Long COVID in Children

The challenges of the coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) are now extending to its long-term sequelae. Since the beginning of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic outbreak [1], evidence of persistent symptoms in adults has emerged with a prevalence of long COVID as high as 80% [2].

The spectrum of symptoms is extensive and the most commonly reported include fatigue, headache, attention disorders, hair loss, and dyspnea. [2].

Various health organizations have issued different definitions of this new syndrome in adults [3–5]. Recently, a research definition of long COVID in children was derived from a Delphi process [6].

Children rarely develop severe respiratory illness in the acute phase of COVID-19, although a limited number of patients exhibit a well-defined multisystem inflammatory condition, which can lead to multiorgan failure and shock, known as pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) [7] or multisystem inflammatory syndrome in children (MIS-C) [8].

Since October 2020, parental concerns are emerging about persistent symptoms in children months after acute SARS-CoV-2 infection [9]. In November 2020, a case series from Sweden described a group of 5 girls with long COVID [10]. Since then, studies on long COVID in the pediatric population have accumulated, although high variability is reported in terms of definition, prevalence and symptoms [11]. Therefore, the authors conducted a systematic literature review to summarize the current evidence regarding this emerging condition in children, focusing on prevalence and clinical presentation.

 > Design

A systematic review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline recommendations [12]. The research was conducted through MEDLINE via PubMed and MedrxiV, for articles available until February 15, 2022. The references of all relevant articles were also evaluated, and relevant articles were included. Search terms, limited to title or abstract, were as follows: “Post-acute COVID-19,” “long COVID-19,” “SARS-CoV2,” “sequel,” “COVID-19,” “children ", "child", "pediatric".

 > Inclusion and exclusion criteria

The research was restricted to the English language. Articles reporting COVID prevalence and symptoms based on original data in the pediatric population were included regardless of study design. Review articles, comments, editorials and letters to the author without original data were excluded. The size of the sample was not an exclusion criterion. Studies on PIMS-TS were excluded, except where the number of patients with PIMS-TS was minimal [13, 14].

 > Data extraction

Duplicate publications were removed, then two separate authors (RP and EC) checked the titles and abstracts and removed irrelevant studies based on the inclusion and exclusion criteria. The articles were classified as cohort studies or case series and, depending on the source of information, based on surveys or questionnaires or based on clinical data. From each study on children, the included population, the test used to diagnose SARS-CoV-2 infection, the follow-up time, the definition of long COVID, and the clinical presentation were extracted. Studies including a minimal number of patients with PIMS-TS were included and the prevalence of persistent symptoms was recalculated after excluding PIMS-TS cases for the sake of comparability.

 > Quality evaluation

For observational studies, adherence recommendations to the Strengthening Report for Observational Studies in Epidemiology (STROBE) [15] were evaluated. The quality of the case series was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series [16].

 > Ethics

Ethics approval was not required for the systematic review component of this study.

 > Characteristics and quality of the study

Overall, 214 articles were initially retrieved and after screening and selection, 22 articles were included in the review. The types of studies were as follows: 12 cohort studies (8 prospective [13, 14, 17–22], 3 retrospective [23–25], and 1 ambidirectional [26]), 7 cross-sectional studies [27–33], and 3 case series [10, 34, 35]. Seven studies were based on directly assessed data [13, 17, 23, 25, 31, 34, 35], including one study with a control group [31].

Fifteen studies were based on interviews or questionnaires, of these 2 were directed at pediatricians [28, 30] and 13 at caregivers or patients [10, 14, 18–22, 24, 26, 27, 29, 32, 33], among these 8 provided a control group [18–20, 22, 24, 26, 32, 33]. The median age of the children ranged from 9.16 [31] to 17.6 years [32]. The terms and definitions were quite variable. The most commonly used definition was based on symptoms persisting more than 4 weeks from acute infection or hospital admission [13, 19, 20, 24, 26, 27, 31, 34]. However, other definitions used varied from symptoms persisting 2 months [10, 19, 32] to 5 months [21]. Follow-up time ranged from 4 weeks [34] to 13 months [24].  

 > Reported prevalence of long COVID in pediatric studies

The prevalence of long COVID varies markedly from 1.6 [34] to 70% [26]. The lowest prevalence was reported in a French case series describing 7 cases of long COVID out of 661 children with a positive COVID-19 diagnosis [34]. The highest prevalence was found in a Latvian study reporting ongoing symptoms after 4 weeks in 70% of the positive cohort [26]. An Italian cross-sectional study based on the ISARIC questionnaire [36] to caregivers, showed a similar prevalence of 58.1% of children with persistent symptoms after 4 weeks from acute infection. By excluding 3 patients diagnosed with PIM-ST, the prevalence of long COVID decreased to 56.7% [27].

The latter prevalence was consistent with data from a study based on a standardized clinical examination in 92 outpatients with a median follow-up time of 55 days after acute COVID-19 [23]. On the contrary, in a subsequent study, according to the majority of Italian pediatricians interviewed, the persistence of symptoms after COVID-19 was less than 20% [30].

