Impact of the Covid-19 pandemic on the care of rare and undiagnosed diseases patients in France: a longitudinal population-based study

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However, few data are reported for rare and undiagnosed diseases (RUDs). We aimed to assess the impact of the COVID-19 pandemic on the activities of the French reference network for RUDs in 2020. Results: In this observational, cross-sectional study, we extracted and analyzed the data of the French national registry for RUDs collected between Jan 1, 2019 and Dec 31, 2020. We compared the annual longitudinal evolution of face-to-face and remote care activities between 2019 and 2020 focusing on adult and pediatric patients. Compared to 2019, 2020 was marked by a decrease in rare diseases (RD) care activities (-12%) which mostly occurred during the first lockdown (-45%) but did not catch up. This decrease mostly concerned face-to-face care activities albeit a third of this decrease was compensated by telehealth activities which was multiplied by 9 during the first lockdown but decreased afterwards as in person care resumed. Finally, the total number of patients receiving care was lower in 2020(-9%) with a drastic decrease of cases with newly confirmed diagnosis (-47%). Conclusion: Although telehealth was quickly introduced, RUD patient care was strongly affected by the COVID-19 pandemic in France with a decline in the number of patients treated and new patients included. This is likely to result in delays in patient diagnosis and care over the next few years. Rare diseases COVID-19 Health policy National health registry National health program Telehealth Figures Figure 1 Figure 2 Figure 3 Background France was the ninth most impacted country by the COVID-19 pandemic in terms of confirmed cases per million people between 22 January and 31 December 2020[ 1 ]. Like several countries facing the coronavirus outbreak, France’s government triggered nationwide lockdowns to limit the spread of the virus. In 2020, two lockdowns were promulgated from 17 March to 11 May 2020 and from 30 October to 1 December 2020. These periods are associated with restricted access to health facilities giving priority to emergencies and COVID-19 patients. There are 6100 diseases identified as rare and undiagnosed diseases (RUDs) according to the online database on rare diseases Orphanet[ 2 – 5 ], i.e., disease with a prevalence less than 1 in 2,000. The current pandemic has had many impacts on people with RUDs, including health status, daily life, social life, financial status and mental health[ 6 , 7 ]. Indeed, people with RUD are particularly vulnerable to a pandemic such as COVID-19, due to structural factors, such as the small number of specialized centers, the need of multidisciplinary and high level of care required, but also to patient-related factors[ 8 ]. Indeed, RUDs are usually associated with multiple co-morbidities, some of which favor the development of severe forms of COVID-19 and anxiety among patients[ 7 ]. This has led some patients with RUDs to avoid coming to the hospital as much as possible for fear of contracting COVID-19[ 7 – 9 ]. The COVID-19 pandemic has thus led to the cancellation or postponement of a large number of follow-ups and sometimes even treatment procedures both by practitioners and by the patients themselves[ 6 , 8 , 10 ]. To cope with these difficulties, many health centers have switched from face-to-face encounters to telehealth activities [ 13 ]. However, no quantitative assessment of these organizational changes and their persistence after lockdowns have been published at a national scale. In this study, we aimed to use the French national RUDs data registry, an unprecedented support for epidemiological, clinical and therapeutic studies in the field of RUDs [ 14 , 15 ], to quantify the impact of COVID-19 pandemic longitudinally throughout the year 2020, taking 2019 as the reference year. In particular, we studied the temporal trends of face-to-face and remote activities according to French health policies, especially lockdowns. Methods Study design In 2004, France launched a national plan for rare diseases to improve patients’ care for individuals with RUDs. This plan led to the labelling of 131 reference centers, mainly multicentric, dedicated to a given a rare disease or a group of similar rare diseases, and split into 23 specialty networks. These reference centers cover the entire French territory and now include 2114 sites within the centers, either constituent or associated. In 2017, a nationwide initiative launched with the rare diseases data registry BNDMR aiming to include all rare disease sites activities in France[ 15 ] aiming to collect a common set of data shared by all rare diseases [ 16 ]. We conducted an observational, retrospective study based on the BNDMR population-based cohort. We included rare disease patients’ visits in 2019 and 2020 reported in BNDMR corresponding to the following type of care activities: day and conventional hospitalizations and encounters either face-to-face or remotely. This project was assessed by the scientific committee of the BNDMR as requested by data governance authorized by the French Data Protection Authority (Authorization DR-2019-113). Statistical Analysis We first excluded data from sites without comparable activity trend between January/February 2019 and January/February 2020, both periods being before pandemics. This was necessary because of the progressive deployment of the software application provisioning data into the BNDMR data base. First, we discarded sites with no activity at any given month of 2019 or 2020. Then, we used the isolation forest method[ 17 ] to detect site with abnormal behavior regarding the proportions of activities on January/February 2019 over the entire year of 2019, the proportions of activities in January/February 2020 over the entire year of 2020 and in January/February 2019 and January/February 2020. Median with the interquartiles provide the descriptive statistics for all the variables of interest. We used the non-parametric Wilcoxon tests to identify differences in distributions of site activity between 2019 and 2020. First, we compared the distributions of activities by sites. We then investigate differences between adult and child patients’ activities by testing the difference in the number of activities by site on adult patients only and child patients only between 2019 and 2020. The threshold for adult patient followed the majority age in France of 18 years old calculated on December 31th 2020. Third, we compared the differences in distribution of sites activities between the lockdown and non-lockdown periods of 2019 and 2020. Then, we compared activities by sites during the different periods of the year using Wilcoxon test on the following periods: pre-pandemic period (from January 1st to March 17th and from September 1th to October 14th), first lockdown (from March 17th to May 11th), deconfinement (from May 11th to July, 4th), summer break (from July, 4th to September 1th), second lockdown (from October 14th to December 15th ) and Christmas break (from December 15th to December 31th). We repeated the same analyses for face-to-face encounters on one hand and telehealth activities on the other hand. The distance that patient had traveled to their care sites was calculated using Haversine distance which computes the smallest distance between two points on a sphere[ 18 ]. The analysis was performed using R version 4.0.3 [ 19 ]. A p-value < 0.05 was considered as statistically significant, and a p-value < 0.1 as a tendency. Results Characteristics of the population and evolution of overall activities during 2020 Among the 232,204 patients for which at least one activity recorded in 2019–2020 in BNDMR, 209,403 were included in the analyses. Patients were seen in 522 active RUDs reference sites and generated 563,399 activities (Fig. 1 ). Table 1 summarized the characteristics of the patient population in 2019 and 2020 with a focus on adult and child populations. The number of patients having activities recorded in the different reference sites decreased from 145,056 in 2019 to 132,282 in 2020, the year of the COVID-19 pandemic (-9%). The number of patients with a newly confirmed diagnosis decreased from 16,799 in 2019 to 8,949 in 2020 (-47%). There was