key: cord-0977310-wpq1492g
authors: Ritschl, Paul V.; Nevermann, Nora; Wiering, Leke; Wu, Helen H.; Moroder, Philipp; Brandl, Andreas; Hillebrandt, Karl; Tacke, Frank; Friedersdorff, Frank; Schlomm, Thorsten; Schöning, Wenzel; Öllinger, Robert; Schmelzle, Moritz; Pratschke, Johann
title: Solid organ transplantation programs facing lack of empiric evidence in the COVID‐19 pandemic: A By‐proxy Society Recommendation Consensus approach
date: 2020-05-10
journal: Am J Transplant
DOI: 10.1111/ajt.15933
sha: ebb7fa663acbeee7524c2e84df51ac40149c607c
doc_id: 977310
cord_uid: wpq1492g

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has a drastic impact on national health care systems. Given the overwhelming demand on facility capacity, the impact on all health care sectors has to be addressed. Solid organ transplantation represents a field with a high demand on staff, intensive care units, and follow‐up facilities. The great therapeutic value of organ transplantation has to be weighed against mandatory constraints of health care capacities. In addition, the management of immunosuppressed recipients has to be reassessed during the ongoing coronavirus disease 2019 (COVID‐19) pandemic. In addressing these crucial questions, transplant physicians are facing a total lack of scientific evidence. Therefore, the aim of this study was to offer an approach of consensus‐based guidance, derived from individual information of 22 transplant societies. Key recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found for temporarily suspending nonurgent transplant procedures and living donation programs. Systematic polymerase chain reaction‐based testing of donors and recipients was broadly recommended. Additionally, more specific aspects (eg, screening of surgical explant teams and restricted use of marginal donor organs) were included in our analysis. This study offers a novel approach to informed guidance for health care management when a priori no scientific evidence is available.

Currently, the global public health sector is facing an unprecedented challenge in dealing with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Readjustments in the sector of organ transplantation are critically important for several reasons.

All stages of the transplant procedure (pretransplant care, the surgical procedure itself, posttransplant care, and long-term follow-up) require high capacities of trained staff, operating rooms, and-crucially during the pandemic-intensive care unit (ICU) treatment. In apportioning ICU and staff capacities, all involved sectors are forced to triage essential treatments from those that can be delayed or substituted by less complex therapy options. Second, conduction of an organ transplant imposes a state of high-level medication-induced immunosuppression to the recent transplant recipient. Furthermore, the management of long-term immunosuppressed (transplanted) patients has to be reassessed in the given pandemic to account for the risk of infection. [1] [2] [3] [4] At the moment, the "Adult Elective Surgery and Procedures

Recommendations" by the Centers for Medicare & Medicaid Services (CMS) label transplants as a "tier 3b" (high acuity surgery/ unhealthy patients) with the consecutive action directive, "Do not postpone." 5 In practice, there is a rather wide degree of medical urgency among solid organ transplants ranging from elective operations to ultima ratio options. Therefore, the reasonable execution of a transplant program that is affected by capacity shortage during the pandemic demands complex consideration and decision-making.

Given the high-speed dynamic of the SARS-CoV-2 outbreak, no scientific evidence is currently available to guide medical policymakers during this crucial period of readjustment.

Also, comparable viral outbreak in the past, such as the SARS outbreak in 2002-2004, did not impose such a challenge to transplant medicine. Therefore, no official recommendations or guidelines on the subject of transplantation programs during the viral outbreak were published. A single center report from the University of Toronto-an area with relatively high disease burdenis to be found including a case report describing a severe course of suspected SARS in a liver transplant recipient 9.5 years after transplantation. 6 As no consensus guidelines or international recommendations have been published on coronavirus disease 2019 (COVID- 19) and organ transplant, the aim of this study was to offer a consensus-based approach to manage transplant programs until reliable data on risk and benefits of conducting organ transplants in times of a viral pandemic are available. societies out of all 19 support the statement, >25%) or "low recommendation" (SRC = C, if 1 to 4 societies support the statement, <25%).

The number of negative recommendations was subtracted from the count of positive recommendations. Individual statements were then discussed to available literature.

