key: cord-0801829-540h8p1x authors: Sacristán, Pilar Galindo; García, Elena Clavero; Pereira, Elisa Berta; Marfil, Almudena Pérez; Sánchez, María José Torres; Moratalla, José Manuel Osorio; Guindo, Carmen De Gracia; Fuentes, María Carmen Ruiz; Ortega, Antonio Osuna title: RISK OF SEVERE COVID-19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS date: 2021-11-12 journal: Transplant Proc DOI: 10.1016/j.transproceed.2021.08.060 sha: b4191a21ffc2a39ab888619bc7d345ac78d1915e doc_id: 801829 cord_uid: 540h8p1x INTRODUCTION Despite all efforts, the incidence of severe COVID infection has been high in renal transplant recipients, as in other groups (elderly, patients with comorbidities or immunosuppression). The detection of any possible predictor of gravity could improve the early approach in these patients. PATIENTS AND METHODS We registered data from renal transplant recipients with SARS-COVID infection in our area during a year (March 2020-2021). We collected demographics, comorbidity, body mass index, lymphocyte count and vitamin D level before the diagnosis. We performed statistical analysis using SSPS.20. RESULTS Of 63 patients, 57.1% required hospital admission and 14.3% intensive care. The incidence of acute renal failure was 28.6%. 34.9% developed hyperinflammatory syndrome. 67% had lymphopenia, which was severe in 13.1%. Eleven patients died. There was significant correlation between lymphocyte count before and during the infection. For hospitalization, we found differences in age, pulmonary disease and renal function. For admission in an intensive care unit the related factors were obesity, severe lymphopenia, altered renal function and low level of vitamin D. According mortality, the predictors were age, renal function and minimum lymphocyte count. CONCLUSIONS - In kidney transplant recipients with COVID infection, renal function determines hospitalization, and body mass index the admission in an intensive care unit. Previous vitamin D level also looks significantly lower in patients requiring intensive care. - The analysis of lymphocyte count previous to infection is correlated with the minimum level during the disease, which is a predictor of mortality, and that could be a prognosis factor. INTRODUCTION: Despite all efforts, the incidence of severe COVID infection has been high in renal transplant recipients, as in other groups (elderly, patients with comorbidities or immunosuppression). The detection of any possible predictor of gravity could improve the early approach in these patients. We registered data from renal transplant recipients with SARS-COVID infection in our area during a year (March 2020-2021). We collected demographics, comorbidity, body mass index, lymphocyte count and vitamin D level before the diagnosis. We performed statistical analysis using SSPS.20. Of 63 patients, 57.1% required hospital admission and 14.3% intensive care. The incidence of acute renal failure was 28.6%. 34.9% developed hyperinflammatory syndrome. 67% had lymphopenia, which was severe in 13.1%. Eleven patients died. There was significant correlation between lymphocyte count before and during the infection. For hospitalization, we found differences in age, pulmonary disease and renal function. For admission in an intensive care unit the related factors were obesity, severe lymphopenia, altered renal function and low level of vitamin D. According mortality, the predictors were age, renal function and minimum lymphocyte count. -In kidney transplant recipients with COVID infection, renal function determines hospitalization, and body mass index the admission in an intensive care unit. Previous vitamin D level also looks significantly lower in patients requiring intensive care. -The analysis of lymphocyte count previous to infection is correlated with the minimum level during the disease, which is a predictor of mortality, and that could be a prognosis factor. For over a year SARS COV-2 has afflicted millions of people all over the world. Despite the combined effort to prevent its spread in our community, many patients with kidney chronic disease have gone through COVID infection. Thanks to the early intervention of Medical Societies in recording cases, we have been able to obtain precise and useful epidemiologic data 1 . As expected, hospitalization and mortality rates have been higher among transplant recipients 2-3 . However, the evolution of disease has been variable, in some cases similar to the general population 4 . Research groups have worked in identifying potential predictors of severity, trying to improve early management and to reduce complications as much as possible [5] [6] . In our population, kidney disease and other comorbidities are common. All of them are associated with an increased risk for a severe infection, they