Pediatric heart transplant rejection following COVID-19 infection

Abstract

Background

Infections have been associated with rejection episodes in solid organ transplant recipients. We report an association between COVID-19 infection and heart transplant (HT) rejection.

Case Description

The patient was 14 years old and 6.5 years post-HT. He developed symptoms of rejection within two weeks of COVID exposure and presumed infection.

Conclusions

In this case, COVID-19 infection closely preceded significant rejection and graft dysfunction. Further study is needed to establish a correlation between COVID-19 infection and rejection in heart transplant patients.

Introduction

A patient at a pediatric heart transplant program experienced their first episode of graft rejection closely following COVID-19 infection. While causation is unproven, immune activation from COVID-19 is suspected to be the potential stimulus for rejection.

COVID-19 infection continues to have widespread effects worldwide, the impact of which is difficult to quantify. The implications of COVID-19 for pediatric solid organ transplant patients remain an area of great interest and ongoing research. COVID-19 infection carries risk for cardiac involvement with associated myocarditis and multisystem inflammatory syndrome in children (MIS-C). COVID-19 infection in solid organ transplant patients is a growing area of research, with currently limited publications (1) (2) (3).

Narrative

The patient is a 14-year-old male 6.5 years status-post heart transplant who presented with first-time acute cellular and antibody mediated rejection in the setting of recent COVID-19 exposure and presumed infection. His past medical history was notable for severe dilated cardiomyopathy requiring left ventricular assist device support. He had historically excellent compliance with no history of rejection, donor specific antibodies, or cardiac allograft vasculopathy.

He presented to the emergency department with dyspnea, fatigue, nausea, peripheral edema, and chest and abdominal pain. SARS-CoV-2 PCR was negative at that time. Typically, a very active young man, he was newly unable to play basketball due to shortness of breath. Two weeks prior to onset of his symptoms, his parents both tested positive for COVID-19. While he was not tested at the time, he also had mild, self-limited congestion and a sore throat that family presumed to be due to first-time COVID-19 infection. He was unvaccinated against SARS-CoV-2 and had not received any treatment for his presumed COVID-19 infection. He was found to be positive for SARS-CoV-2 Total Antibody, Nucleocapsid Antibodies and SARS-CoV-2 Total Antibody on the day of admission. His immunosuppression included sirolimus and tacrolimus and both drug troughs were within goal range (4.9ng/mL and 3.3ng/mL respectively) on routine surveillance obtained one week prior to symptom onset.

Upon evaluation, he was noted to have elevated BNP and HS troponin. Echocardiogram revealed moderately depressed left ventricular systolic function (left ventricular ejection fraction (LVEF) of 37%) and severely depressed right ventricular systolic function. This was markedly changed from his baseline of normal biventricular systolic function and previous LVEF of 64%. Given his new onset heart failure and functional limitations, graft rejection seemed likely, and he underwent cardiac catheterization and endomyocardial biopsy. Hemodynamics on catheterization were notable for elevated filling pressures (right atrial pressure 19mmHg), elevated pulmonary capillary wedge pressure (PCWP) (20mmHg), and cardiac index by Fick of 2.4 L/min/m².

He developed new class I and class II donor specific antibodies (DSA) (see Figures 1 and 2 ). Endomyocardial biopsies revealed diffuse mild acute cellular rejection (1B/1R) and antibody mediated rejection (pAMR 1, I+) with developing histologic features, mild (paucicellular) endocardial and interstitial mononuclear infiltrate with a mixture of CD3 positive (T lymphocytes), CD20 positive (B lymphocytes) and CD68 positive macrophages. There were focal morphologic features of antibody mediated rejection and C4d immunostaining showed weak and focal vascular staining (Figure 3, Figure 4 ). COVID-in situ hybridization of the biopsies was negative.

Figure 1.

Patient Class 1 Donor Specific Antibody Levels since transplantation

Figure 2.

Patient Class 2 Donor Specific Antibody Levels since transplantation

Figure 3.

Hematoxylin eosin-stained slide shows mild endocardial and interstitial mononuclear infiltrate of the myocardial biopsy.

Figure 4.

