key: cord-263365-ymnbktm5 authors: Dube, Geoffrey K.; Husain, S. Ali; McCune, Kasi R.; Sandoval, P. Rodrigo; Ratner, Lloyd E.; Cohen, David J. title: COVID‐19 infection in pancreas transplant recipients date: 2020-06-09 journal: Transpl Infect Dis DOI: 10.1111/tid.13359 sha: doc_id: 263365 cord_uid: ymnbktm5 Coronavirus Disease 2019 (COVID‐19) has become a pandemic since first being described in January 2020. Clinical manifestations in non‐transplant patients range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome, multiorgan system failure and death. Limited reports in kidney transplant recipients suggest similar characteristics in that population. We report here the first case series of COVID‐19 infection occurring in pancreas transplant recipients. SARS-CoV-2, a novel coronavirus first reported in December 2019, rapidly developed into a global pandemic, with more than 1.8 million cases and 100,000 deaths reported worldwide. 1 Clinical manifestations of COVID-19, the disease caused by SARS-CoV-2, range from asymptomatic infection to mild upper respiratory tract symptoms or viral pneumonia. The most severe cases of COVID-19 can lead to respiratory failure, multiorgan system failure and death. 2, 3 Mortality rates between 2-3% have been reported in the general population. 4 Death is more common in those with preexisting conditions, including hypertension, diabetes and cardiovascular disease. 4 Due to chronic immunosuppression, transplant recipients are at increased risk both of acquiring infections and developing more severe clinical disease. Additionally, there is a high burden of comorbid disease in the transplant population. Several case reports and single-center series have described COVID-19 in transplant patients, with most series describing kidney transplant patients who were sick enough to require hospitalization. [5] [6] [7] [8] [9] To date, there have been no reports of COVID-19 in pancreas transplant (PT) recipients. We report here our experience with COVID-19 disease in four PT recipients in New York, the epicenter of the outbreak in the United States. Four simultaneous pancreas-kidney (SPK) transplant recipients, representing 4.3% of all patients with functioning PT followed by our program, were diagnosed with COVID-19 disease between March 22, 2020, and April 11, 2020. Three patients tested positive by nasopharyngeal swab for SARS-C0V-2 after presenting to the hospital for evaluation. The fourth patient received a clinical diagnosis of COVID-19 based on symptoms; due to a critical shortage of testing supplies during the epidemic, outpatient confirmatory testing was not able to be offered. Cases are described below and summarized in table 1; case 4 was also included in a large multi-center cohort that was previously reported but did not include patient level data. 9 This study was approved by the Columbia University Medical Center Institutional Review Board. Case 1: This article is protected by copyright. All rights reserved A 53 year-old man end-stage renal disease (ESRD) secondary to type 1 diabetes presented to an outside hospital for evaluation 107 months after receiving his second SPK. His immunosuppression regimen was tacrolimus monotherapy. Presenting symptoms included fever and cough. Creatinine on presentation was 0.9 mg/dl; other lab results are not available. He tested positive for SARS-C0V-2. Due to normal oxygen saturation, he was discharged home with outpatient monitoring. His tacrolimus was held for two days, and he was prescribed azithromycin. He did not develop dyspnea at home, and his symptoms gradually resolved over 18 days. He monitored his fingerstick glucose intermittently at home and never developed hyperglycemia. Five weeks after initial symptom resolution, he remains asymptomatic with normal fingersticks. Outpatient labs have not been rechecked due to his desire to avoid health care settings. A 40 year-old man with ESRD secondary to type 1 diabetes presented for telehealth evaluation 20 months after receiving an SPK. His immunosuppression regimen was tacrolimus and mycophenolate. Post-transplant course was notable for uncontrolled hypertension, for which he had undergone angioplasty of the transplant renal artery three weeks earlier, during the first week of the COVID-19 outbreak in New York. Presenting symptoms included fever, headache, anosmia, chest pain, diarrhea and myalgias. A clinical diagnosis of COVID-19 disease was made. Due to the absence of respiratory symptoms he was not referred to the emergency department and did not receive confirmatory testing for SARS-C0V-2 infection. Mycophenolate was discontinued and he was monitored at home with daily telehealth check-ins. Outpatient labs were not checked during this period. His fevers persisted at home for 15 days before his symptoms resolved completely. He did not monitor his fingerstick glucose during his illness but reported no symptoms of hyperglycemia. His mycophenolate was resumed five days after symptom resolution. Five weeks later, he remains asymptomatic, with normal glucose readings. His