key: cord-0870735-yrlzfnpr
authors: Ravanan, Rommel; Callaghan, Chris J.; Mumford, Lisa; Ushiro‐Lumb, Ines; Thorburn, Douglas; Casey, John; Friend, Peter; Parameshwar, Jayan; Currie, Ian; Burnapp, Lisa; Baker, Richard; Dudley, Jan; Oniscu, Gabriel C.; Berman, Marius; Asher, John; Harvey, Dan; Manara, Alex; Manas, Derek; Gardiner, Dale; Forsythe, John L.R.
title: SARS‐CoV‐2 infection and early mortality of wait‐listed and solid organ transplant recipients in England: a national cohort study
date: 2020-08-11
journal: Am J Transplant
DOI: 10.1111/ajt.16247
sha: c2accc69fc3615cb6df61ddf0e812f44f687ff51
doc_id: 870735
cord_uid: yrlzfnpr

Patients wait‐listed for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting SARS‐CoV‐2 and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services we examined the incidence of laboratory confirmed SARS‐CoV‐2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of 1st February 2020 with follow up to 20th May 20202. Univariate and multivariable techniques were used to compare differences between groups and to control for case‐mix. 197 (3·8%) of the 5,184 wait‐listed patients and 597 (1·3%) of the 46,789 SOT recipients tested positive for SARS‐CoV‐2. Mortality after testing positive for SARS‐CoV‐2 was 10·2% (20/197) for wait‐listed patients and 25·8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS‐CoV‐2 test. Of the 1004 transplants performed in 2020, 41 (4·1%) recipients have tested positive for SARS‐CoV‐2 with 8 (0·8%) deaths reported by 20th May. These data provide evidence to support decisions on the risks and benefits of SOT during the COVID‐19 pandemic.

The at-risk cohorts of interest were all patients resident in England who were either active on the wait-list for any deceased donor SOT, or were a SOT recipient with a functioning graft, as of 1 st February 2020.

Patients who were suspended on the waiting-list on that date or recipients of tissue or cell transplants (e.g. cornea, sclera, bone, bone marrow, hepatocyte) were not included. Patients who were on the waiting-list on 1 st February but were subsequently transplanted before 20 th May 2020 were classified within the SOT recipient group. Patients on the waiting list for, or recipients of, islet transplants were reported jointly with solid organ pancreas-alone transplants. Any recipient of more than one simultaneous organ transplant (other than simultaneous pancreas-kidney transplants) were defined as receiving a multi-organ transplant.

In both cohorts, the outcome variables of interest were (1) laboratory confirmed SARS-CoV-2 infection, (2) amongst those positive for SARS-CoV-2, vital status and date of death if applicable. Patients were followed for outcomes of interest from 1 st February to 20 th May 2020.

Testing for SARS-CoV-2 was performed using PHE validated, Real Time-Polymerase Chain Reaction (RT-PCR) test kits with a probes specific for B-betacoronavirus (target E gene) and SARS-CoV-2 (target S gene).

This enabled parallel detection of B-betacoronavirus and SARS-CoV-2 specific RNA.

This was a national cohort study enabled by linkage of three national registries in England, UK. National

Health Service Blood and Transplant (NHSBT) database is the central repository that holds records, including identifiable information and demographics, on all patients wait-listed for a deceased donor SOT or in receipt of a SOT in the UK. The NHSBT database includes data on patients from all four nations in the UK (population ~66 million) with the majority of the population in England (population ~56 million).

Access to a valid NHS number, a unique identifier for all patients in England with care provided on the NHS, enabled accurate data linkage. Forty-seven (0·9%) of the 5,184 wait-listed patients and 803 (1·7%) of the 46,789 SOT recipients had a missing NHS number and were excluded from outcome analyses. The atrisk cohorts were identified from the NHSBT database.

