Standardized Approach to Pediatric Post-COVID Syndrome and Its Impact on Children and Adolescents: A Perspective From a Tertiary Center

Abstract

Background:

Pediatric post-COVID syndrome (pPCS) affects a notable number of children. This study aims to describe its clinical manifestations, biopsychosocial impact and management strategies.

Methods:

A prospective, single-center study was conducted to analyze data of pPCS patients presenting to our institution between May 2021 and November 2022. Functional impact was evaluated by assessing school absenteeism and by using the Adolescent Depression Rating Scale (ADRS), Pediatric Quality of Life Inventory (PedsQL) and Fatigue Severity Scale.

Results:

Among the 50 patients included [median age (interquartile range): 14.0 (12.9–15.8) years; females: 70%], the most common symptoms were extreme fatigue (84%), exertion intolerance (82%), orthostatism (66%), dyspnea (66%) and headache (66%); 25% had an abnormal Schellong test. Median (interquartile range) ADRS, PedsQL and Fatigue Severity Scale scores were 3.0 (1.0–5.0), 56% (49%–71%) and 45.0 (32.0–53.0), respectively. Sixty percent experienced partial (34%) or complete (26%) school absenteeism. The most common referrals to specialized consultations were child psychiatry (48%), pulmonology (46%), physiotherapy (36%) and an ear-nose-throat specialist (24%). Eighty percent had a typical form of pPCS, whereas 20% had a clinical presentation suggestive of a functional disorder triggered by COVID-19. The latter had more frequent thoracic pain (P = 0.012) and more referrals to pediatric neurology (P = 0.01), gastroenterology (P = 0.011), ophthalmology (P = 0.037) and child psychiatry (P = 0.035), but less to pulmonology (P = 0.014). School absenteeism and social withdrawal were also more common in this group, with more severe PedsQL and ADRS scores.

Conclusion:

pPCS is associated with a significant socio-educational burden that should be taken into account in medical, social and educational care.

In 2021, the World Health Organization defined post-COVID syndrome (PCS) as the persistence of symptoms 3 months after the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with these symptoms lasting for at least 2 months with no other explanation.¹ However, it was only in 2023 that World Health Organization issued an expert consensus document on a pediatric-specific definition.² Symptoms may be a new onset following initial recovery from an acute COVID-19 episode or persist after the initial illness.

Although less common than in adults, adolescents, and to a lesser extent children, are susceptible to PCS.³ The prevalence of pediatric PCS (pPCS) has varied tremendously between studies, ranging from 4% to 66%.^3–5 This can be explained by heterogeneities in study design, patient age, outcome measurements, data collection methods and the severity of the acute COVID-19 episode. When focusing on case-control studies, the prevalence of symptoms compatible with pPCS was 2%–9% in SARS-CoV-2 seropositive children, with a rather similar prevalence in negative controls.³ A large-scale, population-based study performed in the canton of Geneva, Switzerland, showed an adjusted prevalence difference of symptoms compatible with a pPCS of 4.1% between SARS-CoV-2-positive and SARS-CoV-2-negative children.⁶ Documented risk factors for pPCS syndrome were older age, female sex, lower socioeconomic status and pre-existing chronic comorbidities.^3–5

PCS symptoms vary widely between patients. They may also fluctuate or relapse over time, with a general impact on daily functioning.^1,2 Similar to the adult population, the most frequently reported symptoms in pPCS are fatigue, headache, cognitive impairment, myalgia or arthralgia, dyspnea and anosmia.^3–5 Interestingly, abdominal symptoms seem to be more frequent in children than in adults,⁶ thus mirroring symptoms of acute COVID-19. Due to the lack of specificity and the diversity of symptoms, the diagnosis of PCS, including pPCS, remains a clinical challenge.

In May 2021, the General Pediatrics Division of Geneva University Hospitals, a tertiary pediatric center, opened the first pPCS clinic in the country at a time when no national or international guidance was available. The purpose of this study is to systematically describe the children’s clinical presentation and their functional impact using several severity scores and to describe the implemented standardized approach and management of our patients.

