key: cord-0720226-hozlj1hq
authors: Devresse, Arnaud; Belkhir, Leila; Vo, Bernard; Ghaye, Benoit; Scohy, Anaïs; Kabamba, Benoit; Goffin, Eric; De Greef, Julien; Mourad, Michel; De Meyer, Martine; Yombi, Jean-Cyr; Kanaan, Nada
title: COVID-19 Infection in Kidney Transplant Recipients: A Single-Center Case Series of 22 Cases From Belgium
date: 2020-06-15
journal: Kidney Med
DOI: 10.1016/j.xkme.2020.06.001
sha: 01b169e991a3c88225697f477700df334405d4dd
doc_id: 720226
cord_uid: hozlj1hq

RATIONALE & OBJECTIVE: The world is facing a global pandemic caused by Sars-CoV-2 virus. Although kidney transplant recipients are at increased risk of viral infections, the impact of their chronic immunosuppressed status on the risk of acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown. STUDY DESIGN: All cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mTOR inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients. SETTING & PARTICIPANTS: 22 COVID-19 infections were diagnosed in our cohort of 1200 kidney transplant recipients. RESULTS: Most common initial symptoms included fever, cough, or dyspnea. Eighteen patients (82%) required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Chest computerized tomography (CT) at admission (performed in 15 patients) showed mild (n=3), moderate (n=8), extensive (n=1), severe (n=2), and critical (n=1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. Eleven patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non- ICU, 1 was in ICU, and 2 patients had died. LIMITATIONS: Small sample size and short follow-up. CONCLUSIONS: Clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19.

Specific questions arise for kidney transplant patients who are facing COVID -19 infection. As with other infections, the risk of acquiring COVID-19 might be increased due to the chronic state of immunosuppression. Also, the disease could present with increased severity with eventually poor outcome. Moreover, handling immunosuppression in that context can be challenging. We report our experience with 22 kidney transplant recipients followed at our academic center in Belgium, in whom we applied a standard strategy of immunosuppression minimization and treatment. Clinical symptoms were similar to those reported in the general population. Among kidney transplant recipients hospitalized with COVID-19, 11% died. Our study expands the knowledge base of COVID-19 infection in kidney transplant recipients.

Since the first case was diagnosed in Wuhan, China, in December 2019, the world has faced a rapidly growing outbreak of a newly discovered contagious infectious disease: coronavirus disease 2019 . COVID-19 is caused by SARS-CoV-2 virus and primarily manifests as an acute respiratory illness with interstitial and alveolar pneumonia, but can affect multiple organs, such as heart, kidney, digestive tract, blood and central nervous system. 1 As of April 18, 2020, 2,338,335 cases of COVID-19 have been confirmed in more than 185 countries and territories and at least 161,030 deaths have been reported so far. 2 In Belgium, the first case of COVID-19 in the general population was diagnosed on 4th February 2020. To date, more than 42,000 cases have been reported, including over 12,000 hospitalizations. 3 Specific questions arise for transplant patients who are facing COVID -19 infection. As with other infections, could the risk of acquiring COVID-19 be increased due to the chronic state of immunosuppression? Will the infection be more severe than in patients with normal immunity? Moreover, how should immunosuppressive therapy be handled in that context?

Case reports of COVID-19 in kidney transplant recipients [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] and limited case series [14] [15] [16] with a small number of patients have been published so far. In this study, we report 22 COVID-19 disease cases among our cohort that currently includes 1200 kidney transplant recipients followed in our academic institution in Belgium.

Before the outbreak onset, about 1200 kidney transplant recipients who were transplanted and followed in our hospital in collaboration with peripheral centers were recorded in our database as alive with a functioning graft. Since the first case of COVID-19 was diagnosed in Belgium, we have been prospectively monitoring all cases of proven COVID-19 in our cohort of kidney transplant recipients followed in our academic center.

Colleagues from peripheral centers with whom we share routine follow-up and managerial decisions of patients were invited by mail to report on all their patients with COVID-19 infection. To date, 22 kidney transplant recipients have been diagnosed with COVID-19 (n=14 in our transplant center and n= 8 in peripheral centers). Clinical features, management and outcomes were recorded.

