key: cord-0968672-gh0jqft2 authors: Ballout, Jad A.; Ahmed, Taha; Kolodziej, Andrew R. title: COVID19 and Heart Transplant: A Case Series and Review of the Literature date: 2021-02-25 journal: Transplant Proc DOI: 10.1016/j.transproceed.2021.02.015 sha: 0874598602a896fade169dba8595ca85bf24e24f doc_id: 968672 cord_uid: gh0jqft2 COVID19 has resulted in many challenges in patient care especially high-risk populations such as heart transplant patients. Patients with heart transplant experience a significantly higher mortality rate with COVID19 infection, and management is based on extrapolation from clinical trials done on non-transplant patients, and from clinical experience. Here we report four cases of heart transplant patients who presented in late 2020 with COVID19 infection. Patients presented with symptoms similar to those seen in the general population. All four patients were admitted to the hospital, and they were all treated with dexamethasone. In addition, two patients received remdesivir. Immunosuppressive medications were adjusted to maintain adequate levels of immunosuppression, but at the same time allowing for an adequate immune response against the infection. All patients were discharged alive from the hospital. We then performed a literature review on studies that included heart transplant patients who developed the infection, and suggest a standardized management approach accordingly. The COVID19 pandemic started in December 2019, and has so far affected more than 20 million people, and claimed the lives of more than 750000 worldwide. [1] As such it became inevitable that high-risk populations, such as heart transplant recipients, will be infected. Thus far there have been several case reports and case series on outcomes and management of heart transplant recipients with COVID19. Here we add to the growing body of knowledge with a case series on four heart transplant recipients who developed COVID19. Patient demographics, presentation, and management are summarized in tables 1, 2, and 3 respectively. Sixty-two-year-old male with history of ischemic cardiomyopathy and end-stage renal disease who received a combined heart and kidney transplant in 2016. He is maintained on tacrolimus, and mycophenolate sodium. Other medical problems include history of stroke, coronary artery disease, hypertension, and type II diabetes. He presented to an outside hospital in 7/2020, with generalized weakness, shortness of breath, productive cough, and diarrhea. He was found to have an acute kidney injury with a serum creatinine of 6.22 mg/dL from a baseline of 1.9 mg/dL. On arrival to our facility, his blood oxygen saturation was 100% on room air. SARS-CoV-2 PCR was positive. Tacrolimus level was supratherapeutic, and other labs showed leukopenia with lymphopenia, as well as elevated LDH, D-dimer, and ferritin. Chest Xray showed clear lung fields. He was seen by infectious disease and nephrology and started on dexamethasone 8 mg IV daily empirically for concerns for kidney rejection, and as part of treatment for COVID19. Tacrolimus and mycophenolate were both held, and subsequently tacrolimus was restarted once the level dropped to 6.8 ng/mL. The patient's renal function recovered, and he was discharged on tacrolimus, but off mycophenolate (restarted 2 weeks later during heart failure clinic follow up). Sixty-two-year-old male with history of ischemic cardiomyopathy and coronary artery bypass who received an orthotopic heart transplant (OHT) in 3/2020. Immunosuppression is maintained with cyclosporine, mycophenolate mofetil, and prednisone. His other medical problems include history of coronary artery disease, type II diabetes, and hypertension. He presented in 8/2020 with a 3-week history of decreased oral intake, nausea, and vomiting, and a few-day history of shortness of breath, and non-productive cough. SARS-CoV-2 PCR assay was positive on presentation. Labs showed leukopenia with lymphopenia, and elevated LDH, D-dimer, CRP, and ferritin. His chest Xray was clear, but he required 2 L of supplemental oxygen by nasal cannula. He was continued on cyclosporine, but mycophenolate was held. He was started on Remdesivir 200 mg intravenously once daily for a total of 10 days, and dexamethasone 6 mg intravenously once daily for a total of 10 days. His hospital course was uncomplicated, and he was weaned off supplemental oxygen. His first negative SARS-CoV-2 PCR test was 24 days from presentation. He was restarted on mycophenolate and prednisone once he completed the Remdesivir and dexamethasone courses. He was subsequently discharged to a rehab facility following a 35-day hospitalization. Sixty-five-year-old male with history of ischemic cardiomyopathy and history of HeartMate II LVAD, who received an OHT in 8/2017, and maintained on tacrolimus, and mycophenolate mofetil for immunosuppression. His other medical problems include history of coronary artery disease, and hypertension. He presented to an outside hospital in mid 9/2020 with cough, fever, chills, and shortness of breath. His SARS-CoV-2 PCR test was positive, and he was started on remdesivir, and dexamethasone. He was transferred to our hospital a few days later for increasing oxygen requirements. He was initially admitted to the medical ICU given that he needed supplemental oxygen by high-flow nasal cannula. Remdesivir and dexamethasone were continued. Labs on presentation showed leukocytosis with lymphopenia, and elevated LDH, ferritin, and D-dimer. His tacrolimus level was 27.2 ng/mL and so tacrolimus was held, as well as mycophenolate in the setting of lymphopenia. Chest X-ray showed bilateral airspace opacities. His hospital course was uncomplicated, and he was weaned off supplemental oxygen. Inflammatory markers improved, and tacrolimus was restarted once the blood tacrolimus level went back down to 8 ng/mL. He completed a 10-day course of remdesivir and a 10-day course of dexamethasone (total course of 10 days for each medicine that were started at the outside hospital prior to his transfer), and was discharged home, with plans to restart mycophenolate as an outpatient. Sixty-two-year-old male with history of ischemic cardiomyopathy who received OHT in 3/2020 and is maintained on mycophenolate mofetil, prednisone, and tacrolimus. His other medical problems include history of coronary artery disease, chronic kidney disease, COPD, hypertension, and type II diabetes. He developed myalgias, nasal congestion, anosmia, dysgeusia, cough, shortness