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Children and adolescents with COVID had more prevalent long-lasting symptoms than those never infected with SARS-CoV-2, the study showed.

In every age group, previously infected children in Denmark had higher odds of experiencing at least one symptom lasting more than 2 months than their uninfected peers, reported Selina Kikkenborg Berg, PhD, of Copenhagen University Hospital, and co-authors.

Among children 3 and younger, 40% who had COVID had persistent symptoms compared with 27.2% of controls (OR 1.78, 95% CI 1.55-2.04), Berg and colleagues wrote in .

In children 4-11 years old, 38.1% with COVID and 33.7% without COVID had long-lasting symptoms (OR 1.23, 95% CI 1.15-1.31). Persistent symptoms also were reported in 46% of adolescents ages 12-14 with COVID and 41.3% without COVID (OR 1.21, 95% CI 1.11-1.32, P<0.0001 for all).

"Our results reveal that, although children with a positive COVID-19 diagnosis are more likely to experience long-lasting symptoms than children with no previous COVID-19 diagnosis, the pandemic has affected every aspect of all young people's lives," Berg said in a statement.

The study involved surveys of mothers or guardians of 10,997 children who had tested positive for SARS-CoV-2 infection between January 2020 and July 2021 in Denmark and 33,016 children who weren't infected, matched 1:4 by age and sex.

The survey included assessments of pediatric quality of life and information from the Children's Somatic Symptoms Inventory-24 to evaluate overall health, plus questions about 23 of the most common long COVID symptoms. The researchers used the World Health Organization's definition of long COVID -- persistent symptoms lasting more than 2 months without an alternative diagnostic explanation -- in their analysis.

The most commonly reported symptoms in children age 3 and younger were mood swings, rashes, and stomach aches. Mood swings, trouble remembering or concentrating, and rashes were most common in 4-11 year-olds; fatigue, mood swings, and trouble remembering or concentrating were most common in those 12-14.

Differences in somatic symptom inventory scores were not clinically relevant, Berg and colleagues reported. But, in some age groups, children who had COVID had better quality-of-life scores than those not infected, they noted.

Median pediatric quality-of-life emotional functioning scores were 80 for cases and 75 for controls among children ages 4-11, and 90 for cases and 85 for controls among those 12-14 (P<0.0001 for both).

Quality-of-life social functioning scores also were higher for COVID cases than controls among those 12-14 (100 vs 95, P<0.0001).

These findings may be because controls "experienced fear of the unknown disease and had a more restricted everyday life because of protecting themselves from catching the virus," Berg and co-authors observed. "Pandemic symptoms in children have been suggested and might be caused by poor thriving from lockdown and social restrictions."

How to interpret this data is challenging, noted Maren Johanne Heilskov Rytter, PhD, of University of Copenhagen, in an .

Not only were response rates in the survey low for both cases (27%) and controls (22%), the differences between symptom rates in the two groups were slight and "probably of limited clinical significance," Rytter wrote.

Research into COVID-19 "is like trying to hit a moving target," she pointed out, noting this study already is "somewhat historical" because cases were infected with a different strain of SARS-CoV2, not the dominant variant today.

"More recent strains also appear to cause less severe symptoms," Rytter added. "For most children with non-specific symptoms following COVID-19, the symptoms are more likely to be caused by something other than COVID-19 and if they are related to COVID-19, they are likely to pass with time," she wrote.

Berg called for further research into the long-term consequences of the pandemic in all children, not just those infected, before a window of opportunity closes. Over half of children in Denmark already had lab-confirmed SARS-CoV-2 infection as of February 2022, narrowing the ability to isolate the long-term effect after acute infection in this population.

"The window for investigating long COVID is closing up," Berg wrote in an email. "In my opinion, we desperately need clinical studies examining these children suffering from long-lasting symptoms who need symptom relief."

A reliance on parental proxy may have skewed survey results, leading to selection bias and an overrepresentation of affected children, Berg and colleagues acknowledged. Given a lack of public testing for COVID-19 before August 2020, some children with undetected asymptomatic infections might not have been included in the study.

"Because long COVID symptoms are the same as some ailments that are common in children, possible differences between groups could be masked by competing diseases and vaccine side-effects," the researchers noted.

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