key: cord-0693520-3dvt6uj7 authors: Demir, Erol; Uyar, Murathan; Parmaksiz, Ergun; Sinangil, Ayse; Yelken, Berna; Dirim, Ahmet Burak; Merhametsiz, Ozgur; Yadigar, Serap; Atan Ucar, Zuhal; Ucar, Ali Riza; Demir, Mehmet Emin; Mese, Meral; Akin, Emin Baris; Garayeva, Nurana; Safak, Seda; Oto, Ozgur Akin; Yazici, Halil; Turkmen, Aydin title: COVID‐19 in kidney transplant recipients: A multicenter experience in Istanbul date: 2020-07-13 journal: Transpl Infect Dis DOI: 10.1111/tid.13371 sha: d61851a09429015fdf01d3794c8eb8d32d21b4b6 doc_id: 693520 cord_uid: 3dvt6uj7 INTRODUCTION: Management of COVID‐19 in kidney transplant recipients should include treatment of the infection, regulation of immunosuppression, and supportive therapy. However, there is no consensus on this issue yet. This study aimed to our experiences with kidney transplant recipients diagnosed with COVID‐19. MATERIAL AND METHODS: Kidney transplant recipients diagnosed with COVID‐19 from five major transplant centers in Istanbul, Turkey, were included in this retrospective cohort study. Patients were classified as having moderate or severe pneumonia for the analysis. The primary endpoint was all‐cause mortality. The secondary endpoints were acute kidney injury, the average length of hospital stay, admission to intensive care, and mechanical ventilation. RESULTS: Forty patients were reviewed retrospectively over a follow‐up period of 32 days after being diagnosed with COVID‐19. Cough, fever, and dyspnea were the most frequent symptoms in all patients. The frequency of previous induction and rejection therapy was significantly higher in the group with severe pneumonia compared to the moderate pneumonia group. None of the patients using cyclosporine A developed severe pneumonia. Five patients died during follow‐up in the intensive care unit. None of the patients developed graft loss during follow‐up. DISCUSSION: COVID‐19 has been seen to more commonly cause moderate or severe pneumonia in kidney transplant recipients. Immunosuppression should be carefully reduced in these patients. Induction therapy with lymphocyte‐depleting agents should be carefully avoided in kidney transplant recipients during the pandemic period. The strain of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 was detected for the first time in Wuhan, China in December 2019. 1 The data on kidney transplant recipients diagnosed with are limited, and recommendations are based on case series and expert opinion. [1] [2] [3] [4] [5] [6] [7] Although uremia and kidney transplantation are not considered a risk factor in COVID-19, SARS-CoV-2 often causes a moderate or severe infection in kidney transplant recipients. [1] [2] [3] [4] [5] [6] [7] Lymphopenia, increased inflammatory markers, prothrombin time, and creatine phosphokinase are prognostic factors for COVID-19. 8, 9 Acute kidney injury is also associated with increased morbidity and mortality in COVID-19 patients. 9 However, it is unclear which markers are useful for the monitoring of kidney transplant recipient patients. Major complaints are fever, dry cough, fatigue, shortness of breath, and diarrhea. [1] [2] [3] [4] [5] [6] Pneumonia is the most common manifestation of the infection, characterized by infiltrates in the lung. Cytokine storms also cause organ dysfunction, which may lead to death. [1] [2] [3] [4] [5] [6] Diagnosis is usually based on fever, respiratory symptoms, contact history, typical chest radiology, and biochemical findings. [6] [7] [8] [9] Positive reverse transcription-polymerase chain reaction (RT-PCR) results for COVID-19 in oral and nasopharyngeal swabs confirm the diagnosis. 10 Kidney transplant recipients diagnosed with COVID-19 from five major transplant centers in Istanbul, Turkey, were included in this retrospective cohort study. Initially, 44 kidney transplant recipients diagnosed with COVID-19 and identified between February 1, 2020 and May 4, 2020 were enrolled. The following exclusion criteria were applied for the study: (a) patients without typical findings (n = 1), (b) loss to follow-up after diagnosis of COVID-19 (n = 3). After the diagnosis of COVID-19, the remaining 40 participants were followed up for a period of at least 15 days or until death ( Figure 1 ). The Medical Ethics Committee of the Istanbul Faculty of Medicine approved this study. The patients were categorized into two groups for analysis. Patients with respiratory failure requiring mechanical ventilation, septic shock, or multiple organ dysfunction were defined as having severe pneumonia. All