COVID-19 is designated as a 'notifiable disease' and Public Health England (PHE) centrally collects reports on all patients living in England who test positive for SARS-CoV-2 under the Health Protection Regulations 2010, with a statutory requirement to report within three days. Merger of the at-risk cohorts identified from the NHSBT dataset with the PHE database was performed using two unique identifiers (NHS number and date of birth).

This article is protected by copyright. All rights reserved The death data reported in this study describes all-cause mortality and does not exclusively describe COVID-19-associated mortality.

The merged NHSBT and PHE dataset comprising all laboratory confirmed SARS-CoV-2 infected wait-listed patients or SOT recipients in England was securely linked with the NHS Digital Tracing Service using three unique identifiers (NHS number, date of birth, and sex). The final dataset therefore had near real-time, complete mortality information on all wait-listed and transplanted patients who tested positive for SARS-CoV-2 in England.

Demographic characteristics (type of organ awaited/received, sex, age, ethnicity, and NHS region) were summarized for wait-listed patients, SARS-CoV-2 positive wait-list patients, SARS-CoV-2 positive wait-list patient deaths, SOT recipients, SARS-CoV-2 positive SOT recipients, and SARS-CoV-2 positive SOT recipient deaths. In addition, type of donor and year of transplant were also summarised for SOT recipients, SARS-CoV-2 positive SOT recipients, and SARS-CoV-2 positive SOT recipient deaths.

Differences in characteristics for SOT recipients versus wait-listed patients were tested univariately using the Chi-Squared and Kruskal-Wallis tests.

Cumulative number of SOT recipients and wait-listed patients testing positive for SARS-CoV-2 and subsequent all-cause mortality in England, was compared to the general English population using data provided by the UK Government (https://coronavirus.data.gov.uk/).

Kaplan-Meier estimates of patient survival for those testing positive for SARS-CoV-2 were compared for SOT recipients versus wait-listed patients using the log-rank test.

Multiple logistic regression analyses were used to identify factors associated with testing positive for SARS-CoV-2 in the SOT cohort and factors associated with SARS-CoV-2 positive recipient deaths in the SARS-CoV-2 positive SOT cohort. Variables included in the multivariable models were type of organ received, sex, age, ethnicity, NHS region, type of donor, and year of transplant. P-values of less than 0·1 were judged to be significant. The multivariable analysis excluded 25 recipients with missing sex data.

Analyses were undertaken using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

The analyses described in this paper were carried out at NHSBT, who maintain the UK Transplant registry on behalf of transplant centres in the UK. NHSBT are reliant on the General Data Protection Regulation

On 1 st February 2020 there were 46,145 SOT recipients alive with a functioning graft and 5,615 patients on the active wait-list for a deceased donor SOT. Six hundred and forty-four patients received a SOT between 1 st February and 20 th May 2020, 431 of whom were active on the waiting list at 1 st February 2020, leaving 46,789 SOT recipients and 5,184 wait-listed patients for analysis ( Figure 1 ). The majority of recipients had received a kidney-only transplant (69·5%), and most patients were waiting for a kidneyonly transplant (79·0%) ( Table 1 ). The demographic characteristics of SOT recipients and wait-listed patients are also shown in Table 1 . The median (interquartile range (IQR)) age of recipients was 56 (43-65) years versus 53 (41-61) years in the wait-listed cohort. SOT recipients were more likely to be older (p=0·001), white (p<0·001), and have a history of liver disease (p=0·001) than those patients on the waiting list ( Table 1 ). The majority (66·9%) of recipients had their transplants prior to 2016, with 1004 (2·1%) being transplanted in 2020 up to 20 th May ( Table 2 ).

The risks of testing positive for SARS-CoV-2 were higher for those on the wait-list than SOT recipients. As Infection rates were lower in transplanted patients (0·7-1·7%). Despite these lower infection rates, the overall risk of becoming SARS-CoV-2 positive and then dying during the study period were similar between wait-listed and transplanted patients across different organ types (0·0-0·5%), as mortality rates in infected patients were higher in SOT recipients. The median (IQR) age of recipients and wait-listed patients with SARS-CoV-2 was 59 (49-67) and 53 (45-62) years, respectively. The median (IQR) age of

This article is protected by copyright. All rights reserved recipients and waiting list patients dying after testing positive for SARS-CoV-2 was 64·5 (58-70) and 59 (50·5-62) years, respectively.

