Researchers map eight distinct long Covid symptom paths across COVID-19 study

An analysis from the United States National Institutes of Health RECOVER Initiative has identified eight distinct long Covid symptom trajectories in adults infected during the Omicron era, with more than four in five affected patients still unwell after one year

Millions of patients worldwide have developed long Covid, a chronic condition that can include a wide range of symptoms such as fatigue, cognitive difficulties often described as ‘brain fog’, dizziness, palpitations and breathlessness that persist for at least three months after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinicians and researchers use the term long Covid, also known as post-acute sequelae of SARS-CoV-2 infection, to describe this constellation of ongoing or relapsing symptoms that can disrupt work, family life and daily functioning for many months.

In a recent analysis of adults enrolled in the US National Institutes of Health (NIH) funded Researching COVID to Enhance Recovery (RECOVER) Initiative, investigators at Mass General Brigham, Boston, Massachusetts, have identified eight distinct symptom trajectories that long Covid can follow, defined by severity, duration, and whether symptoms ease or worsen over time. The work has provided one of the most detailed longitudinal pictures to date of how long Covid evolves after infection in the Omicron variant era.

“This study addressed the urgent need to define the differing long Covid trajectories,” said senior author Dr. Bruce Levy, of the Mass General Brigham Department of Medicine and the Division of Pulmonary and Critical Care Medicine.

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“Our findings will help determine what resources are needed for clinical and public health support of individuals with long Covid and will also inform efforts to understand long Covid’s biological basis,” he said.

By ‘trajectories’, the team referred to recognisable patterns in symptom burden and change over time which can help clinicians to counsel patients about likely courses of illness and support planning for services.

To characterise these trajectories, the researchers followed 3,659 adult RECOVER participants who first contracted COVID-19 during the Omicron variant period, after 1 December 2021. All participants had laboratory-confirmed coronavirus infection and enrolled in the study within the first year after illness. They then completed a comprehensive symptom questionnaire at 3, 6, 9, 12 and 15 months after infection, which allowed the investigators to track how symptom profiles shifted over time instead of relying on a single time point.

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The team used the long Covid research index, a symptom-based scoring tool previously developed by Mass General Brigham investigators, to identify participants with long Covid. This index integrates the presence and severity of multiple symptoms that earlier work has linked to long Covid and produces a composite score that distinguishes likely long Covid from typical recovery after acute infection.

Overall, 10.3% of patients met criteria for long Covid symptoms three months after infection. Among this long Covid group, 81% continued to experience persistent or intermittent symptoms one year later, which highlighted the extent to which long Covid can represent a long-term condition rather than a brief post-viral period.

Female patients and those who had required hospital admission during their acute SARS-CoV-2 infection were more likely to develop long Covid with symptoms that remained severe over time, which reinforced earlier observations that sex and acute disease severity influence long-term outcomes.

The researchers then applied statistical clustering methods to symptom scores across all time points and identified eight distinct long Covid trajectories. These included groups with persistently severe symptoms that remained high throughout follow-up, intermittently severe symptoms that flared and eased, and gradually improving symptoms in which patients started with a heavy symptom burden that slowly decreased.

Other groups had gradually worsening symptoms that intensified months after infection, or predominantly mild symptoms that only emerged or became apparent after 15 months, which underlined that long Covid does not follow a single typical pattern.

“The variability we identified will enable future studies to evaluate risk factors and biomarkers that could explain why patients vary in time of recovery, and help identify potential therapeutic targets,” said first author Dr. Tanayott Thaweethai, assistant professor at Massachusetts General Hospital Biostatistics.

By aligning biological samples, imaging data or digital health measures with each of the eight symptom patterns, researchers aim to discover signatures that distinguish, for example, a persistently severe trajectory from a gradually improving one. Such information could guide stratified trial designs and help clinicians match possible treatments to the patients most likely to benefit.

The RECOVER team has emphasised that these findings support the need for sustained clinical services for long Covid, because a large majority of affected patients still have symptoms one year after infection. The recognition of distinct trajectories has also provided a framework for public health planning, since different groups may require different levels and types of support. As additional data accrue and as more biomarker and mechanistic studies align with these trajectories, the field has moved closer to a clearer biological understanding of long Covid and to the development of targeted interventions.

For further reading please visit: 10.1038/s41467-025-65239-4