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Original Clinical Science—General

Mortality Rates in Transplant Recipients and Transplantation Candidates in a High-prevalence COVID-19 Environment

Mamode, Nizam FRCS1; Ahmed, Zubir FRCS1; Jones, Gareth FRCP2; Banga, Neal FRCS2; Motallebzadeh, Reza FRCS2; Tolley, Hannah BSc3; Marks, Steve FRCPCH4; Stojanovic, Jelena FRCPCH4; Khurram, Muhammad A. FRCS5; Thuraisingham, Raj FRCP5; Popoola, Joyce PhD6; Ghazanfar, Abbas FRCS6; Game, David FRCP1; Sran, Kiran FRCS1; Dor, Frank J.M.F. PhD7,8; Lucisano, Gaetano MD7; Sinha, Manish PhD1; Olsburgh, Jonathon FRCS1; Willicombe, Michelle MRCP7

Author Information
doi: 10.1097/TP.0000000000003533
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Abstract

INTRODUCTION

Immunosuppressed patients are thought to be at increased risk of death from the SARS-Cov-2 virus, when compared with the general population. Solid organ transplant recipients (TRs) are not only immunosuppressed, but often have a number of comorbidities, such as diabetes, which have been associated with worse outcomes following COVID-19 infection. London has had the highest prevalence of COVID-19 infections in the United Kingdom, and one of the highest per million population worldwide, with 6966 deaths on May 1, 2020.1 All 6 kidney transplant centers in London suspended their programs in March 2020, in response to the pandemic and anecdotal reports of poor outcomes in TRs. As cases decline following public health measures, transplant programs across the world are attempting to balance the risks of transplantation against the risks of patients remaining on hemodialysis. In the center, hemodialysis requires thrice weekly attendance with a risk of viral spread by staff and other patients, as well as transportation to the dialysis site, which may increase the exposure to infected individuals.

This study considers the outcomes in all kidney TRs admitted to hospital with COVID-19 from the start of the pandemic until April 27, 2020, and compares this with all admissions of patients on the waiting list for transplantation from the same units.

The primary aim was to determine the mortality rates for TRs admitted to hospital with COVID-19, and to compare this with the rate for patients on the waiting list.

MATERIALS AND METHODS

Audit data from March and April 2020 were collected from each of the 6 transplanting centers in London; Guys, Evelina and St Thomas Hospitals, the Imperial College Renal and Transplant Centre, the Royal Free Hospital, the Royal London Hospital, Great Ormond Street Hospital, and St Georges’ Hospital. Ethical approval was not required. Participants were included if they had undergone a kidney or kidney/pancreas transplant and the graft was still functioning, and had been admitted to hospital. All were over 18 y except 1 pediatric TR, 4 y of age. Demographic data, comorbidities, blood results, and outcome data were collected from patient records and anonymized. Data were also collected for patients who had been active on the waiting list before the pandemic, and were admitted with COVID-19.

Each center advised both groups of patients to observe shielding, even if symptomatic, unless their condition was deteriorating, according to Government guidance.2 Most of these patients did not undergo viral PCR testing, and therefore, patients who were not admitted to hospital were not included in this analysis, since an accurate assessment of the total number of cases within the community would be impossible. Screening protocols for dialysis patients varied, and changed during the study period, so that the incidence of positive tests in those patients is similarly difficult to interpret.

Individual hospitals had their own criteria for escalation of treatment and admission to intensive care (ITU), but essentially those thought to have a low chance of survival were not admitted to ITU. Mortality was defined as all-cause mortality in hospital.

Statistical analysis was undertaken using Stata version 16 software (StataCorp. 2019. Stata Statistical Software: Release 16; StataCorp LLC, College Station, TX). All continuous variables were normally distributed and comparative analyses were undertaken using Student’s t test. Categorical variables were analyzed using the Chi-squared test of association. Odds ratios were generated by univariate and multivariate binary logistic regression.

