key: cord-0710910-mgryo2t9 authors: Silva, Filipa; Cipriano, Ana; Cruz, Hugo; Tavares, Joana; Fragoso, Joana; Malheiro, Jorge; Almeida, Manuela; Martins, La Salete; Abreu, Miguel; Pedroso, Sofia; Dias, Leonídio; Henriques, António Castro title: SARS‐CoV‐2 infection in kidney transplant recipients: Early report of five cases date: 2020-07-14 journal: Transpl Infect Dis DOI: 10.1111/tid.13394 sha: 06ba61aeba84809341715d3c44625099daa7b67c doc_id: 710910 cord_uid: mgryo2t9 From December 2019 to March 2020, China was the epicenter of the SARS‐CoV‐2 infection pandemic, but from that moment on, Europe surpassed China in the number of new cases and deaths related to this novel viral respiratory infection. The emergence of this world pandemic is particularly important for solid organ transplant recipients, who might have an increased risk of mortality, not only due to their chronic immunosuppression status, but also to the cardiovascular risk that correlates with several years of chronic kidney disease. To the extent that there is still a lack of knowledge about the clinical characteristics, evolution, and prognosis of SARS‐CoV‐2 infection in kidney transplant recipients, we will report the first 5 cases diagnosed and followed in our transplant unit, as well as share the therapeutic strategies adopted. To the extent that there is still a lack of knowledge about the clinical characteristics, evolution, and prognosis of SARS-CoV-2 infection in kidney transplant recipients, we will report the first 5 cases diagnosed and followed in our transplant unit, as well as share the therapeutic strategies adopted. We performed a retrospective, single-center study of adult kidney transplant (KT) recipients observed with SARS-CoV-2 infection in our tertiary care center. Epidemiological, demographic, clinical, management, and outcome data were analyzed. Nasopharyngeal and oropharyngeal swab samples were collected upon validation of suspected cases. The laboratory diagnosis of SARS-CoV-2 infection was carried out through nucleic acid amplification tests (NAAT) that detect unique sequences of the virus, using real-time reverse transcription-polymerase chain reaction (RT-PCR). At this point, we used Liferiver Novel Coronavirus (SARS-CoV-2) real-time multiplex RT-PCR kit (Liferiver/Shanghai ZJ Bio-Tech Co.), which is a CE-IVD marked test for the simultaneous qualitative detection of 3 SARS-CoV-2 target viral genes (gene E, gene N, and gene ORF1ab). Laboratory procedures were strictly performed according to the manufacturers' instructions, and appropriate biosafety practices were applied. To the best of our knowledge, there are no analytical performance issues, such as inappropriate false-positive or false-negative rates, directly associated with the laboratory use of this commercial kit. KT patients admitted, blood cultures and chest X-ray or computed tomography (CT) was also performed. According to clinical severity, the patients were admitted to hospital or home hospitalization. While in home hospitalization patients stayed in isolation according to World Health Organization (WHO) 5 and were called daily by clinicians to monitor the clinical evolution and the need of reassessment at the emergency department. Concerning treatment, upon diagnosis, the antimetabolite was immediately suspended with the reduction or suspension of the calcineurin inhibitor (CNI) discussed on a case-by-case basis according to the severity of the clinical condition. In all cases, the steroid dose was increased slightly (usually from 5 to 10 mg/d). Regarding to antiviral treatment, all patients with documented pneumonia or respiratory failure started hydroxychloroquine 400 mg twice daily on day one, followed by 200 mg twice daily until day 5-10. In all these patients, an electrocardiogram were performed before starting treatments to access Qtc interval. The study was approved by the Health Ethics Committee of our hospital. Requirement to obtain informed written consent from everyone was waived as the study was limited to the review of existing medical records. To ensure confidentiality, each case was anonymized by the assignment of a random identification number. After 7 to 14 days of symptoms resolution, a patient was considered cured, when two negative SARS-CoV-2 RNA test samples were obtained 24-48 hours apart. The clinical outcome was evaluated until April 30th or until death. In our hospital center, during March 2020, 2178 NAAT were performed to screen for SARS-CoV-2 infection in adult patients (range 18-101 years-old). Of these, 26% were positive (n = 559) and 74% were negative (n = 1619). Of the positive tests, five were in KT patients, four from deceased and one from living donor. One of them had a simultaneous renal and pancreas transplant. The baseline characteristics of each patient are shown in Table 1 . Three patients were males, and the median age was 56 (range 35-63) years old. Regarding the etiology of chronic kidney disease (CKD), two had diabetic nephropathy, one was due to reflux nephropathy, and in the last two it was unknown. The median time from transplantation was 28 (range 7-303) months. The median baseline serum creatine (pCr) and estimated glomerular filtration rate (eGFR) by CKD-EPI were 1.77 (range 0.8-2.5) mg/dL and 48 (range: 18-95.5) mL/min/1.73 m 2 , respectively. All the patients had hypertension but none of them were on angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker. Symptoms and laboratory findings are presented in Unfortunately, this patient died 10 days after the onset of symptoms. No anti-retroviral or anti-IL-6 receptor mAb tocilizumab was used. Clinical evolution, outcomes, and follow-up were resumed in Table 4 . The median follow-up time since diagnosis was 30 days (range 10-37). At last evaluation, the median pCr and eGFR by CKD-EPI were 2.09 (range 1.42-4.5) mg/dL and 35.9 (range 9.7-54.8) mL/ min/1.73 m 2 , respectively. After hospital discharged, patients maintained home care hospitalization with daily telephone contact by a doctor to assess symptoms and fever. The clinical presentation of SARS-CoV-2 infection can vary widely in severity, ranging from asymptomatic or mild symptoms to ARDS and death. 