Exploring Long COVID in Pediatric Patients: Clinical Insights from a Long COVID Clinic

doi:10.21203/rs.3.rs-4909371/v1

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Exploring Long COVID in Pediatric Patients: Clinical Insights from a Long COVID Clinic

https://doi.org/10.21203/rs.3.rs-4909371/v1

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Background: Long COVID or post-acute sequelae of SARS-CoV-2 infection is a persistent condition following acute SARS-CoV-2 infection, affecting both adults and children. However, studies exploring the clinical spectrum and the impact of vaccination on long COVID in children remain limited.

Methods: We conducted a retrospective chart review and data analysis of children aged 0-21 years who were seen at the long COVID clinic at Children’s Hospital Los Angeles between August 2021 and November 2023. All statistical analyses were performed using R Studio 4.2.2.

Results: The study included 123 patients with a mean age of 13.1 years, of whom 63 (51.2%) were males. The mean onset of symptoms occurred 5 weeks after SARS-CoV-2 infection, with an average symptom duration of 31.3 weeks at presentation. Notably, 23 patients (18.6%) experienced symptoms lasting over 12 months. The most commonly reported symptoms were fatigue (92.7%), headache (69.9%), exercise intolerance (52.8%), dizziness (43.9%), and brain fog (40.7%). Among 74 patients with at least one follow-up visit, a general decrease in symptom severity was observed over time. No significant difference was found in the mean number of symptoms at 6 or 12 months between vaccinated and unvaccinated groups. Of the 43 patients vaccinated after the onset of long COVID, 19 (44.2%) reported symptom improvement.

Conclusion: Fatigue and headache are the most prevalent symptoms of long COVID in pediatric patients across various age groups. A reduction in symptom burden was observed over time, and vaccination appears to have a beneficial effect in alleviating long COVID symptoms in some children. Larger studies with extended follow-ups are necessary to further validate these findings.

Health sciences/Diseases/Infectious diseases

Health sciences/Diseases/Infectious diseases/Viral infection

Long COVID also known as post-acute sequelae of SARS-CoV-2 infection (PASC) has now been recognized as a long-term consequence of acute SARS-CoV-2 infection that affects adults and children.¹ There is more than one proposed definition for long COVID. The NIH definition refers to ongoing, relapsing, or new symptoms that are at least persisting or emerging 4 weeks after SARS-CoV-2 infection.² The WHO has defined long COVID as a condition characterized by symptoms occurring 3 months from the onset of acute COVID-19 manifestations, lasting for at least 2 months and not explained by an alternative diagnosis.² Per CDC, long COVID is an infection-associated chronic condition that can occur after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.³ All the definitions also note that symptoms fluctuate over time and may significantly affect daily functioning and academic achievement.^1,4,5 Lack of a uniform definition adds to the complexity of identifying and diagnosing this condition.

Long COVID in adults presents with a variety of physical, cognitive, and mood symptoms that includes fatigue, muscle weakness, shortness of breath, sleep difficulties, anxiety, and depression. ⁶ However, children, particularly younger children, may have a different presentation.

There is growing evidence that long COVID widely affects children and recent reports have raised attention to the burden of long COVID in pediatrics. ^6–8 It is estimated to affect 10–20% within the first 6 months after acute infection. ⁹

The current study aims to characterize the clinical spectrum of long COVID in pediatric patients seen at a dedicated long COVID clinic and to explore the impact of vaccination on its development and progression.

We conducted a retrospective EMR chart review and data analysis of all children aged 0–21 years seen in the COVID Recovery Clinic at Children’s Hospital Los Angeles between August 2021 to November 2023. IRB approval was obtained. COVID Recovery clinic is a part of the infectious diseases clinic which is run by pediatric infectious diseases physicians. Patients were seen in this clinic if they had persisting or emerging symptoms 4 weeks after SARS-CoV-2 infection that significantly affected their quality of life. Patients with alternative explanations for symptoms were excluded. Demographics and characteristics were summarized using mean and standard deviation (SD) for continuous variables, and a frequency and percentage for categorical variables. Differences in the prevalence of each symptom between males and females were assessed by Fisher’s Exact test. Longitudinal data was summarized as the number of recorded symptoms at the specified duration and analyzed using a linear mixed effects model with a random participant effect. We defined statistical significance using a two-sided p-values < 0.05. All statistical analyses were conducted in R Studio 4.2.2.

