Transplant International ORIGINAL ARTICLE Low seroprevalence of SARS-CoV-2 antibodies in a liver transplant cohort Isabel Campos-Varela1,2,3,4,5 , Oscar Len2,5,6 , Ares Villagrasa1,5, Ester Marquez-Algaba2,5,6 , Juliana Esperalba 2,5,7 , Cristina Dopazo4,5,8 , Ibai Los-Arcos 2,5,6 s Anto , Andre  n2,5,7 & Lluıs Castells1,2,3,4 1 Liver Unit, Hospital Universitari Vall SUMMARY d’Hebron, Barcelona, Spain Solid organ transplant recipients might be at greater risk for acquisition and 2 Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona mortality because of SARS-CoV-2. There are no data regarding SARS-CoV-2 Hospital Campus, Barcelona, Spain seroprevalence among liver transplant (LT) recipients, and whether it is dif- 3 Centro de Investigacion Biomedica ferent from that of the general population or other immunosuppressed de Enfermedades Hepaticas y groups. We evaluated the prevalence of IgG SARS-CoV-2 antibodies among Digestivas (CIBERehd), Instituto de LT recipients to estimate the frequency of asymptomatic SARS-CoV-2 infec- Salud Carlos III, Madrid, Spain tion using serological assays in our outpatient clinic. We conducted a cross- 4 Facultat de Medicina, Universitat sectional analysis from 10 May to 26 October 2020 of all adult (>18 years) Autonoma de Barcelona, Bellaterra, LT recipients that underwent a routine laboratory test for the outpatient Spain clinic follow-up at the Hospital Universitari Vall d’Hebron (Barcelona) in 5 Hospital Universitari Vall d’Hebron, which we included serological testing for SARS-CoV-2. Nine out of 294 LT Vall d’Hebron Barcelona Hospital recipients (3.1%) tested positive for anti-SARS-CoV-2 IgG antibodies. Five Campus, Barcelona, Spain 6 Department of Infectious Diseases, of them (55.5%) had suffered clinically symptomatic SARS-CoV-2 infection Hospital Universitari Vall d’Hebron, confirmed by RT-PCR, four (44.4%) had presented compatible symptoms Barcelona, Spain but without microbiological confirmation and only one patient (1/9, 11.1%) 7 Department of Microbiology, tested positive without any previous symptom. SARS-CoV-2 seroprevalence Hospital Universitari Vall d’Hebron, among LT recipients in an area highly affected by the pandemic is lower than Barcelona, Spain in the general population in the same area. These results render the possibil- 8 Department of ity of asymptomatic infection in LT recipients very unlikely. Hepatobiliopancreatic Surgery and Transplantation, Hospital Universitari Vall d’Hebron, Barcelona, Spain Transplant International 2021; Key words Correspondence COVID-19, liver transplant recipient, SARS-CoV-2 antibodies, seroprevalence Isabel Campos-Varela MD, MPH and Oscar Len MD, PhD, Vall d’Hebron Received: 19 March 2021; Revision requested: 21 May 2021; Accepted: 7 June 2021 Institut de Recerca, Hospital Universitari Vall d’Hebron, Barcelona 08035, Spain. Tel.: 34-932746140; fax: 34-932746068; e-mails: icampos@vhebron.net (I.C.- V.) and Oscar.len@vhir.org (O.L.) factors associated with worse outcomes include age and Introduction comorbidities such as hypertension, diabetes mellitus or Coronavirus disease 2019 (COVID-19) is a new emerg- chronic lung disease among others [1]. Because of the ing infectious disease caused by severe acute respiratory impairment in cell-mediated and humoral immunity syndrome coronavirus 2 (SARS-CoV-2). The main risk caused by immunosuppressive agents, solid organ ª 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd 1 doi:10.1111/tri.13946 Campos-Varela et al. transplant (SOT) recipients might be also at greater risk This study was approved by the Vall d’Hebron Insti- for disease and mortality because of SARS-CoV-2 infec- tutional Review Board and conducted according to the tion [2–5]. Otherwise, the impaired activation of naive 2000 Declaration of Helsinki as well the Declaration of B cells and B-cell antigen presentation as well as T-cell Istambul 2008. All patients gave their informed consent stimulus to T-cell dependent responses may prevent the prior to their inclusion in the study. development of antibodies against SARS-CoV-2 [6]. The impact of the current pandemic on SOT is being Serological testing for SARS-CoV-2 antibodies extraordinary, with early data showing a significant reduction in total waitlist additions and transplant surg- During the study period, serological status could be eries across all transplant domains, with an increase in determined by two commercial chemiluminescence waitlist mortality for kidney, liver and lung transplant immunoassays (CLIA) targeting specific SARS-CoV-2 candidates [7]. antibodies: (i) Elecsys Anti-SARS-CoV-2 (Roche Diag- Seroprevalence