6 At the onset of disease, the most common symptoms are fever, nonproductive cough, dyspnea, myalgia, and fatigue, but some patients can experience gastrointestinal symptoms. 7 In SOTs, presentation with febrile illness accompanied by gastrointestinal symptoms may be quite common, described in 15% in one series. 8 In our experience, all patients presented with fever combined with either respiratory symptoms, myalgia, or gastrointestinal symptoms. In the few case reports in kidney transplant recipients, the symptoms were quite variable. Gandolfini et al 9 reported that the clinical presentation and the course of disease did not vary significantly between kidney transplant and non-kidney transplant patients, while Guillen et al 10 pointed to more atypical clinical presentations, which proved to be a challenge in the differential diagnosis process. In our experience, patients presented with both typical and atypical symptoms, with fever being detected in all cases. Decreased lymphocyte count, prolonged prothrombin time, and elevated dehydrogenase were the blood test abnormalities most frequently found. 7 Laboratory findings in our patients are detailed in Table 2 . In Wang et al report, the decrease in absolute lymphocyte count was seen more frequently in patients who progressed rapidly to ARDS and sepsis. 7 Curiously, in our case series, the single patient with lymphopenia was also the only one who worsened clinically with the development of ARDS and subsequent death. However, she already had chronic renal graft dysfunction with proteinuria and presented with the most severe AKI. Other laboratory tests were elevated as triglycerides, ferritin, partial thromboplastin time, D-dimer, and pro-calcitonin levels. Platelets, liver enzymes, markers of myocardial necrosis, and rhabdomyolysis remained normal. IL-6 levels were not available. In all cases of KT recipients with COVID-19 that described poor outcomes the immunosuppression had been withdrawn. [9] [10] [11] Considering the cytokine storm and previous publications that show that immunosuppression might be a protective factor in sepsis providing a survival advantage, 12,13 the concept of removing all the immunosuppression should be subject of discussion considering that could contribute to poor prognosis. Another factor to take in consideration is the number of years under immunosuppression. In Bhoori et al report, the deaths occurred in long-term patients rather than recently transplanted, fully immunosuppressed patients. 14 Additionally, the many years of evolution and the several comorbidities associated with chronic kidney disease seem to be associated with an increased risk of severe disease and poor outcomes 3,6,7 of SARS-CoV-2 infection. Chen et al justify that with a weaker immune function associated with the underlying chronic diseases, such as diabetes, hypertension and cardio and vascular disease. 6 Their susceptibility seems to be related with reduced lymphocytes. 6 Our series reports five patients with different ages and with different comorbidities. The outcomes were also variable; however, the only case that evolved unfavorably occurred in the patient with more Most of the patients ( Understanding of COVID-19 based on current evidence World Health Organization. Coronavirus disease (COVID-19) Pandemic Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study COVID-19 in solid organ transplant recipients: Initial report from the US epicenter World Health Organization. Home care for patients with COVID-19 infection Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Management of patients on dialysis and with kidney transplant during SARS-COV-2 (COVID-19) pandemic in Brescia, Italy COVID-19 in kidney transplant recipients Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? COVID-19 in post-transplantation patients-report of two cases Is bacteremic sepsis associated with higher mortality in transplant recipients than in nontransplant patients? a matched case-control propensity-adjusted study Inpatient Mortality Among Solid Organ Transplant Recipients Hospitalized for Sepsis and Severe Sepsis COVID-19 in longterm liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression Mechanisms of action of cyclosporine Mycophenolate Mofetil: Selective T Cell Inhibition Does the evidence support the use of Mycophenolate Mofetil therapeutic drug monitoring in clinical practice? A Systematic Review Management of kidney transplant immunosuppression in positivecoronavirus infection requiring hospital admission HCoV-NL63 and HCoV-229E is inhibited by the drug FK506 How should I manage immunosuppression in a kidneytransplant patient with COVID-19? An ERA-EDTADESCARTES expert opinion SARS-CoV-2 infection in kidney transplant recipients: Early report of five cases