key: cord-0890804-rvtvyirr
authors: Villanego, Florentino; Mazuecos, Auxiliadora; Pérez‐Flores, Isabel M.; Moreso, Francesc; Andrés, Amado; Jiménez‐Martín, Carlos; Molina, María; Canal, Cristina; Sánchez‐Cámara, Luis A.; Zárraga, Sofía; Ruiz‐Fuentes, María del Carmen; Aladrén, María José; Melilli, Edoardo; López, Verónica; Sánchez‐Álvarez, Emilio; Crespo, Marta; Pascual, Julio
title: Predictors of severe COVID‐19 in kidney transplant recipients in the different epidemic waves: Analysis of the Spanish Registry
date: 2021-04-12
journal: Am J Transplant
DOI: 10.1111/ajt.16579
sha: f9b77bda0185b9b71cd67edd776e3fcd5224ea0c
doc_id: 890804
cord_uid: rvtvyirr

SARS‐CoV‐2 infection has produced high mortality in kidney transplant (KT) recipients, especially in the elderly. Until December 2020, 1011 KT with COVID‐19 have been prospectively included in the Spanish Registry and followed until recovery or death. In multivariable analysis, age, pneumonia, and KT performed ≤6 months before COVID‐19 were predictors of death, whereas gastrointestinal symptoms were protective. Survival analysis showed significant increasing mortality risk in four subgroups according to recipient age and time after KT (age <65 years and posttransplant time >6 months, age <65 and time ≤6, age ≥65 and time >6 and age ≥65 and time ≤6): mortality rates were, respectively, 11.3%, 24.5%, 35.4%, and 54.5% (p < .001). Patients were significantly younger, presented less pneumonia, and received less frequently specific anti‐COVID‐19 treatment in the second wave (July–December) than in the first one (March–June). Overall mortality was lower in the second wave (15.1 vs. 27.4%, p < .001) but similar in critical patients (66.7% vs. 58.1%, p = .29). The interaction between age and time post‐KT should be considered when selecting recipients for transplantation in the COVID‐19 pandemic. Advanced age and a recent KT should foster strict protective measures, including vaccination.

SARS-CoV-2 infection has produced high mortality in kidney transplant (KT) recipients, especially in the elderly. Until December 2020, 1011 KT with COVID-19 have been prospectively included in the Spanish Registry and followed until recovery or death. In multivariable analysis, age, pneumonia, and KT performed ≤6 months before COVID-19 were predictors of death, whereas gastrointestinal symptoms were protective. Survival analysis showed significant increasing mortality risk in four subgroups according to recipient age and time after KT (age <65 years and posttransplant time >6 months, age <65 and time ≤6, age ≥65 and time >6 and age ≥65 and time

COVID-19 is a global pandemic that has affected more than 66 million people and caused more than 1.5 million of deaths all over the world. 1 This rapid expansion led to the collapse of healthcare systems, negatively affecting transplant programs. 2, 3 Since the first confirmed case was isolated in Spain on January 31, 2020, the curve of new infections increased, reaching the peak of highest incidence at the end of March 2020. 4 As a result, there was a dramatic decrease of transplantation activity during the critical early weeks of the outbreak. 5 To better know the impact of SARS-CoV-2 infection in kidney transplant (KT) patients, the Spanish Society of Nephrology (S.E.N.) set up a voluntary registry in March 2020. 6 The analysis of data registered until May 2020 showed that COVID-19 has a high mortality in KT patients, especially in elderly recipients and in the early post-KT period. [7] [8] [9] In this scenario, recommendations on preventive strategies in waitlisted and solid organ transplant patients emerged, and transplant activity progressively recovered over the next weeks. 10 Starting mid-July and peaking in October, a second wave of COVID-19 was documented in Spain and many other regions. 4 Several differences have been reported between the first and the second wave in the general population, with a lower proportion of severe cases and younger patients in the second phase. [11] [12] [13] This evolution allowed us to continue with the transplant activity, so in this context it is crucial to clarify the pre-infection risk factors in KT patients to assess properly the benefit of the procedure. Likewise, data comparing the characteristics of the infection in KT patients between both epidemic phases are scarce. Herein, we present the predictors of severe COVID-19 and the differences between the first and second phase of the pandemic in a Spanish multicenter KT recipient cohort.