MATERIALS AND METHODS

Study Population and Design

A prospective study was conducted to analyze data on all children and adolescents followed at our pPCS clinic between May 1, 2021, and November 30, 2022, using a standardized case report form. Patients 8–18 years of age with persisting symptoms compatible with PCS were eligible for an appointment at the clinic within the General Pediatrics Division of Geneva University Hospitals, a tertiary pediatric center in the western part of Switzerland. The decision to arbitrarily set a lower age limit in our clinic was based on available literature at the time when the clinic was created, suggesting that pPCS almost only affected older children and teenagers. If not previously documented, prior SARS-CoV-2 infection was assessed using the quantitative Elecsys anti-RBD and semiquantitative Elecsys anti-N assays (both measuring total immunoglobulin levels) on the Cobas e801 analyser (Roche Diagnostics, Rotkreuz, Switzerland). Only patients with no alternative diagnosis documented were included in the analysis.

During the first appointment, a standardized form was completed by the physician in charge of the pPCS clinic. This form contained information regarding the acute SARS-CoV-2 infection, SARS-CoV-2 vaccine history, persisting symptoms, clinical examination findings and blood test results when clinically indicated, as well as the impact of symptoms on schooling (see Figure, Supplemental Digital Content 1, http://links.lww.com/INF/F775). When necessary, additional clinical data were retrospectively retrieved from electronic medical records. The standardized form also included details of patient management, including referral to specialty clinics, additional workup and outcome, including functional scale scores. The study was approved by the local ethics committee (CCER #2020-0835) and all patients included in the dataset signed an informed consent form.

Functional Scales

To evaluate the functional impact of pPCS, 3 scales were used during the first appointment. First, the Pediatric Quality of Life Inventory (PedsQL) assessed the quality of life, using a 23-item multidimensional scale evaluating independently 4 areas of functioning (physical, emotional, social and school) (see Figure, Supplemental Digital Content 2, http://links.lww.com/INF/F776).⁷ Each item is scored from 0 (“never affected”) to 4 (“almost always affected”). For ease of interpretability, items are then reverse-scored and linearly transformed to a 0–100 scale where higher scores indicate a better quality of life (eg, 1 = 75, 2 = 50, 3 = 25, 4 = 0).⁸ Second, the Adolescent Depression Rating Scale (ADRS) assessed the risk of depression using a scale ranging from 0 (“no reported depressive symptom”) to 10 (“all listed symptoms present”), with results >4 suggesting a moderate to higher risk of depression according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (see Figure, Supplemental Digital Content 3, http://links.lww.com/INF/F777).⁹ Finally, even though not validated in the pediatric setting, the Fatigue Severity Scale (FSS) assessed fatigue using 9 items, each rated from 1 to 7, with a higher score indicating increased fatigue and an overall score ≥36 being suggestive of fatigue.^10–12

Schellong and Tilt Table tests

The Schellong test was proposed to all study patients. The Schellong test measures the blood pressure and heart rate in a supine position after a supine resting phase of 10 minutes, followed by an active standing phase with repeated measures at 1-3-5-10 minutes. The diagnosis of orthostatic hypotension was retained if the Schellong test showed a decrease in systolic blood pressure ≥20 mm Hg without a corresponding increase in the heart rate. The diagnosis of postural orthostatic tachycardia syndrome (PoTS) was retained if an increase ≥40 bpm in the heart rate lasting longer than 1 minute was observed, or if the heart rate increased to ≥120 bpm within 10 minutes of standing, without orthostatic hypotension.¹³ In certain circumstances (such as to rule out a differential diagnosis or to strengthen the therapeutic alliance), the Tilt Table test was performed to confirm the diagnosis of PoTS, using the same diagnostic criteria as mentioned earlier. During the Tilt Table test, the patient is strapped on a table; after a resting phase where the patient is in the supine position, the bed or table is slowly tilted to an angle, usually between 60 and 80 degrees, simulating a standing position, while blood pressure, heart rate and heart rhythm are recorded.

