key: cord-0874347-w6mtq3wk
authors: Ahluwalia, Monica; Givertz, Michael M.; Mehra, Mandeep R.
title: A Proposed Strategy for Management of Immunosuppression in Heart Transplant Patients with COVID‐19
date: 2020-07-04
journal: Clin Transplant
DOI: 10.1111/ctr.14032
sha: fadb36c5042b71f29a3d1068593a6bd6a9a727e3
doc_id: 874347
cord_uid: w6mtq3wk

There is limited experience in management of orthotopic heart transplant (OHT) patients with COVID‐19. In this study, we present our initial experience using a standardized management algorithm. Data collection was performed on OHT patients with COVID‐19 after March 10, 2020 (declaration of state‐of‐emergency in Massachusetts). Among the 358 OHT patients currently followed at our program, 5 patients (1.4%) tested positive for COVID‐19 (median age 50 years [IQR, 49‐58], duration post‐OHT 21 years [IQR, 6‐25], and 4 of 5 (80%) were men). Among the 5 OHT patients, 2 of 5 (20%) had mild disease, and had no change in baseline immunosuppression therapy. Two of 5 (20%) had moderate disease, and received remdesivir as part of a clinical trial, and reduced immunosuppression therapy. One patient (20%) died prior to presenting to the hospital, consistent with 20% case fatality rate.

As the coronavirus disease 2019 (COVID-19) pandemic ensues, it has posed a greater challenge in heart transplant recipients, a particularly vulnerable patient cohort. Transplant recipients are likely susceptible given the immunosuppressed state, presence of comorbidities including hypertension, diabetes mellitus and chronic kidney disease, and frequent contact with the healthcare system, leading to an overall increase in mortality. The attributable risk, however, is largely unknown. Preliminary reports suggest that the clinical course of COVID-19 may be similar in orthotopic heart transplant (OHT) and non-transplant patients. 1 Calcineurin inhibitors (CNIs) are the cornerstone treatment that block T cell activation, effectively suppressing alloimmunity. In vitro studies have demonstrated that CNIs may inhibit viral replication of coronaviruses and hepatitis C 2 , whereas there has not been consistent data to support the same with the use of mycophenolate mofetil (MMF). 3,4 mTOR inhibitors may also suppress viral replication and thus, clinical investigation is ongoing. 5 Although there may be inhibitory effects of these medications, lowering the dosage or withholding Accepted Article select immunosuppressive drugs in the early disease course may attenuate clinical expression of the disease depending on severity albeit with increased risk for rejection. The impact of change of immunosuppressive therapy needs to be further evaluated.

Early in the course of the COVID-19 crisis, we developed a prospective standardized management algorithm for our heart transplant patients with COVID-19 [ Figure 1 ]. In addition, heart transplant recipients are strongly advised to practice prevention measures 6 , including minimizing routine clinical visits, use of video or telephone visits, and to post-postpone any non-essential routine surveillance testing (echocardiography, right heart catheterization and endomyocardial biopsy).

In this report, we summarize our initial experience and challenges in managing heart transplant patients at Brigham and Women's Hospital [BWH] from the time of declaration of state-of-emergency by the Governor of Massachusetts on March 10 th , 2020 and to describe short-term outcomes of COVID-19 patients after implementing the prospective clinical management algorithm.

Data was collected by the electronic medical record on all heart transplant patients with either a confirmed diagnosis of COVID-19 or those persons under investigation (PUI) admitted to BWH or cared for as an outpatient from March 10, 2020 to May 15th, 2020. Information including demographics, transplant history and complications, co-morbidities, clinical presentation and course, medications and laboratory values was reviewed. COVID-19 positive patients were confirmed by positive nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2. Outpatients who tested positive were also included. All testing was performed based on self-reporting of symptoms. Management of immunosuppression therapy is outlined in Figure 1 . Continuous data is reported as medians with interquartile ranges (IQRs). This project was undertaken as a quality improvement initiative, and as such was exempt from ethics committee review per institutional policy.

