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The Impact of COVID-19 on the state of clinical and laboratory research globally in transplantation in May 2020

Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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 centres and regional and national databases. It is becoming clear that transplant patients are more likely to catch SARSCov2 and when infected have a much increased mortality risk. Impact on clinical services, through reduction in ICU 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 centres 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.
Corresponding Author
Editor-in-Chief
Institutions
We will not mention individual institutions
Contributors
Jonathan Bromberg
Carla Baan
Jeremy Chapman
Ignacio Anegon
Daniel C. Brennan
Aron Chakera
Anita S. Chong
Edward K Geissler
Carole Guillonneau
Nigel Heaton
Dennis A. Hesselink
Wayel Jassem
Christopher M. Jones
Regis Josien
Bruce Kaplan
Christina L. Kaufman
Wai Lim
Yun Ma
Emma Massey
Darin B. Ostrander
Mark S. Slaughter
Stefan Tullius
Piotr Witkowski
Germaine Wong
Regional Reports
Scroll down this page to see regional reports (below conclusions)

Regional Reports

Africa

South Africa

The South African population have varying levels of economic development; however, a large percentage belong to the low- and middle-income population groups. With the onset of COVID-19 in our country, we are especially concerned about the resources available, specifically in the state sector hospitals. Unfortunately, in South Africa, there is a poorly and unevenly structured health care service: 85% of our population is depending on the state sector for medical care, but the resources are mostly situated in the private sector. In large parts of the country we have limited ICU capacity and ventilators and therefore we are currently making contingency plans for critically ill patients. The availability of transplantation services are also constrained by the availability of specialist physicians and surgeons and pathology facilities. Transplant services in the state sector have stopped. In the private sector there is still capacity for transplant services, but this is limited by a lack of deceased donors. In the Western Cape most donors come from the state sector hospitals, resulting in a lack of organs available for transplantation. Living donation has come to a complete standstill in South Africa. Deceased transplantation will continue to take place in facilities that have enough staff and infrastructure available. In most state hospitals this is not possible or feasible, due to a lack of deceased donors and health care resources. We are currently trying to reduce our outpatient workload and concentrating on discharging non urgent cases from the hospital. South Africa is locking down as of 25 March 2020 and nobody will be allowed to travel. All restaurants have been closed and only essential services are taking place.

South Africa also has some of the highest rates of HIV and TB in the world which we fear might result in an increased mortality from COVID-19 if the virus spreads widely in our population.

Across the rest of sub-Saharan Africa, in those places where transplantation is active, almost all living donor transplantation has ceased and there is no deceased organ donation. No transplant patients have yet been identified with COVID-19 and logistical problems of clinical follow up and drug supply are the major issues at present.   

Asia

China - Hong Kong

April 8 Update - CHINA-HONG KONG: Kidney, heart and lung transplantation

Submitted by Dr Maggie Ma (Vice President of HKST) on behalf of the Hong Kong Society of Transplantation

Hong Kong experiences a surge of COVID-19 since mid-March as there was huge influx of Hong Kong Resident (including students and traveler) returning back to Hong Kong after the global pandemic. As of 8 April 2020, there are total of 960 confirmed COVID-19 cases and 4 deaths. We initiate early anti-viral treatment irrespective of symptomatology and adjust the anti-viral regime according to viral titre. Whether such approach contributes to the low mortality in Hong Kong requires further studies.

One of our kidney transplant recipients was infected with COVID-19 on the Diamond Princess Cruise. She was treated with lopinavir/ritonavir monotherapy. She achieves viral clearence in around 2 weeks. She was monitor closely for 2 more weeks after initial clearance of virus and had been discharged after 4-week hospitalization. Lopinavir/ritonavir is an inhibitor of CYP3A and we observed significant drug interaction with calcineurin inhibitor. Allograft function remains stable after meticulous titration of immunosuppressant. Patient tolerated the anti-viral treatment well except mild gastrointestinal side effects including nausea and diarrhoea.

During the COVID-19 outbreak, living donor kidney transplantation (LDKT) has been suspended in Hong Kong since mid-February 2020. All other organ transplantation programs continue. The number of transplantation operations performed between January to March 2020 were summarized in Table 1.

Table 1. Transplantation statistics in Hong Kong between January to March 2020


Kidney

(DDKT)

12

 

(LDKT)

1

Heart

2

Lung

2

DDKT: deceased donor kidney transplantation; LDKT : living donor kidney transplantation; DDLT: deceased donor liver transplant; LDLT: living donor liver transplantation


Hong Kong, Update 6th April 2020
Nancy Kwan Man

In response to the COVID-19 outbreak, general infection control measures in the Hong Kong public health system include universal masking in all hospitals and clinics, routine temperature screening and travel history checking for all hospital visitors. Febrile patients were managed in segregated area. From mid-March onwards, medical staff who return from overseas travel have been instructed to refrain from going to their workplace for 14 days and undergo self-isolation at home.
For the transplant-specific measures, deceased donors are screened for COVID-19 infection if they have recent travel history or positive contact history. In general, transplant candidate is not recommended to undergo transplantation within 14 days of return from travel. Living donation is not advised to be performed within 14 days of return from travel. Out-patient follow-up of transplant recipients continues. In order to limit the number of visitors in the hospital, stable transplant cases are allowed to space out their follow-up visit with interval blood taking.
Living donor kidney transplantation (LDKT) has been suspended in Hong Kong since mid-February 2020. Deceased donor kidney transplant (DDKT) continues and we have total of 12 DDKT between January to March 2020. One of our kidney transplant recipients was infected with COVID-19 on the Diamond Princess Cruise. She was treated with lopinavir/ritonavir monotherapy and viral clearance was achieved despite continuation of immunosuppressant. Lopinavir/ritonavir is an inhibitor of CYP3A and we do observe drug interaction with calcineurin inhibitor. Patient tolerated the anti-viral treatment well except mild gastrointestinal side effects including nausea and diarrhoea.
Because of the low deceased donor donation rate, only 2 heart transplantation and 2 lung transplantations were performed since January 2020.


Original March update

As of March, 25th, 2020, there have been 410 cases of COVID 19 in Hong Kong with a population of just under 8 million.  Since the first outbreak in January 2020, we saw an initial surge in the number of infections by mid-February 2020 after the Chinese New Year, followed by a rapid decline in the number of cases from late February to early March (averaging 2-3 cases per day).  However, with the recent global increase, we have seen a huge influx of returning local residents to Hong Kong. As a result, we are now witnessing a second surge in the number of new cases with over 100 new cases reported just within one week. 

The liver transplant service at Queen Mary Hospital has seen a 50% reduction in elective living donor liver transplants (LDLT) in response to the hospital’s request to optimize the utilization of available PPE for frontline staff in ICU and isolation wards and to assure the availability of healthcare providers to fight the infection.  LDLT for urgent conditions, however, remained unaffected.  On the other hand, deceased donor liver transplantation service was severely affected with an all-time low organ donation rate from brain dead donors and only 2 DDLT occurred in February.  Paradoxically, there has been a sharp increment in the number of LDLT, mostly for liver failure.  As of today, a total of 12 LDLTs have been performed as compared to 5 LDLTs in the previous year.  Both potential living donors and recipients are only screened for COVID infection if they have symptoms, or a history of recent travels.  For deceased donors, screening is only performed in the presence of clinical symptoms, or a recent travel history.

 

Europe

England - London

With the recognition of the scale of the epidemic in the UK 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, post-transplant 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 post-transplant 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 post-transplantation, 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. 

France - Nantes

As a consequence of the national lockdown, which started on March 16th, 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 two or three days. This shutdown involved basic, pre-clinical 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 consequences will be delay in clinical trials and clinical translation across a wide range of topics. The clinical activity was profoundly affected by the COVID-19 epidemic with the French kidney transplantation program halted. Given the urgency to better understand the pathophysiology of severe COVID-19, several immunologists and virologists of our center have embarked on a new research project, written in 72 hours and funded by the National Research Agency. This has been a unique opportunity to develop collaboration with clinicians from Infectious Disease and Intensive Care Units which will allow for other projects in the future. Redeploying resources and expertise from our Center and from the associated Clinical Immunomonitoring platform to analyze immune responses in COVID-19 patients has been an interesting, necessary and efficient process, though time consuming and with limited institutional support. Members of the center have also provided help to the hospital virology laboratory developing RT-PCR and serology assays for SARS-CoV-2 infection. For most of us, work during the lockdown has comprised writing research papers and reviews, on line meetings and planning new experiments once our confinement ends. New contracts for researchers due to start, were mostly cancelled by the public institutions. Funding from the national agency of research (ANR) and other sources have been pivoted to Covid-19 research, likely negatively impacting future funding in other areas.

