key: cord-0973054-rt7lstqv authors: Kim, Yaerim; Kwon, Ohyun; Paek, Jin H.; Park, Woo Y.; Jin, Kyubok; Hyun, Miri; Lee, Ji Y.; Kim, Hyun A.; Han, Seungyeup title: Two distinct cases with COVID‐19 in kidney transplant recipients date: 2020-05-16 journal: Am J Transplant DOI: 10.1111/ajt.15947 sha: 4e55d07c1e95f1e4355ea6662f7be6d44b1c76a0 doc_id: 973054 cord_uid: rt7lstqv The fatality of novel coronavirus disease 2019 (COVID‐19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID‐19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36‐year‐old man who underwent KT 3 years ago. He was diagnosed with COVID‐19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID‐19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug‐to‐drug interaction. The second case was developed in a 56‐year‐old man without any symptoms. He received a second KT from an ABO‐incompatible donor 8 years ago. He was diagnosed with COVID‐19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID-19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug-to-drug interaction. The second case was developed in a 56-year-old man without any symptoms. He received a second KT from an ABO-incompatible donor 8 years ago. He was diagnosed with COVID-19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors. clinical research/practice, immunosuppressant, infection and infectious agents -viral, infectious disease, kidney (allograft) function/dysfunction, kidney transplantation/nephrology a critical issue for improving long-term outcomes in KT. Because the overall immunity is decreased due to lifelong use of immunosuppressant drugs, KT recipients are vulnerable to infections. 6 In addition, all recipients show different clinical manifestations with various underlying diseases and immunosuppressant regimens. Therefore, it is more challenging to propose proper management guidelines for infectious diseases in these patients than in the general population. However, the accumulation of diverse experiences could help to improve the overall outcomes; thus, we aimed to share our experience with two recipient cases with COVID-19 showing distinct clinical courses. Changes in the clinical parameters, laboratory results, and drug administrations. The blue-colored boxes show the use of immunosuppressants with dosages. The red-colored boxes show the antiviral agents used in each day. The gray-colored boxes show a skipped day for immunosuppressants. In the line plot, the left-sided vertical axis represents body temperature and tacrolimus trough level in top and bottom plots, respectively. The right-sided vertical axis represents the estimated glomerular filtration rate (eGFR) and C-reactive protein (CRP) level in the top and bottom plots, respectively. The horizontal axis represents the days in hospital, in common. The admission date is represented as hospital day 1. The latest day before admission was demonstrated by −26 and −27 in Case 1 and Case 2, respectively. Case 1 is shown in the (A) plot, and case 2 in the (B) plot. MMF, mycophenolate mofetil; PDN, prednisolone; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein A 36-year-old man was admitted to our hospital with fever, cough, rhinorrhea, diarrhea, and decreased urine output. He was diagnosed with ESRD due to focal segmental global sclerosis and received living unrelated donor KT in April 2016. The donor-recipient HLA-A, -B, -DR mismatch grade was 5. The maintenance immunosuppressants were long-acting tacrolimus (2 mg, q24hours), mycophenolate mofetil (MMF) (500 mg, q12hours), and prednisolone (10 mg, qd) ( Figure 1A ). At the latest follow-up date on February 19, 2020, the level of serum creatinine (sCr), estimated glomerular filtration rate (eGFR), and tacrolimus trough were 1.47 mg/dL, 54.5 mL/min/1.73 m 2 , and 3.8 ng/ mL, respectively. In addition, there was no proteinuria. On March 12, 2020, he felt a febrile sensation with coughing and rhinorrhea. After 2 days, diarrhea occurred, and urine volume decreased. He reported no history of travels abroad or exposure to infected or suspected patients of contagious COVID-19. On March 16, 2020, he visited the hospital and real-time polymerase chain reaction (RT-PCR) for COVID-19 was performed by nasopharyngeal swab. After 1 day, he was diagnosed with COVID-19 and was admitted to the hospital. His vital signs were stable, with mild fever at 37.6°C when he was admitted. The initial laboratory findings showed decreased lymphocyte count, increased C-reactive protein (CRP), sCr level, and urine protein-to-creatinine ratio (uPCR) ( Table 1) . Chest radiograph showed subsegmental atelectasis on both lower lung field and peribronchial infiltration in the left upper lobe ( Figure 2 ). On hospital day 2, the fever spiked to 38.5°C, and we decided to discontinue the MMF and to start lopinavir/ritonavir (400/100 mg, bid). Two days later, the tacrolimus trough level abruptly