a 13% decrease from 300,019 activities in 2019 to 263,380 activities in 2020. Activities per site were not statistically different for the entire cohort and for the focus on child patients but there was an almost statistical tendency for the adult patients from 175,431 activities in 2019 to 143,654 activities in 2020 (101 [22, 383.5] activities per site in 2019 to 87 [18, 298.5] activities per site in 2020, p = 0.14). The number of activities per site significantly decreased during lockdowns from 64 [15, 189] in 2019 to 23 [8, 82] in 2020, yet the decrease outside of the lockdown periods was not statistically significant. When looking into the difference of activity between the periods, the first lockdown was the only part of the year that showed statistical significance from 46,019 activities in 2019 to 25,444 activities in 2020 (33 [8, 105.25] activities per site in 2019 versus 19 [6, 59] activities per site in 2020, p < 0.001) while the other periods did not show significant difference between 2019 and 2020 (Table 2a). More precisely, this decrease mostly concerned face-to-face activities. In particular, consultations went from 65% of the whole care activities in 2019 to 59% in 2020 while day hospitalization went from 16% in 2019 to 14% and conventional hospitalization went from 8.5–7.5% (Table 3). However, telehealth activities increased in 2020 by 277.1% (n = 27,846, i.e., from 2.5% in 2019 to 10.6% of the whole care activities in 2020). This evolution was very heterogeneous depending on the rare diseases specialty networks. While there was only a small difference in care activities between 2019 and 2020 for the network specialized in somatic or cognitive developmental anomalies (+ 2.5%) as well as for the rare and undiagnosed autoimmune and auto-inflammatory diseases (-1%), there was a major drop for the rare and undiagnosed endocrine diseases (-33%) or the neuromuscular diseases networks (-22%), (see Table 4). Focus on face-to-face care activities evolution during 2020 The year 2020 was associated with a 20% decrease in the number of face-to-face activities from 292,634 in 2019 to 235,534 in 2020. There was a statistical tendency of the number of activities per site between 2020 and 2019 (with 217.5 [51, 638.75] face-to-face activities per site in 2019 compared to 170 [50, 545.25] per site in 2020, p = 0.09). This decrease in face-to-face care appears to have affected mostly the adult patients (100.5 [22, 384.5] per site in 2019 versus 72 [16, 284.5] in 2020 for adults’ care site, p = 0.03) but seem to have had a limited impact on the child patients (64 [13, 304] activities per sites in 2019 versus 54 [12.75, 259] in 2020 activities per children’s care site, p = ns, Fig. 2 A). Concerning the type of activities, all the face-to-face activities but more particularly the regular consultations were the most negatively impacted from 194,328 in 2019 to 154,348 (143 [32–417] activities per site in 2019 versus 115 [28–319] in 2020, p = 0.066) followed by the day hospitalization with 48,217 in 2019 to 38,520 (23 [5–90] activities per site in 2019 versus 17 [4, 71] in 2020, p = 0.14), (see Fig. 2 B and Table 3). The number of activities decreased significantly during the lockdowns from 85,995 in 2019 to 33,987 in 2020 (per site : 64 [15, 179] in 2019 to 16 [6, 51], p < 0.001) while it was not statistically different during the non-lockdown periods of the year. For the face-to-face encounters, there were statistically significant differences between 2019 and 2020 during the first lockdown (33 [8, 103] in 2019 and 10 [ 4 , 31 ] in 2020, p < 0.001) and a statistical tendency during the end of lockdown period (37 [9, 109] in 2019 and 39 [8, 93] in 2020, p = 0.09) but other periods of the year were not significantly different (Table 2B, Fig. 2 C & 2 D). Focus on the evolution of telehealth during 2020 The year 2020 was marked by the emergence and development of telehealth (27,846 versus 7,385 in 2019, + 277% increase). Indeed, in 2019, only 50 sites provided this type of encounters (9.6%) compared to 359 (68.8%) in 2020. The number of telehealth activities thus increased from 2 [ 1 – 14 ] per year per site in 2019 to 19 [4–72] in 2020 (p < 0.001, Fig. 2 A). This increase was heterogeneous in France and was mostly used in reference site in large cities over 200,000 inhabitants. Indeed, these eleven cities alone account for 86.9% of the telehealth activities during COVID-19 pandemic (n = 24,224 encounters, Fig. 2 B). The number of telehealth activity rose significantly for both adult patient from 3194 in 2019 to 15812 in 2020 (2 [ 1 , 11.25] activities per site in 2019 versus 12 [3, 43] activities per site in 2020, p < 0.001) and child patient from 4004 activities in 2019 to 11640 activities in 2020 (2 [ 1 , 14.25] activities per site in 2019 versus 9 [2, 44.5] activities per site in 2020, p < 0.001). The teleconsultation activities were significantly different between 2019 and 2020 during the first lockdown from 1165 in 2019 to 11527 in 2020 (3 [ 1 , 12 ] activities per site in 2019 versus 13 [3, 38.75] activities per site in 2020, p < 0.001), end of lockdown from 1253 in 2019 to 6935 in 2020 (2 [ 1 , 16 ] activities per site in 2019 versus |7 [ 3 , 26 ] activities per site in 2020, p = 0.002), and the second lockdown from 720 to 2627 (2 [ 1 , 14.5] activities per site in 2019 versus 4 [ 2 , 14 ] activities per site in 2020, p = 0.03) but the other periods were not significantly different when it comes to the number of telehealth activities per site (Table 2C). This shift in the number of telehealth activities nationwide between 2020 and 2019 has greatly reduced patient travel. Thus, we estimated that telehealth activities in 2019 saved 1,544,234 km of total patient travel, or 39 times around the earth, compared to 11,863,158km in 2020, or 297 times around the earth (+ 668% in 2020). Discussion While the COVID-19 pandemic has had an impact on care networks, little is known about the longitudinal impact of COVID-19 pandemic on RUDs in a national-health system during the whole year of 2020[ 20 ]. In this study, we used the BNMDR registry to quantify this impact on face-to-face and remote cares. We have noticed a decline in face-to-face activity, starting in March and continuing through the rest of 2020. This decline in face-to-face activity was very marked during the first lockdown (-69%). At the same time, there was a strong increase in telehealth activities (+ 890%) during the first lockdown and during 2020 (+ 277.1% in total for the whole French rare disease network), particularly during the first lockdown and the following end of lockdown, which filled 35% of the gap. However, it is important to note that we did not identify a catch-up in the number of patients managed in 2020 when public health conditions improved. Thus, the French RUD networks have recorded a decrease in the total number of first and follow-up activities (-12%) and a decrease in the number of individuals followed (-9%) in 2020. The impact of the COVID-19 pandemic as a break in the continuum of care has been well identified in many chronic diseases. On one hand, in response to the pandemic, many countries have reallocated resources from chronic pathologies to the care of individuals suffering from COVID-19. On the other hand, due to the fear of being contaminated by COVID-19, a number of individuals postponed their medical follow-up[ 6 ]. This has had a major impact on the organization of rare disease care networks. In the Asia-Pacific region, 89% of rare disease organizations have been affected by the pandemic, 63% have had their capacity decreased and 42% have had their funding reduced[ 10 ]. In Hong-Kong, 71% of individuals with RUDs reported a reduction in clinical visits[ 6 ]. In our study, we found a very strong impact of the first lockdown on the number of encounters in the French rare disease network (-74% per centre). These data are consistent with those of the Campania Rare Disease Registry, which show a 77% decrease in the number of new rare disease diagnoses in March-April 2021 compared to the same period in 2019[ 21 ]. But it is important to note that this delay linked to first-lockdown period did not catch up during the rest of the year 2020. Indeed, the number of encounters in the rest of the year remained below that of 2019. Adult patients, especially