Phenotypic Heterogeneity of Fulminant COVID-19--Related Myocarditis in Adults

Abstract

Background: Adults who have been infected with SARS-CoV-2 can develop a multisystem inflammatory syndrome (MIS-A), including fulminant myocarditis. Yet, several patients fail to meet MIS-A criteria, suggesting the existence of distinct phenotypes in fulminant COVID-19-related myocarditis.

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.

Keywords: COVID-19; RNA polymerase III autoantibodies; SARS-CoV-2; VA-ECMO; cytokines; fulminant myocarditis; multisystem inflammatory syndrome.

Graphical abstract

Figure 1

Circulating Cytokines Levels in Fulminant COVID-19–Related Myocarditis Comparison of 6 circulating serum cytokines levels (IL-8, -10, -17, -22, IFN-α2, and TNF-α) in patients with MIS-A⁺/MIS-A⁻ and healthy controls. MIS-A⁺ had higher IL-22, IL-17, and TNF-α, whereas MIS-A⁻ had higher IFN-α2 and IL-8. Methods: serum concentrations of IL-8, IL-10, IL-22 and TNF-α were measured on a Quanterix SP-X imaging and analysis platform using the Human CorPlex Cytokine Panel Array kit (Quanterix). Single-plex bead-based ultrasensitive immunodetection of IL-17A and IFN-α was performed by digital ELISA using the Simoa (single molecule array) HD-1 analyzer (Quanterix), according to the manufacturer’s instructions. For box and whisker plots: the center line denotes the median value (50th percentile), whereas the box contains the 25th to 75th percentiles of dataset. The whiskers mark the 5th and 95th percentiles. IFN = interferon; IL = interleukin; MIS-A = multisystem inflammatory syndrome in adults; TNF = tumor necrosis factor.

Figure 2

PCA of Parameters Associated With COVID-19–Related Myocarditis Unsupervised PCA was performed using R software v3.6.2 with the FactoExtra and FactoMineR functions, on z-scaled log10-transformed cytokine concentrations. Samples with missing data were excluded from the PCA analysis for 1 MIS-A⁺ patient and 2 MIS-A⁻ patients. Ellipses with 66% CI are drawn for each group. (A) The principal component analysis of 10 circulating serum cytokines. (B) The principal component analysis including clinical findings, laboratory findings and immunological profiles highlight the main features of MIS-A⁻ and MIS-A⁺ fulminant COVID-19–related myocarditis phenotypes. CRP = C-reactive protein; LVEF = left ventricular ejection fraction; PCA = principal component analysis; RT-PCR = reverse transcription polymerase chain reaction; SOFA = Sequential Organ Failure Assessment; other abbreviations as in Figure 1.

Central Illustration

Main Phenotypic Differences Between Fulminant COVID-19–Related Myocarditis With and Without Multisystem Inflammatory Syndrome in Adults MIS-A⁺ and MIS-A⁻ fulminant COVID-19–related myocarditis patients have 2 distinct phenotypes with different clinical presentations, prognosis and immunological profiles. For box and whisker plots: the center line denotes the median value (50th percentile), whereas the box contains the 25th to 75th percentiles of dataset. The whiskers mark the 5th and 95th percentiles. ICU = intensive care unit; MIS-A = multisystem inflammatory syndrome in adults; RT-PCR = reverse transcription polymerase chain reaction; U.S.-CDC = U.S. Centers for Disease Control and Protection.