The animal experimentation in our Center is performed in two distinct rodent facilities (in different buildings) and one large animal facility. All rodents in ongoing experiments were sacrificed with loss of many expensive experiments and all colonies of animals from commercial vendors were euthanized. The only rodents kept, and to a minimal extend, are genetically modified rats and mice generated in-house. Primates were maintained for future experiments but new projects have been delayed. A project on the generation of a genetically modified rat as a model of SARS-CoV-2 infection is due to start by the end of June.

The research laboratory has finally reopened on May 11th, with very limited activity as we could only allow 10% of the staff to come into the laboratory for the first week and 20% for the second week. Priority has been given to projects involving 3rd year PhD students, last year post-doctorates, non-permanent young researchers, and experiments required to submit or revise publications and to support industrial partnerships.

Germany - Regensburg

Laboratory research activities at our institution in Germany have been limited since mid-March, but maintained at a basic level, as long as those activities did not utilize supplies or personnel that were potentially necessary for patient care during the early period of the COVID-19 outbreak. Widely used social distancing measures were utilized with reduced activities. In cases where human samples were collected as part of ongoing clinical research trials, all possible efforts were made within the guidelines to process and analyze those samples. While research personnel were reduced to an absolute minimum during the early period of the crisis, it has gradually become more apparent that our hospital capacity is not overloaded, so basic research activities are increasing and at this time are nearing a normal level. Research involving animal experiments remains highly restricted.
Research personnel during the most restrictive period of the slow down were allowed to enter the laboratories, but under controlled conditions. However, the majority had and used the option to work on research projects at home in the form of data analysis or manuscript preparation. Return to the research laboratory has been most difficult for people with small children needing day care. If personnel were deemed essential for the care of patients, emergency day care was provided to least some degree by our institution. The restrictions on day care have very recently been loosened, allowing more possibilities for taking care of children so that parents can return to their research activities. Furthermore, in our region of Germany, classes for children up through high school are opening again for many, freeing up time for researchers to return to work under increasingly normal conditions.

The human ethics commission at our institution continued to operate with only slightly reduced capacity throughout the COVID-19 crisis. While the highest priority was given to COVID-19-related studies, all other applications for human studies and trials were also processed. At present, there is essentially no reduced capacity with regard to handling human ethics applications.

The Netherlands - Rotterdam

The laboratory research program at the Erasmus MC, Rotterdam was mostly stopped on March 16th, 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 30th. 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 lab data have been generated. Consequently, our Ph.D. students and postdocs swapped their priorities to writing manuscripts and grant proposals. Virtual lab 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 one 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 15th, 2020. 

The clinical transplant program of the Erasmus MC was put on hold on March 13th, 2020 and was restarted on May 7th 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 check-ups. 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 behaviour, 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 re-established. One of the main challenges with such studies is the inclusion of sufficient patients in order to be able to demonstrate an effect. Anticipating difficulty recruiting participants in the out-patient 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 centre (Dutch trial register NL8599).

Middle East

Turkey - Ankara

Turkey update 04 April 2020

Mehmet Haberal, Baskent University, Ankara
As of 04.04.2020, the number of confirmed cases in Turkey is 20921 with 425 deaths.  A total of 484 people have fully recovered following treatment. Most of the victims in Turkey have been elderly.

