key: cord-1011867-nas1zena authors: Singhvi, Aditi; Barghash, Maya; Lala, Anuradha; Mitter, Sumeet S.; Parikh, Aditya; Oliveros, Estefania; Rollins, Brett M; Brunjes, Danielle L.; Alvarez-Garcia, Jesus; Johnston, Erika; Ryan, Kieran; Itagaki, Shinobu; Moss, Noah; Pinney, Sean P.; Anyanwu, Anelechi; Mancini, Donna title: Challenges in Heart Transplantation during COVID-19: A Single Center Experience date: 2020-06-25 journal: J Heart Lung Transplant DOI: 10.1016/j.healun.2020.06.015 sha: ae0a536f5b5f124177283d56882a91b1ffa7b54b doc_id: 1011867 cord_uid: nas1zena BACKGROUND: Orthotopic heart transplantation (OHT) recipients may be particularly vulnerable to coronavirus disease (COVID-19). OHT during the pandemic presents unique challenges in terms of feasibility and safety. METHODS: Chart review was performed for consecutive OHT recipients with COVID-19, and waitlisted patients who underwent OHT from March 1, 2020 to May 15, 2020. RESULTS: Of the approximately 400 OHT recipients followed at our institution, 22 acquired COVID-19. Clinical characteristics included median age 59 (Range, 49 - 71) years, 14 (63.6%) were male, and median time from OHT to infection was 4.6 (2.5 – 20.6) years. Symptoms included fever (68.2%), gastrointestinal complaints (55%) and cough (46%). COVID-19 was severe or critical in 5 (23%). All patients had elevated inflammatory biomarkers. Immunosuppression was modified in 85% patients. Most (n=16, 86.4%) were hospitalized, 18% required intubation, and 14% required vasopressor support. Five patients (23%) expired. None of the patients requiring intubation survived. 5 patients underwent OHT during the pandemic. They were all males, ranging 30 to 59 years of age. Two were transplanted at UNOS status 1 or 2, one at status 3, and two at status 4. All were successfully discharged and are alive without allograft dysfunction or rejection. One contracted mild COVID-19 after the index hospitalization. CONCLUSION: OHT recipients with COVID-19 appear to have outcomes similar to the general population hospitalized with COVID-19. OHT during the pandemic is feasible when appropriate precautions are taken. Further study is needed to guide immunosuppression management in OHT recipients affected by COVID-19. The coronavirus disease 2019 global pandemic caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 7 million people and accounts for over 400,000 deaths worldwide. While disease manifestations range from mild upper respiratory symptoms to multiorgan failure and death (1) , disease severity among orthotopic heart transplant (OHT) recipients on chronic immunosuppression is less well studied (2) (3) (4) . The interplay of immunosuppression and SARS-COV-2 infection may render OHT recipients more susceptible to acquiring COVID-19 and predispose to more severe disease. Conversely, immunosuppression could be protective by mitigating host immune responses that result in adverse outcomes (5) . The pandemic has also impacted the delivery of care for advanced heart failure (HF) patients awaiting OHT. Specifically, the risk of contracting COVID-19 and exposure to healthcare workers must be balanced against the high risk of mortality on the waitlist. OHT is life-saving therapy and as such judicious use should continue through the pandemic. At the peak of the crisis in New York, logistic factors such as limited intensive care unit (ICU) beds, shortage of blood products and ventilators resulted in restriction of organ transplantation. Additionally, the pandemic limited donor offers, and in some instances precluded transplant donor teams from retrieving organs. The following report describes the landscape of heart transplant care during the COVID-19 pandemic at our institution in New York, the disease epicenter. Our objectives were to recognize the varied presentations in OHT recipients with COVID-19, report outcomes and highlight the clinical dilemmas encountered in their management, particularly pertaining to immunosuppression. We also sought to describe our practice and experience with performing five heart transplants during the peak of the pandemic and emphasize relevant considerations. interquartile ranges (IQRs) or as means + standard deviation (SD) as appropriate. Differences in continuous variables were tested by analysis of variance (ANOVA) or Student's t-test for independent samples. Due to the small sample size, a non-adjusted binary regression logistic analysis was performed in order to obtain the odds ratio for risk factors for mortality. Two-sided significance levels of 0.05 were used in all analyses. Data were analyzed using STATA SE Version 13.0 (StataCorp LLC, College Station, TX, USA). This study was approved by the Institutional Review Board at Mount Sinai Hospital. All SARS-CoV-2 tests performed used either reverse transcriptase polymerase chain reaction (RT-PCR) via Roche cobas 6800 or the Cepheid GeneXpert Xpress system of nasopharyngeal swab or bronchoalveolar lavage specimens. Disease severity was categorized as: Mild: SpO2 >94% and