Clinical Phenotypes of pPCS

Within our pPCS clinic, we were able to identify 2 distinct phenotypes of patients. The majority of patients had a clinical presentation that was in line with published reports of pPCS at the time of study initiation; these will be referred throughout the manuscript as patients with a typical form of pPCS or “group 1” for the sake of readability. A smaller subset of patients had a phenotype more suggestive of a functional disorder, with a more profound functional impact and different clinical presentation; these patients will be referred throughout the manuscript as “group 2” for the sake of readability. The assignment of the patients to a given group was performed before the constitution of the database and prior to any descriptive or statistical analyses.

Circulating SARS-CoV-2 Variants During the Study Period

During the study period, predominant SARS-CoV-2 circulating variants were Alpha (May 1–June 21, 2021), Delta (June 21–December 20, 2021), Omicron BA.1 (December 20, 2021–February 28, 2022), BA.2 (February 28–June 6, 2022), BA.5 (June 6–November 7, 2022) and BQ.1 (November 7–30, 2022; source: https://covariants.org).

Statistical Analysis

For continuous variables, the normality of distribution was checked graphically. Continuous variables were expressed by their mean ± standard deviation or median [interquartile range (IQR)] dependent upon variable distribution. Categorical variables were presented by their frequencies and relative proportions. Analyses were performed to compare group 1 and group 2. For comparisons of continuous variables between the 2 groups, parametric Student t tests or nonparametric Mann-Whitney tests were used dependent upon variable distribution. For categorical variables, either χ² or Fisher exact tests were performed, depending on applicability. As reported above, the 2 groups were created before the constitution of the database and prior to any descriptive or statistical analyses. There was no a priori hypothesis. Statistical significance was defined as P < 0.05 (2-sided). Statistical analyses were performed using SPSS software, v23.0 (IBM Corp., Armonk, NY).

RESULTS

Demographics and Clinical Presentation of pPCS

Of 95 patients seen at the clinic, 50 were diagnosed with pPCS and included in the study [median age (IQR): 14.0 (12.9–15.8) years; range: 9.4–18.8 years; females: 70%] (Fig. 1). Diagnosis of SARS-CoV-2 infection was confirmed by reverse-transcription polymerase chain reaction (84%), serology (12%) and/or a rapid antigenic diagnostic test (6%). Symptoms of acute infection are described in Table, Supplemental Digital Content 4, http://links.lww.com/INF/F778. Median time between SARS-CoV-2 diagnosis and referral was 153 (IQR: 97–240) days. Most patients were referred by their family doctors/pediatrician (72%) or parents (10%). The most common persisting symptoms were extreme fatigue (84%), exertion intolerance (82%), orthostatism (66%), dyspnea (66%), headache (66%) and difficulty concentrating (62%) (Fig. 2).

FIGURE 1.

Study flowchart.

FIGURE 2.

Proportion of persisting symptoms of children included in the study.

Functional Impact of pPCS and Management

Thirty percent of patients experienced social withdrawal and 60% experienced partial (34%) or complete (26%) school absenteeism. Median PedsQL score was 56% (IQR: 49–71) (Fig. 3). More specifically, areas particularly affected within the PedsQL score were school, physical and emotional functioning with median scores of 40% (IQR: 25–65), 56% (IQR: 38–72) and 60% (IQR: 45–75), respectively. By contrast, social functioning was preserved with median scores of 80% (IQR: 70–95). The median ADRS score was 3.0 (IQR: 1.0–5.0), with 34% (17/50) of patients meeting criteria suggestive of a depressive state (score >4) (Fig. 3). Finally, the median FSS score was 45.0 (IQR: 32.0–53.0), with 72% (36/50) of patients meeting criteria for significant fatigue (overall score ≥36) (Fig. 3).

FIGURE 3.

PedsQL, ADRS and FSS Scores in group 1 and group 2. PedsQL in percent (0–100 scale): the higher score indicates a better quality of life. The first column represents the average PedsQL score and the others represent the 4 areas of functioning (ie, physical, emotional, social and school). ADRS (0–10 scale): >4 being the threshold suggestive of a depressive state. FSS (0–63 scale): ≥36 is the threshold where fatigue is considered to be significant.

