key: cord-0982474-tn03dgsc
authors: Pérez‐Sáez, María J.; Blasco, Miquel; Redondo‐Pachón, Dolores; Ventura‐Aguiar, Pedro; Bada‐Bosch, Teresa; Pérez‐Flores, Isabel; Melilli, Edoardo; Sánchez‐Cámara, Luis A.; López‐Oliva, María O.; Canal, Cristina; Shabaka, Amir; Garra‐Moncau, Núria; Martín‐Moreno, Paloma L.; López, Verónica; Hernández‐Gallego, Román; Siverio, Orlando; Galeano, Cristina; Espí‐Reig, Jordi; Cabezas, Carlos J.; Rodrigo, María T.; Llinàs‐Mallol, Laura; Fernández‐Reyes, María J.; Cruzado‐Vega, Leónidas; Pérez‐Tamajón, Lourdes; Santana‐Estupiñán, Raquel; Ruiz‐Fuentes, María C; Tabernero, Guadalupe; Zárraga, Sofía; Ruiz, Juan C; Gutiérrez‐Dalmau, Alex; Mazuecos, Auxiliadora; Sánchez‐Álvarez, Emilio; Crespo, Marta; Pascual, Julio
title: Use of tocilizumab in kidney transplant recipients with COVID‐19
date: 2020-08-04
journal: Am J Transplant
DOI: 10.1111/ajt.16192
sha: 2cef05e5fb3fdc69b25badad010fc43f453221ab
doc_id: 982474
cord_uid: tn03dgsc

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin‐6 (IL‐6) release. The IL‐6‐receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID‐19) . In this pandemic, kidney transplant (KT) recipients are a high‐risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID‐19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL‐6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D‐dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C‐reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004‐1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID‐19 but randomized trials are needed.

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed.

clinical research/practice, infection and infectious agents -viral, kidney transplantation/ nephrology, patient survival

The World Health Organization declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak a pandemic on March 11, 2020. 1 During the last 9 weeks, Spain has been one of the most affected countries worldwide, with more than 235 000 people infected by May 26th and almost 27 000 deaths (fatality rate of 11.4%). 2 At the same time, in Spain we have the privilege of enjoying one of the highest kidney transplantation (KT) rates across the world, with 72.8 procedures p.m.p performed in 2019 and more than 33 000 prevalent KT recipients with a functioning kidney. 3 This specific population is considered to be at risk for coronavirus disease 2019 (COVID-19) disease because of several conditions as their intrinsic comorbidities, their immunosuppressed status, and their frequent contact with health facilities. [4] [5] [6] In fact, more than 500 KT recipients have been reported to have COVID-19 through the Spanish Society of Nephrology registry, 7,8 resulting in a global incidence of 1.5%, triple that of the general population.

The clinical presentation of COVID-19 includes fever, cough, dyspnea, gastrointestinal symptoms, and, eventually, respiratory failure. 9 So far, no treatment has solidly proven to be effective in stopping or ameliorating COVID-19 evolution. 10, 11 Tocilizumab is a humanized antibody against the receptor of interleukin-6 (IL-6) that has been mostly used in rheumatoid arthritis, although its indications include other rheumatic conditions and severe cytokine release syndrome induced by chimeric antigen receptor T cells. 12 In the setting of transplantation, tocilizumab has been used to treat chronic antibody-mediated rejection. 13 Considering that the acute respiratory distress syndrome (ARDS) that occurs in some patients throughout COVID-19 is a consequence of an inflammatory response, tocilizumab appears as a reasonable drug to target the presumable cytokine storm triggered by the virus. Preliminary data in the general population [14] [15] [16] [17] and transplant patients [18] [19] [20] show promising results.

Herein we present the results of tocilizumab use in a multicenter cohort of 80 Spanish KT recipients affected with SARS-CoV-2.

KT patients were identified from the Spanish Society of Nephrology COVID-19 registry, which included dialysis and KT patients with confirmed diagnosis of COVID-19 since March 18, 2020. 7 Only patients with a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive assay of a specimen collected on a nasopharyngeal swab or bronchoalveolar lavage were included. Initially, from 468 KT recipients included in the registry up to May 9, 73 were identified to have been treated with tocilizumab in 29 different hospitals in Spain. In a second step, a complete database was created in order to gather granular information from these patients. Each center was contacted and invited to participate in the study by completing the additional variables. Twenty-seven centers completed the database and 7 more patients were added, resulting in a final number of 80 patients. Median time to follow-up since symptom onset was 25 days, interquartile range (IQR) 17-35 days.

The registry already included demographics, baseline kidney disease information, immunosuppressive and renin-angiotensin-system inhibitors treatments, and epidemiological and clinical data regarding COVID-19: date of diagnosis, symptoms, lymphopenia, pharmacological treatments, need of mechanical ventilation or intensive care, and outcome. More specific and detailed data regarding tocilizumab treatment and inflammatory markers were added in the expanded database.

Obesity was defined as a body mass index (BMI) over 30 Kg/m 2 .

Respiratory symptoms included cough, sneezing, and rhinorrhea but excluded dyspnea, which was collected separately. The ratio of arterial oxygen partial pressure (PaO2 in mm Hg) to fractional inspired oxygen (FiO2 expressed as a fraction) or PaFi index (Pa/FiO2) was calculated when available (n = 38). If data to calculate it were missing, oxygen saturation was included (n = 40).