RESULTS

One hundred twenty-one kidney or kidney/pancreas TRs were admitted to hospital during the study period, while 52 patients on the waiting list (WL) for a transplant were admitted. Of the TR group, 36 died (30%), while 14 WL patients died (27%, P = 0.71). There were 1239 waitlisted patients at the 6 London transplant centers at the February 29, 2020 (NHSBT personal communication) giving an overall mortality rate of 1.1%. The demographic data of the 2 groups are shown in Table 1, with a higher proportion of ethnic minority patients in the WL group; otherwise, there were no significant differences between the groups. The mean time from transplant was 79 mo, and 8.3% were kidney/pancreas TRs, with the remainder being kidney only. Thirty-eight patients had received a depleting agent at induction (alemtuzumab or antithymocyte globulin), while the remainder had been given basiliximab.

TABLE 1. - Demographic data of transplant recipients and patients active on the transplant waiting list, admitted to hospital with SARS-CoV-2 infection
Transplant recipients (n = 121) Waiting list patients (n = 52) P
Mean age, y (SD) 56.2 (13.2) 54.4 (11.6) 0.4
Female gender 45 (37 %) 19 (36.5%) 0.93
Non-White ethnicity 79/120 (65.8%) 44/52 (84.6%) 0.012
Obesity (BMI >30 kg/m2) 50/121 (41%) 13/37 (35%) 0.5
Diabetes 59 (48.8%) 29 (55.7%) 0.4
Hypertension 103/120 (85.8%) 43/52 (82.7%) 0.6
Chronic lung disease 6/82 (7.3%) 7/37 (18.9%) 0.06
ACE inhibitor use 35/97 (36%) 15/38 (39%) 0.714
Denominators vary due to missing data. Differences tested by Chi-square, except age (t test).
ACE, angiotensin converting enzyme; BMI, body mass index.

Table 2 shows the outcomes in each group. There were no significant differences in mortality, admission to intensive care, or ventilation between the groups—the relative risk of death for TRs compared with the waiting list group was 1.1 (0.65–1.86). When comparing those who were within a year of transplantation with those beyond a year, the only difference in outcomes was a higher rate of ventilator support in the former. Almost a quarter (24%) of TR required renal replacement therapy during their admission, and 12 of 102 recipients with recorded data lost their grafts (12%). Two patients received treatment with anakinra, 1 with hydrocortisone and 1 with tocilizumab, but no other experimental therapies such as hydroxychloroquine or remdesivir were used.

TABLE 2. - Outcomes in transplant recipients and patients active on the transplant waiting list
Transplant recipients (n = 121) Waiting list patients (n = 52) P (Chi2 test)
Died 36 (30%) 14 (27%) 0.71
Ventilated 22/109 (20.2%) 7/45 (15.6%) 0.5
Admitted to ITU 30/101 (29.7%) 17/52 (32.7%) 0.7
Renal replacement therapy during admission 19/78 (24.4%) N/A
Outcomes comparing those within a year and over a year after transplant
Transplant recipients <1 y after transplant Transplant recipient 1 y or more after transplant P (Chi2 test)
Died 7/21 (33%) 29/92 (32%) 0.87
Ventilated 7/14 (50%) 15/72 (21%) 0.02
Admitted to ITU 9/20 (45%) 22/80 (27.5%) 0.13
Renal replacement therapy during admission 7/16 (44%) 12/61 (19.7%) 0.047
ITU, intensive care.

The symptoms at presentation are listed in Table 3, with fever, fatigue, and cough being the most common, and fatigue and nausea occurring more commonly in TRs. All but 8 TRs had their calcineurin inhibitor or antimetabolite modified or withdrawn.

TABLE 3. - Symptoms at presentation: patients in both groups did not have a complete set of data recording for symptoms
Transplant recipients Waiting list patients P
Fever 86/110 (78%) 26/38 (68%) 0.3
Fatigue 53/94 (56%) 12/38 (32%) 0.008
Cough 78/112 (69%) 37/52 (71%) 0.498
SOB Not recorded 23/30 (77%) n/a
Nausea 19 / 50 (38%) 2/23 (9%) 0.008
Diarrhea 28 / 88 (32%) 7/38 (18%) 0.091
Headache 9/63 (14%) 3/37 (8%) 0.280
Myalgia 17/44 (38%) 9/23 (39%) 0.586
SOB, shortness of breath.

