French Researchers Identify Two Unique Phenotypes of SARS-CoV-2 Infections Related Myocarditis

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A new study conducted by researchers from Sorbonne University-France has identified two distinct phenotypes of fulminant COVID-19-related myocarditis in adults, with totally different and unique clinical presentations, immunologic profiles, and outcomes.

The study findings were published in the peer reviewed Journal of the American College of Cardiology. https://www.jacc.org/doi/10.1016/j.jacc.2022.04.056

Objectives

This study sought to compare the characteristics and clinical outcome between patients with fulminant COVID-19–related myocarditis fulfilling MIS-A criteria (MIS-A+) or not (MIS-A).

Methods

A monocentric retrospective analysis of consecutive fulminant COVID-19–related myocarditis in a 26-bed intensive care unit (ICU).

Results

Between March 2020 and June 2021, 38 patients required ICU admission (male 66%; mean age 32 ± 15 years) for suspected fulminant COVID-19–related myocarditis. In-ICU treatment for organ failure included dobutamine 79%, norepinephrine 60%, mechanical ventilation 50%, venoarterial extracorporeal membrane oxygenation 42%, and renal replacement therapy 29%.

In-hospital mortality was 13%. Twenty-five patients (66%) met the MIS-A criteria. MIS-A patients compared with MIS-A+ patients were characterized by a shorter delay between COVID-19 symptoms onset and myocarditis, a lower left ventricular ejection fraction, and a higher rate of in-ICU organ failure, and were more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). In-hospital mortality was higher in MIS-A patients (31% vs 4%).

MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), whereas MIS-A had higher interferon-α2 (IFN-α2) and IL-8 levels. RNA polymerase III autoantibodies were present in 7 of 13 MIS-A patients (54%) but in none of the MIS-A+ patients.

Conclusion

MIS-A+ and MIS-A fulminant COVID-19–related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles. Differentiating these 2 phenotypes is relevant for patients’ management and further understanding of their pathophysiology.


Worldwide, there have been more than 6.2 million deaths resulting from SARS-CoV-2 infection to date. Although COVID-19 is associated with higher mortality in pa- tients with pre-existing heart failure, it has also been associated with de novo myocardial dysfunction.1 Acute myocarditis (AM) has been recognized as a rare complication of SARS-CoV-2 infection and of the COVID-19 mRNA vaccination.2,3

In a retrospective international cohort of 56,963 hospitalized pa- tients with COVID-19, the prevalence of AM varied from 2.4 to 4.1 per 1,000 patients if cases of only def- inite or probable AM cases were considered or if possible AM cases were also included.4 Patients with AM were young (median age 38 years) and were more often male.

The mortality was 6.6% at 120 days, and all deaths occurred in patients with concomitant pneumonia. Among patients with defi- nite or probable AM, 39% had fulminant myocarditis requiring inotropic support or mechanical circulatory support.
Fulminant myocarditis is associated with cardio- genic shock, ventricular arrhythmias, multiorgan dysfunction, and a frequent need for mechanical circulatory support, including venoarterial extracor- poreal membrane oxygenation (VA-ECMO).5

There has been an evolving understanding of the patho- genesis of fulminant myocarditis in COVID-19. Direct myocardial injury and inflammatory-mediated myocardial dysfunction have been 2 suggested pathways for development of COVID-19–associated fulminant myocarditis. Immunologic dysregulation can lead to the multisystem inflammatory syndrome (MIS) in young adults,6 as first described in children (MIS-C), with an onset occurring 2-6 weeks after acute infection.7

The clinical profile includes fevers, elevated inflammatory markers, rash, conjunctivitis, gastrointestinal symptoms, and myocardial dysfunc- tion. In a report from New York State, 53% of MIS-C patients had evidence of AM.8 Seen at a later time point, results of SARS-CoV-2 polymerase chain reac- tion (PCR) testing were not always positive, yet serologic testing and history implicated COVID-19 as the culprit.

However, our knowledge of COVID-19–associated fulminant myocarditis remains limited. In this issue of the Journal of the American College of Cardiology, Barhoum et al9 differentiate 2 phenotypes of this condition. One phenotype appeared to be associated with the adult MIS (MIS-Aþ), whereas the second occurred in adults who failed to meet MIS criteria (MIS-A).

This study was a single-center retrospective analysis from Paris, France of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit (ICU)  (March  2020  to  June 2021) for suspected fulminant COVID-19 myocarditis. Patients were confirmed to have SARS- CoV-2 infection by positive reverse transcription (RT)-PCR and/or by serologic testing.

Myocarditis

was defined as definite (76%) and probable (24%) by the criteria described by Bonaca et al10 for cancer therapeutics–related myocarditis. As noted in other studies, patients were predominantly young men (median age 27.5 years). The patients had severe left ventricular dysfunction (median left ventricular ejection fraction [LVEF] 20%), 79% presented with cardiogenic shock, and 42% required VA-ECMO. Overall, the mortality was 13% during hospitaliza- tion. Most patients had normalized their LVEF by discharge, and LVEF remained preserved at a median follow-up of 235 days.