C4d immunostain shows focal weak linear vascular staining of the myocardial biopsy.

Upon arrival, he was treated with high-dose methylprednisolone. Once pathology confirmed cellular and antibody mediated rejection, he continued steroids and underwent five rounds of plasmapheresis and IVIG, followed by rituximab. Oral heart failure therapies were prescribed and optimized in the setting of severely depressed function and elevated cardiac pressures from catheterization.

A month following presentation, his echo showed moderately to severely depressed RV function, moderately depressed LV function (LVEF 45%), At that time heart catheterization showed minimally improved hemodynamics with elevated filling pressures (RA 16 mmHg) and elevated PCWP (18 mmHg). He had decreased class I DSA, though class II DSA remained elevated. Endomyocardial biopsies revealed persistent antibody mediated rejection (pAMR 2), with increased histologic features of prominent endothelial cells and intravascular mononuclear infiltrates but decreased distribution and intensity of C4d and C3d immunostaining. Biopsy revealed resolved acute cellular rejection (0/0R). Coronary angiography showed no vasculopathy, but filling was sluggish in the setting of elevated filling pressures. Subsequent biopsies remain indeterminate for antibody mediated rejection with focal prominent endothelial cells and intravascular mononuclear infiltrates though the prominence of the findings have decreased over time. He has two persistent class II donor specific antibodies. He continues to receive regular IVIG and rituximab infusions, now spaced to every three months for persistent DSA and indeterminate biopsy findings. Eight months after presentation, his PCWP remains slightly elevated (14mmHg) from his baseline, his LVEF improved to 52% and his exercise tolerance has slowly improved and is approaching his baseline prior to rejection.

Discussion

This patient had no history of prior rejection, medication nonadherence, or DSA prior to presenting with this episode of rejection which was temporally related to COVID-19 infection. Shortly after having mild, self-limited symptoms with his infection, he developed both acute cellular and antibody mediated rejection with multiple DSA which resulted in significant graft dysfunction.

Immune system activation is complex and many possible relationships between COVID-19 infection and transplant rejection may exist. There have been limited studies evaluating this potential relationship. Vinson et al. showed COVID-19 infection had an association with rejection in kidney transplant patients (4). Others have shown no significant difference in rejection (2) (3). From an orthotopic heart transplant standpoint, Hanson's group demonstrated the difficulty in differentiating from antibody mediated rejection versus viral myocarditis (5). In our case, the pathologic findings in addition to the newly formed DSA made the diagnosis of AMR straightforward.

Historically, various studies have suggested a relationship between non-SARS-CoV-2 infection and rejection in transplantation. One such hypothesis states stimulation of the cellular and/or antibody immune response to infection leads to further activation, sensitization and, ultimately, a rejection episode. The exact mechanism or mechanisms remain unknown. Winters demonstrated patients more than a year post orthotopic heart transplant found to have new moderate to severe acute rejection by endomyocardial biopsy had significantly higher numbers of infections and were often within 1 month of a self- limited infection (6). Cardiac viral infection/myocarditis as a trigger for rejection is yet another hypothesis. Studies have demonstrated presence of adenovirus, CMV, enterovirus, herpes simplex virus and parvovirus PCR in endomyocardial biopsies showing rejection (7) (8). A prospective study of 553 pediatric heart transplant biopsies from 1149 patients showed identification of viral PCR in the myocardium—especially adenovirus—was predictive of graft loss due to cardiac allograft vasculopathy, chronic graft failure or acute rejection (9). Research suggests that bacterial induced inflammation activates graft reactive T cells, and the infection may induce direct organ injury leading to the release of endogenous activators, further prompting inflammation and graft rejection. These mechanisms remain to be proven (10).

Just as with any other infection, we describe a temporal relationship between COVID-19 infection and acute cellular and antibody mediated heart transplant rejection in one patient. It is plausible that his infection resulted in immune system activation and subsequent rejection. Given the prevalence of COVID-19, it is unlikely that this consequence is common in transplanted patients. Still, having a high index of suspicion for rejection after COVID-19 infection is prudent. Multi-center studies of heart transplant patient outcomes after COVID-19 infection are needed.

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