imply biological aging and the majority are not modifiable 7 . Adjustments to the inmunosuppresive regime is often used in many infections of different etiologies and we have also applied it to COVID 8 , although the optimal approach is not defined. Several clinical and analytical risk parameters that involve worse prognosis (hypoxemia, inflammatory syndrome, lymphopenia…) had been identified before and throughout the evolution of the disease 9-10 . We carried out an observational study with kidney transplant recipients diagnosed with SARS COV-2, in order to know its course and complications, and to try to find predictor factors previous and during the disease. We created a register (from March 2020 to March 2021) of COVID cases among our renal transplant recipients. We collected data such as demographics, diabetes, cardiac or pulmonary disease and body mass index (BMI). We also considered if there was nosocomial or community contact, the initial and late symptoms, the need of hospitalization, admission in an intensive care unit and orotracheal intubation. Regarding the analytical parameters, we registered data about hyperinflammatory syndrome, renal function (creatinine and estimated glomerular filtrate by MDRD), total lymphocytes (average of the last three analysis previous to the infection), proteinuria and vitamin D, all of them before and during COVID disease (Table 1) . We also registered the different treatments and changes of immunosuppressive therapy. We defined hyperinflammatory syndrome when patients met any two or more of the following criteria : ferritin > 500 ng/ml, protein C reactive > 100 mg/dl, lactate dehydrogenase > 300 U/L, D-dimer > 1000 ng/ml or interleukin-6 > 40 pg/ml. For severe lymphopenia we established a value of < 300 cels/µL, based on the definition of severe immunodeficiency with CD4 < 200 cels/µL (CD4: 65% of total lymphocytes) 11 . The statistical analysis was performed using Statistical Packages for the Social Sciences (SPSS, v.20). For qualitative variables we used the Chi2 test and the Student t-test for the quantitative ones. We analysed correlations and applied the binary Logistic Regression for severe lymphopenia, ICU admission and primary outcomes: death and hospitalization. A total of 63 cases were detected (36 males; 57.1%) with a median age of 54.5±12.9 years. 57.1% needed hospitalization and 14.3% needed ICU admission. 20.6% and 28.6% of the patients had diabetes and pulmonary disease preceding the COVID infection. More than a half (50.8%) had blood type A and 41.2% type B. The immunosuppressive therapy included Tacrolimus in 82.5% of the patients. The infection was nosocomial in the 28.6% of the cases. Mortality rate was 17.5% (11 patients) (Table 1 ). In two outpatients with mild symptoms we didn´t find any laboratory follow up. Of the remaining patients, 67% had mild lymphopenia, being severe in 13.1% of them. 34.4% of the patients met the criteria for hyperinflammatory syndrome. The rate of acute renal failure was 28.6%, with worsening of proteinuria in 13.1%. All the patients were under low-dose corticoid therapy and 53.9% of them received a higher dose during COVID disease (oral or intravenous). Mycophenolate was reduced or suspended in 46% of the cases. We found significant correlation between previous lymphocytes and minimum lymphocyte count during the infection (R 0.568; p 0.000). It was also inversely correlated with body mass index (R -0.307; p 0.016) ( Table 2 ). In the univariate analysis for hospital admission (Table 3) , we found significant differences regarding pulmonary disease, age and renal function. Those who had pulmonary disease, were older or had worse renal function required hospital admission. Concerning ICU admission, BMI was higher, renal function was worse, vitamin D level and minimum lymphocyte count were lower in patients admitted to the ICU than non-ICU hospitalized patients. Results for mortality showed significant differences in the following variables: age, renal function, minimum lymphocyte count and nosocomial contact. For the Regression analysis (Table 4) Previous factors to diagnosis: Several studies of potential predictors of gravity in COVID infection showed consistent results for the elderly and comorbidity 5 (specially pulmonary disease, obesity and immunosuppression). Among our patients, 28.6% had some type of pulmonary disease, being obstructive in the majority (COPD and OSAS). These groups have significantly higher rates of hospitalization and mortality because of the acute pulmonary injury. Regarding obesity, it had been associated with a chronic inflammatory condition and altered immune regulation 12 which favour infections. With a noteworthy prevalence of overweight in kidney transplant recipients, the median of BMI in our study was higher in