creatinine is 1.24 and lipase 42 U/L. A 60 year-old woman with ESRD secondary to type 1 diabetes, presented for telehealth evaluation 8 months after receiving an SPK. Her immunosuppression regimen was tacrolimus and mycophenolate. Presenting symptoms included fever, cough, dyspnea, headache, anosmia and diarrhea. Her mycophenolate was discontinued and she was monitored at home with frequent check-ins. Glucose readings over the next 10 days were 120-130, similar to her baseline. Due to worsening dyspnea and the development of hypoxia 10 days after symptom onset, she was referred to her local hospital. Her room air oxygen saturation was 89% Accepted Article and she was started on supplemental oxygen. She tested positive for SARS-C0V-2. Admission labs were notable for white blood cells 1.3x10 3 , absolute lymphocyte count 200, creatinine 0.96 mg/dl, and random glucose 118 mg/dl; pancreas enzymes were not checked. Other values are shown in table 1. Chest x-ray showed bilateral infiltrates. She was treated with hydroxychloroquine, azithromycin and methylprednisolone. Glucose while on methylprednisolone ranged from 71-206. She had hypoxic respiratory failure 22 days after symptom onset and died 3 days later. Creatinine was 0.6 prior to the respiratory arrest. A 36 year-old woman with ESRD secondary to type 2 diabetes, presented to our hospital three months after receiving an SPK. Her immunosuppression regimen was tacrolimus and mycophenolate. Presenting symptoms included fever, cough and myalgias. She tested positive for SARS-C0V-2. Admission labs were notable for white blood cells 6.24x10 3 , absolute lymphocyte count 310, creatinine 1.9 mg/dl, random glucose 114 mg/dl, and lipase 351 U/L. Other values are shown in table 1. Chest x-ray showed bilateral hazy opacities in the lower lung fields. Her room air oxygen saturation was 94-100%, and she did not require supplemental oxygen during her 7-day hospital stay. Her fevers resolved after 1 week and her cough was slowly resolving after 2 weeks. During her admission, her creatinine ranged from 1.9-2.2 mg/dl, her glucose ranged from 71-114 mg/dl, and her lipase ranged from 248-351 I/L. She was restarted on mycophenolate 1 week after her last fever. Five weeks later, she remains asymptomatic, with fingersticks 95-110, creatinine 1.34, lipase 211 U/L and hemoglobin A1c 5.3%. We present here the first four cases of COVID-19 disease reported in PT recipients, with one case being a presumptive diagnosis based on suggestive symptoms and known nosocomial exposure in the absence of confirmatory PCR testing for SARS-CoV-2. Our cases show several notable findings and raise several key management questions. First, the main presenting symptoms in our PT recipients (fever in 100%, cough in 75%) were similar to what is reported in the non-transplant population. 2,3 Diarrhea is reported in <5% of nontransplant patients, but was found in 2 of our patients, including one without respiratory symptoms. Diarrhea may be more commonly reported in transplant patients with COVID-19 than in the general population. 9 Whether this finding is due to the concurrent use of transplant medications known to cause diarrhea or other Accepted Article factors is unclear. Second, similar to the non-transplant population, PT recipients presented with a spectrum of disease severity ranging from mild illness managed at home to more severe disease requiring hospitalization and need for supplemental oxygen. 4 Three of our 4 patients had mild-moderate disease, characterized by no pneumonia or mild pneumonia, which is similar to the 74% rate of mild-moderate disease reported in solid organ transplant recipients and the 80% rate of mild disease reported in the non-transplant population. 4,9 One patient initially had mild disease but developed respiratory failure 10 days after initial symptom onset and expired. This symptom progression is similar to the biphasic disease course described in non-transplant patients, in whom worsening respiratory status can develop around 7-10 days after symptom onset. 10, 11 Third, in patients for whom glucose levels were available there was no change in glycemic control compared with their premorbid glucose control. Finally, the duration of symptoms in the 3 cases that have resolved was 14-18 days. The clinical deterioration of patient 3 after 10 days highlights the importance of close monitoring of suspected or confirmed COVID-19 in PT recipients followed in the outpatient setting until complete symptom resolution. As the pandemic worsened in New York, most patients without dyspnea or hypoxia were not admitted due to the surge in hospitalized patients. Ambulatory clinics were reduced due to staff redeployment and transition to telemedicine to support social distancing policies, making follow-up challenging. We managed our outpatient COVID-19 PT recipients with frequent check-ins to discuss symptom progression and review vital signs, including pulse oximetry when available. Patients with worsening dyspnea or hypoxia were referred to the emergency department for in-patient