Investigations and Referrals

Among the 49 patients who underwent a Schellong test, 12 (24%) had an abnormal result, with 7 fulfilling PoTS criteria. Among the 9 patients who were referred for a Tilt Table test, 5 (56%) had an abnormal result consistent with PoTS. Overall, 12 (24%) patients were diagnosed with PoTS. Among the 20 patients who underwent pulmonary function tests, 12 (60%) exhibited a pathological result showing air trapping (n = 5) or reduced cardiorespiratory fitness (n = 5) in most cases. Among the 21 patients who were referred for a cardiac stress test, 11 (52%) were considered physically deconditioned. The most common specialty referrals were child psychiatry (48%), pulmonology (46%), physiotherapy (36%) and ear-nose-throat (24%) (Table, Supplemental Digital Content 5, http://links.lww.com/INF/F779).

Two Distinct pPCS Phenotypes

Most patients were identified as group 1 [40/50 (80%)], whereas 20% (10/50) belonged to group 2. Age and gender did not differ between the 2 groups (Table 1). Similarly, persisting symptoms did not differ between the 2 groups, except for thoracic pain, which was less common in group 1 [7/40 (17.5%)] than in group 2 [6/10 (60%); P = 0.012]. In terms of functional impact, social withdrawal was less common in group 1 [9/40 (22.5%)] than in group 2 [6/10 (60%); P = 0.048]. School absenteeism was also less common in group 1 [partial absenteeism: 16/40 (40%); complete absenteeism: 4/40 (10%)] than in group 2 [partial absenteeism, 1/10 (10%); complete absenteeism, 9/10 (90%); P <0.001].

TABLE 1.

Patient Demographics and Persisting Symptoms According to the Phenotype

	Group 1 n = 40	Group 2 n = 10	P Value
Demographics
Median age, yr (IQR)	14.22 (13–15.95)	13.68 (10.45–15.64)	0.308
Female, n (%)	30 (75)	5 (50)	0.123
Persisting symptoms, n (%)
Extreme fatigue	33 (83)	9 (90)	1.0
Effort intolerance	31 (78)	10 (100)	0.174
Dyspnea	29 (73)	4 (40)	0.07
Orthostatism	25 (63)	8 (80)	0.461
Headache	25 (63)	8 (80)	0.461
Concentration difficulties	25 (63)	6 (60)	1.0
Loss of appetite	24 (60)	5 (50)	0.723
Sleep disturbances	22 (55)	7 (70)	0.488
Palpitations	16 (40)	3 (30)	0.722
Anosmia	16 (40)	1 (10)	0.134
Nausea	15 (38)	7 (70)	0.084
Abdominal pain	15 (38)	6 (60)	0.286
Muscular/joint pain	14 (35)	5 (50)	0.474
Dysgeusia	14 (35)	2 (20)	0.468
Acrocyanosis	14 (35)	2 (20)	0.468
Mood disorder	13 (33)	6 (60)	0.15
Anxiety	12 (30)	2 (20)	0.704
Dizziness	11 (28)	5 (50)	0.256
Weight loss	10 (25)	2 (20)	1.0
Chest pain	7 (18)	6 (60)	0.012
Hair loss	7 (18)	1 (10)	1.0
Cough	6 (15)	2 (20)	0.653
Psychomotor slowdown	5 (13)	3 (30)	0.331
Nasal congestion	5 (13)	1 (10)	1.0
Rash	5 (13)	0 (0)	0.569
Fever	4 (10)	2 (20)	0.586
Diarrhea	3 (8)	1 (1)	1.0

Group 1: patients with a clinical presentation suggesting a typical form of pPCS. Group 2: patients with a different phenotype, more suggestive of a functional disorder, with a more profound functional impact and different clinical presentation.