This study does not compare strategies of different countries nor does it draw causal conclusions. Therefore, no specific tests were applied. No study approval was necessary as all information was already published elsewhere. Conforming with the information given on the individual websites (links see Table 1 ), 25 recommendation statements were extracted. Statements were pooled according to four subitems of transplant program management:

A Management of long-term immunosuppressed transplant recipients (Table 2) B General management of transplantation programs (Table 3) C Donor management (Table 4) D Recipient evaluation (Table 5) The following section offers listing, SRC consensus and further discussion of the retrieved recommendations.

Anticipating a higher-than-average susceptibility of transplant patients for COVID-19, a strong consensus was found for the validity of general preventive and hygienic measures for transplant patients. Numerous international sources offer directions, information, and tutorials on preventive policies and lifestyle recommendations such as social distancing, telework, hand hygiene, travel restrictions, and more (Table 2) . On the right-hand side, the sum of supporting society recommendations was subtracted by dissenting votes and a final score was calculated. The final score was converted into a society recommendation consensus (SRC; "strong recommendation" = A, if more than 9 societies support the statement, >50%; "medium recommendation" = B, if 5-9 societies support the statement, >25%; "low recommendation" = C, if 1-4 societies support the statement, <25%). BAL, bronchoalveolar lavage; COVID, coronavirus disease 2019; CT, computed tomography; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. The TTS discusses paying close attention to medication-induced lymphopenic transplant patients because low lymphocyte count in COVID-19 patients is associated with a severe course of disease. 11 

Interpersonal and facility contacts should be reduced to a 

Given the high awareness levels of COVID-19 symptoms such as fever, dry coughing, and sneezing, the alertness regarding altered clinical presentations such as gastrointestinal symptoms or fatigue is considered to be low. In a recent case report, an atypical presentation of COVID-19 infection in a kidney transplant recipient has been described. 4 Early clinical presentation with gastrointestinal symptoms are attributed to 16% of the SARS-CoV-2 population. 14 

the United Kingdom recommend a low threshold for SARS-CoV-2testing in transplant patients after contact with a positively tested person or subject to a broader spectrum of COVID-19-associated symptoms. 15 This situation may reflect a country's quantitative resources for SARS-CoV-2 testing. Therefore, the risk of infection due to facility contact while testing has to be carefully weighed against beneficial therapeutic options after early diagnosis.

According to the WHO, there is no specific treatment or vaccination available to treat COVID-19 infection. 7 

Transplant patients should consider receiving a 90-day medication supply to minimize facility contact and anticipate a quarantine situation. Low-contact supply chains should be enhanced (eg, home mailed, drive-through pharmacies).

A strong consensus was found regarding reduction of elective transplantations to a minimum, if not complete postponement; in particular living donor kidney programs. 5, 21, 22 Living donor liver transplantation is being recommended to be carried out preferably in unstable patients with a model end-stage liver disease score > 25 or >30 depending on the ICU capacities, respectively (Table 3) . 22

Restriction of transplant programs is based on the high requirement of both staff and equipment required for a transplantation procedure and follow-up compared to the withholding of health benefits to potential organ recipients. Only a few countries (eg, Iran, Bulgaria) adopted a "topdown" approach of instructed restriction. 23 

Every consulted society recommendation addresses the crucial need for evaluation of staff and ICU capacity. Kumar 

The AST and Swisstransplant explicitly restrict the use of these organs for transplants due to their key role in the virus' biology and a potentially high parenchymal viral load in case of undetected infection. In

Canada, the lung transplant program was paused due to the pandemic.

The first available data show a 2%-22% rate of false negative-polymerase chain reaction (PCR) results for SARS-CoV-2 tests. 25 

Given the work with associated high-contact profile, the mobility of medical staff bears a risk of infection transmission. 

Recommendations for recipient management from entering the country as of April 2020. 27 The extent of screening (repetitive PCR testing vs screening for symptomatic physicians)

should be adapted to local virus spread, availability of testing, and general risk of transmission.

A unique but equally interesting approach was stated by the British National Health Service. The NHS recommends a qualitative restriction of donor organ retrieval, reducing transplant cases by declining donations from all donors after brain death older than 60 years (reduction by 33%), and all donors after cardiac death older than 50 years (reduction by 33%). 26 This concept may be adapted according to available capacity of the individual center.

The AST guideline defines epidemiological screening as the record- (Table 4 ).

The majority of all societies advise testing for SARS-CoV-2.

Nucleoid acid testing (NAT) via PCR is currently the state of the art and specimens can be nasopharyngeal or bronchoalveolar. 22 Specimen retrieval via BAL on the other side may interfere with availability of bronchoscopes during the COVID-19 pneumonia pandemic should be considered as well as the risk of infection for the examiner.

Although SARS-CoV-2 nasopharyngeal PCR shows reasonable sensitivity, a recently published study demonstrates that of 51 COVID-19 patients only 36 were initially positive in NAT. 28 Hence, repetitive testing should be considered in case of doubt.

As resources differ worldwide, especially in the current massively challenged health care systems, SARS-CoV-2 NAT might not be available due either to lack of time or resources. In this case, a low consensus was found for proceeding with the explantation after screening through clinical presentation and epidemiology given a highly urgent transplant situation.

By publication, no case of the transplant of an organ from a SARS-CoV-2 positive donor has been reported. In a recently pub- 

Given the lack of evidence-based algorithms, the responsibility for ac- 

Given the vast spread of COVID-19 with more than 100 000 recovered cases at the time of publication, the question will arise as to when these patients can be accepted as organ donors. The CST recommends two negative swabs 24 hours aside, whereas the AST guideline requires an additional 28 days after symptom resolution. 12, 20 Repeated testing is recommended due to false negative results.

Whereas consensus is clear about excluding COVID-19positive donors, the TTS additionally warns about retrieving organs from donors with unclear lung disease. This is a relevant issue, because pulmonary parenchyma is often strongly affected by the severity of the premortem course of disease.

Parenchymal defects may be present without further clarification of diagnosis.

Until now, no solid organ transplant procedure has reportedly been performed on a SARS-CoV-2-infected patient. Therefore, the expected negative impact on outcome remains speculative.

It is widely recommended that prior to transplant, a possible infection should be ruled out by NAT. 31 

There is unanimous assent in transplants societies, that patients testing positive should not undergo a transplant procedure. Not a single society recommended differently, although the evidence level is zero to date.

The AST recommends 28 days of symptom resolution prior to procurement of a former COVID-19-positive donor; however, they do not comment on the duration in the recipient. Together with the CST, they recommend two negative NATs before the transplant. 12 According to CST, tests should be performed with a 24 hours gap. In contrast, the British recommendation states that patients "recovering from an acute COVID-19 infection should not undergo transplantation." 26 

The Chinese and the Belgian Transplantation Societies strictly rec- showed no pathological findings in the CT. In this cohort, a CT scan without contrast medium showed a higher sensitivity than the RT-PCR testing (98% vs 71%). 28 Therefore, a temporarily accorded phased reduction of transplant programs is highly recommended. 22 The first tapering steps with strong SRC include: Survey on SARS-CoV-2 Infected Patients (LEOSS) was created and a transplant-specific subunit was incorporated. We strongly encourage participation and promotion of a unified and structured collection of data.

•

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

PVR: research design, paper writing, performance of the research, data analysis. NN: research design, paper writing, performance of the research, data analysis. LW: paper writing, performance of the research. HW: paper writing, performance of the research.

PM: paper writing, performance of the research. AB: paper writing, performance of the research. KH: paper writing, performance of the research. FT: paper writing, data analysis. FF: paper writing, data analysis. TS: paper writing, data analysis. WS: paper writing, data analysis. RO: paper writing, data analysis. MS: research design, paper writing, data analysis. JP: research design, paper writing, data analysis.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Paul V. Ritschl https://orcid.org/0000-0003-4610-1766

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Solid organ transplantation programs facing lack of empiric evidence in the COVID-19 pandemic: A By-proxy Society Recommendation Consensus approach