key: cord-0749990-hsnx9e5n
authors: Crespo, Marta; José Pérez‐Sáez, María; Redondo‐Pachón, Dolores; Llinàs‐Mallol, Laura; Montero, María Milagro; Villar, Judith; Arias‐Cabrales, Carlos; Buxeda, Anna; Burballa, Carla; Vázquez, Susana; López, Thais; Moreno, Fátima; Mir, Marisa; Outón, Sara; Sierra, Adriana; Collado, Silvia; Barrios, Clara; Rodríguez, Eva; Sans, Laia; Barbosa, Francesc; Cao, Higini; Arenas, María Dolores; Güerri‐Fernández, Roberto; Horcajada, Juan Pablo; Pascual, Julio
title: COVID‐19 in elderly kidney transplant recipients
date: 2020-05-29
journal: Am J Transplant
DOI: 10.1111/ajt.16096
sha: e766fb5dab17c6a25ed747c384bd62c045cc5472
doc_id: 749990
cord_uid: hsnx9e5n

The SARS‐Cov‐2 infection disease (COVID‐19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March‐12(th) until April‐4(th) 2020, we diagnosed COVID‐19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti‐retroviral and tocilizumab. Short‐term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic and showed higher D‐dimer, C‐reactive protein, and IL‐6 at their first tests. COVID‐19 is frequent among the elderly KT population and associates a very early and high mortality rate.

Health Emergency of International Concern and characterized it as a pandemic (1,2). Since early March 2020, the Spanish cases curve started to rise, with more than 177.000 people infected in six weeks (3). The reported fatality-rate in the general population with COVID-19 admitted to a large tertiary Spanish Hospital is 20.7%, 34% in the subgroup of age 70-79 years (4) .

More than 60.000 patients are currently on dialysis or transplanted in Spain (5), and they reunite several conditions for being a target population for the virus: age, comorbidities, and a frail immunological system.

There is scarce information regarding the impact of COVID-19 in renal patients. Patients on hemodialysis attending treatment centers are at high risk of acquiring the infection. Our group early designed a protocol to limit the spread of the infection on dialysis facilities (6) . Worried about the potential of infection during transplantation, the Spanish transplant community advised on avoiding active kidney transplantation (KT) for the risk of infection but also for the competing use of facility resources needed by COVID-19 patients during the pandemic (7) . Distinctively, outpatient KT recipients are at a high risk of acquiring the infection. Therefore, we disseminated general protection rules (informing patients, avoiding live consultation) and worked on some consensus on the management of immunosuppression in case of infection (7) . Some publications have reported short series and case reports of COVID-19 in KT recipients (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) , which describe the clinical course and illustrate the management of immunosuppression during the evolution of the disease. Information regarding the impact in a KT program is not available yet. It has been communicated that the fatality-rate of COVID-19 in the general population is higher in older patients with comorbidities, i.e. hypertension and cardiovascular disease (4, 19) . The KT population in Spain is older than in other countries and more comorbid, nevertheless with substantial survival benefit compared to remaining on dialysis (20) . There are no data exploring whether the same variables are important risk factors for mortality in KT recipients.

Here we present the incidence of COVID-19 in our prevalent elderly KT patients, the characteristics of the first 16 symptomatic COVID-19 elderly KT recipients from our program and their outcomes until death or a minimum of 2 weeks after symptoms started.

This article is protected by copyright. All rights reserved Clinical data were prospectively obtained through review of medical records. The data reported here are those available through May 2 nd , 2020. Each patient has been followed until death or at least 28 days of follow-up.

Confirmed COVID-19 corresponds to a patient with positive reverse-transcriptase-polymerase-chainreaction assay of a specimen collected on a nasopharyngeal swab or bronchoalveolar lavage. Only laboratory-confirmed cases were included. This study includes only KT recipients with symptoms.

Quantitative variables with a normal distribution are expressed as mean and standard deviation (SD) and the remaining as median and interquartile range [IQR] . Categorical variables are summarized as counts and percentages. Cox univariate analyses were performed. A p value <0.05 was considered statistically significant. Statistical analysis was performed using SPSS V 21.0 (SPSS Inc., Chicago, IL).