new patients, seemed to be the most affected in this decrease of encounters. The impact of COVID-19 pandemic on the management of non-COVID-19 patients has been well documented in the cancer field[ 22 ]. In this field, a decrease in the number of new diagnoses has been highlighted. This is notably due to the temporary suspension of screening campaigns, a decrease in the number of visits to the general practitioner and an increase in the time taken to carry out investigations[ 23 , 24 ]. For instance in UK, the rate of skin cancer diagnosis was decrease by 68% between march and June 2020[ 23 ]. The number of individuals waiting more than 6 weeks for investigations (CT scan, endoscopies, MRI, ultrasonography) increased tenfold in August 2020 compared to the same period in 2019[ 24 ]. This delay in the management of these patients will lead to late-stage diagnosis and ultimately to excess mortality. Thus, the excess mortality from colorectal and lung cancers is estimated at 10,000 deaths over the next 10 years in the United States[ 25 ]. COVID-19 pandemic have also modified the care trajectories of known individuals too. Indeed, some individuals had their care protocol modified to adapt to the structural impact of COVID-19. Thus, due to the fact that a number of surgeries have been postponed because of the difficulties of the intensive care unit, some patients have had radiotherapy before surgery instead of surgery. In the same way, chemotherapy and/or radiotherapy were sometimes less intensive[ 25 ]. Another important effect of the pandemic is the suspension or the modification of many clinical trials[ 24 , 26 ]. For example, the clinicaltrials.gov website recorded 1052 study suspensions between March and April 2020, 905 of which were due to the COVID-19 pandemic[ 26 ]. It is currently difficult to quantify the impact of these changes on the long-term outcome of these individuals especially for RUDs. However, 46% of people with RUD in the Hong Kong study estimated a decline in their health status, of which 9% were marked2. Moreover, a large number of patients claim that covid-19 pandemic, especially because of the limited access to care and sometimes treatment, has affected their mental condition[ 6 , 12 , 27 , 28 ]. To face these difficulties, national and local guidance have been urgently provided to facilitate telehealth opportunities[ 29 ]. A large number of health care systems have swapped all or part of their encounters for remote ones[ 9 , 11 , 13 , 30 ]. Many studies on telehealth have asked the question: what will be the evolution of this type of encounters after the COVID-19 pandemic[ 9 , 12 , 13 ]? Our study, like others in primary care, shows a strong increase in this practice during the first lockdown (+ 890%)[ 30 ]. During the rest of 2020, we recorded an increase of the number of telehealth activities compared to 2019. Indeed, most sites began to offer telehealth due to the pandemic (9.6% in 2019 versus 68.8% in 2020). However, the evolution of this type of encounters seems to be opposed to face-to-face encounters. We have thus progressively identified a decrease in the number of telehealth activities in parallel with a progressive increase in the number of face-to-face encounters. In a study to assess caregivers’ and physicians’ satisfaction with telehealth, we found that only 19.6% of practitioners agreed to do a second visit in telehealth after a first one, expressing the need to meet physically with their patients on a regular basis[ 12 ]. Although there has been an increase in telehealth activities, there remains a deficit in the total number of encounters in 2020 compared to 2019. We hypothesized that human resources are the limiting factor in this system. This explains why there has been no real catching up in the number of cases after the periods of lockdown. Limitations In this study, we acknowledge some limitations. This is a retrospective study based on a database that is currently being rolled out with new sites opening regularly. The approach to the study relied heavily on selecting comparable sites in term of data entry, which creates by design several biases in the analysis. First, we eliminated sites with incomplete data over the year thus removing sites that had only recently joined the system. Second, we used an anomaly detection method to select sites based on the congruence of its activities during pre-pandemic periods to identify comparable sites. This approach permitted to study the impact of the pandemic on reliable sites with years of logging activity and compare 2019 and 2020 but it kept out the new sites that joined the initiative during that time. It is important to note that the impact of the COVID-19 pandemic has not been the same in different countries, as shown by the study of different national organ transplant registries[ 31 ]. An international study could be useful in order to compare and study those factors and their effects on the impact of the pandemic. Our study confirmed that the covid-19 pandemic had a strong impact on the management of non-COVID individuals with rare diseases. Conclusions Although the healthcare networks were able to adapt quickly to this situation by innovating, in particular by developing telehealth, it is important to note that this adaptation only limited the damage caused by the lockdown and the resulting limitation of face-to-face cares. These results should push healthcare networks to develop solutions in case of health crises such as the COVID-19 pandemic to limit its impact. In addition, it is important that healthcare networks are aware of the possible long-term impact of such a pandemic on the patients being followed. Priority should be given to tracking down patients lost to follow-up and including potential new patients who have yet to enter specialized care for the rare diseases to prevent them from being left behind and to limit delays in care. Declarations Ethics approval and consent to participate This project was assessed by the scientific committee of the BNDMR as requested by data governance authorized by the French Data Protection Authority (Authorization DR-2019-113). Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Funding Funders include French national research agency (INSERM) ATIP Avenir and Fondation Bettencourt Schueller. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Competing Interests The authors declare that they have no competing interests. Author Contributions LS, MK, CM, ASJ, AS, RN contributed to the conceptualization of the project. LS, CM, ASJ, MK, AS, RN all contributed to the methodology section. LS, CM contributed to the data curation and formal analysis with full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis. LS, MK, CM contributed to writing the software code for the project. MK contributed to the validation of the statistical analysis. LS, MK, CM contributed to writing the software code for the project. LS, CM, and MK contributed to the visualization in the draft. MK and LS drafted the paper with LS, MK, CM, ASJ, RN, contributing to review and editing. Acknowledgements Not applicable References Roser M. (2021) COVID-19 Data Explorer - Our World in Data. Aymé S, Urbero B, Oziel D, Lecouturier E, Biscarat A. Information sur les maladies rares: Le projet Orphanet. La Revue de Médecine Interne. 1998;19:376–7. Rath A, Olry A, Dhombres F, Brandt MM, Urbero B, Ayme S. Representation of rare diseases in health information systems: The orphanet approach to serve a wide range of end users. Hum Mutat. 2012;33:803–8. 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Glazier RH, Green ME, Wu FC, Frymire E, Kopp A, Kiran T. Shifts in office and virtual primary care during the early COVID-19 pandemic in Ontario, Canada. Can Med Assoc J. 2021;193:E200–10. Aubert O, Yoo D, Zielinski D, et al. COVID-19 pandemic and worldwide organ transplantation: A population-based study. The Lancet Public Health. 2021;6:e709–19. Tables Tables 1 to 4 are available in the Supplementary Files section. Supplementary Files covidMRtables.