SOUNDING BOARD

FROM THE NATIONAL ACADEMY OF MEDICINE

Long Covid Defined

E. Wesley Ely, Lisa M. Brown, Harvey V. Fineberg., for the National Academies of Sciences, Engineering, and Medicine Committee on Examining the Working Definition for Long Covid

N Engl J Med Published July 31, 2024

DOI: 10.1056/NEJMsb2408466

The Covid-19 pandemic has been perceived mainly as a dangerous acute outbreak of infection that killed more than a million people in the United States and 7 million worldwide.^1,2However, in the pandemic’s wake, Covid-19 has left many millions more with a variety of chronic, systemic, and often disabling conditions collectively known as “long Covid.” In the United States alone, survey data indicate that approximately 7% of adults and more than 1% of children — numbering 15 to 20 million Americans and more than 60 million globally — have had long Covid.^3,4

Because of the novelty and diverse expression of this condition, a variety of terms and definitions have been advanced for long Covid, although none have gained wide acceptance and support from patients, clinicians, researchers, and government agencies. In recognition of the shortcomings of the existing definitions, the Administration for Strategic Preparedness and Response and the Office of the Assistant Secretary of Health in the Department of Health and Human Services tasked the National Academies of Sciences, Engineering, and Medicine (NASEM) with developing an improved definition for long Covid that would take into account the needs of patients as well as the views and understanding of a range of experts.

Here, we describe the process and rationale for the resulting 2024 NASEM long Covid definition.⁵ As committee members and lead staff who produced the definition, we can attest that the process inspired discovery and deepening appreciation for the reality and severity of this condition. As a clinician, one of us (Dr. Ely) can admit to early skepticism. Having worked with severely ill patients in the intensive care unit and researched their survivorship trajectories for 25 years,⁶ we found that the myriad signs and symptoms reported by patients with long Covid seemed to mirror those described by patients after critical illness. At first, it appeared plausible to attribute these numerous adverse outcomes — including cognitive impairment, neuromuscular disease, depression, and severe fatigue — to the acquired chronic disease state called the post intensive care syndrome (PICS).^7-9 This hypothesis faltered when symptoms similar to PICS began cropping up in tens of thousands of patients from the first wave of the pandemic, most of whom had never been admitted to a hospital during their acute SARS-CoV-2 infection and reported only mild initial symptoms. Patient advocacy groups marshalled social media and quickly established themselves as citizen scientists, coining the term long Covid.

Patients with long Covid join the ranks of millions before them with chronic conditions in which associations with infections have been found (e.g., myalgic encephalomyelitis–chronic fatigue syndrome, post-treatment Lyme disease, and multiple sclerosis, among others). These conditions had been identified during the preceding decades without a pandemic to garner concerted attention to their plight. Mindful of these patients, the committee set out to develop a definition for long Covid that offers legitimacy and a path toward therapeutic answers through future clinical trials.

Process

The committee found no standardized guidelines for developing a disease definition, apart from a few cautions about things to avoid, such as stigmatizing a group or place. The committee identified five criteria for such a definition: accuracy and precision, feasibility in application, acceptability to affected parties, accessibility and understandability, and balancing benefits and harms, including the potential effect on health equity and unintended consequences. The committee determined at the outset that engagement with patients who were affected by long Covid and interdisciplinary dialogue were critical to achieving the desired transparency, accuracy, relevance, usefulness, and acceptability of the definition.

The committee used a multiphase process of systematic engagement and information gathering. This process included the use of focus groups, a questionnaire, a public comment portal, and several public meetings, including a 2-day symposium. More than 1300 people participated in these activities, including patients and caregivers, public health and health care professionals, researchers, policy and advocacy professionals, payers, health care business professionals, and members of the public. In this outreach, the committee members sought input from persons who represented the full spectrum of interested and affected patients, geographic areas, and demographic groups. The detailed findings from the engagement process have been published in a publicly available report, What We Heard: Engagement Report on the Working Definition for Long Covid.¹⁰ The committee also scrutinized existing definitions for long Covid and assembled and analyzed primary literature and reviews related to this condition.

Definition

Recognizing the limitations of existing knowledge while taking full advantage of accumulating clinical and scientific data, the committee crafted a three-part definition of long Covid. The 2024 NASEM definition⁵ includes a core description, a list of characteristic symptoms and associated diagnosable conditions, and seven important features (Box 1). The essential elements of the definition are shown in Figure 1.

BOX 1. 2024 NASEM LONG COVID DEFINITION*

Long Covid is an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.

Long Covid manifests in multiple ways. A complete enumeration of possible signs, symptoms, and diagnosable conditions of long Covid would have hundreds of entries. Any organ system can be involved, and patients can present with the following:

• Single or multiple symptoms, such as shortness of breath, cough, persistent fatigue, postexertional malaise, difficulty concentrating, memory changes, recurring headache, lightheadedness, fast heart rate, sleep disturbance, problems with taste or smell, bloating, constipation, and diarrhea.

• Single or multiple diagnosable conditions, such as interstitial lung disease and hypoxemia, cardiovascular disease and arrhythmias, cognitive impairment, mood disorders, anxiety, migraine, stroke, blood clots, chronic kidney disease, postural orthostatic tachycardia syndrome and other forms of dysautonomia, myalgic encephalomyelitis–chronic fatigue syndrome, mast-cell activation syndrome, fibromyalgia, connective-tissue diseases, hyperlipidemia, diabetes, and autoimmune disorders such as lupus, rheumatoid arthritis, and Sjögren’s syndrome.

Important Features of Long Covid

• It can follow asymptomatic, mild, or severe SARS-CoV-2 infection. Previous infections may have been recognized or unrecognized.

• It can be continuous from the time of acute SARS-CoV-2 infection or have a delayed onset for weeks or months after what had appeared to be full recovery from acute infection.

• It can affect children and adults, regardless of health, disability, or socioeconomic status, age, sex, sexual orientation, race, ethnic group, or geographic location.

• It can exacerbate preexisting health conditions or present as new conditions.

• It can range from mild to severe and can resolve over a period of months or can persist for months or years.

• It can be diagnosed on clinical grounds; no biomarker that is currently available conclusively determines the presence of this condition.

• It can impair patients’ ability to work, attend school, take care of family, and care for themselves, resulting in profound emotional and physical effects on the patients, their families, and caregivers.

*This definition has been slightly edited from the original report⁵ with no intended change in meaning.

Terminology

To create a consistent definition, we needed to develop consistent terminology. Three notable aspects of terminology were adopted by the committee. First, the committee adopted the patient-coined term “long Covid” as a simple, well understood, and readily communicated label for this condition and urged its uniform use. Fancier or technical terms, such as postacute sequelae of Covid (PASC), lend a patina of arcanity while adding nothing to the meaning. Second, the definition situates long Covid among the larger class of infection-associated chronic conditions. The family of such conditions shares an association with acute infection by viruses, bacteria, fungi, or parasites, with long Covid representing only the most recent and prominent example. Third, the committee applied the term “disease state” to emphasize the reality and potential severity of the condition. We learned from patients’ reported interactions with physicians and other health care professionals that such terms as “syndrome” may connote an amorphous ailment that will be dismissed as not having a physical basis.

Comparisons

Table 1^11-16 compares the 2024 NASEM long Covid definition with six previous definitions of long Covid. Among the key components are attribution to acute infection, duration of symptoms, time course, clinical features, attention to equity, emphasis on functional impairment, relation to other diagnosable conditions, biomarkers, and risk factors.