This study included 123 patients with long COVID with a mean age of 13.1 years (SD3.9), of whom 63 (51.2%) were males. Symptoms developed at an average of 5 weeks (SD 13.8) after SARS-CoV-2 infection. Mean symptom duration at presentation was 31.3 weeks (SD 24.8) (Table 1). Symptoms lasted for > 12 months in 23 (18.6%) of patients.

Table 1

Demographic and vaccination data among the study population.
Characteristics (N = 123)
Age in years	Mean (SD) Range	13.14 (3.89) 0.76,19.33
Sex	Females Males	60 2(48.8%) 63 (51.2%)
Race	African American White Others/mixed Unknown	2 (1.6%) 16 (13%) 16 (13%) 89 (72.3%)
Ethnicity	Hispanic Non-Hispanic Unknown	15 (12.1%) 23 (18.6%) 85 (69.1%)
Onset of long COVID after SARS-CoV-2 infection (weeks)	Mean (SD) Range	5.05 (13.82) 0,100
Duration of symptoms when first seen in clinic (weeks)	Mean (SD) Range	31.31 (24.81) 2,104
Vaccination status prior to onset of long COVID	Unvaccinated Vaccinated Unknown	33 (26.8%) 30 (24.3%) 17 (13.8%)
Vaccination after onset of long COVID (n = 43 [35%])	-No change in symptoms -Improvement in symptoms -Progressions on symptoms	23 (53.5%) 19 (44.2%) 1 (2.3%)

The most commonly reported symptoms were fatigue (92.7%), headache (69.9%), exercise intolerance (52.8%), dizziness (43.9%), brain fog (40.7%), musculoskeletal pain (29.3%), shortness of breath and abdominal pain (28.5%), palpitation (26%), chest pain and nausea (22.8%) as shown in Table 2. Fatigue was the most reported and the most persistent symptom throughout long COVID course persisting in 33.3% at 6 months, 43.8% at 6–12 months, and 61.5% at 12–24 months. Age was further classified into two groups, a younger group < 12 years had 36 patients (29%) and adolescent group ≥ 12 years included 87 patients (71%). Our results showed that fatigue and headache remain the most commonly reported symptoms in both age groups. Fatigue was reported in 80.5% of the under 12 and 97.7% of the 12 an over group. Headache was reported in 58.3% of under 12 and 74.7% of the 12 and over group.

