BREAKING! French Researchers Identify Two Unique Phenotypes of SARS-CoV-2 Infections Related Myocarditis!
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.
According to the study team, typically adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. However, it has been found that several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19–related myocarditis.
The study team 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−).
The study team employed a monocentric retrospective analysis of consecutive fulminant COVID-19–related myocarditis in a 26-bed intensive care unit (ICU).
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%.
The study team found that only 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%).
However, MIS-A+ had higher circulating levels of interleukin (IL)-22, IL-17, and tumor necrosis factor-α (TNF-α), while 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.
The study findings concluded that 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.
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
The study findings showing the differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiologic studies.
It should be noted that the first phenotype occurs early ie typically within a few days in acute SARS-CoV-2 infection, with active viral replication (PCR+) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).
Co-researcher, Dr Guy Gorochov, MD, PhD, Sorbonne University, told Thailand <
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, “It was found that in this early phenotype, there is limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation or ECMO."
He added, “The second phenotype is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A ie MIS-A–.
Dr Gorochov said that this second phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions.
The study findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit (ICU) for suspected fulminant COVID-19 myocarditis.
All study participants were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.
Importantly, it was found that the MIS-A– patients were sicker and had worse outcomes.
When compared with the MIS-A+ patients, the MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction (LVEF) and sequential organ failure assessment (SOFA) scores.
Also, MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs 4%), and a had lower probability of survival at 3 months (68% vs 96%) compared with their MIS-A+ peers.
Interestingly, the study findings also found that the immunologic profiles of these two distinct clinical phenotypes also differed.
It was found that in MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-(IL)-8 are elevated.
However, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.
Dr Gorchov added, “Based from our study findings, we strongly suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A.
He further stated, “Furthermore, it should be studied as to whether IL-17 and IL-22 are also elevated in children with MIS-C.”
Significantly, the study team found extremely elevated serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.
The study team said that the phenotypic clustering of patients with fulminant COVID-19-related myocarditis is important for clinical management of patients.
The study team recommended that MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be urgently referred to a center with venoarterial ECMO and closely monitored to prevent a ‘too-late’ cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes.
The study team noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.
The study team however found that the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases.
The study team added, “However, identifying MIS-A+ cases is all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C treatment.”
Dr Ajith Nair, MD, Baylor College of Medicine, and Dr Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, in a linked editorial said that French researchers should be "commended on their work in furthering the understanding of fulminant myocarditis related to COVID-19 infection."
They said that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.
They added, "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 recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function.”
Both Dr Nair and Dr Deswal concluded, "The research findings highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis.”
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