People who had COVID reported a wider range of post-infection symptoms to their primary care physicians than expected, a retrospective matched cohort study in the U.K. showed.

Overall, 62 symptoms were significantly associated with a history of SARS-CoV-2 infection after 12 weeks, reported Krishnarajah Nirantharakumar, MBBS, MPH, of University of Birmingham in England, and colleagues.

Symptoms with the largest adjusted HRs were anosmia (HR 6.49), hair loss (HR 3.99), sneezing (HR 2.77), ejaculation difficulty (HR 2.63), reduced libido (HR 2.36), shortness of breath at rest (HR 2.20), fatigue (HR 1.92), pleuritic chest pain (HR 1.86), hoarse voice (HR 1.78), and fever (HR 1.75), they wrote in Nature Medicine.

Twenty of the 62 reported symptoms were among the 33 symptoms listed in the World Health Organization (WHO) clinical case definition of long COVID. Overall, 5.4% of people with COVID and 4.3% of people without COVID reported at least one symptom included in the WHO case definition.

Overarching definitions like the WHO’s and the CDC’s are commonly used, but some experts have cautioned against rushing to define long COVID. While persistent post-infection problems like fatigue, shortness of breath, and cognitive dysfunction have a significant effect on people’s lives, long COVID symptoms are more extensive than this, Nirantharakumar’s group noted.

“This research validates what patients have been telling clinicians and policy makers throughout the pandemic, that the symptoms of long COVID are extremely broad and cannot be fully accounted for by other factors such as lifestyle risk factors or chronic health conditions,” co-author Shamil Haroon, PhD, MPH, also of University of Birmingham, said in a statement.

“The symptoms we identified should help clinicians and clinical guideline developers to improve the assessment of patients with long-term effects from COVID-19, and to subsequently consider how this symptom burden can be best managed,” he added.

The researchers evaluated 486,149 adults with confirmed COVID-19 from January 2020 to April 2021 who were not hospitalized with infection, and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection in U.K primary care records. They assessed relative differences in 115 symptoms 12 weeks after people in the COVID group were infected.

Mean age of participants was 43.8 and 55.3% were female. Most (64.7%) were white, while 12.2% were Asian, and 4.0% were Black Afro-Caribbean. In total, 53.8% were overweight or obese and 22.5% were current smokers.

Women had an increased risk of long COVID symptoms than men (adjusted HR 1.52). In univariate analyses, ages over 30 were associated with a higher risk of long COVID symptoms, but after adjusting for baseline covariates, people ages 30-39 had a 6% lower risk and people ages 70 and older had a 25% lower risk than those ages 18-30 years.

Other risk factors included being part of an ethnic minority group, socioeconomic deprivation, smoking, obesity, and a wide range of comorbidities.

The researchers identified three clusters of long COVID phenotypes based on their data: people with a broad spectrum of symptoms, including pain, fatigue, and rash (80.0%); people with mainly respiratory symptoms, including cough, shortness of breath, and phlegm (5.8%); and people with predominantly mental health and cognitive symptoms, including anxiety, depression, insomnia, and brain fog (14.2%).

A key study limitation was its use of routinely coded healthcare information. Primary care records may not reflect the true symptom burden of long COVID, which may be underestimated or overestimated in this data set, the researchers acknowledged.

“The symptom data we used for the study thus cannot be used to make inferences about the absolute prevalence of these symptoms,” Nirantharakumar and colleagues cautioned.

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