A Case Definition of a New Disease: A Review of the US Working Definition (USG) and 2024 NASEM Definition for Long COVID

SARS-CoV-2 infection can be followed by prolonged symptoms, signs and sequelae, collectively known under the term Long COVID. Hundreds of millions are estimated to suffer from Long COVID. Long COVID, therefore, is a public health crisis that deserves the utmost urgency from all relevant stakeholders, from policymakers to advocacy groups, researchers and healthcare providers. The development of effective definitions and guidelines for Long COVID is crucial to support patients and carers. In this review, I address the following two case definitions of Long COVID developed in the US as a case study for a broader discussion on the sequelae of SARS-CoV-2 infection: the U.S. Government (USG) working definition for Long COVID and the NASEM definition published in 2024. In the first part of this review, I provide a critical appraisal of the USG in light of research, pathophysiology and lived experience, building upon my intervention as a patient expert on a National Academies of Sciences, Engineering, and Medicine (NASEM) panel for defining Long COVID, which examined the USG. In the second part, I raise some pressing concerns to address when approaching Long COVID as a disease entity and as a concept, which I originally submitted to NASEM. In the third part, I offer a critical appraisal of the NASEM definition, the most recent benchmark for Long COVID in the US. The review highlights the importance of broad, expansive and inclusive definitions for Long COVID, accounting for the disease’s heterogeneous, fluctuating and multi-system manifestations. Clinical case definitions for Long COVID must retain their focus on the broader spectrum and scope of the disease entity, while incorporating feedback from people with lived experience, advocates and patient-researchers.