no pneumonia; Moderate: SpO2 <94% and pneumonia; Severe: High flow nasal O2, no vasopressors; moderate impairment of renal and liver function; Critical and Cytokine Release Syndrome: on vasopressors, intubated (Table S1 , Supplement). Administration of glucocorticoids and COVID-19 directed therapies as well as consideration for participation in clinical trials was based on the discretion of the treating physicians (details in Supplement). Institutional protocols were followed for anticoagulation administration ( Figure S1 , Supplement). Modification of immunosuppression occurred on a case by case basis. After March 1, 2020, five patients underwent OHT at our institution. Follow-up data were collected through May 15, 2020. Priority for transplantation was given to hospitalized patients or outpatients at moderate to high risk of waitlist mortality. Baseline Characteristics (Table 1) Of the approximately 400 OHT recipients followed at our institution, 6% are within the first year of transplant, 25% within 1 to 5 years and 69% > 5 years from transplant. A total of 22 OHT recipients tested positive for SARS-CoV-2 during the study period. OHT recipients with mild symptoms suggestive of COVID-19 but did not undergo testing (n=4) were not included in this report. The median age was 58.6 years, 14 (63.6%) were men, 14 (64%) were African-American or Hispanic ethnicity. The median time from OHT was 4.6 years, with only 2 being within one year from transplantation. One patient was a heart-kidney transplant recipient. Comorbidities included hypertension in 21 patients (95.5%), diabetes in 12 (54.5%), lung disease in 3 (13.6%), long-term dialysis in 3 (13.6%), and cardiac allograft vasculopathy in 8 patients (36.4%). Two had a recent history of acute allograft rejection, one treated with pulse dose steroids 94 days before COVID-19 diagnosis; and the other received anti-thymocyte globulin and rituximab 20 days prior to diagnosis. Maintenance immunosuppression included tacrolimus in 18 (81.8%), mycophenolate mofetil (MMF) in 13 patients (59.1%), prednisone in 13 (59.1%) (less than 20 mg/day in all), and mammalian target of rapamycin inhibitor (mTORi) in 3 (13.6%). Most were on a two-drug regimen (59.1%). Fever was the most common presenting symptom (68%), followed by gastrointestinal symptoms (55%) and cough (46%). All but one patient tested positive on initial SARS-CoV-2 RT-PCR performed on nasopharyngeal swab specimens. One patient had two negative SARS-CoV-2 RT-PCR tests performed on nasopharyngeal swab specimens, but subsequently tested positive on bronchoalveolar lavage. COVID-19 antibody testing was performed in 6 patients. Of these 4 had positive antibody titers and 2 were negative. The majority of patients (n=19, 86.4%) required hospitalization. 16 were hospitalized at the study institution and 3 at outside institutions. Most were characterized as having mild (n=7, 31.8%) or moderate (n=10, 45.4%) disease, and 5 (22.6%) with severe or critical disease. The 3 patients managed outpatient had mild COVID-19. Median temperature on presentation was 37.5 °C, only two patients had a systolic blood pressure < 100 mmHg (Table S2, Of the 16 patients hospitalized at the study institution, on presentation 8 required supplemental oxygen and one needed intubation. Another patient who did not require supplemental oxygen, ultimately required intubation. All three patients admitted to outside institutions required intubation and ultimately expired. Three patients required renal replacement therapy, of whom one had renal recovery. No patients were placed on extracorporeal membrane oxygenation. A timeline of disease progression in our cohort is depicted in Figure 2 . Most patients received COVID-19 directed therapy including hydroxychloroquine (11), hydroxychloroquine and azithromycin (3), remdesivir (1), convalescent plasma (1), tocilizumab (1) One patient who received hydroxychloroquine and azithromycin developed significant QTc interval prolongation and hydroxychloroquine dose was reduced and azithromycin withdrawn. The patient who received remdesivir, developed significant elevation in transaminases necessitating termination. High dose glucocorticoids were used in 5 (25%) patients and anticoagulation in 11 (55%) patients. Concomitant antibiotics were administered in 9 patients, though only 1 had documented bacteremia and pneumonia with Staphylococcus aureus. In terms of the background immunosuppression, the trough range targeted for calcineurin inhibitors (CNIs) was not modified. 