A registry regarding dialysis and KT patients with COVID-19 in Spain started in 03/18/2020 promoted by the S.E.N. (www.senef ro.org).

Of the 39 existing KT centers in Spain, 38 of them (97.4%) participated. The participating hospitals perform more than 99% of KT in Spain each year. 14 Only cases diagnosed with positive reversetranscriptase-polymerase-chain-reaction (RT-PCR) assay of a specimen collected on a nasopharyngeal swab or bronchoalveolar lavage were included. In Spain, COVID-19 cases are collected in the regional registries and then the regional authorities notify them to the Ministry of Health. The dialysis and KT COVID-19 registry is voluntary, but it is likely that most cases are included.

The characteristics of the S.E.N. COVID-19 registry and the variables included have been previously reported (Table 1) . 7 The first epidemic wave was considered to end in June 2020, when the infection rate in Spain fell below 10 cases/100,000 inhabitants, and the second wave started July 2020 15 (Figure 1 ).

Outcomes were assessed as COVID-19-related mortality or recovery until December 5, 2020. The immunosuppression collected corresponds to that received at the time of COVID-19 diagnosis. Length of the COVID-19 episode was defined as days from COVID-19 diagnosis to death or recovery and recovery as clinical improvement with negative RT-PCR and/or SARS-CoV-2 positive IgG serology. 16 The study was conducted according to the guidelines dictated by the Declaration of Helsinki. All data were recorded anonymously.

Categorical variables were expressed as counts and percentages and continuous variables as the mean and standard deviation or median with interquartile range. All categorical variables were compared using Fisher exact test or Chi-square test, and continuous variables were compared with t test or Mann-Whitney U test, according to variables normality.

Mood's median test was performed to compare median scores.

Survival curves were plotted using the Kaplan-Meier method and compared between patients according to their age (< or ≥65 years) and time post-KT (≤ or >6 months after KT) by log-rank test. Kaplan-Meier survival analysis was also performed to compare patients infected in ≤6): mortality rates were, respectively, 11.3%, 24.5%, 35.4%, and 54.5% (p < .001).

Patients were significantly younger, presented less pneumonia, and received less frequently specific anti-COVID-19 treatment in the second wave (July-December) than in the first one (March-June). Overall mortality was lower in the second wave ( and those whose had not reported an outcome for the episode (n = 150) were excluded. Finally, 1011 fully documented patients had a final outcome, recovery or death, and were included in the study. 

In univariable analysis, infection during the first wave, age (continuous), age ≥65 years, time after KT to COVID-19 diagnosis less than 6 months, fever, respiratory symptoms, pneumonia and lymphopenia were significantly associated with mortality ( Table 2) .

Gastrointestinal symptoms were a protective factor for death.

In multivariable Cox regression analysis, pneumonia and KT within the last 6 months remained as independent predictors of death while gastrointestinal symptoms were associated with better survival. The development of the disease during one or another phase of the pandemic was not an independent risk factor for COVID-19-related mortality. Similar results were observed when age was analyzed as a categorical variable, the models were adjusted for sex, or respiratory symptoms were excluded.

In Table 3 We also observed changes in immunosuppression in relation to time after transplantation, especially with steroids and tacrolimus, which were more frequent in recent transplants. Survival analysis showed a significant increasing mortality: Group 1, 11.3%; Group 2, 24.5%; Group 3, 35.4%; Group 4, 54.5% (Figure 2 ).

Of the 1011 cases included, 548 correspond to the first wave and 463 to the second wave (93.6% and 80.4% respectively of the total of patients collected in the registry) ( When we excluded asymptomatic patients from the analysis, the differences between both phases in age (63 vs. 58 years, p < .001) and pneumonia (82.4% vs. 60.6%, p < .001) remained. There were also no differences in the rest of the variables except in respiratory and gastrointestinal symptoms, which presented a similar incidence in the two waves (Table S3) .