Among the 358 OHT patients currently followed at our program, 19 patients (5.3%) were evaluated during the COVID-19 pandemic after March 10 th 2020 (declaration of state of emergency in Massachusetts). Clinical

This article is protected by copyright. All rights reserved diagnoses among OHT patients during the COVID-19 pandemic are outlined in Figure 2 . A total of 5 OHT patients (1.4% of total OHT cohort currently followed at our program) were confirmed positive for COVID-19

[ Table 1 ]. Among the 5 OHT patients, 3 (60%) were admitted, 1 (20%) was managed as an outpatient and 1 (20%) had a pulseless electrical activity (PEA) cardiac arrest prior to presentation to the hospital, consistent with 20% case fatality rate. All remaining hospitalized patients were ruled out for COVID-19 with two serial for discharge included clinical improvement in symptoms, hemodynamic stability, adequate oral intake and off oxygen therapy for at least 24 hours prior to discharge. Four of 5 patients (80%) are currently doing well with self-isolation precautions at home with marked improvement in clinical symptoms up to 4 weeks post discharge. Following discharge, patients who had a change in their immunosuppression regimen resumed home dose calcineurin inhibitor and steroid therapy. Half-dose adjunctive therapy (MMF, azathioprine or sirolimus) was also initiated two weeks after discharge and full dose was resumed once repeat testing for SARS-CoV-2 was negative. All hospitalized patients tested negative within 4 weeks of the initial positive test.

All patients were closely monitored by our transplant nursing team using telehealth and video calls after discharge. They received ongoing reinforcement to follow CDC guidelines for social distancing, hand hygiene practices and use of facemask.

In this report, we describe 5 OHT patients with COVID-19, which represents a COVID-19 infection rate of 1.4% in our population. In this small cohort, there was one death (20% case fatality rate) in an older patient with multiple co-morbidities including a history of acute cellular and antibody-mediated rejection who had a PEA cardiac arrest at home. This highlights the need to maintain a low threshold to admit and closely monitor these patients. Among the remaining patients, none required mechanical ventilation. All patients who survived had good short-term outcomes up to 4 weeks post-discharge under our current protocol for adjusting immunosuppressive therapy with COVID-19 coupled with very close clinical follow-up.

Similar results were observed in a larger cohort of 28 patients in which cardiovascular co-morbidities were highly prevalent and immunosuppression therapy was reduced, although no patients received remdesivir. 7 The authors reported a case fatality rate of 25%, one of the highest reported in the literature. 7 These experiences differ from an initial report describing 2 OHT patients (one with mild disease 2.5 years post-OHT and the second with more severe disease 15 years post-OHT) from China who both achieved clinical recovery. 1

Since the emergence of the novel coronavirus, there are no current recommendations for management of heart transplant patients with COVID-19 due to limited experience. In the disease process, there is an initial viral response phase, followed by escalating phases of disease progression dictated by the host inflammatory response. 9 In transplant recipients, it is possible that much of the damage in the late phase of disease is a result of an overactive immune system driven by T-cell activation, the primary target of immunosuppressive therapy. Immunosuppressed patients may have a protective mechanism due to impaired T-cell response that can alter the disease severity and clinical course; 10 however, this remains largely speculative and is not supported by our current study. Subsequent case series describe a range of severity of clinical course of COVID-19 in solid organ transplants, although management of immunosuppression regimen and anti-viral strategies varied among institutions. [11] [12] [13] [14] Table 2 summarizes ongoing challenges and potential solutions in the management of transplant patients with COVID-19 15 .

Among the patients who survived (80%) with good short-term outcomes, we cannot exclude the fact that remdesivir or augmentation of steroids may have played a role in clinical improvement. 16, 17 Recently, the RECOVERY trial demonstrated that low dose dexamethasone (6 mg/day for up to 10 days) was associated with an improvement in survival in hospitalized patients receiving invasive mechanical ventilation or oxygen therapy. 17 Overall, very close monitoring, particularly in those on reduced-dose immunosuppression, is imperative in this high-risk patient population. Future investigation is needed to help identify the true risk profile of transplant patients with COVID-19, understand mechanisms of disease progression and help validate the proposed management strategy in a larger cohort of patients.

None

First cases of COVID-19 in heart transplantation from

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Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. ecancermedicalscience

An Update on Current Therapeutic Drugs Treating COVID-19

Epidemiologic and clinical characteristics of heart transplant recipients during the 2019 coronavirus outbreak in Wuhan, China: A descriptive survey report

Accepted Article This article is protected by copyright. All rights reserved

Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease

The COVID-19 outbreak in Italy: Initial implications for organ transplantation programs

COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal

COVID-19: Yet another coronavirus challenge in transplantation

COVID-19 in solid organ transplant recipients: a single-center case series from Spain

A Case of SARS-CoV-2-pneumonia with successful antiviral therapy in a 77-year-old male with heart transplant

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