management. In all 3 of our PT patients who have recovered from COVID-19 infection, symptoms lasted for at least 2 weeks. Despite persistence of symptoms, none of these patients experienced worsening respiratory status. Transplant providers caring for PT recipients with COVID-19 should be aware that a prolonged disease course in these patients does not imply that a clinical deterioration is inevitable. Due to uncertainty regarding the duration of viral shedding and infectivity in recovered transplant patients, to avoid exposing COVID negative patients and staff in our transplant center to the virus we have limited follow-up for our COVID-19 PT recipients to either video visits or in-person visits scheduled for hours that our transplant center has dedicated specifically to follow-up for COVID-19 patients. Unfortunately, due to limited availability of testing, This article is protected by copyright. All rights reserved we were unable to perform serial SARS-CoV2 RNA tests to document time to resolution of viral shedding. We have reached out to the 3 surviving patient to arrange for testing for the development of anti-SARS-CoV-2 antibodies. Immunosuppression is usually decreased in the setting of other systemic infections, typically with dose reduction or elimination of the antimetabolite. When our patients informed us of symptoms consistent with COVID-19 infection, we held mycophenolate in 3 of our patients and temporarily held tacrolimus in 1 patient on monotherapy, a strategy similar to that employed in other solid organ transplant recipients at our center. The effect of commonly used antirejection medications on SARS-CoV-2 is unknown, although both tacrolimus and mycophenolate have been shown to inhibit the growth of other coronaviruses. 12, 13 Mycophenolate, in combination with interferon-ß, was shown to limit viral replication in vivo but was associated with higher levels of viral shedding in vivo. 14, 15 It is unknown whether reduction of immunosuppression at disease onset will affect the likelihood of developing cytokine storm syndrome nor is it known when it is safe to reintroduce immunosuppression in patients who recover from COVID-19 infection. We restarted mycophenolate in 2 patients 5-7 days after resolution of fevers, without any recurrence of symptoms over the next 5 weeks. At the time these cases were diagnosed, there were limited data on the efficacy of various antivral therapies against SARS-CoV-2, including hydroxychloroquine and azithromycin, both of which had been used as adjunctive therapy in COVID-19 infection. 12 Three of our patients with treated with hydroxychloroquine and/or azithromycin. Two of these patients were treated at hospitals away from our center, and decisions as to whether and which adjunctive agent to use were made based on institution-specific protocols in place at the time of presentation. Subsequent studies have suggested an absence of benefits of these adjunctive agents against SARS-CoV-2, and we have stopped using these agents in our PT and other solid organ transplant recipients. 9, 16 Whether there is a role for other potential therapies, such as remdesivir or convalescent plasma, in the treatment of SARS-CoV-2, remains unknown. Ongoing studies of these therapies are being conducted at our hospital, and we have enrolled solid organ transplant recipients when eligible. This article is protected by copyright. All rights reserved ACE2, the receptor which SARS-CoV-2 uses to enter cells, is expressed in the small intestine, pancreas and kidney, and autopsies from non-transplant patients with SARS-CoV-2 have found virus particles in the kidney. [17] [18] [19] It is not known whether the virus may also be found in the donor duodenum or pancreas of PT recipients. Although glucose and lab monitoring were not uniform in our patients, we did not observe any The authors declare that that have no financial conflicts of interest to disclose. COVID-19) Situation Report -85 Clinical Characteristics of Coronavirus Disease 2019 in China. 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A first step in understanding SARS pathogenesis Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China ACE2 Expression in Pancreas May Cause Pancreatic Damage After SARS-CoV-2 Infection MD: Made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, and was involved in drafting and revising the manuscript Made substantial contributions to analysis and interpretation of data and was involved in drafting and revising the manuscript MD: Made substantial contributions to analysis and interpretation of data and was involved in drafting and revising the manuscript MD: Made substantial contributions to analysis and interpretation of data and was involved in drafting and revising the manuscript Made substantial contributions to analysis and interpretation of data and was involved in drafting and revising the manuscript MD: Made substantial contributions to analysis and interpretation of data and was This article is protected by copyright. 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