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 04 Oct, 2022 Reviewers agreed at journal 28 May, 2022 Reviewers invited by journal 25 May, 2022 Editor assigned by journal 24 May, 2022 First submitted to journal 17 May, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1664716","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":108687097,"identity":"6ef4e654-3c25-4aef-b874-690626d1292d","order_by":0,"name":"Louis Soussand","email":"","orcid":"","institution":"AP-HP: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Louis","middleName":"","lastName":"Soussand","suffix":""},{"id":108687098,"identity":"5bd990df-1615-4291-a4da-f83f2e791504","order_by":1,"name":"Mathieu Kuchenbuch","email":"","orcid":"","institution":"Imagine Institute for Genetic Diseases: Institut Imagine Institut des Maladies Genetiques","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mathieu","middleName":"","lastName":"Kuchenbuch","suffix":""},{"id":108687099,"identity":"1b7b0446-4a80-4617-ace8-d1e0abb7861e","order_by":2,"name":"Claude Messiaen","email":"","orcid":"","institution":"APHP: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Claude","middleName":"","lastName":"Messiaen","suffix":""},{"id":108687100,"identity":"77e42f44-272f-494b-b28b-750530db3df3","order_by":3,"name":"Arnaud Sandrin","email":"","orcid":"","institution":"APHP: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Arnaud","middleName":"","lastName":"Sandrin","suffix":""},{"id":108687101,"identity":"2cd11228-a798-416f-abef-c0a1953bd267","order_by":4,"name":"Anne-Sophie Jannot","email":"","orcid":"","institution":"Inria Research Centre of Paris: Inria Centre de Recherche de Paris","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anne-Sophie","middleName":"","lastName":"Jannot","suffix":""},{"id":108687102,"identity":"5ab9909d-9af8-48bc-82cc-2ae7e27ad086","order_by":5,"name":"Rima Nabbout","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBAC+2YInWAAIj8AGQwMjA/wajE4jNDC2DgDrIXZAL+WA0hamnmI0nKcO/ED4w67PHP2HvPHNjV38swZmNk+4PcL72YJxjPJxZY9Zwybc449K7ZsYGaegU+LHTPvBgnGNubEDTdygFrYDiduOMB/GK/DjJl5N/9gbKuHaLH4B9LCzIxXi2Ez7zagLYchWsAMQloMDvNus0hsOw70y7HCmb19zxJ3NhPScv7s5hsf26qBIda84cOPb3cSt7M349cCBgkI5gEGAyI0oACgFhJ1jIJRMApGwfAHAHzaT+zcU9i/AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5877-4074","institution":"Hôpital universitaire Necker-Enfants malades: Hopital universitaire Necker-Enfants malades","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Rima","middleName":"","lastName":"Nabbout","suffix":""}],"badges":[],"createdAt":"2022-05-17 09:22:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1664716/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1664716/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":21979132,"identity":"2d8507e7-6fb4-4391-9512-94b219f0fc41","added_by":"auto","created_at":"2022-05-27 19:30:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49040,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram for the selection of the eligible sites for this study.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1664716/v1/71d1fb70ecdf51054eed32b6.png"},{"id":21979133,"identity":"688b9377-6882-4561-995f-e6cdaba68fdc","added_by":"auto","created_at":"2022-05-27 19:30:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":354612,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of COVID-19 pandemic on face-to-face care activities in 2020 and comparison with the same activities in 2019 in 522 RUDs reference sites. A. Total face-to-face care activities in 2019 (in red) and 2020 (in black) in the paediatric and adult care system, B. Evolution of the different face-to-face activities between 2019 and 2020, C. Evolution of the total number of face-to-face activities per week in the year 2020 (in blue) according to the health policies implemented to face COVID-19 pandemic (in the lower part), the number of deaths in the year 2020 due to COVID-19 pandemic per day (in black) and the activities in the same centres in 2019 (in red) in France. D. Comparison of face-to-face activities between 2019 and 2020 by centre according to the different periods of the health policies implemented in France during COVID-19 pandemic.]\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1664716/v1/2e195bf8efcf7612dda5eb92.png"},{"id":21979135,"identity":"af3f5f24-2af0-47e5-b256-3087de30567f","added_by":"auto","created_at":"2022-05-27 19:30:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":405159,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of COVID-19 pandemic on telehealth in 2020 and comparison with the same activities in 2019 in 522 RUDs reference sites. A. Total telehealth activities in 2019 (in red) and 2020 (in black) in the paediatric and adult care system, B. Location of the telehealth activities made in the different reference centres for RUDs throughout France, C. Evolution of the total number of telehealth activities per week in the year 2020 (in blue) according to the health policies implemented to face COVID-19 pandemic (in the lower part), the number of deaths in the year 2020 due to COVID-19 pandemic per day (in black) and telehealth activities in the same sites in 2019 (in red) in France. D. Comparison of telehealth activities between 2019 and 2020 by centre according to the different periods of the health policies implemented in France during COVID-19 pandemic.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1664716/v1/1def03b75cc737a632fc3ed5.png"},{"id":21979380,"identity":"fd9876f0-bc1c-47e4-bda5-9134c2bbe967","added_by":"auto","created_at":"2022-05-27 19:35:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":339288,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1664716/v1/586f5f5e-d736-46c8-b3fc-84f6c449b9a5.pdf"},{"id":21979379,"identity":"8ad649bb-d1a1-48c0-b1a6-f2ef4fba1e7d","added_by":"auto","created_at":"2022-05-27 19:35:21","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":68004,"visible":true,"origin":"","legend":"","description":"","filename":"covidMRtables.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1664716/v1/987cfd13ddbfb78e0e9397bd.pdf"}],"financialInterests":"","formattedTitle":"Impact of the Covid-19 pandemic on the care of rare and undiagnosed diseases patients in France: a longitudinal population-based study","fulltext":[{"header":"Background","content":"\u003cp\u003eFrance was the ninth most impacted country by the COVID-19 pandemic in terms of confirmed cases per million people between 22 January and 31 December 2020[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Like several countries facing the coronavirus outbreak, France\u0026rsquo;s government triggered nationwide lockdowns to limit the spread of the virus. In 2020, two lockdowns were promulgated from 17 March to 11 May 2020 and from 30 October to 1 December 2020. These periods are associated with restricted access to health facilities giving priority to emergencies and COVID-19 patients.\u003c/p\u003e \u003cp\u003eThere are 6100 diseases identified as rare and undiagnosed diseases (RUDs) according to the online database on rare diseases Orphanet[\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], i.e., disease with a prevalence less than 1 in 2,000. The current pandemic has had many impacts on people with RUDs, including health status, daily life, social life, financial status and mental health[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Indeed, people with RUD are particularly vulnerable to a pandemic such as COVID-19, due to structural factors, such as the small number of specialized centers, the need of multidisciplinary and high level of care required, but also to patient-related factors[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Indeed, RUDs are usually associated with multiple co-morbidities, some of which favor the development of severe forms of COVID-19 and anxiety among patients[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This has led some patients with RUDs to avoid coming to the hospital as much as possible for fear of contracting COVID-19[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The COVID-19 pandemic has thus led to the cancellation or postponement of a large number of follow-ups and sometimes even treatment procedures both by practitioners and by the patients themselves[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. To cope with these difficulties, many health centers have switched from face-to-face encounters to telehealth activities [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, no quantitative assessment of these organizational changes and their persistence after lockdowns have been published at a national scale.