those with severe hyperinflammatory syndrome and those requiring intensive care. It is also common the presence of decreased renal function among transplant recipients. Uremia causes lower immunologic response as it has been proved after vaccination, so the infection and tumour rates are higher 13 . Renal function is also expected to be a risk factor in COVID infection 5 . We found GFR as predictor of hospitalization in our population. Moreover, vitamin D level before the infection was significantly lower in the patients requiring ICU admission, associated with worse prognosis. Lymphocyte count is usually related with infection and death for many causes 6 . Lymphopenia is considered an immunohematologic biomarker 14 that reflects a premature aging with less production of "naïve" lymphocytes in the thymus and increased number of memory cells. This is frequent in the uremic syndrome and it is also present before transplantation, increasing risk of infections predominantly produced by virus. Furthermore, it not seems that transplantation can revert this situation [13] [14] [15] [16] . In COVID infection, lymphopenia has showed a prognostic value before 17 and during the disease [8] [9] [10] . The average of previous lymphocyte count in our study was related with minimum level during the infection, and was predictor of severe lymphopenia. Factors during COVID disease: At the time of diagnosis, symptoms are different from one patient to another. We found dyspnea and fever as the main manifestations in hospitalized. Although we did not collect data from imaging tests, both symptoms are related with established pneumonia. Among the analytical parameters, hyperinflammatory syndrome was more frequent in obeses, lower GFR and lower vitamin D level. These results were associated with severe lymphopenia. Renal injury (either acute kidney injury or superimposed AKI on CKD) and increased proteinuria appeared in 28.6% and 13.1% of patients, respectively, more frequently in the case of low vitamin D level. It had been proposed several pathological mechanisms: direct cell injury or cytokine storm with consequent podocyte and tubular damage. It had also been described some cases of collapsing nephropathy 18 . Lymphopenia clearly seems a marker for bad prognosis, like showed in several studies, becoming a mortality predictor. We also found minimum lymphocyte count as a useful factor. All patients were receiving low-dose steroids and more than a half increased it. This change in treatment took place in different stages in each patient, some of them promptly and possibly coinciding with the viremic phase (which would have stimulated viral replication and lymphopenia). Nevertheless in the majority of cases, high-dose steroids were used in the inflammatory phase of the disease. Some protocols included other drugs such as ritonavir, hydroxychloroquine, remdesivir… Their analysis was not part of the aim of this study. Since the pandemic started, there was a general consensus in decreasing or avoiding antimetabolite treatment, like it is done for the management of other opportunistic infections (poliomavirus, cytomegalovirus…). In our series, mycophenolate was modified in 46% of patients. However, a few number of studies 4 did not find differences between the intensity of immunosuppression and mortality. That possibly reflects the higher influence of immunological baseline condition, related with age, uremia and maybe previous use of antithymocyte globulin producing a premature immunosenescence 19 . This could be the reason why previous lymphocyte count determines the evolution of COVID disease. In any case, mycophenolate, which promotes lymphopenia (overall in association with tacrolimus 20 more than cyclosporine), come across as evident that it should be stopped or at least reduced. In conclusion, previous markers of bad prognosis as it appears to be the case with obesity, hypovitaminosis D and lymphopenia, could help to identify those patients who need additional medical care. Thus, we would improve the accuracy at the time of consider hospitalization and treatment. We could regulate immunosuppression in a more individualized way, including immunomodulatory drugs [21] [22] like lymphocyte stimulating agents, as long as we do not find effective antivirals. -In kidney transplant recipients with COVID infection, renal function seems to determine hospital admission, and body mass index, the admission in an intensive care unit. Previous vitamin D level also looks significantly lower in patients who required intensive care. -The analysis of lymphocyte count previous to infection is correlated with the minimum level during the disease, which is a predictor of mortality, and that could be a prognosis factor. 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