key: cord-0828487-srl4tjpz authors: Matejak-Górska, Marta; Górska, Hanna; Zielonka, Michał; Durlik, Marek title: The course of Covid-19 infection in patients after pancreas and kidney transplantation – a single - centre observation date: 2022-03-16 journal: Transplant Proc DOI: 10.1016/j.transproceed.2022.02.043 sha: 5d90f5294187b5fa14c399f95ae4a8ab8b9ad4da doc_id: 828487 cord_uid: srl4tjpz Solid graft recipients are at an increased risk of serious complications and death. Out of 130 outpatient recipients of pancreas grafts at our Clinic, 20 (15.73%) had a confirmed SARS-CoV-2 infection. Each patient had a different course of the disease and the forms of infection varied from mild to severe and lethal. According to recommendations, after confirmation of the infection mycophenolate mofetil (MMF) was withdrawn and the immunosuppression was based on steroids and a calcineurin inhibitor. In this study, we performed an analysis of the course of Covid-19 infection in patients after pancreatic transplantation. 20 pancreas recipients were confirmed covid 19 infection. 4 required hospitalization due to severe complications. Patients reported weakness, excessive intensity fatigue, shortness of breath with exertion, cough, periodically increased temperature. Weakness and fatigue persisted in these patients for about 6 weeks. In 2 cases there was a need for oxygen supplementation and empirical antibiotic. Mortality was 5% and there was one graftectomy. In no other cases, deterioration of pancreas graft, as well as kidney graft, was observed. The course of SARS-CoV-2 infection in solid graft recipients is similar to the rest of the population. Because of immunosuppression, recipients are used to avoidance of the crowds and accustomed to mask obligation. during the pandemic between 20,000 and 22,000. At the beginning of the pandemic, the incidence was 10 times higher, but dialyzed patients were vaccinated against covid in almost 90%, hence a significant decrease in the incidence in this group of patients [2]. Due to the reduced immunity in dialysis patients and patients after organ transplantation, in Poland and other countries, it is recommended to perform booster vaccinations in this group of patients [3] [4] [5] . The recommendations of the Polish Transplant Society at the beginning of the SARS-CoV-2 pandemic resulted in a significant reduction in the number of organ transplants in Poland. The number of hospitals in which transplantations took place and the number of organ donors decreased. According to Poltransplant data [6], 4 pancreatic transplants were performed in 2020, and 20 transplants in 2021. Our center was transformed into a covid hospital that did not perform any pancreatic transplantation in the period from March 2020 to May 2021, meanwhile in previous years we have performed over 20 such procedures annually. The aim of this study was to describe the experience of our Clinic with pancreas graft recipients with confirmed COVID-19 infection and to evaluate the impact of the infection on graft function. A retrospective analysis of pancreas recipients with confirmed SarsCoV-2 infection was performed. We analyzed the time from transplant, age, sex and data regarding symptoms of the infection. We have described our surgical technique and comprehensive management before [7] [8] [9] [10] . We perform a longitudinal midline incision and anastomose pancreas arterial Y-graft and portal vein to the right iliac vessels of the donor. We create a double-layered hand-sewed side-to-side junction between duodenum and proximal jejunum. We transplant the kidney from the same median incision, into retroperitoneal space behind the left iliac vessels. We use a three-drug immunosuppression scheme with induction with polyclonal antibodies thymoglobulin -in a total dose of 1.5 mg / kg. According to recommendations, after confirmation of the covid-19 infection mycophenolate mofetil (MMF) was withdrawn and the immunosuppression based on steroids and a calcineurin inhibitor. During the SarsCov-2 infection, we did not change anticoagulant treatment in a group of patients with mild symptoms. After 3 months posttransplantation recipients have administrated 75 mg of acetylsalicylic acid daily. In a group of moderate or severe infection symptoms, low molecular weight heparin in a prophylactic dose was administrated. Our center transformed into a COVID hospital in March 2020. To maintain the recipients' observation, outpatient care during the pandemic was under telemedicine services and on-demand personally. Controls and laboratory examinations took place in an exceptionally created ambulatory only for patients on immunosuppression. The aim of the creation of the ambulatory area was to limit possible contact with SarsCov-2 positive patients. Since changes in restrictions, it was mandatory to perform a PCR test for SarsCov-2 infection and a chest HRCT in each solid graft donor. Also, recipients were obliged to have a PCR test and chest X-ray. Currently, after a series of vaccinations against Covid-19, the population of potential organ recipients is less vulnerable to infection, and we are slowly withdrawing from restrictions. In May 2021, at our Clinic, the program of pancreas transplantations was reactivated. Out of 130 recipients in the outpatient observation, 20 (15,3%) were diagnosed with SarsCov-2 infection. Table 1 Weakness and fatigue persisted in these patients for about 6 weeks. 