key: cord-344693-znw3dru4
authors: Lima, Brian; Gibson, Gregory T.; Vullaganti, Sirish; Malhame, Kathryn; Maybaum, Simon; Hussain, Syed T.; Shah, Samit; Majure, David T.; Wallach, Fran; Jang, Kristine; Bijol, Vanesa; Esposito, Michael J.; Williamson, Alex K.; Thomas, Rebecca M.; Bhuiya, Tawfiqul A.; Fernandez, Harold A.; Stevens, Gerin R.
title: COVID‐19 in recent heart transplant recipients: Clinicopathologic features and early outcomes
date: 2020-07-08
journal: Transpl Infect Dis
DOI: 10.1111/tid.13382
sha: 
doc_id: 344693
cord_uid: znw3dru4

BACKGROUND: The impact of COVID‐19 on heart transplant (HTx) recipients remains unclear, particularly in the early post‐transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID‐19 (three within 2 months post‐transplant) from our institution at the epicenter of the pandemic. Results: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID‐19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C‐reactive protein, procalcitonin, and ferritin. All had bilateral ground‐glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID‐19 appears to negatively impact outcomes early after heart transplantation.

With a mounting death toll approaching 300 000 worldwide, 1,2 the COVID-19 pandemic has challenged the global medical community.

A number of studies [2] [3] [4] [5] have emerged since infection with SARS-CoV-2 was first identified in late 2019, elucidating the natural history and pathophysiology of COVID-19. Mortality rates for COVID-19 directly correlate with advanced age and other comorbid conditions that impart increased cardiovascular risk, 4,6-10 such as hypertension, diabetes, and obesity. 11 The question remains whether the inferences drawn from these larger studies in the general population can be extrapolated to immunosuppressed patients, eg, heart transplant (HTx) recipients, a vulnerable population with a high prevalence of cardiovascular comorbidities that continue to be present post-HTx.

Increased risk of severe illness is suggested by a recent study which reported a mortality rate of 25% among HTx patients with COVID-19 in a single transplant center. 12 The current prevailing assumption is that immunosuppression is an additive risk that would predispose HTx patients to a more severe disease course. However, the pathognomonic inflammatory surge [13] [14] [15] that actuates severe COVID-19 disease could be attenuated in an immunocompromised host potentially leading to improved outcomes 16 in some patients. With the exception of the report by Latif et al, 12 the published experience of COVID-19 in HTx is sparse and largely encapsulated within a broader transplant umbrella encompassing kidney transplant series, 17, 18 heterogeneous cohorts of solid organ transplants, 19, 20 and isolated case reports in patients with a remote history of HTx. [21] [22] [23] [24] COVID-19's established predilection for direct myocardial injury 4,7-9,25-27 warrants a more comprehensive examination focusing specifically on HTx cases to improve our understanding of how this illness impacts graft function, occurrence of rejection, presence of donor specific antibodies, and other clinical nuances unique to HTx.

Thus, the goal of the present study is to share novel insights from our experience in five HTx patients with moderate/severe COVID-19 at a large quaternary hospital in the New York City area. Three patients in this cohort presented with COVID-19 within 6 weeks of transplant. To the best of our knowledge, the outcomes of HTx patients infected with COVID-19 within the early post-transplant period have not been previously reported, nor have the findings of electron microscopy to evaluate direct myocardial involvement of SARS-CoV-2 in immunosuppressed patients.

We performed a retrospective analysis of all HTx patients transplanted at North Shore University Hospital who were alive and at risk of infection from SARS-CoV-2. Infection with SARS-CoV-2 was confirmed with nucleic assay microarray analysis of a nasopharyngeal specimen. HTx patients infected with SARS-CoV-2 were subdivided into one of the three groups according to a previously reported clinical severity scale 14, 20, 28 : mild (hospitalization not required), moderate (hospitalization), and severe disease (hospitalization plus need for ICU admission, mechanical ventilation, or death). Baseline characteristics of the COVID-19 HTx patients were also compared to the remaining patients who underwent HTx at our center, of which there were 31 in total. All patients were counseled to abide by the appropriate preventative and quarantine measures. 21, 29, 30 The Northwell Health Institutional Review Board approved this case series as minimal-risk research using data collected for routine clinical practice and waived the requirement for informed consent (Approval # 20-0383).