The study was approved by the local ethics committee. The need for informed consent was waived due to de-identified information.

Since the onset of the COVID-19 outbreak in Belgium, daily transplant activities have been severely impacted in the whole country. Kidney transplantation is considered only in patients with "high-urgency" status (i.e. imminent lack of access for dialysis or psychiatric contra-indication to dialysis) or in hyper-sensitized patients on the waiting-list for more than 5 years. In our center, no kidney transplantations have been performed since March 1st 2020. The activity of the outpatient clinic has also been dramatically reduced. Patients were advised very early to stay at home, avoid public transportation and unnecessary contact, and report every symptom before coming to the outpatient clinic.

The vast majority of consultations are made by phone and patients are asked to come in our center only if they were transplanted less than 6 months ago, or if they have an unstable clinical situation (rise in serum creatinine, new onset proteinuria,…), or newly developed symptoms. In case of COVID-19 suspicion, patients were sent to a dedicated COVID-unit at the emergency department.

All kidney transplant recipients presenting symptoms compatible with COVID-19 infection were tested and fully evaluated by a physician (clinical evaluation, chest X-ray and/or pulmonary CT scan and naso-pharyngeal swab for RT-PCR lab test). The 

In patients in whom a chest CT-scan was performed at admission, type of lesion and the degree of pulmonary parenchyma involvement were reported using the French Society of Radiology classification. 17 Pulmonary involvement is classified as mild (<10%), moderate (10-25%), extensive (25-50%), severe (50-75%), or critical (>75%). Figure 1 illustrates 3 CT patterns: mild, moderate and severe patterns, respectively.

Kidney transplant recipients receive a standard immunosuppression in our center, based on a combination of tacrolimus, mycophenolate and steroids. Daily mycophenolate and steroids doses are 1g and 4 mg, respectively. Tacrolimus trough levels are 10-13 ng/mL during the first month, 7-10 ng/mL for the next two months, and then 5-7 ng/mL.

Everolimus is used in case of history of cancer or calcineurin inhibitor nephrotoxicity with a trough level of 5-7 ng/mL. Cyclosporine is continued in patients transplanted before the use of tacrolimus or because of tacrolimus intolerance with trough levels of 50-70 ng/mL. Azathioprine is used at a daily dose of 1 mg/kg in case of mycophenolate intolerance or pregnancy desire.

For COVID-19 infected kidney transplant recipients, we have designed a standard strategy of immunosuppression minimization and treatment, which was sent to our colleagues from peripheral centers at the onset of the outbreak. In all cases, the antimetabolite drug (mycophenolate or azathioprine) is stopped; the daily dose of tacrolimus, cyclosporine or everolimus is reduced to reach trough levels at 3-5 ng/mL, 30-40 ng/mL, and 3-5 ng/mL; respectively. The routine steroid dose remains unchanged (4 mg/day of methylprednisolone). In case of life-threatening situations (e.g. critical admission in intensive care unit [ICU]), tacrolimus, cyclosporine or everolimus is stopped. Adjunctive treatment with corticosteroids has been provided to some patients after careful case-by-case evaluation, considering the extent of respiratory involvement and hyperinflammatory status.

In all kidney transplant recipients requiring hospitalization, following interim Belgian recommendations 18 , hydroxychloroquine can be administered in patients with no cardiac contra-indication, at the discretion of the physician depending of the patient clinical situation for 5 days (400mg bid day 1 and then 200 mg bid up to day 5; for estimated glomerular filtration rate <30 mL/min/1.73 m 2 400 mg bid day 1 and then 200 mg/day up to day 5). Hydroxychloroquine is initiated only if the corrected QT space on electrocardiogram is > 500 msec. Table 1 . Except for 2 patients, all had co-morbidities, including treated hypertension, treated diabetes, history of cardiovascular event, obesity, dementia/intellectual disability, and active metastatic malignancy.