With regard to the 2 phenotypes, 66% of patients met MIS-Aþ criteria, whereas the other 34% were classified  as  having  MIS-A.  The  2  groups  had  signif- icant differences in presentation, immunologic pro- files, and outcomes, likely driven by pathophysiologic differences.   In   general,   the   MIS-A  patients   were sicker and had worse outcomes. Specifically, compared   with   the   MISA-Aþ  patients,   the   MIS-A group had a shorter time between the onset of COVID-19 symptoms and the development of AM, a shorter time to ICU admission, and more severe pre- sentations as assessed by lower LVEF and sequential organ failure assessment (SOFA) scores. Further, the MIS-A   patients    had    higher    lactate    levels,    were more likely to undergo VA-ECMO (92% vs 16%), had higher ICU mortality (31% vs 4%; P ¼ 0.04), and a had lower 3-month cumulative probability of survival (68% ± 13%) compared with MIS-Aþ patients (96% ± 4%). The immunologic profiles also differed. The MIS-Aþ patients demonstrated markers of severe systemic inflammation (higher white blood cell count, C-reactive protein, procalcitonin, and tumor necrosis

factor-a) and elevated levels of interleukin (IL)-17 and IL-22 consistent with the mucocutaneous manifesta- tions,  as  compared  with  MIS-A  patients,  who  had higher interferon (IFN)-a2  and IL-8 levels. The MIS-A phenotype may thus  represent an exaggerated  innate immune response to the COVID-19 infection, whereas the MIS-Aþ phenotype may represent a maladaptive acquired immune response. Interestingly, more than one-half  of  MIS-A patients  had  RNA-polymerase  III antibodies.

Although the true significance of this finding is uncertain, an association with pre-existing RNA-polymerase III autoantibodies in patients without systemic sclerosis who developed viral myocarditis has been previously reported.11 In- vestigators have postulated that this finding may represent an altered viral defense or immune response. Genetic susceptibility to myocarditis has been described, suggesting that some patients may have vulnerable myocardium prone to inflammatory- mediated injury.12

Barhoum et al9 should be commended on  their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection. However, a few limitations should be acknowledged. Although this study presents the largest case series of COVID-19 related fulminant myocarditis to date, it consists of a modest number of 38 patients from a single center. This study is not able to estimate the incidence of fulminant myocarditis at the center given that the number of all COVID-19 hospitalizations during that time is not available.

Most patients were treated with immunosuppressive medications, although in this observational study, it is unclear whether therapies altered the clinical course. Immunosuppressive ther- apy is generally not well supported for most  acute viral myocarditis, but it does have a role in myocarditis of noninfectious origin (eg, immune checkpoint inhibitors, giant cell myocarditis, necrotizing eosin- ophilic myocarditis).13 Corticosteroids are recommended, however, for treatment of MIS-C, as well as for COVID-19 myocarditis and mRNA vaccine– associated myocarditis.3 Additionally, only 3  patients underwent endomyocardial biopsies, and only

2 of these biopsy specimens were diagnostic of myocarditis and were absent of viral inclusions. Other reports have rarely demonstrated the presence  of  viral inclusions by electron microscopy.14 In addition to an immune-mediated mechanism, viral injury in AM has been hypothesized to occur through myocardial tropism and direct cellular invasion. SARS-CoV-2 targets angiotensin-converting enzyme 2 receptors, which are expressed by a variety of cardiac cells.

In a study by Bailey et al,15 SARS-CoV-2 was shown to infect cardiomyocytes directly through an angiotensin-converting enzyme 2– and endosomal cysteine protease–dependent pathway and cause myocardial dysfunction by sarcomere breakdown and cardiomyocyte cell death. Engineered human tissue demonstrated evidence of cardiomyocyte infection, cell death, and macrophage infiltration.

The inflammatory finding was similar in autopsy and endo- myocardial specimens, where viral RNA staining was positive within cardiomyocytes. These findings are relevant  to  the  current  study,  where  MIS-A patients had evidence of early infection, including positive  PCR results without a positive serologic response.

Thus,  the  primary  finding  of  this  study  was that MIS-Aþ fulminant myocarditis likely represents a postinfectious complication of SARS-CoV-2 infection, characterized by a greater delay from initial symptoms to cardiac manifestations, positive serologic results, and negative RT-PCR results. In contrast, MIS-A  fulminant  myocarditis  occurred  earlier  after viral  infection and  was  marked by negative serologic

results, positive RT-PCR results, and an over- whelming immune response, including profound cardiogenic shock, and higher mortality. COVID-19 has increased the focus on the mechanisms of myocarditis and viral-associated myocardial dysfunction. Myocardial complications are caused by a direct viral insult, a systemic inflammatory response, or microvascular and macrovascular thrombosis. Fulminant myocarditis is rare and may result from either of 2 mechanisms: viral tropism or an immune-mediated mechanism.

It remains to be seen whether using antiviral therapy vs immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits. Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognizedn late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function. This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis.

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