Two distinct phenotypes of patients with sudden and severe COVID-19-related myocarditis have been identified in a new retrospective analysis of French intensive care unit (ICU) patients without a history of COVID-19 vaccination. The findings were published Monday online ahead of the July 26 issue of the Journal of the American College of Cardiology, with authors led by Sorbonne Université’s Petra Barhoum, MD, and Marc Pineton de Chambrun, MD, MSc. Adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can develop multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis, a rare but life-threatening condition. However, some COVID-19 patients who do develop fulminant myocarditis fail to meet MIS-A criteria, the researchers said. “[This suggests] the existence of distinct phenotypes in fulminant MIS-A criteria,” the researchers said; those with (MIS-A+) and those without (MIS-A–). The researchers, therefore, set out to study the clinical, biological, and immunological characteristics of patients with fulminant COVID-19-related myocarditis in 38 patients admitted to a single ICU in Paris between March 2020 and June 2021, who were either MIS-A+ (25 patients, 66%) or MIS-A– (13, 34%) patients. The entire cohort included more men (66%) and had a mean age of 27.5 years (interquartile range [IQR]: 19 to 37 years) and few comorbidities. All had a positive SARS-CoV-2 RT-PCR (37%) or serology (68%) with a median delay of 5 days between COVID-19 symptom onset and the first manifestation of myocarditis, and none had previously received a COVID-19 vaccine. The most frequent symptoms were fever (95%), abdominal pain or nausea (60%), chest pain (47%) and dyspnea (42%). In-ICU treatments included dobutamine (79%), norepinephrine (60%), mechanical ventilation (50%), venoarterial extracorporeal membrane oxygenation (42%), and renal replacement therapy (29%). At admission, the patients had severely impaired left ventricular function, with a median left ventricular ejection fraction [LVEF] of 20% (IQR: 14%-37%) and median left ventricle outflow tract velocity-time integral (LVOT-VTI) of 11 cm (IQR: 6-15 cm). They also had increased high-sensitivity T-troponin (median 1,300 ng/mL [IQR: 486-4,750 ng/mL]), and 79% presented with cardiogenic shock. Two distinct phenotypes Five patients died in the hospital, more of whom were in the MIS-A– group (13% overall: 31% in MIS-A– vs. 4% in MIS-A+; P = 0.04). All survivors recovered a near-normal cardiac function at distant follow-up. Those in the MIS-A– group were characterized by a shorter delay between COVID-19 symptom onset and myocarditis than those who met MIS-A+ criteria (median of 3 days vs. 8 days; P = 0.04); had a lower LVEF (median of 10% on ICU admission vs. 30%; P = 0.01); and a higher rate of in-ICU organ failure (day 0 Sequential Organ Failure Assessment score of 11 vs. 6 in MIS-A+ patients). MIS-A– patients were also more likely to require mechanical circulatory support with venoarterial extracorporeal membrane oxygenation (92% vs 16%; P < 0.0001). Cytokine profiling also “highlighted the presence of 2 distinct cytokine production profiles,” the researchers said. MIS-A+ had higher circulating levels of interleukin (IL)-22 (9.93 vs 1.5 pg/mL; P < 0.0001), IL-17 (3.2 vs 0.15 pg/mL; P < 0.0001), and tumor necrosis factor-a (TNF-a; 21.1 vs 8.0 pg/mL; P = 0.05). MIS-A–, on the other hand, had higher interferon-a2 (IFN-a2; 2.4 vs 0.013 pg/mL; P = 0.001) and IL-8 levels (158.7 vs 65.7 pg/mL; P = 0.02). RNA polymerase III autoantibodies were present in seven of the 13 MIS-A– patients (54%) – 5 of whom were female – but in none of the MIS-A+ patients. “MIS-A+ and MIS-A– fulminant COVID-19–related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis, and immunological profiles,” the researchers concluded. “Differentiating these 2 phenotypes is relevant for patients’ management and further understanding of their pathophysiology,” they added, noting that the role of RNA polymerase III autoantibodies in the fulminant myocarditis setting also requires further investigation. It “remains to be seen” whether using antiviral therapy vs immunomodulatory therapy on the basis of clinical and cytokine profiles could yield benefits, editorialists Ajith Nair, MD, of the Baylor College of Medicine, and Anita Deswal, MD, MPH, of the University of Texas MD Anderson Cancer Center, added in an accompanying editorial. “Most patients were treated with immunosuppressive medications, although in this observational study, it is unclear whether therapies altered the clinical course,” they added. Sources: Barhoum P, Pineton de Chambrun M, Dorgham K, et al. Phenotypic Heterogeneity of Fulminant COVID-19–Related Myocarditis in Adults. J Am Coll Cardiol 2022;80:299-312. Nair A, Deswal A. COVID-19–Associated Fulminant Myocarditis: Pathophysiology-Related Phenotypic Variance. J Am Coll Cardiol 2022;80:313-315. Image Credit: stockcrafter – stock.adobe.com