There was no association between baseline hemoglobin, platelet count or white cell count, and mortality in either group. Similarly, lymphocyte nadir (0.6 versus 0.65 × 109 for WL P = 0.77, 0.54 versus 0.9 × 109 for TR P = 0.12) and D-dimer peak (4291 versus 3356 mg/L for WL P = 0.6, 2058 versus 1617 mg/L for TR P = 0.62) had no association with mortality. However, peak D-Dimer levels were higher in WL (3567 versus 1648 mg/L P = 0.03).

Other common variables showed no association with mortality in either group, except for age (Table 4), with an odds ratio of 4.3 (95% CI 1.8-10.2) for death if over 60 y in the TR group.

TABLE 4. - Potential risk factors for mortality in transplant recipients and waiting list patients
Transplant recipients Whole cohort Died Survived P
Age 56.2 (SD 13) 64.6 (SD 8.6) 52.8 (SD 13.3) <0.001
Female gender 37% 36.1% 38.9% 0.771
Time from transplant (mo) 79 (SD 86.7) 93.2 75.9 0.335
Kidney pancreas transplant 8.3% 5.5% 10.3% 0.4
Deceased donor organ 81% 79.2% 80.6% 0.87
Azathioprine use 10.8% 13.9% 10.4% 0.578
Sirolimus use 4.13% 0 6.5% 0.118
Non-White ethnicity 65.8% 64% 67% 0.737
Obesity 45% 27.3% 32.8% 0.629
T-cell depleting agent at induction 35% 34.3% 34.7% 0.96
Diabetes 48.7% 55.6% 45.5% 0.317
Hypertension 84.8% 88.9% 82.9% 0.41
Waiting list patients
Age 54.3 58 (SD 3.1) 52.9 (SD 1.9) 0.16
Female gender 37.3% 28.5% 40.5% 0.4
Hemodialysis 86.1 87.5 85.7 0.9
Obesity 36.1% 37.5% 35.7% 0.9
Non-White ethnicity 84.3% 92.3% 81.1% 0.3
ACE inhibitor use 39.5% 20% 46.4% 0.142
Diabetes 56.8% 64.2% 54.1% 0.51
Hypertension 82.4% 71.4% 86.5% 0.21
Smoker 10.8% 0 14.8% 0.197
ACE, angiotensin converting enzyme.

There was no difference in survival rates according to how recently the transplant took place (Table 5), although those within 6 mo of transplantation were more likely to have received ventilatory support (6/22 ventilated versus 4/64 not ventilated P = 0.008, OR 5.6 (1.4-22.4).

TABLE 5. - Survival according to transplant timing
Died Survived P (Chi2) Odds ratio (95% CI)
Within 3 mo of transplant 4/36 (11%) 7/77 (9.1%) 0.7 1.25 (0.34-4.6)
Within 6 mo of transplant 7/36 (19.4%) 9/77 (11.7%) 0.27 1.82 (0.62-5.4)
Within 1 y of transplantation 7/36 (19.4%) 14/77 (18.2%) 0.8 0.92 (0.34-2.52)

DISCUSSION

Our study, from an area with one of the highest prevalence rates of COVID-19 worldwide, has shown a mortality rate of 30% (and 12% risk of graft loss) for kidney TRs admitted to hospital due to COVID-19. The mortality rate did not differ between transplanted recipients and patients awaiting transplant. The only significant association with mortality was age, in the TRs, and importantly recent transplantation did not appear to confer an increased risk of death.

These data are particularly important as units consider strategies for transplantation in the COVID era, particularly in the context of a second surge. While high mortality rates have been reported in patients on dialysis,3 many of these patients will be, by definition, unsuitable for transplantation due to age or multiple comorbidities. A comparison with mortality rates in waiting list patients is therefore more appropriate to determine whether TRs are at an additional risk due to their immunosuppressive regimens. Of note, the study by the ISARIC COVID-19 investigators, which prospectively followed 16 749 patients admitted to the UK hospitals with the virus, found a mortality rate of 33%, which is not dissimilar to the rate described in our study.4 They also found that age was strongly associated with mortality.