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to use the French national RUDs data registry, an unprecedented support for epidemiological, clinical and therapeutic studies in the field of RUDs [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], to quantify the impact of COVID-19 pandemic longitudinally throughout the year 2020, taking 2019 as the reference year. In particular, we studied the temporal trends of face-to-face and remote activities according to French health policies, especially lockdowns.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eIn 2004, France launched a national plan for rare diseases to improve patients\u0026rsquo; care for individuals with RUDs. This plan led to the labelling of 131 reference centers, mainly multicentric, dedicated to a given a rare disease or a group of similar rare diseases, and split into 23 specialty networks. These reference centers cover the entire French territory and now include 2114 sites within the centers, either constituent or associated. In 2017, a nationwide initiative launched with the rare diseases data registry BNDMR aiming to include all rare disease sites activities in France[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] aiming to collect a common set of data shared by all rare diseases [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We conducted an observational, retrospective study based on the BNDMR population-based cohort. We included rare disease patients\u0026rsquo; visits in 2019 and 2020 reported in BNDMR corresponding to the following type of care activities: day and conventional hospitalizations and encounters either face-to-face or remotely. This project was assessed by the scientific committee of the BNDMR as requested by data governance authorized by the French Data Protection Authority (Authorization DR-2019-113).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eWe first excluded data from sites without comparable activity trend between January/February 2019 and January/February 2020, both periods being before pandemics. This was necessary because of the progressive deployment of the software application provisioning data into the BNDMR data base. First, we discarded sites with no activity at any given month of 2019 or 2020. Then, we used the isolation forest method[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] to detect site with abnormal behavior regarding the proportions of activities on January/February 2019 over the entire year of 2019, the proportions of activities in January/February 2020 over the entire year of 2020 and in January/February 2019 and January/February 2020. Median with the interquartiles provide the descriptive statistics for all the variables of interest. We used the non-parametric Wilcoxon tests to identify differences in distributions of site activity between 2019 and 2020. First, we compared the distributions of activities by sites. We then investigate differences between adult and child patients\u0026rsquo; activities by testing the difference in the number of activities by site on adult patients only and child patients only between 2019 and 2020. The threshold for adult patient followed the majority age in France of 18 years old calculated on December 31th 2020. Third, we compared the differences in distribution of sites activities between the lockdown and non-lockdown periods of 2019 and 2020. Then, we compared activities by sites during the different periods of the year using Wilcoxon test on the following periods: pre-pandemic period (from January 1st to March 17th and from September 1th to October 14th), first lockdown (from March 17th to May 11th), deconfinement (from May 11th to July, 4th), summer break (from July, 4th to September 1th), second lockdown (from October 14th to December 15th ) and Christmas break (from December 15th to December 31th).\u003c/p\u003e \u003cp\u003eWe repeated the same analyses for face-to-face encounters on one hand and telehealth activities on the other hand. The distance that patient had traveled to their care sites was calculated using Haversine distance which computes the smallest distance between two points on a sphere[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The analysis was performed using R version 4.0.3 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered as statistically significant, and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 as a tendency.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the population and evolution of overall activities during 2020\u003c/h2\u003e \u003cp\u003eAmong the 232,204 patients for which at least one activity recorded in 2019\u0026ndash;2020 in BNDMR, 209,403 were included in the analyses. Patients were seen in 522 active RUDs reference sites and generated 563,399 activities (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Table\u0026nbsp;1 summarized the characteristics of the patient population in 2019 and 2020 with a focus on adult and child populations. The number of patients having activities recorded in the different reference sites decreased from 145,056 in 2019 to 132,282 in 2020, the year of the COVID-19 pandemic (-9%). The number of patients with a newly confirmed diagnosis decreased from 16,799 in 2019 to 8,949 in 2020 (-47%). There was a 13% decrease from 300,019 activities in 2019 to 263,380 activities in 2020. Activities per site were not statistically different for the entire cohort and for the focus on child patients but there was an almost statistical tendency for the adult patients from 175,431 activities in 2019 to 143,654 activities in 2020 (101 [22, 383.5] activities per site in 2019 to 87 [18, 298.5] activities per site in 2020, p\u0026thinsp;=\u0026thinsp;0.14). The number of activities per site significantly decreased during lockdowns from 64 [15, 189] in 2019 to 23 [8, 82] in 2020, yet the decrease outside of the lockdown periods was not statistically significant. When looking into the difference of activity between the periods, the first lockdown was the only part of the year that showed statistical significance from 46,019 activities in 2019 to 25,444 activities in 2020 (33 [8, 105.25] activities per site in 2019 versus 19 [6, 59] activities per site in 2020, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) while the other periods did not show significant difference between 2019 and 2020 (Table\u0026nbsp;2a). More precisely, this decrease mostly concerned face-to-face activities. In particular, consultations went from 65% of the whole care activities in 2019 to 59% in 2020 while day hospitalization went from 16% in 2019 to 14% and conventional hospitalization went from 8.5\u0026ndash;7.5% (Table\u0026nbsp;3). However, telehealth activities increased in 2020 by 277.1% (n\u0026thinsp;=\u0026thinsp;27,846, i.e., from 2.5% in 2019 to 10.6% of the whole care activities in 2020). This evolution was very heterogeneous depending on the rare diseases specialty networks. While there was only a small difference in care activities between 2019 and 2020 for the network specialized in somatic or cognitive developmental anomalies (+\u0026thinsp;2.5%) as well as for the rare and undiagnosed autoimmune and auto-inflammatory diseases (-1%), there was a major drop for the rare and undiagnosed endocrine diseases (-33%) or the neuromuscular diseases networks (-22%), (see Table\u0026nbsp;4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eFocus on face-to-face care activities evolution during 2020\u003c/h2\u003e \u003cp\u003eThe year 2020 was associated with a 20% decrease in the number of face-to-face activities from 292,634 in 2019 to 235,534 in 2020. There was a statistical tendency of the number of activities per site between 2020 and 2019 (with 217.5 [51, 638.75] face-to-face activities per site in 2019 compared to 170 [50, 545.25] per site in 2020, p\u0026thinsp;=\u0026thinsp;0.09). This decrease in face-to-face care appears to have affected mostly the adult patients (100.5 [22, 384.5] per site in 2019 versus 72 [16, 284.5] in 2020 for adults\u0026rsquo; care site, p\u0026thinsp;=\u0026thinsp;0.03) but seem to have had a limited impact on the child patients (64 [13, 304] activities per sites in 2019 versus 54 [12.75, 259] in 2020 activities per children\u0026rsquo;s care site, p\u0026thinsp;=\u0026thinsp;ns, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Concerning the type of