Risk factors associated with the development of SARS-CoV-2 infection and subsequent mortality were examined within the SOT recipient group only, as there were insufficient cases for similar analyses to be undertaken on the wait-list cohort. SARS-CoV-2 infection was significantly more likely in transplant recipients that had received a kidney transplant (p<0·0001), were older (p<0·0001), non-white (p<0·0001), lived in the London NHS region (p<0.0001), had a deceased donor transplant (p<0·0001) or had been transplanted in a more recent year (p<0·0001). Multivariable logistic regression analysis showed that all of these variables were associated with a significantly increased risk of SARS-CoV-2 infection ( Table 3 ). The only variable independently associated with death in those recipients with a positive SARS-CoV-2 test was age. Compared to a reference group aged 50-59 years, odds ratios (95% confidence intervals) were 0·37 (0·19-0·72), 1·86 (1·13-3·04), and 2·37 (1·35-4·16) for recipients aged 0-49, 60-69, and 70+ years, respectively.

This article is protected by copyright. All rights reserved

The COVID-19 pandemic has had a major impact on health services of many countries and disrupted most clinical programmes, including organ donation and transplantation, with intensive care facilities facing extreme pressure due to a surge of COVID-19 admissions. [16] [17] [18] [19] Given the absence of definitive data on the risks of SARS-CoV-2 infections post-transplant, patients on the waiting-list for a transplant and clinical teams are unsure of the relative safety of transplantation versus remaining on the waiting-list. Many transplant programs are either suspended or have significantly curtailed their activity.

The analyses presented are derived from the largest and most comprehensive dataset yet available on the incidence of and outcomes after SARS-CoV-2 infection in SOT recipients during the pandemic.

Furthermore, it is also the first national study from a country with significant rates of infection and deaths from COVID-19 to comprehensively examine the survival of patients on the national deceased donor waitlist over the same period, providing a more valid comparator group for risk-benefit assessment of undertaking transplantation than using general population data. 4 We found that a higher proportion of wait-listed patients tested positive for SARS-CoV-2 than SOT recipients (3·8% versus 1·3%). Since the highest proportion of patients on the list are waiting for a kidney transplant, it is possible that the inability of many haemodialysis patients to self-isolate due to requirement to travel three times/week to a dialysis facility and remain in proximity to other patients and healthcare staff may contribute to a higher risk of COVID-19. After an initial rapid rise in numbers of affected patients, the number of new infections appears to have plateaued by May 2020.

Whilst the overall risk of infection in wait-listed patients was higher, SOT recipients who tested positive for SARS-CoV-2 had a higher all-cause mortality during the follow-up period compared to wait-listed patients (25.8% versus 10·2%). Amongst the patients transplanted in 2020, i.e. during the pandemic, the incidence of SARS-CoV-2 infection was 4% with a subsequent risk of death of less than 1% within the follow-up period. Increasing age, non-white ethnicity, and living in London were associated with higher The only variable independently associated with death in SOT recipients with a positive SARS-CoV-2 test was age. Increasing age has been identified as a strong risk factor for COVID-19-related deaths in other

This article is protected by copyright. All rights reserved studies, 3, 4 and therefore this finding was unsurprising. Although our dataset did not adequately capture co-morbidity data, it is notable that increasing rates of co-morbidities do not appear to explain the apparent association between increasing age and death from SARS-CoV-2 infection, as two large studies from the UK show that age is an independent risk factor for death even after adjustment for multiple major co-morbidities. 3, 4 Transplant clinicians will need to take these findings into account when considering the suitability of older patients to undergo transplantation in countries with a high incidence of SARS-CoV-2 infection.