In London by May 6, 2020, data from the National Renal Registry suggest that 175 TRs had tested positive (but not necessarily admitted to hospital) for SARS Cov2, and 41 had died, while 977 patients undergoing in center hemodialysis had tested positive and 197 had died.5

The NHS Blood and Transplant Registry reported 38 974 kidney TRs alive with a functioning graft in the United Kingdom on March 1, 2020. By May 7, 2020, 477 UK kidney TRs had tested positive for COVID-19 (12.2%). In London, 1105 patients were on the waiting list for a kidney transplant on March 1, 2020, of whom 155 have been reported as testing positive (14%).6 In light of our data showing 14 deaths from the waiting list group, this would suggest an overall mortality rate for waiting list patients is 1.3%. A single-center study from a London center, with 60 patients, reported a higher mortality (1.5% versus 0.6%) and symptomatic Covid-19 rate (9.9% versus 1.9%) in waitlisted patients versus TRs.7

As of April 22, France reported 222 (16%) of 1398 dialysis patients with COVID-19 have died, and 58 of 432 (13%) TRs have died. In Spain, the figures were 470 of 927 (51%) and 108 of 244 (44%), respectively, on May 4, 2020.3 However, these clearly include patients who were not admitted to hospital, and it is therefore impossible to know the true mortality rates, since many patients will have not been tested and some may have been asymptomatic.

A report from New York of 36 TRs testing positive for SARS-Cov-2 suggested a mortality of 28%, although it was unclear how far after surgery these patients were.8 Lymphopenia, especially low CD3 and CD4 T lymphocyte counts (and in 30% low CD8), was a feature, as was thrombocytopenia and raised D-Dimers. We found these features in both our groups of patients, but could not relate these to outcomes. Most of the New York patients were given hydroxychloroquine, and some were given other unproven therapies.

A report from Barcelona describes 26 TRs, of whom 2 died and 1 lost their transplant; most were given antiviral therapy and hydroxychloroquine, as well as having 1 or more immunosuppressants withdrawn, although there were no episodes of rejection.9

International comparisons are inevitably difficult, particularly as policies regarding testing, admission to hospital, or ITU differ between countries.

Another recent report from Spain included 51 patients with renal disease and COVID-19 who required hospital admission; 26 were TRs and 25 were on dialysis, with mortality rates of 23% and 28%, respectively.10 Again, most were treated with hydroxychloroquine.

Finally, a study of factors associated with 5683 hospital deaths from COVID-19 found that organ transplantation carried a hazard ratio of 4.27 in a Cox proportional hazards model.11 However, this is not unexpected, since this was in comparison to all remaining COVID cases, which would potentially include a healthier group.

Our study has a number of limitations. The numbers used in the comparisons, whilst larger than any other report, remain relatively small (particularly considering the recently transplanted), raising the possibility of a Type II error. Given that all programs in London ceased transplantation early during the pandemic, it is difficult to be definitive about the risk of transplanting in the context of continued COVID-19 prevalence. Indeed, one unit in the United Kingdom has experienced significant mortality in kidney TRs before suspension of their program in March (of the last 7 patients, 2 died and 2 others lost their graft- K Graetz personal communication). Nevertheless, a recent report from Oxford describes 24 patients who were transplanted during the COVID pandemic, with excellent outcomes (S. Sinha personal communication, May 2020). Our transplanted cohort included patients who had undergone deceased donor or living donor transplantation, whereas, by definition, our waiting list group was those who were due to undergo deceased donor transplantation only.

Similarly, it is difficult to draw any conclusions about the need for ventilator support or ITU admission, given the variable criteria for admission. The lack of association between age and mortality in the waiting list group may be a reflection of the small numbers, given that age appears to confer a significant risk of mortality in other studies.12

In summary, this study has shown a low absolute mortality risk from COVID-19 in transplanted and waitlisted patients, but a high and similar mortality when admitted to hospital, of around 30%. No factors were found to be associated with mortality, other than age in those who had been transplanted. Timing of transplantation was unrelated to mortality. These data support continuation of transplant programs during the COVID era, but the lack of excess mortality from COVID-19 in waitlisted patients implies that there is no imperative for urgent transplantation from this perspective.

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