key: cord-1039096-ae241pmd
authors: de Vries, A.P.J.; Alwayn, I.P.J.; Hoek, R.A.S.; van den Berg, A. P.; Ultee, F.C.W.; Vogelaar, S. M.; Haase-Kromwijk, B.J.J.M.; Heemskerk, M.B.A.; Hemke, A. C.; Nijboer, W. N.; Schaefer, B. S.; Kuiper, M. A.; de Jonge, J.; van der Kaaij, N. P.; Reinders, M.E.J.
title: Immediate impact of COVID-19 on transplant activity in the Netherlands
date: 2020-05-01
journal: Transpl Immunol
DOI: 10.1016/j.trim.2020.101304
sha: 220174ac0a9a107a0013fc4abde3523f15accdc8
doc_id: 1039096
cord_uid: ae241pmd

Abstract The rapid emergence of the COVID-19 pandemic is unprecedented and poses an unparalleled obstacle in the sixty-five year history of organ transplantation. Worldwide, the delivery of transplant care is severely challenged by matters concerning - but not limited to - organ procurement, risk of SARS-CoV-2 transmission, screening strategies of donors and recipients, decisions to postpone or proceed with transplantation, the attributable risk of immunosuppression for COVID-19 and entrenched health care resources and capacity. The transplant community is faced with choosing a lesser of two evils: initiating immunosuppression and potentially accepting detrimental outcome when transplant recipients develop COVID-19 versus postponing transplantation and accepting associated waitlist mortality. Notably, prioritization of health care services for COVID-19 care raises concerns about allocation of resources to deliver care for transplant patients who might otherwise have excellent 1-year and 10-year survival rates. Children and young adults with end-stage organ disease in particular seem more disadvantaged by withholding transplantation because of capacity issues than from medical consequences of SARS-CoV-2. This report details the nationwide response of the Dutch transplant community to these issues and the immediate consequences for transplant activity. Worrisome, there was a significant decrease in organ donation numbers affecting all organ transplant services. In addition, there was a detrimental effect on transplantation numbers in children with end-organ failure. Ongoing efforts focus on mitigation of not only primary but also secondary harm of the pandemic and to find right definitions and momentum to restore the transplant programs.

The Coronavirus Disease 2019 pandemic is affecting societies worldwide. [1, 2] The scope of this disease is unprecedented and the global delivery of healthcare is under severe stress. [3] The first documented case of COVID-19 in the Netherlands, which counts 17.2 million inhabitants, was on February 27, 2020. In less than 60 days, despite increasingly stringent measures of the Dutch government to halt the spread of the infection, 28, 153 individuals have tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), 9,127 patients have been admitted to hospitals across the country (of which 2,508 in the Intensive Care Units (ICU) [4] ) and 3,134 have died, according to RIVM (National Institute for Public health and the Environment, April 15, 2020).

[5] Because of limited testing capacity many more, untested individuals are likely infected with SARS-CoV-2 in the Netherlands. With increasing numbers of COVID-19 patients being admitted to hospitals, the ability to provide acute, non-COVID-19 care, is at risk. In this context, especially maintaining organ transplantation care is complex, as numerous aspects related to donor and recipient management, need to be taken into account. [6] [7] [8] Main questions that need to be addressed include the following: Under which circumstances can organ donation from deceased donors take place? Is it safe to perform transplants from live donors? What are additional risks for transplant recipients in terms of immunosuppression and COVID-19? How should potential recipients be managed, both pre-and post-transplantation? Which treatments should be considered for transplant recipients with COVID-19? What are logistic implications and, most importantly, what is the impact of the outbreak on donation and transplant volumes and waitlist outcomes? The transplant community in the Netherlands, organized through the Dutch In addition, it demonstrates the immediate devastating effects on donation and transplant volumes and mortality on the waiting list and preliminary efforts to safely restore the programs.

The DTF maintains the national list for patients awaiting organ transplantation and is responsible for organ donation policy, the allocation of organs through the international organ exchange organisation Eurotransplant (ET), and coordination of the Dutch live donor kidney paired exchange program. DTF closely collaborates with national organ advisory committees of the DTS, whose members are content experts and represent all transplant centers. On March 9 th , before the World Health Organization (WHO) declared the pandemic, the advisory committees increased their meeting frequency from once every 3 to 6 months in person to ± three times per week through videoconferencing. DTS, DTF and chairs of the advisory committees similarly met to share the most recent information and policies concerning COVID-19. Guidelines were made public through internet communications and newsletters from DTF for both patients and professionals. [ 

In regard to donation and transplant activity, ICU bed capacity per million inhabitants is of major importance. Under normal conditions, the Netherlands has approximately 1150 ICU beds, which is 6.7 ICU beds per 100.000 people. In comparison: the USA has about 34.7 beds per 100.000, Germany 29.2, Italy 12.5, France 11.6 and the UK 6.6. In the current pandemic, hospital capacity and critical care facilities are severely stressed by the number of COVID-19 patients. In order to provide optimal care for these patients, a centrally coordinated national effort was made to double ICU capacity to a total of 2400 in early April 2020. Regular ICUand medium care, including transplant care was scaled down to meet this demand. Regarding our concerns for donation and transplant rates we therefore raised national awareness through (social) media and by direct contact with the network of intensive care physicians involved in organ donation and organ tissue transplant coordinators. In addition, a letter was sent to relevant professional organizations and the national coordination center for capacity. Currently approximately 500 ICU beds are reserved to allow for (semi-)urgent non-COVID-19 care, including donation and transplantation.

