Identifying commonalities and differences between EHR representations of PASC and ME/CFS in the RECOVER EHR cohort

Introduction

The occurrence of post-acute phenomena in the aftermath of viral infections has been recognized for centuries^1,2, but the emergence of post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has cast a spotlight on these illnesses, emphasizing the critical need for research into their commonalities and distinctions, as well as their underlying mechanisms. PASC can be defined as ongoing, relapsing, or new symptoms, or other health effects occurring after the acute phase of SARS-CoV-2 infection (i.e., present four or more weeks after the acute infection). Literature has particularly identified similarities between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex chronic disorder affecting multiple body systems and frequently heralded by an infection, necessitating empirical studies that compare the two^3,4. Such an examination is vital to advance research into PASC and related infection-associated chronic diseases.

PASC can be characterized by multi-organ effects or autoimmune conditions with symptoms lasting months to years⁵. One of the biggest challenges in studying PASC is the complexity of the disease as it can variously affect the respiratory, gastrointestinal, musculoskeletal, neurological, cardiovascular, and endocrine systems, as well as mental health⁶.

Some research indicates that approximately half of patients with PASC eventually meet criteria for ME/CFS^7,8. This connection is underscored by the similarities in symptoms and proposed pathobiological mechanisms, including redox imbalance, systemic inflammation, and mitochondrial dysfunction⁹. Thus, some patients with PASC might have ME/CFS triggered by the SARS-CoV-2 virus.

While the substantial symptom overlap and biological abnormalities between PASC and other infection-associated chronic illnesses highlight potential common pathophysiological bases¹⁰, it is important to recognize that PASC signifies any long-term symptoms after SARS-CoV-2 infection. Some patients’ pathologic features are centered around damage to specific organs or organ systems, as in cardiomyopathy or lung fibrosis¹¹. Patients may also develop syndromic infection-associated chronic illnesses, including ME/CFS, mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), other dysautonomias, or pediatric acute-onset neuropsychiatric syndrome^12,13.

Given the multifaceted nature and complexity of PASC, it is imperative to delineate and identify its various subphenotypes. Although the symptoms and diagnoses recorded in electronic health records (EHRs) involve subjectivity, systematic differences, and potential clinician biases in what information gets recorded