The Painful Truth About Long Covid

By 2025, the medical community reached a significant consensus regarding the condition known as long Covid. Igho Ofotokun of the Emory University School of Medicine confirmed this shift during the Long Covid International Conference, stating, “I think everybody now agrees that long Covid is a biologic disease. It’s not in your mind. It’s real.”

The Challenge of Definition

Despite this agreement, the path toward effective treatment remains obstructed by a lack of a gold-standard definition. Ofotokun described this as the “big elephant in the room,” noting that the absence of a standardized classification makes the design and execution of clinical trials exceptionally difficult.

The primary barrier to a precise definition is the current lack of definitive biomarkers. Researchers look for genes, antibodies, or unique physiological signatures to identify a specific illness, but these have yet to be established for long Covid. Without these markers, scientists struggle to distinguish patients who have the condition from those whose symptoms may be caused by other underlying issues.

Did You Know? The National Academies of Sciences, Engineering, and Medicine (NASEM) definition of long Covid is intentionally inclusive, meaning a patient does not need a prior positive SARS-CoV-2 test to be considered affected by the condition.

Balancing Inclusion and Accuracy

The search for biomarkers is further complicated by the tension between scientific rigor and patient advocacy. Researchers must establish exclusionary criteria for studies; if these criteria are too strict, they may leave out genuine patients, but if they are too relaxed, they risk including individuals who do not have the condition, which could undermine the accuracy of the science.

In 2024, the National Academies of Sciences, Engineering, and Medicine (NASEM) addressed these concerns by creating an “intentionally inclusive” definition. This framework categorizes long Covid as an infection-associated chronic condition that persists for at least three months following a SARS-CoV-2 infection. It covers a wide spectrum, ranging from continuous to relapsing or progressive states that affect one or more organ systems.

Expert Insight: The push for an inclusive definition reflects the high stakes of clinical research. By prioritizing the patient perspective, the current framework seeks to ensure that no one suffering from these chronic, post-infection symptoms is left without recognition, though this broad approach may continue to complicate the search for the specific, measurable biomarkers needed for targeted therapies like gene therapy or antivirals.

Looking Toward Future Research

The field is now positioned to navigate the complexities of this new, broad definition. Because the NASEM criteria allow for the inclusion of patients with unrecognized infections and a wide array of symptoms—such as fatigue, cognitive changes, or gastrointestinal issues—the clinical trial landscape could change significantly.

Long COVID Conference – Session 4 – Mechanisms of Long COVID

Analysts expect that researchers may now face the challenge of refining these broad cohorts to identify subgroups that respond to specific interventions. If scientists can eventually isolate unique physiological signatures, it may lead to the development of disease-targeting interventions that can reliably distinguish long Covid from other conditions.

Frequently Asked Questions

What is the current medical consensus on long Covid?
Experts agree that long Covid is a real, biologic disease rather than a psychological one.

Why is it difficult to conduct clinical trials for long Covid?
The lack of a gold-standard definition and the absence of definitive biomarkers make it challenging to identify the correct patient population for study and to follow clinical outcomes.

Does a patient need a positive Covid test to be diagnosed with long Covid?
No, according to the NASEM definition, a prior infection may be recognized or unrecognized, meaning a positive test result is not required to meet the criteria.

How do you think the search for biomarkers will evolve as researchers begin to apply these new, inclusive definitions in clinical settings?