This study also supports the assumption that SOT recipients are at high risk of death after SARS-CoV-2 infection, with 154 (25·8%) of 597 patients dying during the study period. Although this mortality rate is similar to that of the general UK population with SARS-CoV-2, the median age of transplant recipients with SARS-CoV-2 infection in our study was far lower (59 years versus 73 years). 3 To our knowledge, the only other national transplant registry that has reported on COVID-19-related deaths identified 21 Swiss SOT recipients between 9 th March and 6 th April that tested positive for SARS-CoV-2. 14 After a median follow-up of 33 days, two patients died. In Spain, Domínguez-Gil et al noted that 363 SOT recipients had developed COVID-19, but no mortality data or denominator were presented. 18 Deaths on the Spanish national waiting list were reported at a rate of 1·3 per week during the pandemic (eight in total), compared to a pre-pandemic rate of 1·4 deaths per week, but without further information on whether those who died had COVID-19. The OpenSAFELY study included 20,130 organ transplant recipients but only 49 in-hospital deaths from COVID-19 were identified, with the general UK population as the comparator group. 4 Many of the previous studies on the outcomes of SOT recipients with COVID-19 have focussed on a single organ type, with the majority on kidney transplant recipients. Of those studies that have included more than ten renal transplant patients, mortality rates varied from 6% 7 to 67%. 6 The largest study thus far on kidney transplant recipients reported on a voluntary Spanish registry of 868 patients on renal replacement therapy with COVID-19 between 18 th March and 11 th April, including approximately 290 renal transplant recipients. 21 There were no linkages to central registries of death or notifiable disease.

The mean age of all patients was 67 years, and the transplant population was younger than those on dialysis. Eighty-five percent of patients were admitted to hospital, and 23% of patients died (18·6% of transplant recipients versus 24·9% of those on dialysis). Age was found to be a risk factor for death after COVID-19 in both transplant and dialysis patients.

Latif et al described outcomes of COVID-19 in 28 heart transplant recipients in New York City with 25% mortality, 22 while a series of 13 patients from Michigan found that two patients (15%) died. 23 Six of 23 heart transplant recipients with SARS-CoV-2 infection died in our study. Reports of COVID-19 outcomes in Accepted Article lung transplant recipients have been limited, with a small number of case-series of fewer than five patients. 12, 24 The largest series of 17 lung patients comes from two centres in New York City, though survival outcomes for this group are not reported. 9 We found that six of thirteen lung transplant recipients with SARS-CoV-2 died.

Similarly, mortality rates from COVID-19 in liver transplant recipients have not been widely described. An international collaborative from 21 countries reported a 23% mortality rate from COVID-19 in 39 liver transplant patients, 25 while a 21% mortality rate in 24 SARS-CoV-2 positive liver recipients was identified in a survey of Italian liver transplant programmes. 26 Our results suggest that liver transplant recipients have a lower SARS-CoV-2 infection rate than recipients of other solid organ transplants, though larger analyses with longer follow-up are needed. To our knowledge, no COVID-19-related deaths have previously been reported in heart, lung, or liver transplant waiting list populations.

The strengths of our study include a complete national dataset of the at-risk population, accurate identification of all at-risk patients who tested positive for SARS-CoV-2, near real-time ascertainment of all-cause mortality in at-risk patients, and analysis of outcomes between wait-listed and transplanted patients. It highlights the value of routine, national, embedded data collection allowing systems to analyse comprehensive data and respond accordingly.

We acknowledge the weaknesses of this study. Although the NHSBT database holds data on SOT recipients and wait-listed patients in Wales, Scotland, and Northern Ireland, this study examined patients residing in England only, as linkages with the relevant notifiable diseases and mortality registries in other nations were not in place at the time of writing. Given the notifiable disease status, data on patients testing positive for SARS-CoV-2 was reported and collated centrally and available for analysis but data on patients testing negative were not available. Due to the relatively low number of events in the waiting-list group, multi-variable analyses comparing the mortality rates between the two cohorts was not possible.

