to participate was requested in the Universitari Parc Taulí Sabadell, Spain 58 email invitation sent to professionals which included information about Pediatric Clinical Immunology and Primary Immunodeficiencies what data would be collected and how data provided would be used. Unit, Hospital Sant Joan de Déu, Barcelona, Spain 13 214 Journal of Clinical Immunology (2023) 43:206–216 Conflict of interest BN was contracted to work on this project by Royal and has received support for this manuscript from Hospital Universitario Free Hospital and Great Ormond Street Hospital; ­SB1 has received grant y Politecnico La Fe—Valencia, and support for attending meetings and/ support from the European Union, National Institute of Health Research, or travel expenses from CSL Behring; JS-M has received payment or UCLH and GOSH/ICH Biomedical Research Centers, and CSL Behring honoraria for lectures, presentations, speakers bureaus, manuscript writ- and personal fees or travel expenses from Immunodeficiency Canada/ ing, or educational events from Pfizer, and meeting/travel expenses from IAACI, CSL Behring, Baxalta US Inc, and Biotest; M ­ C1 has received AbbVie; LA has received consulting fees from CSL Behring, Grifols, grant support from the National Institute of Health Research, PIDUK, Shire, and Takeda, honoraria for lectures from CSL Behring, Shire, and CSL Behring and the Royal Free Charity and personal fees or travel Takeda, and meeting/travel expenses from CSL Behring, Grifols, Shire, expenses from Biotest, BPL, CSL Behring, Grifols, HAEUK, Shire, and Takeda; MERS participates on the Data Safety Monitoring Board or and Takeda; LR-S has received consulting fees from Pfizer and AbbVie, Advisory Board for Takeda has received meeting/travel expenses from and support for attending meetings or travel expenses from Novartis, CSL Behring and ALK, and payment or honoraria for lectures, pres- Sobi, Medac, AbbVie, and Pfizer; ARG has received research funding entations, speakers bureaus, manuscript writing, or educational events from Mallinckrodt and JAZZ Pharmaceuticals; AG and ASK receive from Takeda and CSL Behring; LIG-G is a medical advisor for AEDIP research funding from CSL Behring and Takeda; ­SB2 has received pay- and has received grant support from Fondo de Investigación Sanitaria, ment or honoraria for speakers bureaus from Sobi and Novartis; PSP has co-financed with FEDER funds; OE has received grant support from received grant support from the European Union, Instituto Carlos III, the Swedish Research Council; LAD has received funding to attend an Grifols, and CSL Behring and personal fees or travel expenses from CSL educational event from CSL, and support to attend a speaker meeting for Behring, Takeda, and Grifols; JA has received grant support from the GPs from ALK; AJJW is a participant on the advisory board for Orchard European Union, Insituto Carlos III, Fundación Daniel Bravo, research Therapeutics; PB is a trustee of UK charity Societi, treasurer of Inter- support from Novartis, Sobi, Novimmune, Roche, Pfizer, Lilly, AbbVie, national Society of Systemic Autoinflammatory Diseases, and partici- and Amgen, and personal fees or travel expenses from Novartis, Sobi, pant on the NOVARTIS gene therapy advisory board, PB has received Roche, Pfizer, Lilly, AbbVie, and Gebro; M ­ C2 has received speaking grant support from the European Union for an investigator-led clinical fees from Novartis Farma, AbbVie, Sobi, and Pfizer; KW is on the advi- trial of Prednisolone in Kawasaki disease, consulting fees from Sobi and sory boards for Shire Deutschland GmbH and LFB biomedicals, and has Novartis, payment or honoraria for lectures, presentations, speakers bu- received grant support from BMS, honoraria for lectures, symposiums, reaus, manuscript writing, or educational events from Sobi, Roche, and and meetings from CSL Behring and Shire, and travel expenses from Novartis, and payment for expert testimony from