of SARS-CoV-2 antibodies in a cer- nostics, Mannheim, Germany) was performed on the tain population serves as a sensible measure of exposure Cobas 8800 system (Roche Diagnostics) for qualitative risk. There are few data regarding SARS-CoV-2 sero- determination of total antibodies (including IgG, IgM prevalence among liver transplant (LT) recipients [8], and IgA) against nucleocapsid (N) SARS-CoV-2 proteins and whether it is different from that of the general pop- (the manufacturer reported sensitivity of 100% in ulation or other immunosuppressed groups. patients with more than 14 days after infection, and The aim of the present study was to systematically specificity of 99.81%), and, (ii) Liaison SARS-CoV-2 S1/ determine the presence of SARS-CoV-2 antibodies S2 IgG (DiaSorin, Saluggia (VC), Italy) was performed on among LT recipients to evaluate the prevalence of the LIAISON XL Analyzer (DiaSorin) for quantitative asymptomatic SARS-CoV-2 infection using serological determination of the spike (S) glycoprotein subunits 1 assays in our outpatient clinic. and 2 (S1/S2) (the manufacturer reported sensitivity of 97.4% in patients with more than 15 days after infection, and specificity of 98.5%). According to the protocol of Methods our Hospital, firstly, patients were screened with the determination of total antibodies against nucleocapsid. If Study population the result was positive, or there was clinical or epidemio- Since 1988, our adult liver transplantation program has logical suspicious, or the patient had a previous positive performed 1300 LT, and currently, we follow-up respiratory sample by real-time reverse transcription approximately 700 patients. We performed a cross- polymerase chain reaction (RT-PCR), the determination sectional analysis from 10 May to 26 October 2020 of of IgG antibodies against spike was also performed. all adult (>18 years of age) LT recipients that under- went a routine laboratory test for the outpatient clinic Definitions follow-up at the Hospital Universitari Vall d’Hebron (Barcelona) in which we added serological testing for Confirmed-SARS-CoV-2 infection was diagnosed by SARS-CoV-2. There were no exclusion criteria. RT-PCR assay of nasopharyngeal swab specimens fol- During lockdown all outpatient visits were converted lowing suggestive symptoms of acute presentation such into telematic visits. Also, laboratory tests and other as fever, cough, rhinorrhoea, sore throat, headache, dys- evaluations (image, endoscopy, etc.) were cancelled and pnoea, diarrhoea, anosmia or ageusia. rescheduled months later. Patients were instructed to Suspected-SARS-CoV-2 infection was defined by the follow lockdown restrictions and to stay at home as presence of symptoms described above, but without much as possible. RT-PCR confirmation. Data were prospectively collected in a database created A patient was considered to have a positive serology for the study. All clinical information was extracted by against SARS-CoV-2 if either SARS-CoV-2 IgG anti-S1/ experienced transplant physicians from reliable electronic S2 or SARS-CoV-2 Ig anti-N waspositive. medical data sources. Demographic data, comorbidities and transplant-related information including baseline Statistical analysis immunosuppressant therapy were recorded. During the scheduled routine visit, all patients were asked about pre- Descriptive statistics were expressed as medians and sent or past symptoms compatible with COVID-19. interquartile ranges (IQRs) for continuous variables and 2 Transplant International 2021; ª 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd SARS-CoV-2 antibodies in liver transplant Table 1. Main characteristics of the cohort by SARS-CoV-2 antibody status. Total SARS-CoV-2 (+) SARS-CoV-2 ( ) Variable (N = 294) (N = 9; 3.1%) (N = 285; 96.9%) P-value Age at LT (years) 54 (46–61) 53 (48–55) 54 (46–61) 0.83 Age at serology testing (years) 63 (56–70) 66 (65–69) 63 (56–70) 0.38 Time from LT to SARS-CoV-2 serology (years) 9.6 (3.2–16.0) 13.7 (3.2–14.1) 9.5 (3.2–16.0) 0.75 Sex Male 211 (71.8%) 6 (66.7%) 205 (71.9%) 0.72 Aetiology of liver disease Alcohol 75 (25.5%) 2 (22.2%) 73 (25.6%) 0.62 HCV 105 (35.7%) 2 (22.2%) 103 (36.1%) HBV 31 (10.6%) 2 (22.2%) 29 (10.2%) NASH 10 (3.4%) 0 (0%) 10 (3.5%) Other 73 (24.8%) 3 (33.4%) 70 (24.6%) HCC as indication of LT 98 (33.3%) 1 (11.1%) 97 (34.0%) 0.28 Blood type A 140 (48.0%) 4 (44.5%) 136 (48.1%) 0.05 B 25 (8.6%) 1 (11.1) 24 (8.5%) O 117 (40.0%) 2 (22.2%) 115 (40.6%) AB 10 (3.4%) 2 (22.2%) 8 (2.8%) Arterial hypertension 157 (53.4%) 5 (55.6%) 152 (53.3%) 1.00 Diabetes 113 (38.4%) 6 (66.7%) 107 (37.5%) 0.09 Chronic renal