Discover how persistent symptoms and unexpected autoimmune risks are reshaping our understanding of COVID-19’s long-term impact on the youngest patients.

Study: Characteristics and predictors of Long Covid in children: a 3-year prospective cohort study. Image Credit: Gladskikh Tatiana / Shutterstock

In a recent study published in the journal eClinicalMedicine, researchers examined the predictors and characteristics of long coronavirus disease (long COVID) among the pediatric population assessed up to three years after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

They investigated whether coronavirus disease 2019 (COVID-19) vaccines could prevent reinfections and the development of long COVID or autoimmune diseases.

The study is particularly significant as it provides the longest follow-up data available on pediatric long COVID, underscoring the need for continued research and clinical focus on this condition.

Background

Long COVID, also known as post-acute sequelae of  COVID-19 (PASC) or post-COVID condition, consists of persistent symptoms of COVID-19 that last long after the patient has recovered from the initial SARS-CoV-2 infection.

The symptoms are often debilitating and consist mainly of fatigue, dyspnea, musculoskeletal aches, post-exertional malaise, and headaches. However, the symptoms of long COVID are known to impact almost every organ system, with neurological symptoms such as brain fog and memory impairments being reported.

Importantly, the study highlighted that these symptoms significantly interfere with children’s daily activities, including their education and social interactions, which can lead to long-term developmental challenges.

Numerous studies have suggested that long COVID can also occur in children, especially adolescents, after asymptomatic to mild infections.

Recent research has focused on understanding the underlying mechanisms of long COVID in adults, and factors such as immune dysregulation, persistent activation of immune responses, and thromboinflammation have been implicated.

However, the current study is unique in its rigorous clinical assessments and exclusion of other conditions, offering a more precise characterization of long COVID in children.

About the study

In the present study, the researchers examined the risk factors associated with the development of long COVID in children and the persistent symptoms and characteristics of long COVID in the pediatric population.

They used in-clinic assessment data for up to 36 months after the initial infection and also evaluated the probability of reinfections and new onset autoimmune disorders due to long COVID among children.

The study’s methodology stands out due to its in-person assessments at multiple intervals, ensuring a high level of accuracy and reliability in diagnosing long COVID, as well as its use of a standardized protocol aligned with WHO’s definition of post-COVID-19 condition.

The study included children up to the age of 18 years who were referred to the post-COVID outpatient clinic after recovering from an initial SARS-CoV-2 infection.

The in-clinic assessments occurred twice in the first six months and then every six months for the next two years. The last follow-up was conducted 36 months after the infection.

Notably, the study did not only rely on self-reported symptoms but involved detailed medical evaluations conducted by experienced clinicians, which is a critical advancement over previous studies that often used online surveys.

The first two follow-ups were conducted in person by doctors for all the participants. Subsequent follow-ups for patients who reported returning to normal pre-COVID levels of health were conducted telephonically. For patients who reported long COVID symptoms, all the follow-ups were in-person.

Baseline data included information on the initial SARS-CoV-2 infection severity, medication and hospitalization information, COVID-19 symptoms, vaccination doses and status, demographic information, and data on any pre-existing health conditions.

The study also carefully excluded other potential causes of symptoms, such as glycemia, anemia, and other infections, ensuring that the diagnosis of long COVID was accurate and reliable.

A detailed symptom log of a wide range of gastrointestinal and neurological symptoms was recorded during the follow-ups. Any reinfections were documented, and the researchers investigated the development of any new autoimmune disorders after the SARS-CoV-2 infection.

The meticulous documentation and analysis of these symptoms provided valuable insights into the persistence and evolution of long COVID symptoms over time.

The World Health Organization’s definition of post-COVID-19 condition, which includes persistent symptoms beyond three months and the appearance of new symptoms not reported before the SARS-CoV-2 infection that any alternate diagnoses cannot explain, was used to define long COVID.

A range of tests were also conducted to rule out other conditions such as glycemia, anemia, intestinal parasites, celiac disease, hematologic diseases, and thyroid, liver, or kidney issues. This rigorous approach allowed the researchers to confidently attribute the symptoms to long COVID, rather than other potential causes.

Results

The study found that long COVID exerted a significant long-term burden on children with SARS-CoV-2 infections.

Furthermore, an infection with the ancestral SARS-CoV-2 variant was associated with an increased risk of developing autoimmune disorders.

Specifically, 1.1% of the children developed new-onset autoimmune disorders, such as Hashimoto Thyroiditis and Celiac Disease, which is notably higher than the general prevalence of autoimmune diseases in the pediatric population.

Commonly reported symptoms included fever, rhinitis, and cough. Approximately 1,300 children were assessed for long COVID at the three-month follow-up, out of which 23.2% met the criteria.

The proportion of children who were symptomatic for long COVID decreased to 13.2% by the six-month follow-up and further dropped to 7.9% one year after the initial SARS-CoV-2 infection.

However, the study noted that a small but significant percentage of children continued to experience symptoms even at the 36-month follow-up, indicating the potential for very long-term health impacts.

At 18 months, 6.1% of the participants continued to exhibit long COVID symptoms. Of the 47 patients who were assessed during the follow-up at 36 months, 11 still had persistent long COVID symptoms, including respiratory problems and fatigue.

Interestingly, the study also observed a paradoxical increase in long COVID risk among older adolescents (17-18 years) who received three vaccine doses, which may be due to a selection bias in the study population.

Infections from the ancestral and Alpha variants, as well as factors such as pre-existing comorbidities, female sex, and older age, increased the risk of developing long COVID.

However, three doses of the COVID-19 vaccine were found to protect against long COVID, with the effect being more apparent among older children.

The rate of reinfections was close to 19%, with two reinfections observed in 2.58% of the participants. Two or more doses of the COVID-19 vaccine were also found to protect against reinfections. Infections with the early variants of SARS-CoV-2 were linked to a 1.1% risk of new-onset autoimmune disorders.

The study highlighted that despite the overall low severity of reinfections, they remain a concern, particularly for children who had long COVID after their initial infection.

Conclusions

Overall, the findings indicated that long COVID was a significant health concern among children, with some experiencing persistent symptoms for up to 36 months.

Long COVID was also found to increase the risk of new-onset autoimmune disorders in children. Given these findings, the researchers emphasized the urgent need for dedicated pediatric long COVID clinics and research centers to develop effective diagnostic tools and treatments.

They also called for ongoing public health efforts to raise awareness of the risks associated with long COVID in children, especially as vaccine uptake declines in many populations.