The clinical, laboratory and radiological presentation of the 18 hospitalized patients is summarized in Table 1 . Interestingly, patient 18 (Table 2) , currently in the ICU, showed the highest CRP level. Fifteen had a chest CT-scan at admission.

Pulmonary lesions were classified as mild (n=3), moderate (n=8), extensive (n=1), severe (n=2), and critical (n=1), respectively.

The management and outcomes of hospitalized patients are described in Table 2 .

With the exception of one patient (patient 7, discussed below), our local protocol of immunosuppression minimization was applied: the antimetabolite was stopped and the tacrolimus/cyclosporine/everolimus dose was reduced to reach trough level targets, as per protocol. Fifteen out of the 18 hospitalized patients (83%) were treated with hydroxychloroquine and 2 (11%) had an increase in steroids doses (Table 2) . We did not observe any cardiac side effects during hydroxychloroquine treatment. However, we observed an increase in tacrolimus trough levels in 5 patients after the initiation of hydroxychloroquine. One patient (patient 2) also received 5 days of intravenous (IV) cefuroxime because of suspected additional pulmonary infection.

Eleven patients (61%) received supplemental oxygen during hospitalization. Only two patients were transferred to the ICU and received invasive ventilations (patient 2 and patient 18). Both were receiving everolimus because of a past history of cancer. Patient 2 was a man in his 60s with a history of osteosarcoma of the thigh and was known for advanced dementia with Lewy bodies. He was admitted for dyspnea and worsening confusion. Chest X-ray was compatible with COVID-19 infection that was confirmed by RT-PCR in nasopharyngeal swab. Oxygen saturation level was normal at admission, but his neurologic status deteriorated within hours, associated with severe hypercapnia. He was admitted in the ICU and rapidly intubated. Nevertheless, the clinical situation improved promptly and invasive ventilation was stopped after 48 hours. He was sent back home 10 days after admission. Patient 18 was a man in his 40s with a past history of Hodgkin cervical lymphoma at age 15. He was admitted for fever, dyspnea, dry cough and diarrhea. Clinical workup showed mild hypoxemia requiring 2L/min with nasal cannula. Chest CT-scan showed bilateral pneumonia classified as moderate.

Mycophenolate was stopped and hydroxychloroquine was started. However, oxygen needs increased progressively. Five days after admission, the patient showed signs of severe respiratory distress with hypoxemia. He was admitted to the ICU and rapidly intubated. Everolimus was stopped and steroids were increased at 16 mg/day of methylprednisolone for two days and then, at 1 mg/kg (80 mg)/day as he did not improve.

At the time of writing of this manuscript, his condition remains critical, requiring invasive ventilation with high level of oxygen (FiO2 100%).

Five cases of acute kidney injury (AKI) (defined as a plasma creatinine increase over 50% from baseline creatinine or a plasma creatinine increase ≥ 0.3 mg/dL) 19 were observed during hospitalization (28%). However, AKI rapidly resolved with IV hydration, and no patient required dialysis. Overall, kidney function remained quite stable in the hospitalized patients (Table 2) Conversely, patient 18 who is currently intubated in ICU, needing very high levels of oxygen, had moderate pulmonary involvement on CT-scan at admission.

Because of their chronic immunosuppressed status, kidney transplant recipients are at increased risk of many viral infections (Cytomegalovirus, herpes zoster, Norovirus infections…). 20,21 Thus, higher rates of infection with COVID-19 and/or increased severity of the disease in our transplant population was feared. However, in past epidemics with MERS and SARS-Cov-1 this increased risk was not observed. 22 As in the general population 1 , the most common symptoms in our cohort of kidney transplant recipients with COVID-19 infection were fever, dry cough, and dyspnea. As already reported 5,23,24 , we also observed some atypical presentations with predominant digestive symptoms and acute confusion. Interestingly, the severity of pulmonary involvement at the chest CT-scan at admission was not associated with worse clinical outcome. Indeed, some patients with images of severe pulmonary involvement recovered quite well while the only patient currently in ICU had moderate involvement at admission with subsequent dramatic evolution. This suggests that chest CT-scan at admission is useful for diagnosis but does not provide prognostic information. However, other factors may impact the severity of the pulmonary involvement on the first chest CTscan such as the time interval between the onset of symptoms and the CT-scan and the presence of underlying chronic pulmonary diseases. Little is known about early markers that may predict the clinical evolution. Tan et al. recently showed that CRP increased early in severe COVID-19 infection, prior to CT findings 25 , suggesting that the initial evolution of CRP levels might provide more prognostic information than early CT scan.

