The Impact of COVID-19 on the State of Clinical and Laboratory Research Globally in Transplantation in May 2020 (2020)

INTRODUCTION The impact of the COVID-19 pandemic is very wide and occupies almost every aspect of life across the world with the wave of direct health impacts cutting across each nation at different paces. The impact on the economies of all countries has been dramatic and has yet to become fully apparent. The effect of the pandemic on the health of transplant patients has been extensive with data published across a number of journals from both single centers and regional and national databases. It is becoming clear that transplant patients are more likely to catch SARS-CoV-2 and when infected have a much increased mortality risk. Impact on clinical services, through reduction in intensive care unit bed availability and decreased deceased organ donors, as well as diversion of clinical staff and other resources from transplantation, has led to dramatic decreases in clinical transplant activity. We have documented these impacts through the pages of Transplantation and through the COVID-19 Transplantation map established with the cooperation of The Transplantation Society.1,2 What has not yet been documented to any degree so far is the impact on clinical and basic laboratory research in Transplantation. This round up of experiences from around the world shows substantial closure and diversion of effort from Transplantation research both in the clinic and in the laboratory with a future that is uncertain. Some countries and some centers have been more impacted than others. We hope by illuminating this feature of the pandemic we can assist in resuscitating research in our field as soon as compatible with the phases of the pandemic in each country. LONDON, ENGLAND With the recognition of the scale of the epidemic in the United Kingdom in early March, all research associated with our hospital unrelated to COVID-19 was closed with immediate effect. All research staff were redeployed to centrally funded COVID-19 studies. Plans to appoint new research staff were cancelled, and all research collaboration with international colleagues suspended. Clinically orientated basic research projects on liver transplantation have been deeply affected by these decisions. Research projects put on hold include those on hepatic innate immunity and hepatocellular carcinoma in explanted livers, hepatocyte transplantation, and studies on hepatic innate and adaptive immune response. Clinical trials that involve antiviral therapies, posttransplant tolerance, and gut microbiota have also been put on hold as most patients are managed by virtual clinics and samples cannot be collected. Research grants have been frozen with the majority of funding now directed to investigate COVID-19. Following the general community lockdown in late March, all clinical academics have been working fulltime on projects involving therapeutic trials for COVID-19. A project on posttransplant patients infected with COVID-19 is being formalized, however, sample collections will be problematic, since the majority of transplant patients are in self-isolation. Since March 2020, the number of new transplants performed has collapsed and the associated research projects have thus been put on hold for the lack of clinical samples. Research into the molecular and immunological mechanisms of ischemia/reperfusion damage and the impact of machine perfusion on marginal livers has been affected. We are currently not using marginal livers because of the potential for prolonged intensive care needs posttransplantation, the potential risk of infection, and the lack of junior personnel. Additionally laboratories have been closed down and all basic science research staff have been asked to stay at home for their safety. Now in May, some research staff are being released back from frontline duties, but it is not clear when transplant-related research can be resumed. PERTH AND SYDNEY, AUSTRALIA The COVID-19 pandemic has posed considerable challenges and uncertainty within the broad research environment in Australia, with enforced changes to the ability of researchers to conduct studies within the confine of the restrictions imposed by the research institute or hospitals. The National Health and Medical Research Council (NHMRC), Australia’s peak body for research funding has acknowledged the difficulties in performing research during the pandemic and has made allowances for variations to the milestones for project completion. The current priorities for the NHMRC and the Australian Research Council are COVID-19-related research. Some of the current funding schemes for trials and cohort studies, and the Synergy grants initiative have been delayed and rescheduled, leaving financial and career uncertainties among our research staff. At a local level, there have been important caveats when determining the continuation of study and trial activities, as opposed to the safety and willingness of participants to engage in these activities. The temporary discontinuation of acute kidney transplant services in Australia and the apprehension of excess immunosuppression in transplant recipients have led to the suspension of investigator and contract transplant study and trial activities. Although acute transplant service has recommenced in Australia in early May, there continues to be a general reluctance to reinitiate clinical research activities, in accordance with the advice