Table 2

Clinical characteristics of long COVID and sex differences among the study population
Characteristic	Overall, N = 123	Female, N = 60	Male, N = 63	p-value
Fatigue	114 (92.7%)	56 (93.3%)	58 (92.1%)	> 0.9
Headache	86 (69.9%)	45 (75.0%)	41 (65.1%)	0.2
Exercise intolerance	65 (52.8%)	37 (61.7%)	28 (44.4%)	0.071
Dizziness	54 (43.9%)	36 (60.0%)	18 (28.6%)	< 0.001
Brain fog	50 (40.7%)	30 (50.0%)	20 (31.7%)	0.045
Musculoskeletal pain	36 (29.3%)	22 (36.7%)	14 (22.2%)	0.11
Shortness of breath	35 (28.5%)	22 (36.7%)	13 (20.6%)	0.071
Abdominal pain	35 (28.5%)	20 (33.3%)	15 (23.8%)	0.3
Palpitations	32 (26.0%)	24 (40.0%)	8 (12.7%)	< 0.001
Chest pain	28 (22.8%)	18 (30.0%)	10 (15.9%)	0.085
Nausea	28 (22.8%)	18 (30.0%)	10 (15.9%)	0.085
Insomnia	24 (19.5%)	12 (20.0%)	12 (19.0%)	> 0.9
Anxiety	23 (19.0%)	12 (20.3%)	11 (17.7%)	0.8
Weight loss	20 (16.5%)	8 (13.6%)	12 (19.4%)	0.5
Loss of appetite	19 (15.4%)	4 (6.7%)	15 (23.8%)	0.012
Blurry vision	17 (13.8%)	11 (18.3%)	6 (9.5%)	0.2
Anosmia	17 (13.8%)	9 (15.0%)	8 (12.7%)	0.8
Hypersomnia	17 (13.8%)	8 (13.3%)	9 (14.3%)	> 0.9
Persistent fever	15 (12.2%)	7 (11.7%)	8 (12.7%)	> 0.9
vomiting	14 (11.4%)	6 (10.0%)	8 (12.7%)	0.8
Cough	13 (10.6%)	6 (10.0%)	7 (11.1%)	> 0.9
Sore throat	12 (9.8%)	4 (6.7%)	8 (12.7%)	0.4
Altered taste	12 (9.8%)	7 (11.7%)	5 (7.9%)	0.6
Rash	12 (9.8%)	5 (8.3%)	7 (11.1%)	0.8
Loss of taste	11 (9.0%)	4 (6.7%)	7 (11.3%)	0.5
Passing out	11 (8.9%)	9 (15.0%)	2 (3.2%)	0.027
Low mood	11 (8.9%)	6 (10.0%)	5 (7.9%)	0.8
POTS	10 (8.1%)	8 (13.3%)	2 (3.2%)	0.050
P-values generated from Fisher’s Exact tests.

Males and females did not vary significantly in duration of symptoms on presentation (p = 0.8). However, females were more likely to experience brain fog (p = 0.04), dizziness (p < 0.001), palpitations (p < 0.001), and have a diagnosis of POTS(p = 0.05). Males had a higher prevalence of loss of appetite (p = 0.012). Table (2)

Figure (1) shows the overall trend of reported symptoms over time reported in 74 patients who had at least one follow-up visit. The estimated mean number of symptoms at onset is 8.5 (95% CI: 8.3, 8.), and on average, the number of symptoms decreases by 2.6 (95% CI: -3.2, -2.1; p < 0.001) per 6 months. For each specific follow-up timepoint, compared to onset, the number of symptoms decreased by -5.4 (95% CI: -6.5, -4.4) at 6 months, -6.0 (95% CI: -6.9, -5.0) at 6–12 months, -4.9 (95% CI: -6.1, -3.7) at 12–18 months, and − 4.1 (95% CI: -5.4, -2.8) at 18 months and after. All changes were statistically significant (p < 0.001). (Fig. 2)

We reviewed COVID-19 immunization status and our cohort included 33 patients (26.8%) who were unvaccinated, 30 (24.3%) who were vaccinated before the onset of long COVID, and 17 (13.8%) who had unknown vaccination status (Table 1). There was no significant difference in the mean number of symptoms at 6 or 12 months between the vaccinated and unvaccinated groups (Supplemental Table 1).

We then reviewed data on patients who got vaccinated after the onset of long COVID, our data showed that of the 43 (35.0%) who were vaccinated after the onset of long COVID, 23 (53.5%) reported no change in symptoms, 19 (44.2%) reported improvement in symptoms while 1 (2.3%) continued to have progression of symptoms. (Table 1)

Long COVID is a long-term health problem that is now well-recognized to affect children. We outline the clinical characteristics of children with long COVID drawing from a substantial cohort of pediatric patients attending a long COVID clinic. Adolescence emerges as the primary age group affected with the most common symptoms being fatigue and headache. There were notable gender differences with females experiencing more brain fog, dizziness and palpitations and more likely to have a diagnosis of POTS.