The first batch of rapid COVID-19 tests arrived last week and 50,000 quick diagnostic kits --which allow comprehensive results in 60 minutes-- came from China on 25.03.2020 and an additional 300,000 kits arrived the day after. All private and foundation hospitals have been designated as pandemic hospitals as of 20.03.2020.
Currently, as Baskent Ankara Hospital, we have assigned one floor for the patients, but it will be reorganized based on the circumstances. Transplant surgeries and all except acute liver failure transplantation, cancer and urgent surgery are postponed in all public and private hospitals in Turkey.
We are closely monitoring our transplant patients in our centers located in different cities of Turkey. Our transplant committee has prepared the following immunosuppressive  protocol for COVID-19 transplant recipients:

Antiproliferative immunosuppressant drugs (antimetabolites; mycophenolate mofetil, mycophenolate sodium and azathioprine) should be stopped. Dose reduction or cessation of calcineurin inhibitors (tacrolimus, cyclosporine) has not been clearly defined. Patients who need intubation and have severe pneumonia may benefit from cessation of calcineurin inhibitors. Anti-inflammatory drugs, like tocilizumab may be useful in severe cases. In mild cases, dose reduction of calcineurin inhibitors is preferred. However, calcineurin inhibitors should be stopped if antiviral therapy starts.  Steroid therapy should be tapered instead of cessation. Antiviral therapy should be started according to computed tomography scans and continued according to nasopharyngeal swap pcr results.

Fortunately, so far, there are no transplant patients diagnosed with COVID-19 at the Baskent University centers located in various cities. Interestingly, the rate of COVID-19 has been really low among our dialysis patients. We have 21 dialysis centers all over the country, with 2420 hemodialysis patients and 30 peritoneal dialysis patients. Only 3 patients have been diagnosed with COVID-19, which makes a prevalence of about one per thousand. We have commenced a randomized sample study of our 2420 dialysis patients at Baskent University. While negative for SARS-CoV2, 94.7% were hepatitis A antibody positive so we will continue this study of virus prevalence.

According to the authorities in Ministry of Health there are no transplant patients who are COVID-19 positive reported officially to date. 

Detailed information on measures taken to prevent the spread of SARS-CoV2 in Turkey can be reached through https://hsgm.saglik.gov.tr/tr/covid19

COVID-19 Committees for TOND (The Turkish Transplantation Society), MESOT (Middle East Society for Organ Transplantation) and TDTD (Turkic World Transplantation Society) have also been formed.


 


March Update

As of today, the number of confirmed cases is 1872 with 44 deaths. Most of the deaths in Turkey to date have been elderly, two were age 50-60, one was 91, and all the others were older than 61. Schools, universities, mosques, shopping malls and hairdressers have been temporarily closed and professional sports have been halted as part of measures to contain the virus. The Ministry of Health also announced that cafes, restaurants, pastry shops, and similar workplaces are closed and will only fulfill online orders and takeaway. There are restrictions on supermarkets, banks and public transport systems are obliged to limit their numbers to a maximum of 50% of their licensed capacity. Turkish citizens who are older than 65 and/or suffer from chronic illnesses are restricted from leaving home or even walking in open areas such as parks and gardens.

The first batch of rapid COVID-19 tests arrived last week. 50,000 quick diagnostic kits allowing comprehensive results in 60 minutes arrived today with an additional 300,000 kits arriving this week. All private and foundation hospitals have been announced as pandemic hospitals as of last Friday. At Baskent Ankara Hospital, we have currently assigned one floor for COVID-19 positive patients. Transplant surgery and general surgeries, except for transplants for acute liver failure, as well as cancer and emergency surgery are postponed in all public and private hospitals in Turkey. Detailed information can be reached through following link provided by the Ministry of Health  https://hsgm.saglik.gov.tr/tr/covid19