Health care workers (HCW) involved in organ donation are at increased risk of acquiring and spreading SARS-CoV-2, since they work closely together and travel to various hospitals and visit virus hotspots. To preserve a safe organ donation chain, recommendations to reduce the risk of infection of HCW and transplant recipients were made recognizing limitations of available scientific evidence. First, SARS-CoV-2 testing of all deceased donors was implemented, since asymptomatic carriers and transmission through organ transplantation because they could not bear the extended waiting times. So far, no donor has been tested positive for SARS-CoV-2; in one donor the retrieval procedure was cancelled because of a high suspicion of COVID-19 based on chest CT, but with a negative PCR. This was followed by discussions about necessity of CT scan for donor screening. [13] A CT scan provides rapid information on COVID-19 in patients with moderate to severe symptoms and is of additional value in patients with a single false negative nasopharyngeal swab for SARS-CoV-2. [14] To date, there is no data on sensitivity and specificity in asymptomatic patients and therefore not recommended in international guidelines. [15] The risk of losing additional organ donors because of false negative COVID-19 associated abnormalities on CT-scan such as groundglass opacities and consolidation in e.g. neurogenic oedema is deemed high. In this light, chest CT-scan is now only used in potential organ donors with negative nasopharyngeal swab but an inconclusive history for excluding COVID-19. To maintain social distancing during organ procurement, additional vehicles for transport to donor hospitals are used, and chauffeurs and HCW were advised to wear facial personal protection equipment (PPE). So far, no donation professionals were infected during procedures. To facilitate extra time needed for recipient test results to become available, allocation for liver, heart and lung transplantation is initiated before donor SARS-CoV-2 screening is known (Table 1A) . Additionally, the second recipient on the allocation list is allocated to minimize risk of donor loss related to prolonged cold ischemia times. Despite these efforts, donation volumes markedly decreased in the first month as the pandemic unfolded (15 March 2020-15 April 2020) compared to the months before ( Figure 1A ). The reasons for this are not completely clear. Traffic has decreased due to increased working from home, leading to less traffic accidents and trauma patients becoming organ donors. Also, there have been signs that people have become more reluctant to call for medical help, fearing to be a burden for medical professionals or to be infected with COVID-19 at a health care facility. This could also be the case when urgent medical assistance is needed, as in acute coronary syndromes, subarachnoidal bleedings et cetera. Finally, donor awareness among emergency physicians and intensivists could have decreased due to the strain put on them by the COVID-19 epidemic. Currently, we are investigating these issues. 

As has been discussed in several other reports, the attributable risk of immunosuppression on the development and severity of COVID-19 is unknown. Current knowledge is mainly based on recently published case reports. [16] [17] [18] [19] [20] Previous reports on transplant recipient outcome for other respiratory viruses and Acute Respiratory Distress Syndrome are contradictory [21, 22] and several immunosuppressive agents are even hypothesized to have antiviral J o u r n a l P r e -p r o o f Journal Pre-proof properties. [23, 24] It is however evident that frail individuals, including patients with multiple comorbidities, are at increased risk of COVID-19.

[5] , One could therefore argue that transplantation may in fact, in the longer run, ameliorate that risk. In light of limited and contradictory evidence, and in part driven by stretched and overwhelmed hospital capacity, the Dutch transplant community was an early adopter of the recommendations made by Kumar et al. (Table 1B) . [6] In general, this led to prudence in performing kidney transplantation until the impact of induction and maintenance immunosuppression on COVID-19 is more understood. Deceased-donor kidney transplantation is considered case-by-case in a shared decision process with the patient, carefully weighing the urgency and benefit of transplantation against risks. This approach allowed for regional differences among centers while sharing a (Table 1B) . As discussed before, with progression of the COVID-19 pandemic, ICU capacity across the country is limited. As a result, per March 25, all heart and lung transplantcenters have limed their capacity for now to urgent cases with low life expectancy if not transplanted (Table 1B) . It is expected that the need for urgent lung transplantation may rise in the upcoming weeks for patients with severe ARDS. [25] As community acquired risk for COVID-19 is high, it is agreed that COVID-19 positive patients could return on the active organ waiting list after resolution of clinical symptoms and negative COVID-19 nasopharyngeal swab or sputum PCR (Table 1B) 

The total amount of all organ transplants markedly decreased from 100-150 to 40 transplants per month in the first COVID-19 month, a decrease of 67% ( Figure 1B ). This is in contrast to the COVID-19 outbreak in Italy, were the activity remained stable for each type of solid organ. [30] However, here the first 4 weeks of the outbreak was taken into account, while we have taken the period 27 th of February till the 15 th of April. Pancreas transplants decreased to 0 and renal transplants from 80-100 to 20 per month ( Figure 1C-D) . The number of liver and lung transplants markedly declined from a mean of 16 to 8 per month and from 18 to 7 per month, respectively, a decrease of approximately 50% ( Figure 1E-G) . There was no pediatric transplant activity in the first COVID-19 month ( Figure 1H ). Related to the focus on patients with the highest need there was a change in transplantable and non-transplantable status on the liver transplantation waiting list as shown in Figure 2A . Another alarming and slightly unexpected finding was the higher number of renal patients removed from the waiting list because of mortality or deterioration in the first 6 weeks since the first COVID-19 case in the Netherlands was observed ( Figure 2B ). It is too early on in the pandemic to determine cause and effect, and similar trends have not been observed for other organs yet, but this should be 

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The authors would like to thank the remaining members of the Dutch Transplant Society