key: cord-0763062-khjyi4p8 authors: Duran, Jason M.; Barat, Masihullah; Lin, Andrew Y.; King, Kevin R.; Greenberg, Barry; Adler, Eric D.; Aslam, Saima title: Low mortality in SARS‐CoV‐2 infected heart transplant recipients at a single center date: 2021-07-28 journal: Clin Transplant DOI: 10.1111/ctr.14443 sha: b593e3db1aab716c5ffc089f8657537131789496 doc_id: 763062 cord_uid: khjyi4p8 Immunosuppressed heart transplant (HT) recipients are thought to be at higher risk of infection and mortality from SARS‐CoV‐2 infection coronavirus disease 2019 (COVID‐19), however evidence guiding management of HT patients are limited. Retrospective search of electronic health records from February 2020 – February 2021, identified 28 HT recipients out of 400 followed by UC San Diego who tested positive for SARS‐CoV‐2. Patient demographics, COVID‐19 directed therapies, hospital course and outcomes were compared to control HT recipients who tested negative for SARS‐CoV‐2 during the same period (n = 80). Among 28 HT recipients who tested positive for SARS‐CoV‐2, 15 were admitted to the hospital and 13 were monitored closely as outpatients. Among inpatients, five developed severe illness and two died (7% mortality). Nine patients were treated with remdesivir, and four received dexamethasone and remdesivir. Two outpatients received neutralizing monoclonal antibody therapy and one outpatient received dexamethasone for persistent dyspnea. Immunosuppressed HT recipients, especially Hispanic patients and patients with higher body mass index, were at greater risk of infection and mortality from COVID‐19 than the general population. Use of remdesivir and dexamethasone may have improved outcomes in our HT recipients compared to HT recipients at other centers. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. age was 57 years old (Table 1-2) . Most (24, 86%) had HT only, while 4 patients were dualorgan transplant recipients. Most patients (93%) were taking a calcineurin inhibitor in combination with at least one other immunosuppressant when they tested positive for SARS-CoV-2 (Supplemental Table S -1). The majority (21, 75%) of HT recipients who tested positive for SARS-CoV-2 were Hispanic (Table 2) . When compared to control patients transplanted at UCSD in the past year who were not infected with SARS-CoV-2 (n=80), patients who tested positive had significantly higher body mass index (BMI) and there were significantly more Hispanic patients and significantly fewer white patients than controls (Table 2) . Five patients (18%) had a prior history of either cellular mediated rejection (CMR), antibody mediated rejection (AMR) or both that required escalation of immunosuppression (Table 2 ). For 4/5 patients with history of rejection, the episode of rejection and treatment with burst and taper of immunosuppression occurred more than 1 year prior to COVID-19 diagnosis. The fifth patient had AMR2 without graft dysfunction and had completed treatment with steroid burst/taper 8 months prior to his COVID-19 diagnosis. Seven patients in the study (25%) had history of coronary allograft vasculopathy (CAV) detected on routine surveillance angiography after transplant ( Table 2) . While there was an observed trend toward higher rates of CMR and CAV in the COVID-19 infected HT recipients, the proportion of patients with COVID-19 and rejection were not significantly different compared to the control group (Table 2) . Although we noted evidence of elevated inflammatory markers in HT recipients admitted with COVID-19 infection, including C-reactive protein (CRP), high sensitivity-CRP (hsCRP) and D-dimer (Table 4 ), all patients who experienced prior episodes of rejection had completed their burst and taper of immunosuppression at least 8 months prior to COVID-19 diagnosis and thus their rejection was not clearly temporally associated with their infection. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. Among 28 cases of COVID-19, 15 (54%) were admitted to the hospital for closer monitoring (Table 3 , Figure 1 ). The most common presenting symptoms were cough (36%), fevers (25%), gastrointestinal symptoms (25%), shortness of breath (21%), loss of taste/smell (21%) and myalgias (7%), which is similar to the presenting symptoms reported in other studies on HT recipients [1] [2] [3] [7] [8] [9] [10] [11] [15] [16] [17] and in the general population. 12, 13 Atypical symptoms were also quite common (reported in 46% of patients) and included chills, generalized pain and weakness, dizziness, sore throat, altered mental status, chest pain, headache, diffuse tingling and rhinorrhea. Among 15 inpatients, the median length of stay was 6 days (IQR 2-14 days), 7/15 (47%) were symptomatic without requiring oxygen and 3/15 (20%) required oxygen by nasal cannula. Five patients became critically ill and were upgraded to the ICU (Figure 1 ), among which 3 required intubation, mechanical ventilation, paralytics, proning and pressor support ( Table 3) . None of the patients required inotropes, renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO). Two of the 3 mechanically ventilated patients ultimately died in the ICU despite the above measures. Both patients who expired had initially presented to outside hospitals and were subsequently transferred after respiratory failure and intubation, but only Patient #1 had significant delay from onset of symptoms to receipt of COVID-19 directed therapies (he was given remdesivir + dexamethasone 5 days after intubation on arrival to UCSD). The second transfer, Patient #2, did receive a dose of steroids, remdesivir and convalescent plasma at the outside hospital. None of the other patients died during the study or follow up period ( Figure 1 ). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. All 15 inpatients underwent serum laboratory assessment of inflammatory and cardiac biomarkers (Table 4) . Patients did not have significant elevation of cardiac biomarkers but we noted elevated C-reactive protein (CRP), high sensitivity CRP (hsCRP), and D-dimer. Most inpatients (9/15) had evidence of acute kidney injury, with a significant increase in their median peak serum creatinine compared to their baseline outpatient creatinine from prior to admission (1.4 (1.1-2.1) v. 1.1 (1.0-1.5) mg/dL; p=0.0009). There were no differences in total white blood cell counts, absolute lymphocytes, absolute neutrophils or neutrophil/lymphocyte ratio ( Table 5 ) between patients infected with COVID-19 (n=28) or control HT recipients without COVID-19 (n=80). All patients in our study had recent documentation of normal cardiac function within 1 year of COVID-19 diagnosis. Seven inpatients (47%) had repeat echocardiogram during index hospital admission due to hemodynamic instability and/or concern for graft dysfunction. None demonstrated any change in left ventricle (LV) size or function; and no patient developed new RV dysfunction or pulmonary hypertension. Among the 15 inpatients, those who had oxygen saturation < 94% or abnormalities on chest imaging concerning for pneumonia received remdesivir (n=9). In all cases, patients received a 200 mg intravenous (IV) loading dose followed by 100 mg IV once daily x 4 more doses (total of 5 doses) per the ACTT-1 clinical trial protocol (Table 1) . Three patients had continued symptoms despite this treatment with ongoing hypoxia, or worsening of pneumonia following 5 doses of remdesivir, and an additional 5 days of 100 mg IV daily were given to these patients (for a total of 10 doses). Because many of these patients were admitted and treated prior to publication of the results of the RECOVERY Trial, only 4/9 patients who received remdesivir also received therapy with dexamethasone. Of note, both This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. patients in the study who expired received 10 days of remdesivir and dexamethasone and were intubated, paralyzed and proned. The first patient had only 1 day of symptoms prior to arrival at the outside hospital ( Figure 1 ; Patient #1). The second patient ( Figure 1 ; Patient #2) had 4 days of symptoms prior to arrival at the outside hospital where he was given a dose of convalescent plasma, remdesivir and dexamethasone prior to transfer to UCSD. Ten admitted patients had the antimetabolite either held or reduced (typically the mycophenolate mofetil (MMF) or sirolimus was held) and the calcineurin inhibitor was continued with doses adjusted using daily serum trough levels. Seven patients were treated with antibiotics during the course of their hospitalization. Five patients received empiric antibiotics that were discontinued after cultures resulted negative, and two patients had positive cultures and received full course of antibiotics (both critically ill patients who later expired developed ventilator associated bacterial pneumonia and urinary tract infection). No patient at our center received hydroxychloroquine, azithromycin, tocilizumab, or antiviral therapy other than remdesivir (Table 1 ). All patients received prophylactic anticoagulation per hospital protocol to prevent venous thrombosis, but no patient received empiric therapeutic anticoagulation to prevent COVID-19 related blood clots as has been reported in other studies (Table 1) . 1, 3, 11 Two outpatients with mild disease received casirivimab and imdevimab (REGN-CoV-2) neutralizing antibody treatment within first 5 days of symptom onset without complications. Of note: this therapy received emergency use authorization in November 2020, which is why only 2 patients in our study received this drug. A third outpatient, who was not admitted due to local pandemic surge conditions and lack of hospital beds, had ongoing dyspnea two weeks into illness which resolved with an outpatient course of dexamethasone. These three patients did not require admission during the follow up period. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. Two of the severely ill patients died in the ICU (7% overall mortality, 13% in-hospital mortality). Six patients out of 28 HT recipients in this study had a total of 10 admissions after their initial COVID-19 diagnoses (Supplemental Table S -2), however none of these readmissions were clearly related to COVID-19. Four patients were readmitted only once (and one of these admissions was for a planned ablation for a supraventricular tachycardia that was present prior to COVID-19 diagnosis). Two patients were readmitted twice and one patient was readmitted 3 times (Supplemental Table S We note a mortality of 7% in our HT recipients infected with SARS-CoV-2 (Table 1) . Compared to reports from other large transplant centers with estimated mortality rates of 15-33%, 1-3,11 the mortality seen in our patients seems lower. This may be related to the overall decrease in mortality seen since the start of the pandemic, with improvement in disease management as more evidence-based therapeutics became available including remdesivir, dexamethasone and monoclonal antibodies. As noted in Table 1 , few patients in the 5 studies from large transplant centers with higher COVID-19 related mortality received either remdesivir or dexamethasone. [1] [2] [3] 11 In the largest multicenter study of 99 patients from across the United States, steroids were used in 19% of patients, remdesivir in 11%, and convalescent plasma in 11% of patients. 