Latin America

Brazil

Brazil, 6 April 2020
Prof. Jose Osmar Medina Pestana, MD, PhD
Nephrology Division, Hospital do Rim – Federal University of São Paulo
In Brazil, the first confirmed case of COVID-19 infection was registered on February 26th in São Paulo, just after the Carnival. On March 16th, with the initial exponential growth in the number of confirmed cases, social distancing measures began, with closure of schools and offices, followed by bars and restaurants and strict recommendations to stay at home. The first death occurred on March 17th, when the number of confirmed cases was 234. After 20 days 11,254 cases were recorded in all 27 Brazilian states, and there were 486 deaths (4.3%). Forecasts based on the current models predict about 45,000 cases up to April 20th. Given the known shortage of diagnostic tests, only symptomatic patients admitted to the hospital have been tested.
Currently, Brazil has 210 million inhabitants and about 2.6 ICU beds for every 10,000 inhabitants. We are dealing with the usual challenges, primarily lack of sufficient coordination between the federal and state governments, and lack of screening tests, personal protective equipment and other supplies.
In our hospital we postponed routine clinic visits and started using telemedicine. We are still performing deceased donor kidney transplants (we are now testing all donors) but those from living donors are temporarily on hold. From March 20th we started disseminating through all available media the message for patients with mild symptoms to stay at home, isolated if possible, and to call the transplant center before coming to the hospital. These home based patients then receive frequent calls from our institution to update their clinical conditions. Only symptomatic patients presenting at the emergency department have been tested. As of April 6th, the cumulative number of kidney transplant recipients who were tested positive for COVID-19 is 20. There are 5 in the ICU, 5 have already been discharged from the hospital, and 3 have died. Given the wide spectrum of the disease and the demographics of the kidney transplant population, there are no predefined protocols to handle immunosuppression. We are collecting data prospectively to report a case series. We are also developing a national database to analyze data from different centers across the country.
We believe that the control of this pandemic, considering the universal geographic dissemination requires a collective alignment among all countries to mitigate its impact on the society, especially in most under resourced regions.

North America

USA - Illinois - Chicago
The University of Chicago research laboratories have been closed to non-COVID19 research from the week of March 16, 2020.  We had about one week to wind down experiments, and prepare the lab for a 4 week shutdown, which unfortunately was extended for another 6 weeks as a result of state mandate.  We reduced our mouse colony by about 30%, keeping breeding cages and long-term post-transplant and control mice. We were allowed to designate three essential personnel to come into and check on the lab, and to complete long-term experiments.  However, we are not allowed to start new experiments or order supplies or mice, unless they are directly COVID-19-related.  After over approximately 45,000 confirmed COVID-19 cases and 2000 deaths, the city of Chicago has seen the flattening in the numbers of new COVID-19 cases.  Our institution has issued a plan for a phased research resumption, with on-campus research moving from the current 10% of pre-COVID-19 levels, to 25% and then 50% over the summer.  We have developed a plan for safe return to work for our research team members exercising social distancing and safety measures, including working shifts, proper distancing at work space, utilizing personal protective equipment and sanitizers. Taken together, we anticipate that we will have no experiments involving the study of long-term post-transplant tolerant mice for at least 6 months, and no short-term experimentation for at least 3 months.  It has been especially challenging for the training of new students and post-docs in the laboratory, and for post-docs hoping to complete their research and leave the laboratory this summer.   Fortunately, no research personnel has been furloughed.   

We have managed to maintain weekly meetings for the entire laboratory staff, meetings with smaller research groups, and inter-laboratory meetings, using Zoom.  These meetings have allowed post-docs, students and technicians to work on finalizing figures and developing outlines of new manuscripts, and completing manuscripts for submission/resubmission.  Some laboratory members have spent the time learning to analyze and present multi-parameter flow cytometry data, while others learnt programming to analyze RNA-seq data.  Finally, because we also conduct research in nanoparticulate vaccines, we have pivoted that research program to focus on SARS-CoV2.  We are leveraging rapidly developing institutional resources to support grant proposals on SARS-CoV2 vaccines to the National Institutes of Health for funding.

Clinical non Covid-19 related research has been reduced, maintaining only essential follow-up contacts, testing and procedures applying common rules for prevention of spreading the infection.  Recruitment of new subjects has been on hold since March 16th. Patients after participating in the interventional trial in kidney transplantation continue to come for outpatient intravenous infusion of the immunosuppressive study agent.  Follow up clinic visits have been limited and performed via telehealth. Our last patient with type 1 diabetes received islet transplantation at the beginning of March. She is currently insulin independent and without any complications. Patient went back home to Orlando, Florida one week after the procedure and has been followed remotely. Remaining islet transplant and transplant study patients has been followed via telehealth utilizing blood testing at local laboratories. Planning ahead, we have already amended clinical study protocols addressing new risk related to covid-19, implementing additional patient testing, infection prevention measures, remote telehealth visits, local lab and home testing as well as electronic consents.  All has been approved by our IRB. According to the University policy, such plan needs to be approved by the department chair. Since our clinical organ transplantation program has resumed full activity after adjustment to the current stage of pandemic in Chicago, we are expecting to resume clinical studies soon.
USA - Kentucky - Louisville