KD Scotland; SS is Shire; HL is the President-Elect for ISSAID, Council Member of the the Chair of UKPIN, and has received grant support from CSL Behring, Nephrology section of the Royal Society of Medicine, and Vice-Chair and consulting fees from Takeda and Novartis; SF is a participant on the of MHRA EAG; HL has received grant support for ImmunAID from advisory boards for AstraZeneca, Medimmune, Sanofi, Pfizer, Seqirus, EUH2020, consulting fees from Novartis, Sobi, and Roche, payment Sandoz, Merck, and J&J, and was the chair of UK NICE Sepsis (2014– or honoraria for lectures, presentations, speakers bureaus, manuscript 2016) and Lyme Disease (2016–2018) Guidelines, SF has received the writing, or educational events from Novartis and Sobi, and support for NIHR Senior Investigator Award, grant support from Pfizer, Sanofi, attending meetings and/or travel from DADA2 patient society and Sobi; GSK, J&J, Merck, AstraZeneca, and Valneva, and payment for symposi- IM is the president of European Society for Immunodeficiencies, a board ums from Pfizer. No other authors have competing interests. member of Astra Zeneca Foundation, and a senior clinical investigator at FWO Vlaanderen, IM has received grant support from CSL Behring Open Access This article is licensed under a Creative Commons Attri- Primary Immunodeficiencies Chair, European Research Council under bution 4.0 International License, which permits use, sharing, adapta- the European Union’s Horizon 2020 research and innovation program, tion, distribution and reproduction in any medium or format, as long FWO Vlaanderen, VIB Grand Challenges Program, KU Leuven Onder- as you give appropriate credit to the original author(s) and the source, zoeksraad, and the Jeffrey Modell Foundation, IM has received hono- provide a link to the Creative Commons licence, and indicate if changes raria for lecturing by CSL Behring; JVDH has received consulting fees were made. The images or other third party material in this article are from Novartis and Sobi, and payment for lectures, presentations, speak- included in the article's Creative Commons licence, unless indicated ers bureaus, manuscript writing, or educational events from Sobi; LG is otherwise in a credit line to the material. If material is not included in a participant on the Data Safety Monitoring board or Advisory Board for the article's Creative Commons licence and your intended use is not Novartis, and has received payment for presentations from Novartis, and permitted by statutory regulation or exceeds the permitted use, you will support for attending meetings and/or travel expenses from AbbVie and need to obtain permission directly from the copyright holder. To view a Novartis; ŠF has received payment or honoraria for presentations and copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. meeting/travel expenses from Sobi; AS has received payment or hono- raria for presentations, lectures, speakers bureaus, educational events, or manuscript writing from Takeda, CSL Behring, and Octapharma; TH has received payment for lectures from Novartis, and support for attend- ing meetings from Sobi; TRL is a participant on the advisory board for References Sanofi-Pasteur, and has received support for attending meetings and/or travel from Takeda; VM is the president of the Vaccine Committee of 1. Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, the Italian Society of Pediatric Allergy and Immunology, and has re- et al. Human inborn errors of immunity: 2019 update of the IUIS ceived personal fees from Takeda and CSL Behring, and travel/meeting phenotypical classification. 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HIV Med. 2021;22(8):631–40. 