Criteria for tocilizumab treatment was based on the protocol of each hospital although all patients presented with 1 of the following:

increased levels or IL-6 (usually >40, ranged between >20 to >60 pg/ mL), increased levels of other inflammatory markers (such as C-reactive protein [CRP], D-dimer, ferritin, or lactic acid dehydrogenase [LDH]), and/or rapidly progressive ARDS (usually with PaFi <300).

Generally, tocilizumab dose was 8 mg/kg, adjusting to 600 mg for patients >75 or 80 kg body weight and 400 mg for those <75-80 kg. Depending on the clinical and analytical response, patients could receive 2 doses of tocilizumab, separated by 12 hours in the majority of the cases.

Clinical follow-up and laboratory tests were collected at 3 points: at admission, at the time tocilizumab was administered and early after tocilizumab infusion (median 72 hours, IQR 48-96 hours).

Outcomes were assessed as COVID-19-related mortality or recovery until May 15, 2020. Recovery was defined as hospital discharge.

The study was performed under the principles of the Declaration of Helsinki and was approved by the hospital ethics committee.

Quantitative variables with a normal distribution are expressed as mean and standard deviation (SD) and the remaining as median and IQR. Categorical variables are summarized as counts and percentages. Univariate analyses were performed according to variables normality, with Student t test for normal variables and nonparametric test for nonnormal distributed ones. Cox multivariate analysis was assessed for predictors of patient mortality. Results are expressed as hazard ratio (HR) with their 95% confidence intervals (95% CIs). In the multivariate analysis only those variables with a P value < .05 and clinically relevant for the outcome were included. A receiver operating characteristic (ROC) curve was plotted to illustrate the diagnostic ability of a binary classifier system as its discrimination threshold is varied. In general, a P value < .05 was considered statistically significant. Statistical analysis was performed using SPSS V 22.0 (SPSS Inc, Chicago, IL).

Fatality rate in this cohort was 32.5%. Table 1 to administration was 6 days, and median time from admission to ICU was 5 days. Sixteen patients received more than 1 dose of tocilizumab.

These patients were not more severely affected at baseline, but respiratory deterioration was more profound, with more frequent ICU admission and a higher mortality (Table S1) Outcomes are also detailed in Table 2 . Those who died were more often admitted to the ICU and had more frequent and severe acute kidney failure as COVID-19 complication.

The percentage of patients with severe respiratory disease (PaFi index <300 mm Hg or oxygen saturation <96%) at admission was higher in patients who ultimately died than in survivors (68% vs 41.5%, P < .01).

At the moment of tocilizumab treatment these percentages were not different between survivors and nonsurvivors (81.6% vs 87.5%) (Figure 1 ).

Predictors for mortality were analyzed through multivariable Cox analysis (Table 3) . Recipient age over 60 and CRP serum level after tocilizumab were associated with an increased risk of death.

Each mg/L of CRP soon after tocilizumab administration increased the risk of death by 1% (P = .003). A worse baseline respiratory situation and obesity were not significantly related to mortality in the multivariate adjustment. ARDS did not help on differentiating between survivors and nonsurvivors on final outcome.

We also analyzed laboratory parameters at different points during hospital stay (Figure 2 TA B L E 2 Management and outcomes of KT with COVID-19 infection who received tocilizumab as part of their treatment. Comparison between those who survived and those who died in a report from New York. 20 In the latter, Pereira et al used tocilizumab in patients who deteriorated rapidly, with 5 of them receiving the initial dose after intubation. Of these 14 patients, 3 died and 4 remained in the ICU at last follow-up, so it is likely that the final mortality was around 40%, quite similar to ours. In our series, tocilizumab was used in around 20% of all Spanish COVID-19 registered KT recipients 7 and it is likely that this subset comprised the most severely affected patients.

Patients who finally died were more severely ill at the admission, but with similar severity at the time of tocilizumab administration.

In addition, we did not find differences in respiratory improvement 72 hours after tocilizumab administration between survivors and nonsurvivors, and, therefore, this might not be an early predictor of good outcome. Previous experiences have reported early response to tocilizumab administration regarding respiratory parameters, 16, 17 although in the largest series of patients this improvement seems to be more important 10 days after tocilizumab administration. 17 In terms of other drugs, patients who died received more frequently steroids and interferon. It is likely that this simply reflects a higher severity of the disease. We analyzed bacterial infections after tocilizumab administration and 10% of patients presented with bacterial microbiological finding after tocilizumab infusion.

We observed that most inflammatory markers increased after tocilizumab in the whole cohort, although we could speculate that we had prevented an even higher increase. IL-6 levels have been described to increase and then decrease in most patients after starting tocilizumab therapy. 15, 17 The explanation is that binding of tocilizumab to IL-6 receptor inhibits receptor-mediated clearance of IL-6, leading to its accumulation in serum. A later decrease of IL-6 by interfering the stimulus for the exaggerated immune response might result in stabilization or improvement of clinical outcome. Additionally, not only IL-6

but also D-dimer may increase up to 10 days after tocilizumab treatment. 17 In our study, CRP was the only marker that decreased within 72 hours after tocilizumab administration and differentiated those who finally resolved the infection from those who died. This is not an isolated finding from our data. CRP has been reported to decrease rapidly in patients treated with tocilizumab for COVID-19 15, [17] [18] [19] and might help to predict outcomes soon after the treatment.

Our study has limitations. The retrospective nature of the study made it impossible to get the whole set of variables in all patients. 

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 on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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