Laboratory research and research based on experimental models was significantly impacted by University directed ramping down of non-essential research starting on March 11, 2020 followed by cessation of all non-essential basic science and clinical research activities on March 26, 2020.  The University remained open, however all researchers were strongly encouraged to perform data analysis and writing remotely and come into the University only if functions could not be performed at home.  IT resources were made available to ensure secure access to research data and documents so that faculty and personnel could continue to work on data analysis, manuscripts and grant applications.  Because of potential loss of animal facility personnel and the unknown duration of the COVID-19 pandemic policies, research animal stocks were depleted of all but critical strains and animals for essential research which was defined as activity that if discontinued would cause significant and irreplaceable data loss or was required for maintenance of equipment, data, samples, animal populations.  With specific approval from the Dean, faculty and staff could continue to conduct experiments for “essential” research.  The current experimental transplantation experiments were not deemed essential and there was some loss of commercially available strains of animals. However, these experiments will be able to restart as soon as the University gives permission.  Time and effort cannot be charged to grant funds if experiments are not being conducted. In April and May, research staff and technicians who did not have sufficient work to perform at home were furloughed which further increased the economic impact on laboratory research.

The transition to a remote research environment was fairly smooth.  The university provided multiple platforms for online meetings, and provided daily and weekly updates. All University related domestic and international travel was banned and campus events were cancelled or moved to online meetings. The remote research mandate for laboratory research has been extended to May 31 at least and a potential restart of all research and teaching is planned for the fall semester, assuming the COVID-19 infection rate continues to decline. 

The brighter spots include the excellent communication between the University and research faculty and the community in general. Severe financial impacts have been distributed fairly and commercial animal vendors are offering a 25% discount to ease the financial burden of replacing the animals that were sacrificed in the shutdown. We have been able to use the time to reassess research direction, tidy up neglected manuscripts and data, and prepare grants for shared equipment and improved research facilities.
 
Clinical transplantation research, with the exception of drug studies, or clinical trials that if stopped, might endanger study subjects, was put on hold by the pandemic.  This was due primarily to cessation of all elective procedures at University affiliated hospitals, in preparation for large numbers of COVID-19 patients.  Clinical research procedures deemed non-essential were halted, and those with federal funding were reported to regulatory agencies as on hold. These included studies related to function and physical therapy in hand transplant recipients and new mechanical circulatory support devices used to bridge critically ill patients to heart transplant.  Experimental clinical trials such as the current study of allotransplantation of the hand have been put on hold, as was done by colleagues at other VCA centers in the United States.  Follow up of VCA study subjects is currently limited to telemedicine, and deviations have occurred with some study procedures, such as timing of blood draws to measure immunosuppression drug levels.  Subjects were counseled that drug levels were critical to maintain their health and the health of their graft, but to use their judgement on the safety of exposure to COVID-19 at local health centers.  Annual evaluations and other study interventions have been postponed until late summer/fall.

Where possible, solid organ transplantation data studies have continued as have procedures conducted in the course of standard clinical care of the patients.  Of the 24 active clinical studies in transplantation, more than half could not continue. All living related kidney transplants were postponed, resulting in a 10% reduction in volume of kidney recipients who could participate in research protocols.  Deceased donor abdominal transplants continued as normal.  All lung transplant candidates with a LAS of < 50 and heart transplant candidates with a Status of 4,5 or 6 were put on hold, greatly reducing the number of available research candidates.  Restrictions on travel imposed outside the University impacted the availability of on-site help for implant studies. There was also a transient lack of the ability to test donors for COVID-19 prior to transplant and potential donors were not accepted if COVID-19 status was unknown, however this situation has now been resolved.  
As with experimental studies, when clinical studies are placed on hold, personnel effort cannot be charged to the grant.  We hope for, but cannot depend on, the extension of these funds to account for the time lost due to the pandemic. Time points in clinical studies will be altered.  We do not predict significant impact on outcomes at this time. Our hospital and university administration performed admirably with daily, sometimes multiple daily communications via conference calls and email seven days a week. The University Institutional Review Board remained functional and continues to meet on a regular schedule online.  Access to federal grant funding administration was and is also excellent, with no interruption in processing new awards or new grant applications.  The University has remained open with online access to libraries, and with hospital and university IT support to ensure that faculty had remote secure access to protected patient information. 