20% of patients presented moderate symptoms of the infection. In one case the course of SarsCov 2 was serious. The overall mortality was 5% and there was one graftectomy. In no other cases, deterioration of pancreas graft, as well as kidney graft, was observed. 1 patient vaccinated before the SarsCov-2 infection required hospitalization due to severe diarrhea and need of intravascular fluid administration. In 2 cases there was a need for oxygen supplementation and empirical antibiotic. Cases of 3 other hospitalized patients are described below. Patient after SPK in 28/09/2017 qualified due to insulin-dependent diabetes and chronic renal disease, dialyzed for 18 months before the transplant. Table 2 summarizes the most important data regarding transplantation and treatment. In March 2021 was diagnosed with covid-19. The initial symptoms included weakness, fatigue, cough, headache, and muscle pain. No shortness of breath, decrease in saturation or fever were observed. Conservative treatment was carried in home isolation conditions. The drug modification included the withdrawal of mycophenolate mofetil (MMF). The maintains of the rest of the drugs, steroids, tacrolimus, and acetylsalicylic acid was prescribed. After 3 weeks, the PCR test was still positive. Because of increasing dyspnea the patient was referred to an infectious hospital and hospitalized for 7 days. The thoracic CT revealed bilateral scattered irregular areas of the frosted glass type, with a predominance of peripheral segments, locally with visible densities and thickening of interlobular septa (a symptom of paving stones), moderate lesions affecting 25-50% of the lungs [ Figure 1 ]. No deterioration of kidney or pancreas graft function was observed, Table 3 presents the results at the admission to the hospital. The patient was treated with low molecular weight heparin in a prophylactic dose, as well as empirically administrated ceftriaxone, amoxicillin with a beta-lactamase inhibitor. After improvement of the general condition, he was discharged home. In May and June, September 2021 patient was vaccinated with the mRNA (Moderna) vaccine and obtained the level of Ig> 2080 BUA / ml in the tests. Currently both grafts have a sufficient function (creatinine 1.36 mg / dl, eGfr> 60 ml / min / 1.73 m2). The patient is independent from insulin (HbA1 -5.7%). No further episodes of fatigue or shortness of breath were reported. Patient after PTA 30.01.2015, qualified due to insulin-dependent diabetes without renal complications. Table 4 shows transplantation details. In April 2021 a positive test for SarsCov-2 was detected. Initially, the patient manifested only mild symptoms. After 2 weeks she was hospitalized because of severe muscle pain, headaches, and dry cough. The patient required oxygen supplementation. Thoracic CT showed peripheral inflammatory lesions of matt glass and paving stones, taking up a total of about 8% of the lungs [ Figure 2 ]. During first days of hospitalization there was no grafts' function deterioration observed (creatinine 1.68 mg/dl, eGFR 46 ml/min, c-peptide 3.13 ng/ml, HbA1 -5.5%), but only leukopenia 2.38 1000/ul was found. The conservative treatment was modified according to our standard (MMF withdrawal and LMHW heparin in prophylactic dose). After 2 weeks she was discharged from the hospital with a recommendation to reduce steroid therapy within 2 weeks of discharge. After four months patients reported fatigue, abdominal pain, and hyperglycemia> 500 mg%. In abdominal CT scan -transplanted pancreas was enlarged, heterogeneous, with edema, arterial vascularization of the graft from the right iliac artery only in the initial segment, venous outflow only slightly visible in the proximal part [ Figure 3 ,4]. Conservative treatment consisted of insulin therapy, therapeutic dose of heparin, and empiric antibiotic therapy. Endoscopic examination showed mucosal necrosis of the graft's duodenum, mucosal surface without visible vessels. Patients wad qualified for graftectomy. In the histopathological examination of the specimen of the transplanted pancreas -atrophy and fibrosis of the graft, changes related to chronic rejection and damage as well as vascular thrombosis -hemorrhagic necrosis. After the graft was removed, the patient's condition improved and was discharged home. On discharge, the level of IgG was checked -791.0 BAU / ml, IgM 51.8 [index]. Patient after SPK 29.12.2017, qualified due to insulin-dependent diabetes, with chronic renal disease, dialyzed for 32 months (peritoneal dialysis). Table 5 shows transplantation details. In December 2020 a positive test for SarsCov-2 was detected. The patient required referral to the local infectious hospital due to fever and severe diarrhea. Two weeks later the general condition worsened, and she was referred to our Clinic, the 3rd level hospital for Covid treatment. The patient required mask with a reservoir with oxygen flow 15l / min. In