and guidance of the NHMRC to prioritize the safety and well-being of research participants and staff. In addition, the decisions of hospitals and research institutions to impose restrictions on external personnel attending research centers, including study and trial participants have further added to the complexity of conducting research. Particularly affected are studies that assess the impact of modification of healthcare service and delivery on the health outcomes of vulnerable participants such as in children with chronic kidney disease or have received kidney transplants. The approach to recruitment and consent for participants in studies and trials has led to transformation from face- to-face recruitment to use of video conferencing and telephone, subjected to ethics committee approval. This has proved especially problematic for the recruitment of pediatric and adolescent participants of nonconsenting ages. COVID-19 has had an equally severe effect on laboratory research, with trials of experimental therapies largely halted due to concerns related to the risk of COVID-19 and potential for increased severity of infections in affected individuals. Usual monitoring practices have become problematic, with closures of regional boundaries and shipping of samples to central laboratories has in some circumstances ceased. Furthermore, the impact of social distancing and closures of university campuses and institutes has limited laboratory work to critical experiments, which jeopardizes completion dates for students and limits data collection for future grant funding applications. Although Australia has started to relax COVID-19 restriction, which may have a favorable impact on restarting and increasing current research activities, the engagement with international collaborators from “higher risk” countries with a greater number of COVID-19 cases remains very restricted. Each country is at a different phase of the pandemic response and research activities governed by their internal organizational structures are hetergeneous. Consequently, reliance on international collaborators to participate in jointly funded studies and trials remains unpredictable. The research landscape has changed with the effects likely to be felt for many years. ROTTERDAM, THE NETHERLANDS The laboratory research program at the Erasmus MC, Rotterdam, was mostly stopped on March 16, 2020. Since then, researchers have no longer been allowed to be physically present in the Erasmus MC. This was a far-reaching step which heavily impacted our laboratory research activities. Only for experiments with living material (cells and animals), laboratory personnel have been allowed to come to the research facilities to finalize experiments with all others working from home up to April 30. Our clinical research programs have been minimized, which impacted the transplant-related laboratory research. For example, hardly any patient blood and urine samples have been drawn and transferred to the laboratory for analysis. Also, no patients have been enrolled in (new) studies, and no new laboratory data have been generated. Consequently, our PhD students and postdocs swapped their priorities to writing manuscripts and grant proposals. Virtual laboratory meetings were organized to discuss progress and share information, which has worked quite well. As of early April, the number of people infected and hospitalized patients slowly declined, and scientists were allowed to restart their research under strict governmental (Dutch) guidelines. Of importance is that our employees (1) have to adhere to the principle of “social distancing,” the 1.5-meter rule, and (2) continue to work from home as much as possible. We are currently working in shifts to limit the number of people in our facility and offices at any 1 time, while group meetings and supervision sessions are still performed online from home. As a result of the improved situation with fewer COVID-19 patients in our hospital, the transplant program also restarted, which together with the relaxed research guidelines improved “hands-on” work back to about 50%–60% of normal levels from May 15, 2020. The clinical transplant program of the Erasmus MC was put on hold on March 13, 2020, and was restarted on May 7 when we performed the first living donor kidney transplant in 2 months. This patient was included in a prospective clinical trial. In the meantime, however, no patients have been included in de novo kidney transplant studies. In addition, no patients who are in the maintenance phase after transplantation have been included in any clinical study, apart from a validation study of a dried-blood spot analysis. We aim to fast track this dried-blood analysis method (which enables measurement of immunosuppressive drug concentrations and creatinine in a drop of blood) for clinical implementation, enabling minimization of patient visits to the outpatient clinic. Patients who were already participating in clinical studies have been followed as usual, with study visits combined as much as possible with routine outpatient checkups. The clinical research activities have been further impacted by the transfer of our transplant research nurses to the intensive care and hemodialysis units to take care of patients with COVID-19. Much of the research on health behavior, self-management, and mental health of transplant patients incorporates face-to-face interviews or interventions. As such, upon the commencement of the