other cases were classified as having moderate pneumonia. The demographics, clinical data, comorbidities, laboratory and radiological results, data on anti-viral and anti-cytokine treatments, and management of immunosuppression were extracted from electronic medical records. Nasal and oropharyngeal swabs were collected and tested for SARS-CoV-2 RNA with RT-PCR assay. All patients underwent non-contrast chest computerized tomography (CT) scanning in the supine position during end-inspiration. All cases demonstrated early or progressive radiographic deterioration on CT at the initial admission. The COVID-19 diagnosis was based on contact history, symptoms, laboratory, and radiological findings. A positive RT-PCR test was used to confirm the diagnosis. Indications for hospitalization were moderate, severe pneumonia and cytokine release syndrome (persistent fever, blood lymphocyte count <800/mm 3 , serum C-reactive protein > 40 mg/L, aspartate aminotransferase >45 IU/L, ferritin > 500 ng/mL, D-dimer > 1000 ng/mL, and triglyceride > 150 mg/ dL). Criteria for admission to the intensive care unit (ICU) were a partial pressure of arterial oxygen and inspiratory oxygen fraction (PaO 2 /FiO 2 ) ratio less than 300, oxygen saturation under 90% and All of the patients were initially treated with hydroxychloroquine (400 mg BID for the first day, and then 200 mg BID for four days; oral) and azithromycin (500 mg QD for the first day, and then 250 mg QD for four days; oral). Tocilizumab (400 mg QD for two days; intravenous) or anakinra (100 mg QD for 7-14 days or until hospital discharge; subcutaneous) were used in the treatment of cytokine release syndrome. Resistant cases were treated with favipiravir (1600 mg BID for the first day, and then 600 mg BID for four days; oral). Antibiotic therapy was administered based on the infection specialist's decision in the presence of confirmed or suspected invasive bacterial infection. The patients were also monitored for adverse drug reactions during the hospital stay. The QT interval of all patients was regularly monitored. A standard protocol was used to manage immunosuppression, antiviral, and cytokine-targeted therapy ( Figure 2 ). Antimetabolites (mycophenolate derivatives and azathioprine) were discontinued in all cases. Steroid doses were increased to a stress dose in the early period and then continued at a maintenance dose. Calcineurin doses were halved in patients with a stable clinic course and were discontinued in hypoxemic patients. The calcineurin and mammalian target of rapamycin (mTOR) levels were also monitored twice a week. Low-molecular-weight heparin was used in all patients unless there were contraindications. Doses were adjusted according to the patients' risk of bleeding and coagulation. Oxygen treatment was provided to patients whose oxygen saturation was below 92% via a nasal cannula, and with a mask with a reservoir, if this was insufficient. If respiratory failure continued despite these treatments, mechanical ventilation was provided after non-invasive ventilation. The primary endpoint was all-cause mortality. The secondary endpoints were acute kidney injury, the average length of hospital stay, admission to intensive care, and mechanical ventilation. Categorical variables were summarized with counts and percentages. Quantitative variables were summarized with means and standard deviations or medians and interquartile range statistics, where appropriate. The chi-square and Fisher's exact tests were performed for qualitative variables, whereas the Mann-Whitney U test was used for quantitative variables with the non-parametric distribution. Logistic regression analysis was used to identify patient loss and the associated risk in terms of odds ratio and 95% confidence intervals. Variables were selected by backward elimination using likelihood ratio tests. A P-value of <.05 was considered significant. (Table 3) . Age (mean ± SD, y) 44. was associated with a lower incidence of death. P-values in bold showed statistically significant differences. Abbreviations: SpO2 = blood oxygen saturation levels; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; LDH, lactate dehydrogenase. Early mortality in kidney transplant recipients varies at a rate of 6%-25%. [1] [2] [3] [4] [5] [6] In our study, almost all of our patients were hospitalized with moderate or severe pneumonia. Five patients died during the follow-up. The lower mortality rate compared with the data from Italy and the USA may be due to several reasons. 