4 (22.2%) patients presented with supratherapeutic tacrolimus levels. All 3 patients on mTORi either had their drug held or dose reduced. One of 2 patients on sirolimus had an elevated level of 26ng/mL on admission. Antimetabolite doses were reduced in 3 (23.1%) patients and held in 7 (53.8%). For those managed as outpatients, one had his MMF held during the acute infection. Overall mortality was 22.7% with a mortality of 26.3% in hospitalized patients. None of the patients admitted at outside institutions survived. Four patients (21% of all hospitalized) required ICU admission, all of whom expired, two from progressive respiratory failure and acute respiratory distress syndrome, one from intracranial hemorrhage, and one from refractory shock. Another patient who died from respiratory failure elected to pursue comfort care. At the study institution, 2 (12.5%) patients required ICU admission, 14 (87.5%) patients recovered and were discharged. Mortality among those hospitalized at the study institution was 12.5%. Mortality including those managed in the outpatient setting by the study institution was 10.5%. There were no episodes of rejection or diagnosed thromboembolic events. None of the demographic variables, including age, sex, BMI, time since transplant or comorbidities had a statistically significant association with mortality. Baseline immunosuppression, ACEi or ARB use or statin use were not associated with mortality either. Lymphocyte count was lower, and peak creatinine, peak troponin I level, peak D-dimer and peak ferritin were higher in the patients that did not survive, however the result was not statistically significant. Patients who were transplanted were all men, ages ranged from 30 to 59 years. We report 22 cases of COVID-19 in OHT recipients, with a wide spectrum of presentations and with a 23% overall mortality. We also demonstrate the feasibility of performing transplantation with favorable short-term outcomes during the pandemic. OHT recipients may be more susceptible to severe disease than the general population by virtue of chronic immunosuppression. In our population however, 22.7% had severe or critical disease and 18.2% were intubated. This distribution is similar to that reported in the general population by the Chinese Center for Disease Control (1), It is also similar to a recent report by Latif et al in exclusively OHT patients (4). Despite potential for atypical presentation due to chronic immunosuppression, patients in our cohort presented with symptoms similar to the general population (6). The highly prevalent lymphopenia seen in our patients may have resulted from the use of antimetabolites rather than COVID-19. Antimetabolites may also be associated with lower maximum temperatures. The overall mortality rate for our cohort was 22.7%, ICU admission rate was 21% with 80% mortality in those with severe to critical disease. This is higher than the case fatality rates reported by the Chinese and US Centers for Disease Control and Prevention (1, 7) . However, the comparison for overall mortality should be interpreted with caution since the data in OHT recipients represents primarily hospitalized patients. Notably, the outcomes in OHT recipients appear to be similar to that of non-transplant hospitalized patients with similar demographics and medical complexity (8, 9) . A large health system across New York City reported an ICU admission rate of 14.2% and 21% mortality in 2634 patients hospitalized with COVID-19 (8) . Our institution has also reported a mortality of 18.5% in 2736 hospitalized COVID-19 patients (9) . Patients with comorbid conditions have a higher risk of mortality in COVID-19 (10) . 77.3% patients of our cohort had 2 or more comorbid conditions with a median Charlson Comorbidity Index of 5 (IQR, 1-7) . 64.7% of the hospitalized patients in our cohort also had a D-dimer >1 mg/mL, which is associated with an approximately 20 fold risk of mortality (10) . Myocardial injury is also a poor prognostic marker (9, 11) . All three patients with elevated troponin I level in our cohort expired. In regards to mortality in transplant recipients, Latif (4) and Pereira (12) One surprising finding was a lower mortality rate in those patients treated at the transplant center. Similar to our cohort, Latif et al reported a mortality rate of 12.5% for those patients treated at the transplant center. It is unclear whether this reflects that those patients treated at outside institutions were too ill to be transferred or the need for a higher level of expertise in caring for these patients which cannot be provided locally. Our analysis is limited given the small sample size. Though none of the variables had a statistically significant association with mortality, patients who died were older, had a higher BMI, increased incidence of lung disease, and chronic prednisone use. Patients who died also had a lower lymphocyte count on presentation, higher peak creatinine, peak troponin I level, and peak D-dimer. None of the therapies used seemed to have an association with mortality. Immunosuppression could render patients more susceptible to contracting COVID-19. Specifically, MMF prevents lymphocyte proliferation and antibody production. It decreases immune response to influenza vaccine and is associated with a higher frequency of viral infections (13, 14) . Conversely, immunosuppression may make patients less susceptible to contracting the disease and/or ameliorate its severity. Immunosuppressants activate the renin-angiotensin aldosterone system, which could modulate the expression of pulmonary ACE2 receptors which are the binding site for the SARS-CoV-2 viral particles (15) . CNIs actually inhibit the replication of SARS-CoV-2 in vitro (16) . Additionally, in the latter stage of the disease, the clinical phenotype is a consequence of the host immune response, which is attenuated by steroid use. 13 of the 22 recipients in our cohort were on steroids as maintenance therapy, but still had elevated IL-6 levels and 4 (30.8%) of those developed severe or critical disease. COVID-19 is characterized by significant lymphopenia which prompted a decrease or suspension of MMF in 11 of 13 patients. 