13 216 Journal of Clinical Immunology (2023) 43:206–216 Authors and Affiliations Muskan Israni1 · Bethany Nicholson1 · Nizar Mahlaoui2,3 · Laura Obici4 · Linda Rossi‑Semerano5 · Helen Lachmann6 · Georgia Hayward7 · Mojca Zajc Avramovič8 · Aurelien Guffroy9,10 · Virgil Dalm11,12 · Rachel Rimmer13,14 · Leire Solis15 · Carlotta Villar16 · Andrew R. Gennery17,18 · Stephanie Skeffington19 · Julia Nordin15 · Klaus Warnatz20,21 · Anne‑Sophie Korganow9,10 · Jordi Antón22 · Marco Cattalini23 · Tania Amin24 · Stephan Berg25,26 · Pere Soler‑Palacin27,28 · Siobhan O. Burns1,29 · Mari Campbell1,29 · RITA-ERN Transition Working Group Consortium 14 * Siobhan O. Burns http://www.raccuk.com siobhan.burns@ucl.ac.uk 15 International Patient Organisation for Primary * Mari Campbell Immunodeficiencies (IPOPI), Brussels, Belgium mari.campbell@nhs.net 16 Barcelona PID Foundation, Barcelona, Spain 1 17 Department of Immunology, Royal Free London NHS Paediatric Haematopoietic Stem Cell Transplant Unit, Great Foundation Trust, London, UK North Children’s Hospital (GNCH), Royal Victoria Infirmary, 2 Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK Pediatric Immuno‑Haematology and Rheumatology Unit, 18 Necker Enfants Malades University Hospital, Assistance Translational and Clinical Research Institute, Publique-Hôpitaux de Paris (AP-HP), Paris, France Faculty of Medical Sciences, Newcastle University, 3 Newcastle upon Tyne NE2 4HH, UK French National Reference Center for Primary Immune 19 Deficiencies (CEREDIH), Necker Enfants Malades Irish Vasculitis Organisation, Dublin, Ireland University Hospital, Assistance Publique-Hôpitaux de Paris 20 Center for Chronic Immunodeficiency, Medical Center, (AP-HP), Paris, France Faculty of Medicine, University of Freiburg, University 4 Fondazione IRCCS Policlinico San Matteo, Centro Per Lo of Freiburg, Freiburg, Germany Studio E La Cura Delle Amiloidosi Sistemiche, Pavia, Italy 21 Department of Rheumatology and Clinical Immunology, 5 Department of Pediatric Rheumatology, National Reference Division of Immunodeficiency, Medical Center, Faculty Centre for Auto‑Inflammatory Diseases and Amyloidosis of Medicine, University of Freiburg, Freiburg, Germany of Inflammatory Origin (CEREMAIA), Bicêtre hospital, 22 Department of Pediatric Rheumatology, Pediatric Immune Assistance Publique-Hôpitaux de Paris (AP-HP), Dysfunction Disease Study Group (GEMDIP), Institut de Le Kremlin Bicêtre, France Recerca Sant Joan de Déu, Sant Joan de Déu Hospital, 6 Division of Medicine, National Amyloidosis Centre, Barcelona, Spain University College London, London, UK 23 Pediatrics Clinic, University of Brescia, ASST Spedali Civili 7 Paediatric and Adult Rheumatology, Leeds General Infirmary Di Brescia, Brescia, Italy and Chapel Allerton Hospital, Leeds, UK 24 Department of Paediatric Rheumatology, Leeds Children’s 8 Department for Allergology, Rheumatology and Clinical Hospital, Leeds Teaching Hospitals Trust, Leeds, UK Immunology, University Children’s Hospital Ljubljana, 25 Department of Pediatrics, Institute of Clinical Sciences, Ljubljana, Slovenia The Sahlgrenska Academy, University of Gothenburg, 9 Department of Clinical Immunology and Internal Medicine, Gothenburg, Sweden Tertiary Center for Primary Immunodeficiency, National 26 Department of Pediatrics, Queen Silvia Children’s Hospital, Reference Center for Systemic Autoimmune Diseases Sahlgrenska University Hospital, Gothenburg, Sweden (CNR RESO), Hôpitaux Universitaires de Strasbourg, 27 67000 Strasbourg, France Pediatric Infectious Diseases and Immunodeficiencies Unit, 10 Hospital Universitari Vall d’Hebron, Universitat Autonoma Université de Strasbourg, INSERM UMR - S1109, de Barcelona, Bellaterra, Spain 67000 Strasbourg, France 28 11 Jeffrey Modell Diagnostic and Research Center for Primary Department of Internal Medicine, Division of Clinical Immunodeficiencies, Barcelona, Catalonia, Spain Immunology, Erasmus University Medical Center, 29 Rotterdam, the Netherlands University College London Institute of Immunity 12 and Transplantation, London, UK Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands 13 Rare Autoinflammatory Conditions Community – UK (RACC – UK), Oxford, UK 13