2,4 The low average age and lower comorbidity rate of the study population could be important reasons. While the average age of our cohort was 44.9, it was reported as being 60 in Akalin et al's series. 2 In the same study, the frequency of hypertension and diabetes mellitus were 94% and 69%, respectively. We found these frequencies to be 65% and 5%, respectively. Another critical point is that our study group consisted of mostly living-related transplantation patients. This condition may have led to lower induction use and low cumulative immunosuppression, which may have led to a low mortality rate. Similarly to our study, previous studies have demonstrated that induction and anti-rejection therapy may be a risk factor for mortality in COVID-19. [1] [2] [3] [4] [5] [6] For this reason, it may be a rational approach to avoid induction therapy in patients with low immunological risk during the COVID-19 pandemic. Clinicians should be aware that potent immunosuppressants, especially anti-T-lymphocyte globulin, are very risky. P-values in bold showed statistically significant differences. Abbreviations: IS, immunosuppression; mTOR, mammalian target of rapamycin. was associated with a lower incidence of death. Hence, it would be beneficial to investigate the role of cyclosporine A in the treatment of this disease. The use of tocilizumab has been reported in the treatment of cytokine release syndrome triggered by COVID-19. 2, 4, 5 Previous studies have also demonstrated the use of lopinavir-ritonavir and darunavir-ritonavir in the treatment of COVID-19. Drug-drug interaction between anti-viral drugs and calcineurin inhibitors has been reported in these studies. 2, 4, 5 To the best of our knowledge, the use of favipiravir and anakinra in the treatment of COVID-19 in kidney transplant recipients has not been previously reported. Our study was not conducted to investigate the effectiveness of these drugs. However, unlike other anti-virals, favipiravir does not exhibit drugdrug interaction between calcineurin inhibitors. Therefore, regular monitoring of the calcineurin inhibitor levels may not be necessary when using favipiravir. We did not encounter any problems with the CNI levels in patients taking favipiravir. With regard to the hydroxychloroquine treatment given to all patients, we did not observe any side effects such as arrhythmia, QT prolongation, nausea, diarrhea, retinal toxicity, cutaneous rash, or hypoglycemia. Our retrospective study has many limitations; the sample size is small, and the follow-up period is short. Other limitations were that there is no control group and PCR samples were only collected from patients with moderate or severe symptoms rather than all patients. The many restrictions and prejudices involved have meant that we are unable to draw definitive conclusions from these experiences. Hence, our findings are preliminary and will need to be confirmed in large-scale prospective cohort studies with longer follow-up. The use of a standard treatment model may be considered as the strength of the study. In conclusion, COVID-19 has been seen to more commonly cause moderate or severe pneumonia in kidney transplant recipients, possibly due to immunosuppressive therapy. The mortality rate of these patients is higher than that of the general population; therefore, immunosuppression should be carefully reduced in these patients. No anti-viral and cytokine-targeted therapy have been approved yet for the treatment of COVID-19. Hence, all drugs should be used with caution in these patients. Induction therapy with lymphocyte-depleting agents should be carefully avoided in kidney transplant recipients during the pandemic period. I would like to mention those healthcare professionals who have been victims of COVID-19 in Turkey. In Turkey, 7428 health workers have been infected and some of these individuals have died from the disease. In particular, I wish to commemorate our teacher, Professor Murat Dilmener, and Cemil Tasçıoğlu, both of whom died of COVID-19. Both spent many years working as clinicians and teachers at Istanbul University. We remember them with respect and appreciation. The authors declare no conflicts of interest. P-values in bold showed statistically significant differences. Abbreviations: ALT, alanine aminotransferase; ATLG, anti-T-lymphocyte globulin; CNI, calcineurin inhibitors; LDH, lactate dehydrogenase; RT-PCR, reverse transcription-polymerase chain reaction; SpO 2 , blood oxygen saturation levels. 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