From 12 th March until 4 th April we diagnosed COVID-19 in 16 of our 324 KT patients aged 65 years old or over, resulting in an incidence of 4.9% in our elderly KT population. During the same period, we diagnosed only 4 COVID-19 cases among our 479 KT recipients younger than 65 years old (0.8%). The baseline characteristics of the elderly patients are shown in table 1. They were most frequently men, with a good functioning kidney graft and receiving conventional immunosuppression. Only two had been transplanted within the last two months, one still hemodialysis-dependent due to severe rejection. Seventy-five percent of them had had contact with a healthcare facility in the month prior to infection, either the transplant center, other hospital or were institutionalized. Forty-four percent of them were frail (21), 50% diabetics and frequently had arterial hypertension and underlying heart disease.

This article is protected by copyright. All rights reserved These data are summarized in table 2. Symptoms started a median of 7 days before admission. Nine patients were admitted to the transplant center, 6 patients were admitted in other centers and one remained at home. Clinically all patients presented with fever and all but one had pneumonia on the chest X-Ray.

The only one without documented pneumonia was managed at home throughout the whole process.

Anemia was prevalent as well as lymphopenia, high C-reactive protein, ferritin, D-dimer and IL6. SCr was higher at admission compared with baseline creatinine. At least 75% developed acute respiratory syndrome at some point with PaO2 to FiO2 below 300. Symptoms at presentation were similar between patients who died and patients who survived except for respiratory rate, which was higher at admission in those patients who ultimately died. There were some clear differences in analytics. Patients who eventually died were more anemic, lymphopenic, had higher creatinine and showed higher D-dimer and CRP at their first tests;

30% of cases showed renal dysfunction and three of them needed renal replacement therapy.

These data are summarized in table 2. At the onset of infection, mTOR inhibitors or mycophenolate were withdrawn in all cases when the patient was on tacrolimus too, and tacrolimus was withdrawn at different stages of infection in 70% of those who received it. The main treatment combination was antibiotic (100%), mainly azithromycin (87.5%), plus hydroxychloroquine (81.2%). A subset of patients was treated with steroid boluses (37.5%), the anti-retrovirals ritonavir-lopinavir/darunavir (31.2%) and/or tocilizumab (25%). Numerically, patients who survived had received hydroxychloroquine (8/8 vs 5/8 of nonsurvivors) and tocilizumab (3/8 vs 1/8 respectively).

Short-term 14-day fatality rate in this group has been 50%. In tables 1-2 we compared KT recipients alive at follow-up with those who died within the same period. Those who died had worse renal function before infection. They were more frequently obese, frail and had underlying heart disease. Contrarily, they had similar rates of arterial hypertension, diabetes, cancer or lung disease. We found no differences in the treatment they were receiving before infection in terms of immunosuppression or angiotensin blockage.

Interestingly, no survivor showed acute kidney injury (AKI), while 5 of the 8 patients who ultimately died developed AKI (p=0.07).

Three patients required noninvasive mechanical ventilation and two of them survived. Among the 8 dead patients, at least 6 of them had ICU admission criteria. Two of them were intubated and admitted to the ICU, but finally died, other two patients did not accept transition to ICU and denied mechanical ventilation, and the remainder two patients were not finally considered as candidates to intubation. One of them was

This article is protected by copyright. All rights reserved admitted in a nursing home and the other one was 79 years old. Cause of death was respiratory in all cases, and no malignant arrythmia was recorded.

Median time from admission to death was 3 days and to discharge was 14 days (table 3) .

Up to 5% of our elderly cohort of KT recipients suffered from COVID-19 during the first month of Spanish COVID-19 pandemic. This is a much higher incidence than the 0.20% in the whole general population in Spain on the same date (22), and 6-fold higher than our own incidence in younger KT recipients (0.8%).

The proportion of patients of advanced age receiving a KT in Spain is higher than in other countries (20, 22) , and the fact that the COVID-19 pandemic is impacting strongly in this country poses at special risk the elderly KT population.

In addition to this high incidence, mortality is very early and high in our elderly COVID-19 KT patients.

Half of them died during the episode due to refractory respiratory failure at a median time of 3 days after admission. At least 6 of those 8 patients who died had ICU admission criteria, but in two of them their general physicians in charge did not consider intensive care and in another two cases the patients denied consent. Advanced age and the perception of KT as a co-morbid condition itself would have probably increased this mortality rate, especially when the transplant nephrologist was not the responsible physician.

