key: cord-318184-atlslk0e
authors: Germain, N.; Herwegh, S.; Hatzfeld, A. S.; Bocket, L.; Prevost, B.; Danze, P. M.; Marchetti, P.
title: Retrospective study of COVID-19 seroprevalence among tissue donors at the onset of the outbreak before implementation of strict lockdown measures in France
date: 2020-09-11
journal: nan
DOI: 10.1101/2020.09.11.20192518
sha: 
doc_id: 318184
cord_uid: atlslk0e

Background: The COVID-19 pandemic has altered organ and tissue donations as well as transplantation practices. SARS-CoV-2 serological tests could help in the selection of donors. We assessed COVID-19 seroprevalence in a population of tissue donors, at the onset of the outbreak in France, before systematic screening of donors for SARS-CoV-2 RNA. Methods: 235 tissue donors at the Lille Tissue bank between November 1, 2019 and March 16, 2020 were included. Archived serum samples were tested for SARS-CoV-2 antibodies using two FDA-approved kits. Results: Most donors were at higher risks for severe COVID-19 illness including age over 65 years (142/235) and/or presence of co-morbidities (141/235). According to the COVID-19 risk assessment of transmission, 183 out of 235 tissue donors presented with a low risk level and 52 donors with an intermediate risk level of donor derived infection. Four out of the 235 (1.7%) tested specimens were positive for anti-SARS-CoV-2 antibodies: 2 donors with anti-N protein IgG and 2 other donors with anti-S protein total Ig. None of them had both type of antibodies. Conclusion: Regarding the seroprevalence among tissue donors, we concluded that the transmission probability to recipient via tissue products was very low at the beginning of the outbreak.

First identified in Wuhan (China), in early January 2020, the new severe acute respiratory syndrome virus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID- 19) , rapidly spread to other countries worldwide causing an unprecedented pandemic 1 . In France, the first confirmed cases of COVID-19 were identified by the National Reference Center on January 24, 2020, in Bordeaux and Paris in persons who had recently stayed in Wuhan 2 . These imported cases were followed by the onset of new cases who acquired the infection due to subsequent local transmission in Europe, thus confirming an ongoing COVID-19 outbreak 3 .

The situation evolved rapidly, to limit the spread of the virus, on March 16, 2020, the French government declared a full lockdown of commercial and social activities throughout the territory, which ended on May 11, 2020 (Fig. 1 ).

The current COVID-19 pandemic has dramatically modified donation and transplantation practices 4 . COVID-19 knowledge is constantly evolving and potentially, the SARS-Cov-2 could affect the safety and/or quality of several tissues and organs. SARS-Cov-2 primary infects the lungs and airways. Although the main transmission mode is via person-to-person contact, mainly through respiratory droplets, other transmission modes cannot be excluded. Indeed, SARS-Cov-2 was found in the blood as well as multiple organs and tissues well beyond the respiratory tract 5 . Thus, in light of these uncertainties, some questions arise concerning the risk of transmission of SARS-CoV-2 through tissue or organ donations. The incertitude about transmission risk via tissue donors is increased by the fact that in most cases, (over 80% of cases) donors are asymptomatic or present with very little symptoms 6 .

Taking into account the information available, the French Biomedicine Agency updated the guidance on SARS-CoV-2 transmission risk via donated organs and tissues on March 5, 2020 and recommended to exclude donors with symptoms suggestive of COVID-19 (fever, cough, etc.) and donors who had stayed or traveled to high risk regions within the prior 28 days, or . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint were in direct contact with known or suspected COVID-19 cases within the prior 28 days. On March 15, updated recommendations called for the systematic detection of SARS-CoV-2 by RT-PCR for all potential donors (Fig. 1 ).

Since donor testing for COVID-19 was not systematically realized pre-procurement before March 15, 2020, some individuals a priori eligible for tissue donation with mild or asymptomatic COVID-19 could have remained undetected during screening.

While the detection of SARS-CoV-2 nucleic acid by PCR in nasopharyngeal swabs is the reference method for the diagnosis of acute COVID-19 infection, recent data suggest that the identification of anti-SARS-CoV-2 antibodies, now widely available, could be useful in assessing the extent of infection in subpopulations 7 . Notably, serology tests can help estimate whether donors were previously infected even in the absence of symptoms. Seroconversion to SARS-CoV-2 occurs approximatively 1-2 weeks post symptom onset and the antibodies persist for several months 8 . Several laboratory tests with different performance characteristics received an Emergency Use Authorization delivered by the U.S. Food and Drug Administration (FDA) and/or CE marking for European countries. These serologic tests differ on the type of antibodies detected and on antigen specificity. To date, there is no clear advantage to use assays test for IgG, IgM and IgG, or total antibody since kinetics of each isotype remain poorly known.

A correct interpretation of serologic assays depends on their antigen specificity. Schematically, anti-SARS-CoV-2 antibodies target two main viral proteins: the N protein, an internal nucleocapsid protein of the virus, or the S (spike) proteins, surface proteins that bind host cells (via RBD domains) and mediate virus entry into target cells 9 . S protein Antibodies are more specific than N protein ones, their kinetics also differ. For these reasons, it is advisable to use two tests, one targeting the S protein and one targeting the N protein. According to recently published CDC guidelines 10 , it is also recommended to use tests with a specificity over 99.5%, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint which ensures a high predictive value of a positive test in populations low COVID-19 prevalence.

We performed a retrospective cohort study of tissue donors at the Tissue Bank of the university hospital of Lille, France to assess COVID-19 risk. We estimated the seroprevalence of antibodies to SARS-CoV-2 in tissue donors before the systematic implementation of RT-PCR SARS-CoV-2 in all donors. This study documents the risk assessment of tissue donation in a period of community transmission and helped determine the fate of stored tissues. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint

We reviewed the medical files of 235 tissue donors processed at the Lille tissue bank between November 1, 2019 and March 16, 2020 ( Fig.1 and 2 ). Donations were distributed over the months as such: 47 in November, 44 in December, 52 in January, 56 in February and 36 in March. The following data were collected and analyzed: type of donation, age, gender, place of death, cause of death, medical history to assess COVID-19 risk, virology testing, number and type of specimen recovered.

Epidemiological characteristics of COVID-19 infection in "Hauts de France" (location of first cases, number of cases at lockdown, evolution of cases in "Nord" and "Pas De Calais") were also collected 11 .

Archived blood specimens collected on the day of donation for donor screening of infectious diseases were retrospectively tested for SARS-CoV-2 antibodies (Fig.2 ). Anonymized archived specimens were stored at -80°C until the SARS-CoV-2 antibody testing was performed. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. All tests were performed using the same lot. No detection for SARS-CoV-2 was done through direct RT-PCR on nasopharyngeal and oropharyngeal swabs.

This study was performed according to the Declaration of Helsinki and approved by the Medical Ethical Committee of the CHU de Lille. Written informed consent forms were obtained from all enrolled living donors. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint Results:

Our retrospective study was carried out at the Lille Tissue Bank on the entire group of tissue donors over a period ranging from November 1, 2019 to March 16, 2020, prior to the lockdown (Fig. 1) . Figure 3 shows the geographic location of donors throughout the Hauts-de-France region. None of the donors came from COVID-19 hot spots, most of them came from areas where only few cases of COVID-19 were reported as of March, 5, 2020. Table 1 

Next, we assessed the COVID-19 risk profile in the donor population. According to the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. Other tissue donors (183/235) were considered at low COVID-19 risk. (Table 2) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint

To our knowledge, this is the first investigation on SARS-CoV-2 seroprevalence in tissue donors. In our study, many donors were at increased risk of COVID-19 infection (Table 1) .

However, only few donors tested (4/235) were found to be positive for the SARS-Cov-2 antibodies. According to previous studies, seroprevalence rates of SARS-CoV-2 vary considerably, ranging from 0 to more than 25 %, depending on the population studied and methods used 14, 15 . The low prevalence rate among tissue donors can be explained by the fact that patients with an uncontrolled active infection at the time of donation are not eligible for donation according to our selection protocol reducing the risk of symptomatic donors with active COVID-19 enrolled in this study. Another explanation could be that some donors were tested too close to the onset of symptoms before developing antibodies. Classically, antibodies against SARS-Cov-2 seem to appear on day 7 to day10 after illness onset 8 Moreover, it is highly likely that most positive cases from our testing procedure were false positive results for several reasons. Although we used commercially available and FDA-approved tests with a high performance as recommended 12 , due to the different specificities, results should be interpreted with caution 16 . For example, the Abbott anti-N Ig G test we used, with a positive predictive value (PPV) = estimated at 92.9% assuming a prevalence of 5% 12 would likely identify some false positives but no false negative results (NPV 100%). Obviously, we did not know the prevalence of SARS-CoV-2 antibodies in our population during the study period but the real COVID-19 prevalence was probably less than 5 %. According to official data, in France, on is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint cellular receptor for SARS-CoV-2, is widely distributed among human tissues 18 suggests that the transmission risk is low after tissue or organ donation 22 .

In conclusion, our study aligns with the data from the literature and suggests that tissues collected at the beginning of the outbreak, before lockdown, can be used for grafts, taking into account the individual benefit-risk ratio. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. . https://doi.org/10.1101/2020.09.11.20192518 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 11, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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Lille.

Wantai total antibodies positivity threshold ≧ 1.1 NA Not Applicable Table  2 .Characteristics of the 4 SARS-COV2 serology positive tissue donors