activities, all the face-to-face activities but more particularly the regular consultations were the most negatively impacted from 194,328 in 2019 to 154,348 (143 [32\u0026ndash;417] activities per site in 2019 versus 115 [28\u0026ndash;319] in 2020, p\u0026thinsp;=\u0026thinsp;0.066) followed by the day hospitalization with 48,217 in 2019 to 38,520 (23 [5\u0026ndash;90] activities per site in 2019 versus 17 [4, 71] in 2020, p\u0026thinsp;=\u0026thinsp;0.14), (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe number of activities decreased significantly during the lockdowns from 85,995 in 2019 to 33,987 in 2020 (per site : 64 [15, 179] in 2019 to 16 [6, 51], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) while it was not statistically different during the non-lockdown periods of the year. For the face-to-face encounters, there were statistically significant differences between 2019 and 2020 during the first lockdown (33 [8, 103] in 2019 and 10 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] in 2020, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a statistical tendency during the end of lockdown period (37 [9, 109] in 2019 and 39 [8, 93] in 2020, p\u0026thinsp;=\u0026thinsp;0.09) but other periods of the year were not significantly different (Table\u0026nbsp;2B, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC \u0026amp; \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFocus on the evolution of telehealth during 2020\u003c/h2\u003e \u003cp\u003eThe year 2020 was marked by the emergence and development of telehealth (27,846 versus 7,385 in 2019, +\u0026thinsp;277% increase). Indeed, in 2019, only 50 sites provided this type of encounters (9.6%) compared to 359 (68.8%) in 2020. The number of telehealth activities thus increased from 2 [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] per year per site in 2019 to 19 [4\u0026ndash;72] in 2020 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). This increase was heterogeneous in France and was mostly used in reference site in large cities over 200,000 inhabitants. Indeed, these eleven cities alone account for 86.9% of the telehealth activities during COVID-19 pandemic (n\u0026thinsp;=\u0026thinsp;24,224 encounters, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The number of telehealth activity rose significantly for both adult patient from 3194 in 2019 to 15812 in 2020 (2 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, 11.25] activities per site in 2019 versus 12 [3, 43] activities per site in 2020, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and child patient from 4004 activities in 2019 to 11640 activities in 2020 (2 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, 14.25] activities per site in 2019 versus 9 [2, 44.5] activities per site in 2020, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The teleconsultation activities were significantly different between 2019 and 2020 during the first lockdown from 1165 in 2019 to 11527 in 2020 (3 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] activities per site in 2019 versus 13 [3, 38.75] activities per site in 2020, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), end of lockdown from 1253 in 2019 to 6935 in 2020 (2 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] activities per site in 2019 versus |7 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] activities per site in 2020, p\u0026thinsp;=\u0026thinsp;0.002), and the second lockdown from 720 to 2627 (2 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, 14.5] activities per site in 2019 versus 4 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] activities per site in 2020, p\u0026thinsp;=\u0026thinsp;0.03) but the other periods were not significantly different when it comes to the number of telehealth activities per site (Table\u0026nbsp;2C). This shift in the number of telehealth activities nationwide between 2020 and 2019 has greatly reduced patient travel. Thus, we estimated that telehealth activities in 2019 saved 1,544,234 km of total patient travel, or 39 times around the earth, compared to 11,863,158km in 2020, or 297 times around the earth (+\u0026thinsp;668% in 2020).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWhile the COVID-19 pandemic has had an impact on care networks, little is known about the longitudinal impact of COVID-19 pandemic on RUDs in a national-health system during the whole year of 2020[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In this study, we used the BNMDR registry to quantify this impact on face-to-face and remote cares. We have noticed a decline in face-to-face activity, starting in March and continuing through the rest of 2020. This decline in face-to-face activity was very marked during the first lockdown (-69%). At the same time, there was a strong increase in telehealth activities (+\u0026thinsp;890%) during the first lockdown and during 2020 (+\u0026thinsp;277.1% in total for the whole French rare disease network), particularly during the first lockdown and the following end of lockdown, which filled 35% of the gap. However, it is important to note that we did not identify a catch-up in the number of patients managed in 2020 when public health conditions improved. Thus, the French RUD networks have recorded a decrease in the total number of first and follow-up activities (-12%) and a decrease in the number of individuals followed (-9%) in 2020. The impact of the COVID-19 pandemic as a break in the continuum of care has been well identified in many chronic diseases. On one hand, in response to the pandemic, many countries have reallocated resources from chronic pathologies to the care of individuals suffering from COVID-19. On the other hand, due to the fear of being contaminated by COVID-19, a number of individuals postponed their medical follow-up[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This has had a major impact on the organization of rare disease care networks. In the Asia-Pacific region, 89% of rare disease organizations have been affected by the pandemic, 63% have had their capacity decreased and 42% have had their funding reduced[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In Hong-Kong, 71% of individuals with RUDs reported a reduction in clinical visits[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In our study, we found a very strong impact of the first lockdown on the number of encounters in the French rare disease network (-74% per centre). These data are consistent with those of the Campania Rare Disease Registry, which show a 77% decrease in the number of new rare disease diagnoses in March-April 2021 compared to the same period in 2019[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. But it is important to note that this delay linked to first-lockdown period did not catch up during the rest of the year 2020. Indeed, the number of encounters in the rest of the year remained below that of 2019. Adult patients, especially new patients, seemed to be the most affected in this decrease of encounters. The impact of COVID-19 pandemic on the management of non-COVID-19 patients has been well documented in the cancer field[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this field, a decrease in the number of new diagnoses has been highlighted. This is notably due to the temporary suspension of screening campaigns, a decrease in the number of visits to the general practitioner and an increase in the time taken to carry out investigations[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. For instance in UK, the rate of skin cancer diagnosis was decrease by 68% between march and June 2020[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The number of individuals waiting more than 6 weeks for investigations (CT scan, endoscopies, MRI, ultrasonography) increased tenfold in August 2020 compared to the same period in 2019[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This delay in the management of these patients will lead to late-stage diagnosis and ultimately to excess mortality. Thus, the excess mortality from colorectal and lung cancers is estimated at 10,000 deaths over the next 10 years in the United States[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. COVID-19 pandemic have also modified the care trajectories of known individuals too. Indeed, some individuals