CT -HRCT of the chest, extensive consolidation and frosted glass changes, covering 75-80% of lung volume was found [Figure5 ] . Clostridium difficille was detected in stool and per os vancomycin was administrated. Empiric intravenous antibiotic therapy included piperacillin/tazobactam with antifungal per os drugs (voriconazole). Increasing dyspnea and hypotension were observed. The patient developed multiorgan failure and required catecholamines as well as mechanical treatment. Increasing acidosis was an indication to start CRRT (continuous renal replacement therapy). The patients died 4 weeks after initial PCR because of SARS-CoV-2 complications. Since the start of the covid-19 pandemic, the number of reported organ donors and the number of organ transplants significantly decreased [11] . The most important reasons might have been limited access to the hospital resources and a limited number of pancreas donor procurement, surge conditions of the pandemic with a shortage of facilities, changes in the availability of transplant centers due to transformation into infectious centers, as well as deficiency of stuff [12, 13] . Another important factor might have been SarsCov-2 infection among patients on the waiting list. Santos reported that 4,6% of kidney-pancreas waiting-list patients were diagnosed with covid-19. SPK is safe and feasible in covid-19 convalescences [14] . In our clinic, the recipient there was no case of disqualification due to infection. Patients infected with the SarsCov-2 virus were taken of the waiting list for a period of approximately 3 months. In 2021, we performed 2 simultaneous pancreas and kidney transplants in patients who recovered from covid-19 infection, 6 and 7 months before the transplant, respectively. The early results of organ transplantation in these cases are very good. We also described previously SarsCov-2 infection in a kidney recipient [15] . In a Spanish observation pancreas recipients diagnosed with SarsCov-2 infection were just 1% of cases (8 cases out of 778 solid graft recipients registered). The cumulative risk of SarsCov-2 infection among pancreas graft recipients was 5.5/1,000 for the pancreas, same as the risk in the Spanish population [16] . 2 patients required ICU (intensive care unit) stay, 4 were ventilated mechanically and one patient develop multiorgan failure [16] . Dube et all. described 4 cases of pancreas recipients diagnosed with SarsCov-2. 1 patient from the observation died [17] . 50% of cases reported diarrhea as one of the major symptoms of the disease. Also, in our observation, it was one of the most frequent complaints and in 2 cases led to hypovolemia, hospital referral and need of intravenous fluid administration. The reason for the increased incidence of diarrhea is unclear. The course of covid-19 might be serious. Yi reported the use of anakinra in a severe case and respiratory failure [18] . Heron described the successful use of mTOR inhibitors as an alternative to immunosuppression that could change the course of COVID-19 due to their antiviral features [19] . In one case we observed late pancreas venous graft thrombosis (PVGT). The occurrence of PVGTvaries from 10%-20% of cases [20, 21] and is the most frequent indication for graftectomy [20] . Incidence of PVGT is increased by technical issues eg. harvesting method, preservation, cold ischemia time (CIT), donor and recipient characteristics, inflammatory factors, or coagulopathy and prophylactic anticoagulant administration [22, 23] . In our cohort, the incidence of graft failure due to PVGT in association with COVID-19 was 20%. More observations need to be done to verify if COVID-19 increases the risk of PVGT, however, there is data suggesting that COVID-19 patients are predisposed to PVGT [24, 25] . A case of renal allograft late infarction in a 46-year-old COVID-19 positive recipient 13 years after kidneypancreas transplant was reported [26] . The incidence of COVID-19 infection among pancreas recipients is similar to the general population, however, immunosuppression and history of dialysis might increase the risk of death and serious complications. In our study, we did not observe an increased graft loss associated with SARS-CoV-2, but in the general population the infection is related with thrombotic complications. There is a need for a multicenter analysis of solid graft recipients and the creation of guidelines regarding referral to hospital, immunosuppression modifications, and anticoagulants. The thoracic CT revealed a bilateral scattered irregular areas of the frosted glass type, with a predominance of peripheral segments, locally with visible densities and thickening of interlobular septa (symptom of paving stones), moderate lesions affecting 25-50% of the lungs In CT -HRCT of the chest, extensive consolidation and frosted glass changes, covering 75-80% of lung volume was found Table 1 Clinical data of pancreas recipients after SARS-CoV-2 infection Table 2 Case 6, male patient aged 51. History of transplantation Table 3 Case 6, male patient aged 51. Laboratory results on discharge Table 4 Case 17, female patient aged 39. 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