USA - Maryland - Baltimore

Institutional Review Board staff began working remotely at the beginning of March.  All non-essential in-person laboratory activities, for both animal and clinical research, were shut down on March 18.  Although telemedicine visits were supposed to be allowed for Research from that date, it was not actually allowed till May 11.  Johns Hopkins University is postponing all external monitor onsite visits for clinical research protocols until at least May 31. All site initiation visits (SIVs) must take place remotely effective immediately and until at least May 31. Onsite SIVs for COVID-19 trials and other life-saving trials may be allowed in exceptional circumstances where these may not be performed remotely. The Compliance Monitoring Program has cancelled all monitoring visits.  At this time, no new compliance monitoring visits will be scheduled until after June 30, 2020.  On-site monitoring visits will be rescheduled once restrictions on in-person meetings and recommendations for social distancing have been lifted. The Compliance Monitoring Program team members are available via email and telephone for questions. All applicable institutional and regulatory requirements for human subjects’ research continue to be followed, and proper documentation practices are maintained.  The Fundamentals of Good Clinical Practice course has been offered via Zoom.  The eIRB 1010 Training sessions have been cancelled until further notice.

There is now a COVID-19 Biospecimen Committee which evaluates requests from researchers for accessing serum or plasma from COVID-19 patients. The committee’s default position will be for investigators to receive premade specimen collections for pilot studies with requests for custom made collections considered after pilot studies are completed.

There is a Tiered approach to Research and only Tier 1 studies are allowed with the Institutional Review Board totally focused on COVID protocols:

Tier 1 – High Direct Benefit to Research Participants
Research in Tier 1 can continue if the Principle Investigator agrees the research can be conducted in a safe manner that protects subjects, research, and the community. There is a pause on enrolling new research participants unless there is a compelling reason and any in-person visits specifically for research purposes that require subjects to travel from out of state where the Governor of that state has issued a no travel order have ceased. All other in-person interactions may only continue for Tier 1 studies with a compelling justification to continue these interactions and the petition to continue is approved by the IRB.  Studies at the Sidney Kimmel Cancer Center or JH-ACH must seek the approval to continue in-person activities from their respective review committees.  COVID 19 studies may continue in-person interactions subject to IRB approval.

Tier 2 – Moderate Direct Benefit to Research Participants
•Protocols in which research participants are receiving interventions or clinical care that is very interrelated to their research participation (e.g., test results coming back that might have clinical implications for their care)
•Some protocols evaluating treatments for chronic conditions (e.g., asthma, hypertension, depression, etc.).
•Protocols involving assessment of the safety or efficacy of an intervention in which, if stopped, the potential societal benefit of the science would be significantly and adversely impacted, for example where a research assessment (blood collection or imaging study) is only valuable if collected at a very specific time. This must be measured against the risk to participants, including the risk of exposure of COVID-19.
Research activities in Tier 2 must not enroll new participants in studies requiring in-person interaction nor continue to conduct in-person. The IRB will no longer consider requests to continue in-person activities for this Tier. Data collection that does not require in-person participant interaction (e.g. telephone or online) may continue.  
No new enrollment is permitted for Tier 2 studies.

Tier 3 – Low Direct Benefit to Research Participants
•Cohort and natural history studies where delays in data collection have limited impact on scientific objectives
•Protocols in which delays to starting or pausing of research does not substantively impact on research objectives of the research protocol
•Protocols in which risks to research participants are higher (e.g., potentially exposing elderly vulnerable individuals to COVID) and benefits of the study to the participants remain minimal
•Research with healthy volunteers
•Any minimal risk studies that require research subjects to travel, that involve undergraduate students, or that are in a community setting and require direct interaction with researchers
Research activities in Tier 3 must not enroll new participants in studies requiring face to face interaction nor continue to conduct face to face visits. On-line visits or data collection that does not require participant interaction may continue.

Oceania

Australia - Perth and Sydney

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/or rescheduled, leaving financial and career uncertainties amongst 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. Even though acute transplant service has recommenced in Australia in early May, there continues to be a general reluctance to re-initiate 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 centres, including study and trial participants has 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 paediatric and adolescent participants of non-consenting 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.

Even though 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.

Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

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