had their care protocol modified to adapt to the structural impact of COVID-19. Thus, due to the fact that a number of surgeries have been postponed because of the difficulties of the intensive care unit, some patients have had radiotherapy before surgery instead of surgery. In the same way, chemotherapy and/or radiotherapy were sometimes less intensive[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Another important effect of the pandemic is the suspension or the modification of many clinical trials[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. For example, the clinicaltrials.gov website recorded 1052 study suspensions between March and April 2020, 905 of which were due to the COVID-19 pandemic[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. It is currently difficult to quantify the impact of these changes on the long-term outcome of these individuals especially for RUDs. However, 46% of people with RUD in the Hong Kong study estimated a decline in their health status, of which 9% were marked2. Moreover, a large number of patients claim that covid-19 pandemic, especially because of the limited access to care and sometimes treatment, has affected their mental condition[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo face these difficulties, national and local guidance have been urgently provided to facilitate telehealth opportunities[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A large number of health care systems have swapped all or part of their encounters for remote ones[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Many studies on telehealth have asked the question: what will be the evolution of this type of encounters after the COVID-19 pandemic[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]? Our study, like others in primary care, shows a strong increase in this practice during the first lockdown (+\u0026thinsp;890%)[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. During the rest of 2020, we recorded an increase of the number of telehealth activities compared to 2019. Indeed, most sites began to offer telehealth due to the pandemic (9.6% in 2019 versus 68.8% in 2020). However, the evolution of this type of encounters seems to be opposed to face-to-face encounters. We have thus progressively identified a decrease in the number of telehealth activities in parallel with a progressive increase in the number of face-to-face encounters. In a study to assess caregivers\u0026rsquo; and physicians\u0026rsquo; satisfaction with telehealth, we found that only 19.6% of practitioners agreed to do a second visit in telehealth after a first one, expressing the need to meet physically with their patients on a regular basis[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although there has been an increase in telehealth activities, there remains a deficit in the total number of encounters in 2020 compared to 2019. We hypothesized that human resources are the limiting factor in this system. This explains why there has been no real catching up in the number of cases after the periods of lockdown.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eIn this study, we acknowledge some limitations. This is a retrospective study based on a database that is currently being rolled out with new sites opening regularly. The approach to the study relied heavily on selecting comparable sites in term of data entry, which creates by design several biases in the analysis. First, we eliminated sites with incomplete data over the year thus removing sites that had only recently joined the system. Second, we used an anomaly detection method to select sites based on the congruence of its activities during pre-pandemic periods to identify comparable sites. This approach permitted to study the impact of the pandemic on reliable sites with years of logging activity and compare 2019 and 2020 but it kept out the new sites that joined the initiative during that time. It is important to note that the impact of the COVID-19 pandemic has not been the same in different countries, as shown by the study of different national organ transplant registries[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. An international study could be useful in order to compare and study those factors and their effects on the impact of the pandemic. Our study confirmed that the covid-19 pandemic had a strong impact on the management of non-COVID individuals with rare diseases.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAlthough the healthcare networks were able to adapt quickly to this situation by innovating, in particular by developing telehealth, it is important to note that this adaptation only limited the damage caused by the lockdown and the resulting limitation of face-to-face cares. These results should push healthcare networks to develop solutions in case of health crises such as the COVID-19 pandemic to limit its impact. In addition, it is important that healthcare networks are aware of the possible long-term impact of such a pandemic on the patients being followed. Priority should be given to tracking down patients lost to follow-up and including potential new patients who have yet to enter specialized care for the rare diseases to prevent them from being left behind and to limit delays in care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was assessed by the scientific committee of the BNDMR as requested by data governance authorized by the French Data Protection Authority (Authorization DR-2019-113).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eFunders include French national research agency (INSERM) ATIP Avenir and Fondation Bettencourt Schueller. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.\u003c/p\u003e\n\u003ch2\u003eCompeting Interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\n\u003cp\u003eLS, MK, CM, ASJ, AS, RN contributed to the conceptualization of the project. LS, CM, ASJ, MK, AS, RN all contributed to the methodology section. LS, CM contributed to the data curation and formal analysis with full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis. LS, MK, CM contributed to writing the software code for the project. MK contributed to the validation of the statistical analysis. LS, MK, CM contributed to writing the software code for the project. LS, CM, and MK contributed to the visualization in the draft. MK and LS drafted the paper with LS, MK, CM, ASJ, RN, contributing to review and editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoser M. (2021) COVID-19 Data Explorer - Our World in Data.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAym\u0026eacute; S, Urbero B, Oziel D, Lecouturier E, Biscarat A. Information sur les maladies rares: Le projet Orphanet. La Revue de M\u0026eacute;decine Interne. 1998;19:376\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRath A, Olry A, Dhombres F, Brandt MM, Urbero B, Ayme S. Representation of rare diseases in health information systems: The orphanet approach to serve a wide range of end users. Hum Mutat. 2012;33:803\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaendel M, Vasilevsky N, Unni D, et al. How many rare diseases are there? Nat Rev Drug Discovery. 2020;19:77\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, Murphy D, Le Cam Y, Rath A. Estimating cumulative point prevalence of rare diseases: Analysis of the Orphanet database. Eur J Hum Genet. 2020;28:165\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung CCY, Wong WHS, Fung JLF, Hong Kong RD, Chung BHY. Impact of COVID-19 pandemic on patients with rare disease in Hong Kong. Eur J Med Genet. 2020;63:104062.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHalley MC, Stanley T, Maturi J, Goldenberg AJ, Bernstein JA, Wheeler MT, Tabor HK. \u0026ldquo;It seems like COVID-19 now is the only disease present on Earth\u0026rdquo;: Living with a rare or undiagnosed disease during the COVID-19 pandemic. Genet Sci. 2021;23:837\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAktas P. Chronic and rare disease patients\u0026rsquo; access to healthcare services during a health crisis: The example of the COVID-19 pandemic in Turkey. Health Expect. 2021;24:1812\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexander GC, Tajanlangit M, Heyward J, Mansour O, Qato DM, Stafford RS. Use and Content of Primary Care Office-Based vs Telemedicine Care Visits During the COVID-19 Pandemic in the US. JAMA Netw Open. 2020;3:e2021476.