Quality of life determined by the PedsQL scale was significantly better in group 1 [median (IQR): 58% (50–75)] than in group 2 [median (IQR): 48% (35–55); P = 0.005]. The subcategories of the PedsQL questionnaire also showed that group 1 had significantly better scores than group 2 regarding physical [median (IQR): 59% (49–74) vs. 36% (17–57); P = 0.014], social [85% (75–95) vs. 68% (59–81); P = 0.011] and school functioning [50% (28–65) vs. 23% (5–36); P = 0.005] (Fig. 3). There was no significant difference in median emotional functioning between the 2 groups [65% (IQR: 45–75) vs. 55% (IQR: 46–66), respectively; P = 0.607] (Fig. 3). According to the ADRS scale, patients in group 1 were at lower risk of a depressive state [median (IQR): 2.0 (1.0–5.0)] than in group 2 [median (IQR): 4.8 (3.6–8.0); P = 0.009] (Fig. 3). However, the proportion of children meeting criteria suggestive of a depressive state (score >4) did not significantly differ between group 1 [12/39 (31%)] and group 2 [5/10 (50%); P = 0.285]. There was a nonsignificant trend toward reduced fatigue according to the FSS in group 1 [median (IQR): 44.0 (31.0–51.0)] than in group 2 [median (IQR): 53.0 (41.3–55.0); P = 0.094] (Fig. 3). Similarly, there was no statistically significant difference in the proportion of children meeting fatigue criteria (overall score ≥36) between group 1 [27/39 (69%)] and group 2 [9/10 (90%); P = 0.253].

There was no difference in the proportion of abnormal Schellong tests between group 1 [9/39 (23%)] and group 2 [3/10 (30%); P = 0.690]. Similarly, there was no significant difference in the proportion of PoTS diagnosis tests between group 1 [8/40 (20%)] and group 2 [4/10 (40%); P = 0.225]. Pulmonary function tests were more commonly performed in group 1 [19/40 (48%)] than in group 2 [1/10 (10%); P = 0.037]. There was no significant difference in the proportion of patients with a cardiac stress test performed between group 1 [19/40 (48%)] and group 2 [2/10 (20%); P = 0.160] or in the proportion with pathological results (data not shown). In terms of referrals, patients in group 1 were significantly less frequently referred to pediatric neurology (10% vs. 50%; P = 0.010), gastroenterology (5% vs. 40%; P = 0.011), ophthalmology (0% vs. 20%; P = 0.037) and child psychiatry (40% vs. 80%; P = 0.035), but more commonly to pulmonology (55% vs. 10%; P = 0.014) (Table, Supplemental Digital Content 5, http://links.lww.com/INF/F779).

DISCUSSION

In this study, we evaluated the functional impact of pPCS using standardized forms and scales. The main finding confirms the profound impact of PCS on children’s functioning, with more than half of the children experiencing school absenteeism. Furthermore, quality of life as evidenced by the PedsQL score was low in most children, with a particular impact on school, physical and emotional functioning. Further analysis of the PedsQL scale showed that the educational component of the children’s lives was more heavily impacted than the social component and difficulties with memorization, attention and absenteeism were observed.⁷ Reassuringly, despite the potential reduced in-person interaction and the temporary shift to online learning, the quality of social life remained largely unaffected. It raises the question of whether social networks may have participated in keeping social life more active.¹⁴ As expected, almost three-quarters of children with pPCS met the criteria for significant fatigue according to the FSS. In addition, approximately one-third of patients met ADRS criteria suggestive of a depressive state. It is important to note that the risk of depression is generally high among adolescents compared to adults,¹⁵ and this risk was further exacerbated during the pandemic due to significant changes in their environment.^16,17 To our knowledge, this is the first systematic assessment of the functional impact of pPCS using the abovementioned scales.

Impacted quality of life and depression can be caused by the PCS itself, but it can also be caused by the environment in which patients evolved during the pandemic (eg, partial lockdown and social distancing). Indeed, during this period, the quality of life and mental health in adolescents were altered,^18–20 with an increased reporting of anxiety and depression.²¹ Therefore, it is difficult to discriminate between the relative contributions of PCS and the general environment to the children’s quality of life at that time. Interestingly, the median PedsQL score in our cohort was 56%, which is much lower than the PedsQL score of 98% reported in previously SARS-CoV-2-infected children.²² Moreover, one large-scale pediatric cohort study reported similar PedsQL scores between previously-infected and noninfected children but did not investigate specifically into PedsQL scores in children with pPCS.²² Taken together, this strongly suggests that PCS itself profoundly impacted the children’s quality of life, rather than the global environment or SARS-CoV-2 infection itself. This is further supported by the fact that children and adolescents with chronic illnesses had a lower quality of life during the pandemic than their healthy counterparts.²³