of breath, and diarrhea and SARS-CoV-2 PCR was positive. He was initially managed as an outpatient and most of his symptoms improved over 2-3 weeks, however he developed worsening shortness of breath and was therefore admitted to the hospital in mid 9/2020. On presentation he was mildly hypoxic requiring supplemental oxygen at 2 L/min via nasal cannula. His SARS-CoV-2 PCR assay was positive, and labs showed leukopenia with lymphopenia, and elevated LDH, D-dimer, CRP, and ferritin. Chest computed tomography showed bilateral ground glass opacities. Mycophenolate and prednisone were held, tacrolimus was continued, and the patient was started on dexamethasone 6 mg orally daily. With clinical and inflammatory marker improvement, he was weaned off supplemental oxygen. He was subsequently discharged home after a total of 5 days to complete a 10-day course of dexamethasone, with instructions to restart prednisone following completion. Tacrolimus was continued on discharge, but mycophenolate continued to be held to be readdressed during follow up in transplant clinic. Management of patients with COVID19 is challenging, and is more so in patients with OHT where randomized trials are lacking. Several considerations come into play when managing patients with heart transplant and COVID19, including immunosuppressive medication management, as well as extrapolating results from clinical trials for COVID19 directed therapies. Just like the general population, the clinical presentation of OHT patients with COVID19 is variable ranging from asymptomatic symptomatic, to fulminant respiratory failure and death. Symptoms are also similar to the general population including fever, cough, shortness of breath, and less commonly gastrointestinal. [2] [3] [4] However, it does seem that mortality rates in this subset of patients far exceed that in the general population based on some case series and is in the range of 25% -33%. [2] [3] [4] It is unclear whether this increased mortality is related to the immunosuppressed state of patients, or to the fact that these patients are more likely to be older, with more comorbidities, and with more severe infection. In our cohort, management of immunosuppressive medications was similar in all 4 patients. Given that lymphopenia is associated with worse outcomes in patients with COVID19, [5] mycophenolate was held, especially since all patients had lymphopenia on admission labs. Calcineurin inhibitors, similar to previously referenced studies, were continued in our patients, unless trough levels were supratherapeutic, at which point the medications were held until levels were back to the appropriate therapeutic range. This strategy allows for maintaining an appropriate level of immunosuppression while avoiding side effects and end-organ dysfunction. Finally, prednisone was continued at the same home dose, unless there was an indication for treatment with dexamethasone for COVID19, then prednisone was held and restarted after the dexamethasone course was completed. Beyond management of immunosuppression, targeted therapy for COVID19 in our patients, was based on extrapolation from drug trials. In accordance with the "RECOVERY" trial showing reduced 28-day mortality with dexamethasone administration to hospitalized patients with COVID19, [6] all our patients were treated with oral/intravenous dexamethasone. In addition, 2 patients received remdesivir 200 mg daily. This is based mostly on the ACTT-1 trial, which included mostly patients with severe COVID19 disease, and showed decreased duration to recovery with remdesivir compared to placebo. [7] And therefore, in the setting of these results, as well as its relative safety and tolerability, [8] remdesivir should be considered when treating patients with heart transplant and moderate to severe COVID19 infection. None of our patients received hydroxychloroquine given the lack of efficacy of this medication, [9] and none were treated with tocilizumab since none were felt to be ill enough to warrant such treatment, especially in the absence of strong evidence to support treatment with tocilizumab at this time. [10, 11] Moreover, none of the patients were treated with convalescent plasma as the evidence to support the efficacy and safety of this treatment is variable based on clinical trials and systematic reviews. [12] [13] [14] Although convalescent plasma could be considered as a treatment option in patients with very severe or life-threatening disease, the available evidence does not justify its use in patients with mild-moderate disease like that seen in our patients. In November 2020, the FDA issued an emergency use authorization (EUA) for a number of synthetic neutralizing monoclonal antibodies, including Bamlanivimab, directed against viral spike proteins in order to neutralize the virus. This is administered to non-hospitalized patients with mild to moderate COVID19 infection, based on early clinical data of these antibodies. [15, 16] This EUA included immunocompromised patients or patients on immunosuppressive medications. Early trial data has shown that these antibodies reduce viral load and potentially can decrease the risk of an emergency department visit or hospitalization. [17] [18] [19] The four patients in our case series did not receive this regimen as they had presented prior to approval of these antibodies and thus they were not a part of our protocol but currently our institution provides this approach as per recommendations. Finally, OHT status adds another level of complexity, namely patients presenting with possible myocarditis with elevated cardiac biomarkers, ECG changes, and possibly graft dysfunction. Evaluation for rejection can potentially be delayed given restrictions for endomyocardial biopsy. Based on the above discussion, available trial data, experience with immunosuppressive regimen, and a previously developed algorithm for management of COVID19 in OHT patients, [20] we suggest a treatment strategy that is summarized in figure 1. Patients with OHT and COVID19 infection have similar presentation compared to the general population with COVID19 with a higher mortality rate. Management of immunosuppression should be aimed at improving host immune defenses against the infection, while preventing acute graft rejection. There is no treatment data specific for OHT patients and thus management is extrapolated from the general population. 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