lockdown in early March all these research activities were put on hold. For example, outreaching interventions including home-visits are no longer possible. While it is certainly possible to translate a face-to-face intervention to a digital format, it is then essentially a different intervention. This has various methodological consequences. If we continue to deliver our interventions in an adapted format, we are concerned that the findings will not be comparable to the findings among participants in the pre-COVID-19 period. Can we cluster these groups together to maintain the power in the analysis? Might the pandemic influence the key outcomes and how might this affect our findings? We concluded that any continuation in an adapted form would be a significant protocol deviation and findings would therefore not be comparable. Finally, interventional research among transplant recipients that was due to commence in March or thereafter has been suspended until transplant programs are reestablished. One of the main challenges with such studies is the inclusion of sufficient patients to be able to demonstrate an effect. Anticipating difficulty recruiting participants in the outpatient clinic we have decided to postpone initiation of new studies until September 2020 in the hope that transplant programs will then be fully operational. PhD projects will therefore take longer to complete and require additional funding for the extension. Finally, while clinic-based research was put on hold we initiated a telephone interview study to assess the impact of the pandemic on the lives and mental health of patients who received a kidney transplant at our center (Dutch trial register NL8599). NANTES, FRANCE As a consequence of the national lockdown, which started on March 16, all research activities unrelated to COVID-19 have stopped at the Center for Research in Transplantation and Immunology, INSERM University of Nantes, as has been the case in most of the research laboratories in France. A major difficulty was that we were asked by our administrative authorities to shut down in just 2 or 3 days. This shutdown involved basic, preclinical, and clinical research programs and extended to a clinical trial in transplant patients due to start in 2022 in the context of an EU H2020 program RESHAPE. The will be in clinical trials and clinical across a wide of The clinical was affected by the COVID-19 epidemic with the kidney transplantation program the to the of severe and of our center have on a new research in and funded by the National Research This has been a to collaboration with from and intensive care which will for other projects in the resources and from our Center and from the associated Clinical to immune in COVID-19 patients has been an and and with limited of the center have also to the hospital laboratory and for SARS-CoV-2 For most of work during the lockdown has writing research and online and new experiments our for researchers due to start were mostly by the from the national of research and other have been to COVID-19 research, likely future funding in other The in our Center is performed in 2 facilities different and 1 All in experiments were with of many experiments, and all of from were The and to a are and were for future experiments, but new projects have been A project on the of a as a of SARS-CoV-2 is due to start by the of The research laboratory has on May with very limited as we of the staff to come into the laboratory for the first and for the has been to projects involving PhD and experiments to or and to research activities at our in have been limited since but at a basic level, as as those activities not or personnel that were for patient care during the early of the COVID-19 social distancing were with activities. In cases samples were as of clinical research all possible were made within the guidelines to and those samples. While research personnel were to an during the early of the it has become more that our hospital is not so basic research activities are increasing and at this are a normal Research involving experiments remains restricted. Research personnel during the most of the down were allowed to the but under the majority had and the to work on research projects at home in the form of data analysis or to the research laboratory has been most for people with children If personnel were for the care of care was to some degree by our The restrictions on care have very been more for care of children so that can to their research activities. 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The university however, all researchers were to data analysis and writing and come into the university not be performed at home. resources were made to to research data and so that and personnel continue to work on data and grant applications. of potential of facility personnel and the of the COVID-19 pandemic research were of all but critical and for research, which was as that would significant and data or was for maintenance of With from the and staff continue to conduct experiments for research. The current experimental transplantation experiments were not and there was some of of these experiments will be able to restart as soon as the university and effort cannot be to grant experiments are not being In April and May, research staff and who not have sufficient work to at home were which further increased the impact on laboratory research. 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