5 In the other four studies from large transplant This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. centers (n=124 patients), 21-38% of patients received high dose glucocorticoids for COVID-19 but none received a course of remdesivir. Two more recent small case series 16,17 did use remdesivir either alone or in combination with dexamethasone, with 100% survival of all patients receiving these therapeutics (Table 1) . Several neutralizing antibodies have been developed that limit disease severity when given early in the disease course to high risk ambulatory patients, though no benefit is noted when given after hospital admission. These included bamlanivimab, bamlanivimab/etesevimab and casirivimab/mdevimab. [18] [19] [20] [21] The two outpatients in our study who received casirivimab/imdevimab both recovered without complication or need for inpatient admission. 22, 23 Consistent with national data, our study demonstrates that Hispanic patients had This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. to his COVID-19 diagnosis (and the patient with the most severe history of rejection: two episodes of AMR with graft dysfunction) had only mild illness with COVID-19 and was never admitted to the hospital. Similarly, patients with history of CAV had mixed outcomes. Four patients had only mild symptoms and were never admitted, three developed severe symptoms and were admitted for treatment (all 3 were treated with remdesivir, 2 were also treated with dexamethasone), and all recovered without any mortality. Some have also suggested that patients with fresh transplant on triple agent immunosuppression may be at the highest risk for infection. Out of 72 HTs performed at UCSD during 2020, there were 3 cases of COVID-19 infection within 6 months after transplant, but all had mild course of illness and recovered with no mortality. Like most other studies, ours reported that hypertension was the most common comorbidity in COVID-19 infected HT recipients, although this was not significantly more common than in the control population. Interestingly, our study showed a significantly lower rate of diabetes in the COVID-19 infected group compared to control HT recipients; this could potentially play a role in the low mortality of our cohort though we are unable to test this hypothesis. Our COVID-19 protocol evolved over time as new evidence and data became available. However, it is important to note that at the beginning of the pandemic, we never used hydroxycholoroquine, lopinovir/ritonavir, ivermectin, azithromycin or other therapeutic trends that received outsized attention as there was lack of strong evidence for their use, and the use of these drugs was not logical. Of course, remdesivir, steroids and neutralizing antibody cocktails were later added to our protocol as evidence became available. Lack of drug toxicity and lack of drug-drug interactions could potentially have played a role in our improved outcomes as well. With the benefit of the recently published ACTT-1 and RECOVERY trials, we believe the improved mortality observed in this study reflects our center's current treatment algorithm that we have adapted over the course of the pandemic to incorporate new evidence-based therapeutics to utilize close outpatient observation, This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. neutralizing monoclonal antibody therapy for outpatients early in the disease course, and prompt admission with reduction in immunosuppression and evidence-based treatment with remdesivir and dexamethasone for moderate/severe illness with hypoxia. We describe 28 HT recipients who developed SARS-CoV-2 infection during the first year of the pandemic. We demonstrate reduced mortality of 7% in this single center cohort based on a multi-pronged evidence-based treatment strategy. This article is protected by copyright. All rights reserved. 0 0 0 0 0 1 (20%) 0 3 (6%) 3 (6%) 0 0 0 0 0 0 0 4 5 (100%) 2 (50%) 22 (42%) 19 (68%) 13 (59%) 15 (71%) 47 (4 This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. , creatinine kinase-muscle-brain (CK-MB), creatinine kinase index (CK Index), high sensitivity/fifth generation troponin T (TnT Gen V), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), high sensitivity CRP (hsCRP), lactate dehydrogenase (LDH), creatinine (Cr). Table 5 : White blood cell (WBC) count data from HT recipients who tested positive for SARS-CoV-2 (n=28) compared to HT recipients who tested negative for SARS-CoV-2 (n=80). Total WBC count is shown along with absolute counts of lymphocytes and neutrophils, and the ratio of neutrophils to lymphocytes (N/L Ratio). Median and interquartile ranges are reported for each laboratory test result; no statistical significance was detected between the two groups using the Mann Whitney U Test. 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