3 were on mTORi and pneumonitis was considered in their evaluation (17) . We maintained CNIs at therapeutic levels given the potentially beneficial immunomodulatory effects and to offset the known risk of rejection from CNI withdrawal. Drug interactions with medications used in OHT recipients are important to consider and are described in Table S4 (Supplement). Importantly, the metabolism of mTORi and CNIs may be altered by anti-retroviral agents, hydroxychloroquine, and IL-6 inhibitors, necessitating dose reductions and drug level monitoring (18, 19) . Lastly, drug metabolism will also be altered in COVID-19 patients with elevated IL-6 levels as IL-6 inhibits CYP P450 metabolism. We did note elevated tacrolimus and sirolimus levels in some patients who had been on stable doses prior. Weighing the lifesaving benefit of transplantation in the sickest patients against the risk of COVID-19 exposure posed unique challenges to waitlisted patients. While some centers restricted OHT to those listed UNOS Status 1-3, we opted to evaluate recipients on a case-bycase basis. Patient 5 for example was Status 4, however had recurrent low flow alarms due to outflow obstruction, progressive driveline infection, and donor size constraints, thereby facing a high risk of adverse events. Appropriate precautions were undertaken to minimize the risk of exposure to the patients and the healthcare team. Logistic challenges including, shortage of ICU beds, staffing, medical supplies and equipment were navigated without compromising the quality of care. Post-operative care aimed to mitigate the risk of nosocomial COVID-19 spread among recent OHT recipients. Standard immunosuppression was instituted without modifications. For transitional care planning, effective patient and caregiver education was delivered via telephone. Patients were advised to self-quarantine with universal mask wearing, family members were screened for symptoms, and outpatient transplant care was modified to incorporate mobile phlebotomy, telehealth video visits, more frequent telephone follow-up, SARS-CoV-2 testing prior to Embx, and earlier transition to non-invasive rejection surveillance ( Figure 3B ). The short-term outcomes following the 5 OHT do not seem to have been compromised during the COVID-19 pandemic. Only one patient contracted mild COVID-19. While their outcomes in the absence of transplantation cannot be known, mortality risk for deferring transplant was high for all those transplanted. Given the possibility of COVID-19 resurgence, it is necessary to develop strategies whereby life-saving heart transplantation can be carried through such outbreaks. Our experiences provide a useful framework, demonstrating modifications to standard care protocols can be undertaken without obvious detrimental effect on the delivery of care. Broader application could be considered in the non-COVID-19 setting (such as utilization of telemedicine, and screening of caregivers). As more information and understanding of COVID-19 emerges, concrete evidence-based guidelines can be established. The COVID-19 pandemic has posed unique challenges for the management of OHT recipients as well as those awaiting transplantation. In this limited case series across a single institution at the epicenter of the pandemic, we observed intubation and in-hospital mortality rates similar to other hospitalized patients. Further, we found highly judicious pursuance of transplantation feasible and life-saving for select candidates. Further work is needed to understand how practices should evolve to optimize patient outcomes amidst COVID-19. The following relevant disclosures from the authors include: S.P. has received personal fees from Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China Chinese Center for Disease Control and Prevention First Cases of COVID-19 in Heart Transplantation From China The Variety of Cardiovascular Presentations of COVID-19 Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease Epub 2020/05/13 The trinity of COVID-19: immunity, inflammation and intervention Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. 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IMDIAB Study Group Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506 Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavircontaining cART: a pilot study