Our analysis does not include the indication for SARS-CoV-2 testing, symptoms, hospital or intensive care unit admissions, and treatments of COVID-19. We expect that the overwhelming majority of patients with SARS-CoV-2 positive tests had symptoms, as tests were predominantly done in hospitalised patients during the study period in the UK. As such, there was a selection bias towards sicker, symptomatic and hospitalised patients. The study period was short, and further follow-up will be needed to determine definitive case-fatality rates. We were unable at this time to report on excess mortality in the study cohorts. Direct comparisons of SARS-CoV-2 positivity and subsequent mortality between the wait-listed and transplanted groups are limited by inherent demographic, biological, and behavioural differences (e.g. age, immunosuppressive burden, co-morbidities, access to testing, challenges in self-isolating in those on unit dialysis) and should be treated with caution. Finally, whilst we could ascertain all-cause

This article is protected by copyright. All rights reserved mortality in patients testing positive for SARS-CoV-2, we were unable to access cause of death as certified.

The linked dataset did not provide cause of death information. Given the restriction of access for swab testing to symptomatic hospitalised patients and short median time (10.5 days for wait-listed and 7.5 days for SOT recipients) between a positive swab result and death, COVID-19 associated mortality is inferred but not proven by cause of death as certified.

In conclusion, analyses from this large, comprehensive national dataset will enable transplant clinicians and their patients to have a more accurate risk assessment of incidence of and outcomes following SARS-CoV-2 infection, with the first-of-its-kind analysis of risk in wait-listed and SOT recipient groups. Such information will help clinical teams decide on reinstating organ transplant programs and patient selection, and will aid patient consent discussions. Future work should include longer follow up, further case-mix adjustment and multi-variable analyses, along with more detailed understanding of the impact of pharmacological and non-pharmacological interventions on SARS-CoV-2 infection and mortality rates in wait-listed patients and SOT recipients.

team supporting organ donation and transplantation in the UK; and the transplant multi-disciplinary clinical teams and patients across the UK.

This work was carried out by NHSBT, an NHS special health authority with responsibility for organ donation and transplantation in the UK. Other than the authors, no other public or private entity had any role in study design, data analysis, data interpretation, or writing of the report. LM had full access to all of the data and was responsible for merging the linked datasets in the study. All authors had final responsibility for the decision to submit for publication. 

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

Research data are not shared.

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved 

Coronavirus (COVID-19) in the UK

Coronavirus (COVID-19) related deaths by ethnic group

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients

Guidance on shielding and protecting people who are clinically extremely vulnerable from COVID-19

Clinical Course, Imaging Features, and Outcomes of COVID-19 in Kidney Transplant Recipients

Preliminary data on outcomes of SARS-CoV-2 infection in a Spanish single centre cohort of kidney recipients

COVID-19 infection in kidney transplant recipients

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter

Early Description of Coronavirus 2019 Disease in Kidney Transplant Recipients in New York

Coronavirus Disease 2019 Pneumonia in Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan, China

SARS-CoV-2 infection in two patients following recent lung transplantation

Covid-19 and Kidney Transplantation

First experience of SARS-CoV-2 infections in solid organ transplant recipients in the Swiss Transplant Cohort Study

A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia

Organ procurement and transplantation during the COVID-19 pandemic

Immediate impact of COVID-19 on transplant activity in the Netherlands

COVID-19 In Spain: Transplantation In The Midst Of The Pandemic

Risk factors for SARS-CoV-2 among patients in the

Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study

Report of the COVID-19 Registry of the Spanish Society of Nephrology (SEN)

Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease

Coronavirus Disease 2019 in Heart Transplant Recipients in

Southeastern Michigan -Case Series

COVID-19 pneumonia in lung transplant recipients: report of

The authors acknowledge Public Health England and NHS Digital Tracing Service for sharing data; James