In line with this hypothesis, patient 18 (Table 1) Eighty-three percent of our hospitalized kidney transplant recipients received hydroxychloroquine. Early reports suggest a role for hydroxychloroquine in reducing the viral load. 32 However, the impact of hydroxychloroquine on the clinical outcome of COVID-19 patients is largely unknown and highly debated. Even if hydroxychloroquine was safely used in our cohort, we cannot draw any conclusion regarding its efficacy because of the absence of a control group. The currently recruiting DISCOVERY and SOLIDARITY trials (NCT04315948 and NCT04321616, respectively) will provide some answers regarding treatment efficacy in the general population. The results of these trials will then need to be extrapolated to the kidney transplant recipients population. None of our patient received the antivirals currently in the pipeline 33 days after the tocilizumab administration. 15 In our cohort, the kidney function outcome was satisfactory. Although 28% of hospitalized patients experienced AKI, none required hemodialysis. Moreover, kidney function rapidly stabilized after appropriate hydration. To date, we have not observed any acute rejection episodes, but the current follow-up of our patients is short. As there is a correlation between immunosuppression reduction and increased risk of acute rejection 35 , appropriate monitoring of kidney function should be continued and reintroduction of immunosuppressive drugs should be tailored after infection recovery.

At the time of writing this manuscript, two kidney transplant recipients from our cohort died from COVID-19. However, as mentioned above, both patients had very severe comorbidities and were terminally ill. Italian and Spanish teams have reported higher mortality rates of 27.8 and 25 % in the former and latter studies, respectively. 14, 15 Closer to our findings, a British team reported a 14% mortality rate in their series that included 7 kidney transplant recipients. 16 kidney transplant recipients with 28 (78%) requiring hospitalization. Management was not uniform as in our series, as immunosuppression reduction and hydroxychloroquine use was used in 86%, and patients also received Azithromycin (46%), the CCR5 inhibitor leronlimab (21%) and tocilizumab (7%). Interestingly, while kidney transplant recipients from this cohort seem quite similar to ours regarding co-morbidities, the outcome appears more severe with 11 kidney transplant recipients (39%) requiring mechanical ventilation and 6 (21%) requiring kidney replacement therapy. The mortality rate was also higher at the end of follow-up (28% vs 11% in our patients). A possible explanation might be the ethnic origin of the patients in that cohort, as 39% and 42% were black and Hispanic, respectively, which differs from our population. These differences in disease severity and outcomes between centers and countries will need to be closely analyzed in larger cohorts with longer follow-up.

In conclusion, we report our experience of 22 1 These patient received 5 days of intravenous cefuroxim for suspected concomitant bacterial infection 2 3 days course of methylprednisolone 32 mg/day 3 No ICU because of severe comorbidities, death in palliative unit 4 These patient received antibiotics for concomitant acute pyelonephritis 5 Tac already reduced for BK virus viremia 6 16 mg/day for two days and then 1 mg/kg of methylprednisolone (ongoing) Abbreviations : AKI, acute kidney injury ; Aza, azathioprine ; C, cough ; Csa, cyclosporine ; CT, computarized tomography ; D, dyspnea ; Dig, digestive symtoms ; EVL, everolimus ; F, fever ; HC, hydoxychloroquine ; ICU, intensive unit ; IS, immunosuppression ; IV, invasive ventilation ; KT, kidney transplantation ; MPA, mycophenolate ; N, neurological symptoms ; ND, not done ; NC, nasal cannula ; Tac, tacrolimus ; St, steroids Consolidations are preferentially seen in the peripheral parts of both lungs.

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