Other pediatric studies have similarly described fatigue, headache, palpitation, dizziness and brain fog as the most common symptoms ^{6 8}. Long term follow-up studies in children are limited, few that had follow up found that most symptoms improved after 6–8 months, however fatigue, and decline in school performance persisted. ^{6 8}

Few pediatric studies have examined outcomes beyond 12 months.⁹ Our study addressed the trend of symptoms for 74 patients who had at least one follow-up visit up to ≥ 18 months. We noted a trend for symptom reduction over time in this cohort, however there was a subset that continues to struggle with persistent symptoms. These findings are in line with a prior cross-sectional study conducted on 129 children where at least one persistent symptom was reported in 66.6% between 60 and 120 days, 27.1% > 120 days, and 42.6% ≥120 days.^7,10 Another study included 1243 children and found that 11.5 % reained symptomatic at six months, 3% at 12 months, and 1.2% at 18 months.¹¹

The relationship between COVID-19 vaccination and long COVID in children is an emerging research area. To date, no prior research has been published in the literature that has addressed the relationship or the effect of COVID-19 vaccination and the development and course of long COVID in children. In our observational cohort, symptom burden did not vary significantly in those who were vaccinated prior to long COVID diagnosis when compared to those that were unvaccinated.

When we analyzed the potential impact of COVID- 19 vaccine on children who received the vaccine after onset of long COVID, we found that almost half reported symptom improvement over the few weeks following vaccination. While this is a very interesting observation, it must be noted that data is subjective and based on patient and caregiver responses on follow up in clinic and not based on a validated questionnaire. Some studies in adults have also evaluated this question and a metanalysis reported that 20% of the adults with long COVID who received the COVID-19 vaccine reported improvement post vaccine ¹². Our cohort is small to conclude that there are notable differences in response to vaccine in children compared to adults, but this is an important question that should be addressed in larger, prospective studies.

Our study has several limitations. It is a single-center study, predominantly involving self-referred patients, which may lead to an overrepresentation of more severely affected individuals or those with better access to healthcare. Additionally, the absence of a control group limits our ability to draw comparative conclusions. The lack of validated questionnaires for symptom assessment and quality of life evaluation is another significant limitation. Furthermore, our study is constrained by limited epidemiological data. Future research should focus on more structured, well-designed studies with prospective follow-up on larger sample sizes to validate our findings. To better understand the effect of vaccines on long COVID symptoms, a systematic assessment that accounts for confounding factors and other interventions will be necessary to accurately determine the vaccine's contribution.

While our study is confined to a single center, its findings emphasize the critical need for continued research into the symptomatology of pediatric long COVID. Understanding the potential therapeutic impact of vaccines is particularly important as we seek to identify effective interventions. Comprehensive studies will be essential to inform the development of targeted support strategies, ensuring that children affected by this condition receive the care and resources they need to manage and recover from long COVID.

PASC: Post-acute sequelae of SARS-CoV-2 infection

SD : Standard deviation

CI : Confidence interval

POTS: Postural orthostatic tachycardia syndrome

EMR: Electronic medical records

CDC : Centers for Disease Control and Prevention

WHO : World Health Organization

NIH : National Institutes of Health

Conflict of Interest Disclosures (includes financial disclosures): The other authors have no conflicts of interest to disclose.

Funding/Support: No funding was secured for this study.

Role of Funder/Sponsor (if any): N/A.

Clinical Trial Registration (if any): N/A.

Contributors Statement Page

Dr Kamel and Dr Mohandas conceptualized and designed the study, drafted the initial manuscript, and critically reviewed and revised the manuscript.

My Vu designed the data collection instruments, carried out the analyses, and reviewed and revised the results section.

Dr Bender, Dr Warburton, and Dr Wood coordinated and supervised data collection, and critically reviewed and revised the manuscript for important intellectual content.

All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

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There is NO Competing Interest.

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Exploring Long COVID in Pediatric Patients: Clinical Insights from a Long COVID Clinic

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