increased to 16.5 ng/mL. Thus, we discontinued tacrolimus and changed prednisolone to intravenous methylprednisolone (30 mg, qd). After discontinuation of tacrolimus, the trough level peaked at 24.6 ng/ mL and started to decrease, and it took 10 days to reach the therapeutic range ( Figure 1A ). From hospital day 5, diarrhea and chest discomfort were relieved, and kidney function was recovered with decreased uPCR. We reduced the dose of prednisolone by changing from intravenous to per-oral administration on hospital day 8. Two days later, fever and diarrhea redeveloped, and deterioration of allograft function and chest infiltrate were reaggravated ( Figure 2 ). Following the rechallenge of methylprednisolone with increased dose and hydroxychloroquine, the symptoms were relieved, and kidney function was stabilized again ( A 56-year-old man was transferred from a local hospital with cough and sputum. He was diagnosed with ESRD due to type 2 diabetes Table 1 ). The day after admission, we discontinued MMF and maintained tacrolimus and prednisolone. On the same day, hydroxychloroquine (400 mg, qd) was administered ( Figure 1B) . On hospital day 9, his vital signs were stable, coughing was relieved, but the chest infiltrative lesion was slightly aggravated (Figure 3) and he was still positive for COVID-19 on RT-PCR assay. We added azithromycin (500 mg, qd) to hydroxychloroquine. 7 During in-hospital days, he often suffered from coughing; his peripheral oxygen saturation was maintained above 95% without oxygen supply. Finally, the respiratory symptoms were relieved and lung lesions F I G U R E 2 Changes in chest radiograph findings in Case 1. The admission date was represented as day 1 (D1). The infiltrative lesion was aggravated on D5. It started to improve from D14 and further improved on D28 were slightly improved on chest radiograph ( Figure 3 ); COVID-19 was not detected in RT-PCR assay in two consecutive times at hospital day 17 and 18. injury in 5%-15% cases and showed high mortality rate. 9,10 On the contrary, COVID-19 was associated with a high incidence of proteinuria. A recent report showed that 34% of patients showed albuminuria on admission date. 11 Likewise, both cases also showed significant proteinuria when they admitted to the hospital. In addition, with improving the clinical course, proteinuria was subsided. Unfortunately, there is no specific treatment guideline for COVID-19. Lopinavir is an agent used during SARS and MERS epidemics. Because COVID-19 shares 79.5% of sequence identity with SARS-coronavirus, 12 it has been suggested that the treatment strategy could be shared. 13 Also, several cases recovered from COVID-19 after using lopinavir. 14 suggest the efficacy of the treatment regimen, but lopinavir/ritonavir should be cautiously used in KT recipients with tacrolimus. On the basis of these few cases, it is necessary to provide baseline information of better outcomes by accumulating multiple new experiences. We would like to respect and appreciation to all medical staff around the world who are making a dedicated sacrifice against COVID- 19 . This study was approved by the institutional review board of Keimyung University Dongsan Hospital (IRB No. 2020-04-002). The study was conducted in accordance with the principles of the Declaration of Helsinki. 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 from the corresponding author upon reasonable request. Clinical features of patients infected with 2019 novel coronavirus in Wuhan Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention Transmission of 2019-nCoV infection from an asymptomatic contact in Germany Severe outcomes among patients with coronavirus disease 2019 (COVID-19) -United States US renal data system 2017 annual data report: epidemiology of kidney disease in the United States Common viral infections in kidney transplant recipients Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Immune system and kidney transplantation In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East Respiratory Syndrome (MERS) Coronavirus infection Acute renal impairment in coronavirus-associated severe acute respiratory syndrome Kidney disease is associated with in-hospital death of patients with COVID-19 A pneumonia outbreak associated with a new coronavirus of probable bat origin A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-a possible reference for coronavirus disease-19 treatment option Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment Potential antiviral therapeutics for 2019 novel coronavirus Drug treatment options for the 2019-new coronavirus (2019-nCoV) Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug-drug interaction Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis Tacrolimus and lopinavir/ ritonavir interaction in liver transplantation Two distinct cases with COVID-19 in kidney transplant recipients