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung CCY, Ng YNC, Jain R, Chung BHY. A thematic study: Impact of COVID-19 pandemic on rare disease organisations and patients across ten jurisdictions in the Asia Pacific region. Orphanet J Rare Dis. 2021;16:119.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSigurdsson EL, Blondal AB, Jonsson JS, Tomasdottir MO, Hrafnkelsson H, Linnet K, Sigurdsson JA. How primary healthcare in Iceland swiftly changed its strategy in response to the COVID-19 pandemic. BMJ Open. 2020;10:e043151.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeng T, Sareidaki DE, Chemaly N, Bar C, Coste-Zeitoun D, Kuchenbuch M, Nabbout R. Physician and patient satisfaction with the switch to remote outpatient encounters in epilepsy clinics during the Covid-19 pandemic. Seizure - European Journal of Epilepsy. 2021;91:60\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuchenbuch M, D\u0026rsquo;Onofrio G, Wirrell E, et al (2020) An accelerated shift in the use of remote systems in epilepsy due to the COVID-19 pandemic. Epilepsy \u0026amp; Behavior: E\u0026amp;B 112:107376.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMessiaen C, Racine C, Khatim A, et al. 10 years of CEMARA database in the AnDDI-Rares network: A unique resource facilitating research and epidemiology in developmental disorders in France. Orphanet J Rare Dis. 2021;16:345.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJannot A-S, Messiaen C, Khatim A, Pichon T, Sandrin A. The ongoing French BaMaRa-BNDMR cohort: Implementation and deployment of a nationwide information system on rare disease. Journal of the American Medical Informatics Association: JAMIA ocab; 2021. p.\u0026nbsp;237.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoquet R, Maaroufi M, Carrara A de, Messiaen C, Luigi E, Landais P. A methodology for a minimum data set for rare diseases to support national centers of excellence for healthcare and research. J Am Med Inf Association: JAMIA. 2015;22:76\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu FT, Ting KM, Zhou Z-H. (2008) Isolation Forest. In: 2008 Eighth IEEE International Conference on Data Mining. pp\u0026nbsp;413\u0026ndash;422.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026iacute;os J, de My. (2011) Memoria Sobre Algunos Metodos Nuevos De Calcular La Longitud Por Las Distancias Lunares Y Explicaciones Pr\u0026aacute;cticas De Una Teor\u0026iacute;a Para La Soluci\u0026oacute;n De Otros Problemas De Navegaci\u0026oacute;n\u0026hellip; Nabu Press.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTeam RC. (2021) R: A Language and Environment for Statistical Computing.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTalarico R, Aguilera S, Alexander T, et al. The impact of COVID-19 on rare and complex connective tissue diseases: The experience of ERN ReCONNET. Nat Rev Rheumatol. 2021;17:177\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLimongelli G, Iucolano S, Monda E, et al (2021) Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: Data from the Campania Rare Disease Registry. Journal of Public Health (Oxford, England) fdab137.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKempf E, Lam\u0026eacute; G, Layese R, et al. New cancer cases at the time of SARS-Cov2 pandemic and related public health policies: A persistent and concerning decrease long after the end of the national lockdown. Eur J Cancer. 2021;150:260\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndrew TW, Alrawi M, Lovat P. Reduction in skin cancer diagnoses in the UK during the COVID-19 pandemic. Clin Exp Dermatol. 2021;46:145\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreenwood E, Swanton C. Consequences of COVID-19 for cancer care - a CRUK perspective. Nat Reviews Clin Oncol. 2021;18:3\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharpless N. (2021) COVID-19 and cancer.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsaad M, Habibullah NK, Butler CE. The Impact of COVID-19 on Clinical Trials. Ann Surg. 2020;272:e222\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePettinicchio D, Maroto M, Chai L, Lukk M. Findings from an online survey on the mental health effects of COVID-19 on Canadians with disabilities and chronic health conditions. Disabil Health J. 2021;14:101085.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedman C. The COVID-19 pandemic and quality of life outcomes of people with intellectual and developmental disabilities. Disabil Health J. 2021;14:101117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWherton J, Shaw S, Papoutsi C, Seuren L, Greenhalgh T. Guidance on the introduction and use of video consultations during COVID-19: Important lessons from qualitative research. BMJ Lead. 2020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/leader-2020-000262\u003c/span\u003e\u003cspan address=\"10.1136/leader-2020-000262\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlazier RH, Green ME, Wu FC, Frymire E, Kopp A, Kiran T. Shifts in office and virtual primary care during the early COVID-19 pandemic in Ontario, Canada. Can Med Assoc J. 2021;193:E200\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAubert O, Yoo D, Zielinski D, et al. COVID-19 pandemic and worldwide organ transplantation: A population-based study. The Lancet Public Health. 2021;6:e709\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rare diseases, COVID-19, Health policy, National health registry, National health program, Telehealth","lastPublishedDoi":"10.21203/rs.3.rs-1664716/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1664716/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Preliminary data suggest that COVID-19 pandemic has generated a switch from face-to-face to remote care for individuals with chronic diseases. However, few data are reported for rare and undiagnosed diseases (RUDs). We aimed to assess the impact of the COVID-19 pandemic on the activities of the French reference network for RUDs in 2020.\u003c/p\u003e\u003cp\u003eResults: In this observational, cross-sectional study, we extracted and analyzed the data of the French national registry for RUDs collected between Jan 1, 2019 and Dec 31, 2020. We compared the annual longitudinal evolution of face-to-face and remote care activities between 2019 and 2020 focusing on adult and pediatric patients. Compared to 2019, 2020 was marked by a decrease in rare diseases (RD) care activities (-12%) which mostly occurred during the first lockdown (-45%) but did not catch up. This decrease mostly concerned face-to-face care activities albeit a third of this decrease was compensated by telehealth activities which was multiplied by 9 during the first lockdown but decreased afterwards as in person care resumed. Finally, the total number of patients receiving care was lower in 2020(-9%) with a drastic decrease of cases with newly confirmed diagnosis (-47%).\u003c/p\u003e\u003cp\u003eConclusion: Although telehealth was quickly introduced, RUD patient care was strongly affected by the COVID-19 pandemic in France with a decline in the number of patients treated and new patients included. This is likely to result in delays in patient diagnosis and care over the next few years.\u003c/p\u003e","manuscriptTitle":"Impact of the Covid-19 pandemic on the care of rare and undiagnosed diseases patients in France: a longitudinal population-based study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-27 19:30:19","doi":"10.21203/rs.3.rs-1664716/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-10-04T06:47:21+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2022-05-28T05:18:15+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-05-25T10:52:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-05-25T00:52:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2022-05-17T05:19:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7e6691b7-81e2-409b-87e6-7a297c593d8c","owner":[],"postedDate":"May 27th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-11-15T22:24:30+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-27 19:30:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1664716","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1664716","identity":"rs-1664716","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}