Overall mortality was lower (even excluding asymptomatic cases) during the second wave (15.1%). Mortality in hospitalized patients was also lower (22.9%). However, in critical KT recipients, mortality was 66.7%, not significantly different to that reported in the first wave (58.1%) ( Figure 3 ). Otherwise, patients transplanted recently before the COVID-19 episode also have a higher mortality. We have identified a group of patients, the oldest and recently transplanted, with a higher fatality rate compared to the youngest and with a longer time post-KT, who have the best prognosis. Furthermore, this is the first report that compares the first and the second epidemic waves in KT patients, confirming that clinical severity and anti-COVID-19 therapy have changed.

Advanced age is considered the main risk factor for COVID-19-associated severity and death due to the greater prevalence of chronic conditions in older patients. 17 Moreover, in the elderly, alveolar macrophages increase and convert to a pro-inflammatory state that could accelerate COVID-19 in its early stages. 18 In our series, median age was 60 years and more than a third of the patients were ≥65 years old, with a mortality rate of almost 40%.

Several registries have analyzed the impact of time after transplantation on the outcomes of COVID-19, but none of them found significant differences. [19] [20] [21] [22] In these reports, the time from KT to COVID-19 was analyzed globally or in time periods around the first year after KT.

We have focused on the first 6 months after transplantation, finding a higher mortality during this earlier period. The maximum effect of immunosuppression is exerted in the first months after transplantation and recipients are at maximum risk of infection and severity by viral pathogens in this period. 23 patients on the waiting list, especially older patients, should be a priority group in the access to these vaccines.

The evolution of the pandemic in KT recipients is quite similar to the observed in the general population. [11] [12] [13] In the second wave, KT patients infected are younger. According to the reports of the Spanish Ministry of Health, the median age of cases in Spain have decreased from 60 years in May to 41 years in December 2020. 4 In our registry, these differences are not so remarkable, probably due to a high incidence of COVID-19 in our cohort of elderly KT recipients. 4, 10 Apparently, the severity of COVID-19 in KT patients is also lower in the second wave. We found a higher proportion of asymptomatic cases, so the global mortality rate could be underestimated. These changes may be due to the greater availability of testing, as in most countries, during this period. However, when asymptomatic cases were excluded, we still found clinical and epidemiological differences, a decrease of hospitalized patients and a lower mortality rate in the second wave.

When we analyzed only patients who required hospitalization, death rate between both periods also decreased. However, during this second wave, half of our patients developed pneumonia, which is a serious risk factor for death in our population. Further, if we take into account only critical patients, the fatality rate during the second wave has been 66.7%, without significant differences in survival between both epidemic phases. These data show that the mortality due to COVID-19

in KT patients is still markedly higher than in the general population, especially in critical cases. In addition, during the last months of the pandemic, more hospitalized KT patients were admitted to ICU, although probably it is not due to a greater severity of COVID-19, but to the availability of a better prepared healthcare system.

COVID-19 management in KT patients has also changed during the two consecutive waves. Several treatments were used during the first months, but subsequently most of them were deemed inefficient. 26 In conclusion, over a thousand KT have suffered COVID-19 in Spain with a high mortality rate in the first and second waves. Both advanced age and an early post-KT period were related to a higher mortality rate. Thus, in our opinion, the interaction between age and time after transplant has to be considered when selecting recipients during the COVID-19 pandemic and these older patients should access vaccination as soon as possible. Epidemiological aspects of SARS-CoV-2 have changed in this second wave, affecting predominantly younger people with a less serious clinical picture. However, mortality rate remains similar in severe cases. Likewise, we have documented the change in the COVID-19 specific management during these months.

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.

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 from the corresponding author, A.M., upon reasonable request. 

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Predictors of severe COVID-19 in kidney transplant recipients in the different epidemic waves: Analysis of the Spanish Registry