failure (GFR <60 ml/min/1.73 m2) 65 (22.1%) 3 (33.3%) 62 (21.7%) 0.42 HIV infection 10 (3.4%) 0 (0%) 10 (3.5%) 1.00 Simultaneous liver-kidney transplant 10 (3.4%) 0 1.00 Cardiac disease 33 (11.2%) 1 (11.1%) 32 (11.23%) 1.00 Immunosuppressant therapy Tacrolimus 268 (91.2%) 7 (77.8%) 261 (91.6%) 0.18 Cyclosporine 14 (4.8%) 1 (11.1%) 13 (4.6%) 0.36 Mofetil Mycofenolate 106 (36.1%) 3 (33.3%) 103 (33.1%) 1.00 Everolimus 51 (17.4%) 3 (33.3%) 48 (16.8%) 0.19 GFR, glomerular filtration rate; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV; human immunodeficiency virus; IQR, IQR, interquartile range; LT, liver transplantation; NASH, nonalcoholic steatohepatitis; SARS-CoV- 2, severe acute respiratory syndrome coronavirus 2. Data are presented as median (IQR) or n (%). absolute numbers (percentages) for categorical variables. 63 years (IQR 56–70). At assessment, median time since Comparisons among LT recipients with a positive or LT was 9.6 years (IQR 3.2–16.0). The aetiology of liver negative serology were performed using Wilcoxon rank- disease was chronic hepatitis C infection (35.7%), alco- sum for continuous variables and the chi-square test or holic cirrhosis (25.5%), chronic hepatitis B infection Fisher exact test for categorical variables. Two-sided P (10.5%), nonalcoholic steatohepatitis (NASH; 3.4%), values of <0.05 were considered to indicate statistical and other (24.8%). Hepatocellular carcinoma (HCC) significance. STATA v13 (College Station, TX, USA) was was the indication of LT in 33.3% of cases. Regarding used for all statistical analyses. immunosuppressant therapy, 91.2% of patients were on a tacrolimus-based therapy, 36.1% and 17.4% were on mycophenolate-mofetil (MMF) and everolimus treat- Results ment, respectively, both in combination with tacrolimus During the study period, we obtained sera samples dur- or cyclosporine or in monotherapy. ing regular outpatient visits in 294 adult LT recipients Nine out of 294 LT recipients (3.1%) tested positive for serological testing. Patient demographics are pre- for anti-SARS-CoV-2 Ig antibodies (all nine patients sented in Table 1. Recipients were more frequently men were SARS-CoV-2 IgG anti-S1/S2 positive and eight (71.8%), and had a median age of 54 years (IQR 46– were SARS-CoV-2 anti-N positive). Five of them (5/9, 61) at LT and a median age at serology assessment of 55.5%) had suffered clinically symptomatic SARS-CoV2 Transplant International 2021; 3 ª 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd Campos-Varela et al. infection confirmed by RT-PCR (three were hospital- These differences may be related to true geographic ized, and none of them was admitted to the intensive differences and the different degree of assistance to care unit), four (4/9, 44.4%) had presented compatible medical centres during the pandemic. In this sense, can- symptoms but without microbiological confirmation cer patients and patients on haemodialysis are among and only one patient (1/9, 11.1%) tested positive with- the groups of patients who maintained their regular out any previous symptom. Median time from diagnosis attendance to medical facilities, with the consequent risk of COVID-19 to anti-SARS-CoV-2-Ig antibodies deter- of nosocomial infection, along with the risk associated mination was 66 days (IQR 39–99). with traveling [14]. On the contrary, in liver or kidney During the study period, we had 14 RT-PCR con- transplant recipients, in a situation of clinical stability, firmed cases of SARS-CoV-2 infection in LT recipients. the follow-up was mainly done by telematic means dur- Five are still in quarantine and had not yet been tested for ing the pandemic which significantly reduced their serology, three died, and six recovered and are followed exposure to the virus in medical settings. at the outpatient clinic and were included in the study. Despite the fact that LT recipients accumulate many Five of the six patients who had confirmed COVID-19, potential risk factors (diabetes mellitus, chronic renal fail- tested positive for anti-SARS-CoV-2 IgG antibodies ure, arterial hypertension, immunosuppressant drugs), (83.3%) as have been described above, while in only one this low seroprevalence may be partly explained by the case (1/6, 16.7%), the serology was negative 1 and early recommendation towards our LT recipients to limit 3 months after the acute infection. This patient presented the face-to-face contacts and the high compliance with a mild curse of the disease. None of the patients received the isolation and personal cleanliness measures (social convalescent plasma or intravenous immunoglobulin. distancing, hand washing and use of masks). There were no differences in seroprevalence according However, a previous study carried out in the same to age, sex, aetiology of liver disease, HCC as indication area has shown that LT recipients presented an inci- of LT, immunosuppressant therapy, comorbidities, or dence of COVID-19 disease double than in the general being a carrier of a simultaneous liver-kidney trans- population [3]. There might be several explanations plant. SARS-CoV-2 antibodies were less frequently posi- regarding this discrepancy. First, it could be that in the tive among LT recipients with blood group O (two middle of the first wave, LT recipients acutely ill, were patients, 22.2%, P = 0.05). diagnosed in a greater proportion than in the general population, when because of a collapsed system, many individuals remained at home without a COVID-19 Discussion diagnosis confirmed, while immunosuppressed patients The results of the present study show that the sero- were admitted to hospital and tested against SARS- prevalence of SARS-CoV-2 among LT recipients is low CoV-2 infection more often than other populations (3.1%) in the line of results from general population. without significant comorbidities. This under diagnosis Seroprevalence in the Spanish population in the same would have been less significant in the LT population. period of time was 5%, and specifically in the area of Another explanation might be an impaired immune the present study, Barcelona, seroprevalence was 6.8%, response of LT recipients, limiting their capacity to gen- even higher than the general average [9]. Moreover, erate antibodies against SARS-CoV-2 virus, or even in a only one patient out of 294 (0.3%) fulfils the diagnosis titre enough to be detected, despite a true higher inci- of SARS-CoV-2 asymptomatic infection. These results, dence of SARS-CoV-2 infection. This later hypothesis confirm that, even in Spain, one of the European coun- might be supported by the known inferior response to tries most affected by the COVID-19 pandemic, asymp- vaccination against hepatitis B virus in LT recipients tomatic infection among LT recipients is practically [15–17]. Also, time since LT and type of immunosup- nonexistent. Studies of SARS-CoV-2 seroprevalence in pression might play a role in the ability to generate a other populations at risk have shown discordant results, measurable immune response. In a recent study includ- probably related to the specific characteristics of the dif- ing 70 SOT recipients (10 LT recipients) infected with ferent patient populations studied. While in a Spanish SARS-CoV-2, only 51% were antibody positive, three study among cancer outpatients, SARS-CoV-2 preva- months after the infection. However, among the 10 LT lence was 31.4% [10], among patients on haemodialysis recipients, 8 (80%) had developed SARS-CoV-2 anti- in the United States and the United Kingdom (UK) it bodies [18]. This study shows an important discrepancy was 8.0% and 36.2%, respectively [11,12], and 8.1% in among the rate of seropositivity among the different kidney transplant recipients in the UK [13]. organs evaluated that deserves further evaluation. A 4 Transplant International 2021; ª 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd SARS-CoV-2 antibodies in liver transplant similar study conducted by Boyarsky et al. [19] reported and 6 months after infection in the LT group have been a series of 18 SOT recipients with SARS-CoV-2 PCR- found [21]. Similarly, in a US cohort of 658 SOT recip- confirmed, in which 78% of the patients were able to ients, antibody response after the two doses of mRNA develop and maintain SARS-CoV-2 antibodies 98 days vaccines was of 54%, representing a significant reduc- (IQR 55–147) after the COVID-19 infection. Despite tion when compared to the robust response demon- the relevance of the data, both are small series, includ- strated among the general population [22]. ing only 16 LT recipients (or liver-kidney) recipient, The relation between ABO and Rh blood type and whose results would have to be confirmed. COVID has been described with contradictory results. Our result is consistent with the 3.2% SARS-CoV-2 First studies pointed to a protector effect from nontype seroprevalence described in another cohort of LT recipi- A group [23]. However, later studies have questioned ents evaluated between May and August 2020 [8], but sig- this premise, showing contradictory results [24,25], and nificantly, in an area, as it was Germany during the moreover, a large prospective study has not found any evaluated period, much less affected by the pandemic, association among ABO blood type, risk of infection or where the estimated seroprevalence was 1.3–3.2%. Hence, its severity [26]. Our limited in size cohort, does not in this study the seroprevalence in LT recipients was the provide much information, but seems that the propor- same as in the general population. However, the SARS- tion of patients with non-A blood type have a lower CoV-2 seroprevalence reported in the present study came proportion of SARS-CoV-2 antibodies. from an area as Barcelona with a SARS-CoV-2 seropreva- Our study has some limitations. It is a single-centre lence twice as high as that found in our cohort (3.1% vs. study, but carried out in an area highly affected by the 6.8%). Taking as true the seroprevalence figures, we can SARS-CoV-2 pandemic. It is a descriptive study and does only assume that patients evaluated in the present cohort, not have enough cases to evaluate risk factors associated within a much more affected area, were less exposed to with a higher rate of infection. However, it has also some the virus, thanks to isolation and personal cleanliness strengths. Data were prospectively collected, including all measures, which were the first premises that the LT team consecutive patient visited in the outpatient clinic, limit- tried to ensure in these patients, as well as keeping them ing the loss of information and selection bias. Likewise, out of the hospital, if possible. This reinforces the para- serological diagnosis in consecutively tested patients is mount importance of observing social distancing, disin- not affected by the rate of report of the disease. fection measures and masking. In conclusion, SARS-CoV-2 seroprevalence among LT Another important fact is that, in our cohort of 294 recipients in an area highly affected by the pandemic is as patients, we were only able to identify one asymp- low as 3.1% and is reduced to 0.3% for the asymptomatic tomatic case (0.3%), and the remaining patients had infection. These results make the design of futures strate- clinical manifestations, previously confirmed or not by gies to face the next phases of the pandemic, including RT-PCR. These results make the possibility of asymp- vaccination, highly needed and reinforce the need to tomatic infection in LT recipients very unlikely. Proba- maintain public health measures and surveillance to pro- bly, if a LT recipient is infected by SARS-CoV-2 tect the general population and LT recipients. develops clinical manifestations of the disease. Whether clinical manifestations would be more severe than in Authorship general population is still under discussion, with discor- dant results [2,3,19]. Besides, other studies from high IC-V: study concept and design, interpretation of data, incidence areas, like London, have shown a low inci- drafting of manuscript, critical revision of the manu- dence of SARS-CoV-2 infection among LT recipients, script for important intellectual content and statistical supporting our findings, with a seroprevalence half the analysis. OL: study concept and design, analysis and rate found in the Spanish population [20]. interpretation of data, and critical revision of the manu- However, and despite the aforementioned data, we script for important intellectual content. AV: data col- have seroprevalence figures from SARS-CoV-2 infection lection, interpretation of data and critical revision of and postvaccination studies in LT and SOT recipients the manuscript for important intellectual content. EM- that support the concept that immunological response A: data collection, interpretation of data and critical is lower in these patients. In a Spanish study, including revision of the manuscript for important intellectual 71 LT recipients and 71 controls, with RT-PCR con- content. JE, CD, ILA and AA: data collection, interpre- firmed SARS-CoV-2 infection, lower incidence and tation of data and critical revision of the manuscript for lower levels of anti-nucleocapsid IgG antibodies at 3 important intellectual content. LC: study concept and Transplant International 2021; 5 ª 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd Campos-Varela et al. design, data collection, interpretation of data, drafting III. CIBERehd is supported by Instituto de Salud of manuscript and critical revision of the manuscript Carlos III. The work was independent of all for important intellectual content. funding. Funding Conflict of interest Isabel Campos-Varela’s research activity is funded by grant PI19/00330 from Instituto de Salud Carlos The authors have no conflicts of interest to disclose. REFERENCES 1. 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