Another possible bias towards a high mortality is the selection of severe cases admitted. Although we are not aware of older patients that were not admitted at the hospital because a mild course, the inclusion of those cases in our series would likely decrease the mortality rate.

The first large report on COVID-19 outcomes in hospitalized patients in Europe is a Spanish report showing high mortality rates up to 20.7% (4). Age was the main factor associated to mortality, with rates of 3.8% in patients 50-59 years old, 11% in those aged 60-69 and 34% in patients 70-79 years of age (4). This report shows the percentages of patients suffering from associated comorbidities at baseline. Heart disease, hypertension, obesity, reduced GFR and cancer were much more frequent in our COVID-19 KT elderly patients than in the general COVID-19 Spanish population, It is likely that the increased mortality we observed is related to this increased baseline morbidity rather that the KT condition itself.

Searching in the recent literature, 4 more groups have reported COVID-19 in KT recipients aged over 65 years old (15) (16) (17) (18) . In the largest Italian series, Alberici et al reported that 5 out of their 20 COVID-19 KT recipients were older than 65 (15) . Mortality was 40%, and an additional 40% remained inpatient at the time of reporting. The other reported Italian old KT patient with COVID-19 died during admission (16) . In the report from the London hospitals, 2 out of their 7 patients were older than 65 years of age, and one of

This article is protected by copyright. All rights reserved them died. Finally, another small Spanish series of 8 KT recipients with COVID-19 included 6 cases aged over 65 years old (18) . Two of them died, 3 more were still inpatient with severe disease and only one had been discharged home at the time of reporting. Overall, mortality in these 14 elderly previously reported cases has been 43%, with an additional 36% severely ill still inpatient. These results are like our experience.

Interestingly, the elderly patients who died during the COVID-19 episode were not older than survivors but showed some characteristics that may advance an ominous prognosis (24) (25) (26) . The obese, frail, with underlying heart disease and graft dysfunction showed the worst outcomes. Regarding disease presentation, clinical data are not different between survivors and those patients who ultimately died except for a higher respiratory rate in non-survivors, suggesting a more severe pulmonary involvement. In addition, fatal evolution is associated with more severe analytical alterations such as anemia, lymphopenia, increased D- Another potential risk in our elderly KT population could have been the administration of drugs that prolong QT, hydroxychloroquine, and azithromycin (29) . Although arrythmia cannot be completely ruled out, no such cardiac events were recorded in our population.

In our elderly KT population, apart from comorbidities like arterial hypertension or heart disease in increasing mortality, immunosenescence may play a role. In these patients, naïve T-cell population decreases while memory T-cells comprise an important portion of T-cell population (29) . Consequently, the ability of immune system of elderly to never-exposed pathogens is much more limited than in young individuals, who show a very important proportion of naïve T-cells. The central role of inflammatory cytokines in inducing the quick and frequently prompt clinical deterioration in association with worsening chest radiology and speedy oxygen requirements has suggested the use of tocilizumab despite lack of

This article is protected by copyright. All rights reserved previous experiences in KT recipients under infection (30) . Our sample size precludes to establish strong conclusions on any attempted treatment. We tried tocilizumab in 4 patients and 3 of them survived. Again, this approach needs to be sustained in larger and prospective trials.

This study has limitations: the small sample size and the short median follow-up. Our comparisons are univariable and would need a much larger cohort to accurately determine the co-morbidities associated with poor outcome. However, ours is the first series focused on the elderly KT recipient and clinical and analytical work-up is extensive despite the early frequent mortality.

Our frontline experience shows that COVID-19 is frequent among the elderly KT population and associates a very early and high mortality rate. Consequently, preventive measures are of paramount importance in this population, and adaptive treatment trials are urgently needed. 

This article is protected by copyright. All rights reserved 

A cohort of patients with COVID-19 in a major teaching hospital in Europe

Management of the SARS-CoV-2 coronavirus epidemic (Covid 19) in hemodialysis units

Recommendations on management of the SARS-CoV-2 coronavirus pandemic (Covid-19) in kidney transplant patients

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Accepted Article This article is protected by copyright. All rights reserved

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

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Accepted Article Blood test at admission Hemoglobin (gr/dL, mean ± SD)

We are indebted to the many physicians and nurses who take care of these patients and are facing the COVID-19 pandemic in our country. Our transplant group belongs to the REDinREN (RD16/0009/0013).Disclosures: The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved