The trajectory of long-COVID in the general population of Scotland

In a recent Research Square* preprint paper that is under review at Nature Portfolio, researchers presented the findings of the Long-coronavirus disease (COVID) in Scotland Study (Long-CISS) conducted nationwide among the general population of Scotland.

Study: Natural history of long-COVID in a nationwide, population cohort study. Image Credit: View Apart/Shutterstock


Most studies have documented the prevalence of long-COVID at a single time point. Moreover, studies have made outcome measurements in hospitalized, older patients with specific issues (e.g., mental health), not the general population. They also lacked a control group to draw comparisons.

Furthermore, there is a shortage of studies investigating temporal changes in long-COVID. Though it might be a stable condition in some cases, data suggests that it relapses or progresses to a worsened state in most cases. In some cases, a patient recovers from long COVID.

Nevertheless, a better understanding of the scale and natural course of long-COVID is urgently needed to offer care and support to its ever-increasing patients.

About the study

In the current study, researchers investigated the natural history of long-COVID in the Long-CISS cohort using serial questionnaires filled out by enrolled participants at six, 12, and 18 months after the first positive reverse transcription-polymerase chain reaction (RT-PCR) test.

The Long-CISS study began in May 2021 and enrolled eligible participants retrospectively and prospectively. First, the researchers identified eligible adults (>16 years) using the National Health Service (NHS) Scotland notification platform. Then, they invited those with a positive RT-PCR test (from April 2020) via automated text messages.

The inclusion criteria also mandated that people complete a six-month follow-up questionnaire plus one more questionnaire. Next, they enrolled a comparison group with individuals testing COVID-19-negative, matched by age, gender, and deprivation quintile.

The recruited participants also self-reported their recovery status (fully or partially recovered or not recovered) after COVID-19 diagnosis, with the prevalence of its 26 symptoms. Additionally, they provided information on their pre-existing comorbidities and quality of life (QoL). The team computed the median EQ-5D score of the two study groups at six and 12 months.

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Finally, the researchers used McNemar’s tests to compare the changes in the prevalence of the 26 COVID-19 symptoms between the two study groups. They ran separate binary logistic regression models for the presence of each symptom at 12 months and repeated those at 18 months.

Study findings

Of the 80,332 individuals who had RT-PCR diagnosed symptomatic COVID-19, 12,947 and 4196 completed questionnaires at six- and 12-month and six- and 18-month follow-ups, respectively. The number of people in the control group who completed questionnaires at six- and 12-month and six- and 18-month follow-ups were 11,026 and 1,711, respectively.

Regarding recovery status, 41% of the study cohort self-reported full recovery at six- and 12-month follow-ups, while 35% reported no recovery, of which 12% reported improvement, but another 12% reported a deterioration. The 12% whose condition deteriorated between six and 12 months had depression before contracting COVID-19. Six- and 18-month follow-ups revealed a similar pattern.

Thankfully, altered smell, taste, or brain fog-like symptoms resolved over time. However, after accounting for potential confounders, the COVID-19 group reported having a dry cough, productive cough, and hearing problems between six- and 18-months follow-up, which did not resolve on their own. Thus, different symptoms drove these different recovery trajectories. Notably, studies have proposed that severe acute respiratory syndrome coronavirus 2 directly invades the ear via angiotensin-converting enzyme 2 (ACE2) receptors. Moreover, it triggers hearing loss that can persist.

The study findings also revealed that compared to controls, people with symptomatic COVID-19 showed more fall in EQ-5D score. The median EQ-5D scores dipped from 75 to 74 between six and 12 months of follow-up. It also decreased among controls, from 80 to 77.

Beyond six months following symptomatic COVID-19, people barely reported any changes in recovery status or symptoms. However, 70.7% of people in the study group had at least one persistent symptom, such as fatigue or dyspnoea till 12 months. The prevalence of these symptoms was also high among people in the comparison group, further highlighting the importance of having a control group.


To summarize, long-COVID appeared like a stable condition in many cases, with many people self-reporting improvement and deterioration. However, potential confounding could not explain the findings of late-onset cough and hearing problems 12 months post-infection. Thus, future studies with longer follow-ups should investigate the underlying reasons for the persistence of the long COVID symptoms.

*Important notice

Research Square publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Pell, J. et al. (2023) "Natural history of long-COVID in a nationwide, population cohort study". Research Square. doi: 10.21203/

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Brain, Brain Fog, Coronavirus, Coronavirus Disease COVID-19, Cough, covid-19, Depression, Ear, Enzyme, Fatigue, Hearing, Hearing Loss, Mental Health, Polymerase, Polymerase Chain Reaction, Research, Respiratory, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Transcription

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Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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