Objective: This report describes persistent symptoms associated with post-acute COVID-19 syndrome (PACS) and the impact of these symptoms on physical function, cognitive function, health-related quality of life, and participation. Design: This study used a cross-sectional observational study design. Patients attending Mount Sinai’s post-acute COVID-19 syndrome clinic completed surveys containing patient-reported outcomes. Results: A total of 156 patients completed the survey, at a median (range) time of 351 days (82–457 days) after COVID-19 infection. All patients were prevaccination. The most common persistent symptoms reported were fatigue (n = 128, 82%), brain fog (n = 105, 67%), and headache (n = 94, 60%). The most common triggers of symptom exacerbation were physical exertion (n = 134, 86%), stress (n = 107, 69%), and dehydration (n = 77, 49%). Increased levels of fatigue (Fatigue Severity Scale) and dyspnea (Medical Research Council) were reported, alongside reductions in levels of regularly completed physical activity. Ninety-eight patients (63%) scored for at least mild cognitive impairment (Neuro-Qol), and the domain of the EuroQol: 5 dimension, 5 level most impacted was Self-care, Anxiety/Depression and Usual Activities. Conclusions: Persistent symptoms associated with post-acute COVID-19 syndrome seem to impact physical and cognitive function, health-related quality of life, and participation in society. More research is needed to further clarify the relationship between COVID-19 infection and post-acute COVID-19 syndrome symptoms, the underlying mechanisms, and treatment options.

• AM is an important cause of cardiac dysfunction following some viral infections and has been previously linked with genetic host susceptibilities. • Sequencing data for genes related to cardiomyocyte structure and function was compared between patients with AM and sex- and ancestry-matched heart-healthy control subjects. • Putatively DVs among these genes were found in ∼16% of AM cases, contributing to viral susceptibility. • Implicated genes are ones classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement, suggesting shared mechanistic pathways. • Phenotypes, including outcomes, were similar in subjects who have AM with and without DV, therefore genetic testing will be necessary to uncover this subtype and inform risk in relatives.

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2–specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1β, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3 ⁺ cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2 ⁺ CD163 ⁺ monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell–associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine–-associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.