In terms of clinical presentation and as expected, the predominant symptoms of PCS in our dataset were similar to those previously reported in children, with extreme fatigue frequently reported as the most prevalent symptom, followed by shortness of breath, headaches, concentration difficulties, sleep disturbance and loss of appetite.^{1,3,4,6,24,25} Surprisingly though, effort intolerance and orthostatism, which were respectively reported in 82% and 66% of our patients, are usually not among the commonly reported symptoms in pPCS.^3,4,24,25 The difference in reported symptoms between studies is most likely multifactorial and related to the heterogeneity in study design and inclusion criteria, notably regarding severity of acute SARS-CoV-2 infection, time between SARS-CoV-2 infection and data collection, adjustment for symptoms in seronegative controls and method used to collect the data (predefined items vs. open questions). Like in children, extreme fatigue seems to be the most common symptom reported in adults suffering from PCS, with shortness of breath, persistent cough, arthromyalgia and sleep disturbance being also frequently reported.^26–29 Interestingly, abdominal symptoms, which were common in our dataset and are frequently reported in children with PCS,^3,4,24 seem to be somewhat less frequent in adults, whereas persistent cough and memory loss might be more common in adults suffering from PCS.^26–29

The fact that one-quarter of patients had an abnormal Schellong test is also interesting and highlights the previously known association between PCS and dysautonomia in children and adults.^30,31 Similarly, PoTS criteria¹³ were investigated in all patients, with 24% who fulfilled the criteria and orthostatic dizziness being the most common symptom. The prevalence of PoTS in our cohort was significantly higher than in the general population where the prevalence is estimated to be around 6% among adolescents.³² Given the increased frequency in pPCS, children with orthostatism should be investigated for PoTS as previously recommended,^33,34 given its debilitating impact on the quality of life that may be limited if properly managed. It remains to be clarified whether SARS-CoV-2 infection was directly responsible for the dysautonomia or whether it accelerated a pre-existing predisposition.

The fact that most patients referred for pulmonary function tests had pathological results confirms the impact of PCS on lung function^35–37 and should warrant a low threshold for these tests. As for the lowered cardiorespiratory fitness, the respiratory and cardiac systems are commonly affected by SARS-CoV-2, especially in the month following infection,³⁸ with a lowered peak oxygen uptake (VO_2peak),^38,39 impaired carbon monoxide diffusion capacity⁴⁰ and general deconditioning⁴¹ being regularly reported. Furthermore, among children with previous SARS-CoV-2 infection, VO_2peak is significantly lower in those with pPCS compared to those without pPCS.⁴²

One of the most striking findings of our study is the fact that 2 phenotypes emerged with a distinct clinical presentation and functional impact. Indeed, a subset of 20% of patients with pPCS presented more commonly with thoracic pain and increased social withdrawal and school absenteeism. This group was also more likely to experience a depressive state and had a more impacted quality of life in general, particularly regarding social and school functioning. This group also required more frequent referrals to pediatric neurology, gastroenterology, ophthalmology and child psychiatry, but less commonly to pulmonology. In our experience, this latter group was more suggestive of a functional disorder that might have been triggered by SARS-CoV-2 infection.

The strengths of our study are mainly related to the systematic acquisition of standardized data, including scales such as PedsQL, ADRS and FSS. By contrast, the study has several limitations such as its limited sample size, thus limiting the ability to generalize data to a broad range of centers. The fact that not all patients evaluated within the clinic had a final diagnosis of pPCS is consistent with previously published data.⁴³ In addition, the differences between the 2 groups were identified without predefined classification criteria. However, it is important to note that the classification in these 2 groups was only based on a clinical impression and was performed more than 12 months before initial data analysis. Finally, the FSS results should be interpreted with caution as this scale is not yet validated in the pediatric setting, even though it is one of the most commonly used fatigue scales in the adult setting.

In conclusion, the biopsychosocial and educational impact of pPCS is major among affected adolescents and these elements should be systematically characterized using appropriate scales and need to be taken into account by professionals in medical, social and educational care. Larger studies are needed to confirm the 2 different pPCS phenotypes, including their management and outcome.