For comparison of the baseline patient characteristics in the COVID-19 heart transplant cohort vs the uninfected heart transplant patients, Student's t-test and the Fisher's exact test were used for continuous and categorical variables, respectively. A P-value of < .05 was considered statistically significant. All analyses were completed using StatsDirect ® Statistical Analysis Software.

Tissue analysis was performed according to our institution's routine protocol for endomyocardial biopsies post-transplant. For this population, immunohistochemistry (IHC) was performed (in lieu of immunofluorescence) on 4-micron-thick sections of formalin-fixed paraffin-embedded tissue using a fully automated system ("Ventana Ultra with IVIEW detection kit," Ventana Medical Systems Inc) and the following antibody: C4d (polyclonal, 1:30; Biomedica). To evaluate for the presence of viral particles, tissue was submitted for electron microscopy and fixed with 2.5% glutaraldehyde in 0.1 mol/L cacodylate buffer. These were post-fixed in 1% osmium tetroxide, dehydrated in an alcohol gradient, and embedded in an epoxy embedding medium. One-micron-thick sections were cut and stained with toluidine blue stain. Thin sections were stained with uranyl acetate and lead citrate and examined with a JEOL JEM 100 CXII electron microscope.

The initial characteristics of 5700 patients from Northwell are presented elsewhere, 2 

The most common presenting symptom for the COVID-19 heart transplant patients was cough (100%) followed by diarrhea (80%), which was reported in all 4 of the community-acquired cases (Patients #2-5). The next most common symptom was fever (60%), and both dyspnea and rigors were reported in 40% of the cases. 

Lymphocytic leukopenia was present on admission for the major- imaging, but infiltrates were only visible on chest x-ray in the two patients with severe illness.

In an effort to attenuate the severity of COVID-19 and consistent with reports from other centers, 21, 22, 24, 29 the immunosuppressive regimen was modified for each patient ( 

Patients #1, #4, and #5 were within 2 months of their transplant and therefore underwent routine scheduled endomyocardial biopsies with hemodynamic assessments. As such, biopsies for all three of these patients (Table 2) were coincidentally conducted at roughly 2 weeks following confirmation of COVID-19 infection. In addition to evaluating for cellular and humoral rejection by routine H&E and IHC or immunofluorescence studies, we performed electron microscopy on select cases to evaluate for the evidence of direct myocardial involvement by coronavirus. Histologic analysis revealed mild acute cellular rejection (ISHLT grade 1R, Figure 1A ) in Patient #1 and no visible cellular rejection (ISHLT grade 0) in Patients #4 and #5.

In the case of Patient #1, the preponderance of lymphocytes over histiocytes or plasma cells and the absence of overt histologic evidence of myocyte injury was interpreted to favor rejection over viral myocarditis. 

All three of the heart transplant patients with moderate illness were discharged within 30 days of confirmation of SARS-CoV-2 infection ( 

To the best of our knowledge, this report includes the first HTx pa- The constellation of symptoms exhibited by the COVID-19 HTx patients were not dissimilar from those reported in other HTx 12, 19, 22 patients and from non-immunosuppressed individuals. 

The authors gratefully acknowledge the Northwell Covid-19

Research Consortium and our Infectious Disease consultant Dr Marcia Epstein for her input and unwavering commitment to our patients.

Dr Maybaum reports grants from Abbot and Abiomed, unrelated to this submitted work. Dr Stevens is a consultant for Novartis. The remaining authors have no conflicts of interest to disclose. No funding source was provided for this study.

All authors listed contributed to the conceptual design of the study, interpretation of the data, and data acquisition. Drafting of the manuscript and subsequent revisions were also areas of contribution by all of the listed co-authors, with BL taking a lead role in manuscript writing. All co-authors participated in the final approval of the submitted manuscript for publication and share accountability for the all the information included herein.

Brian Lima https://orcid.org/0000-0002-2555-2229

Gerin R. Stevens https://orcid.org/0000-0002-8235-5045

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