 > Clinical picture in children and adolescents

The clinical spectrum evaluated between the studies varied markedly. The most frequently reported symptoms were as follows: fatigue (2 [31] to 87% [28]), headache (3.5 [21] to 80% [19]), muscle or joint pain (0.7 [21] to 80% [19]). 33] to 66% [14]), chest tension or pain (1.3 [33] to 51% [25]), dyspnea (2 [23] to 57.1% [34]), and altered taste or smell (4.7 [21] to 84% [19]).

Limitation in daily function that affected school attendance was reported in 5 studies [14, 17,28, 29,32] ranging from 10.5 [32] to 58.9% [17]. The mean symptom burden was 8 symptoms throughout the disease [19] with a tendency to decrease over time [19, 32]. According to Osmanov and colleagues, headache and sleep disorders tend to decline more slowly than the others [21].

 > Results of controlled studies

Eight of the studies included in this review provided a control group [18–20, 22, 24, 26, 32, 33]. One of the first matched cohort studies in the pediatric population was the CLoCK study [37]. Preliminary results from the latest study showed that 3 months after acute infection, 66.5% of positive children had at least one symptom, in line with the negative control group where 53.4% ​​of children had symptoms. at the same time [22]. The difference increased when comparing children with 3 or more symptoms: 30.3% among the positive test and 16.2% among the negative test [22], suggesting a greater symptom burden in the case group, as seen also in two Danish studies [24, 32].

Molteni and colleagues identified two classes of children based on the duration of the illness, designated LC28 if the duration was greater than 28 days and LC56 if it was greater than 56 days [19]. The observed prevalence was respectively 4.4% and 1.8% among children with a history of SARS-CoV-2 infection, while only 0.9% of children in the control group complained of symptoms that lasted longer. of 28 days [19]. These results are consistent with those derived from the largest cohort to date, in which children with a history of SARS-CoV-2 infection reported persistent symptoms more frequently than the control group with a percentage difference of 0.8 % [24].

A Latvian study compared children with previous SARS-CoV-2 infection with children with other non-SARS-CoV-2 infections indicating that persistence of symptoms is more evident with COVID-19 than any different infection [26]. On the other hand, no significant difference was found in a Swiss cohort that described symptoms lasting more than 4 weeks in 4% of seropositives and more than 12 weeks in 9%, comparable to the prevalence in the seronegative group (respectively 2 % and 10%) [18].

Among controlled studies, the clinical spectrum of long COVID is undefined. Stephenson et al described fatigue (23% vs. 14.2%) and headache (39% vs. 24.2%) as more frequently reported within the case group, and no difference was found in the distribution of scores. of mental health and well-being between the two groups [22]. Similarly, headache and concentration difficulties, with fatigue, were the most frequent symptoms in the case group of the LongCOVIDKidsDK study [32].

Furthermore, in a national cohort study, fatigue, anosmia, and ageusia were significantly associated with prior SARS-CoV-2 infection, while concentration difficulties, headache, arthromyalgia, and gastrointestinal symptoms were more frequent in the control group [24]. The latter two studies reported improved quality of life in children with a prior history of SARS-CoV-2 infection. The authors speculate that the lower sense of well-being in uninfected children could reflect the effects of social restrictions [24, 32].

> Alterations in images and functional tests in children with long COVID

Persistence of long COVID symptoms has been associated with a hypometabolic pattern on 2-[18F]-fuorododoglucose (FDG) positron emission tomography (PET) of the brain, involving bilateral medial temporal lobes, cerebral blood flow, , the cerebellum and the right olfactory gyrus in 7 French children with long COVID [34].

The data on possible cardiac involvement are contrasting. Erol and colleagues described a statistically significant difference in systolic blood pressure, left ventricular posterior wall diameter, relative wall thickness, and tricuspid annular plane systolic excursion values ​​among children with a history of SARS infection. CoV-2 and controls [31].

In a prospective cohort study from Israel, no echocardiographic abnormalities were documented in long COVID in children, although poorer performance on an exercise stress test was observed suggesting some degree of chronotropic incompetence [17]. Electrocardiographic (ECG) abnormalities were described in a minority of outpatients with COVID-19, and none of the affected subjects had echocardiographic alterations. ECG abnormalities resolved over time and were not associated with the severity of acute illness [25].

A mild obstructive reversible pattern was evident on pulmonary function testing in almost half of the children in the Israel cohort [17], while no long-term pulmonary sequelae were evident on lung ultrasound [38, 39] and lung function tests. pulmonary [39, 40] in 3 studies [38–40].

 > Risk factors for long COVID in children

In the CLoCK study cohort, in both the positive and negative groups, those with multiple symptoms were more likely to be female, adolescent, and to have poorer baseline physical and mental health status [22]. The same group of children were more likely to report problems with mobility, self-care, usual activities, and pain/discomfort after acute COVID-19 [22].

Older age was reported as a risk factor for persistent symptoms after SARS-CoV-2 infection in 9 studies [17, 19–21, 23, 24, 26, 29, 32]. Regarding sex, in a Danish cross-sectional study, women were more likely to show symptoms lasting more than 2 months than men, in both case and control groups [32], while according to Roge et al. ., long COVID symptoms were more common among female patients, with the most significant differences in cognitive and neurological sequelae [26]. Furthermore, allergic disease [21] and long-term preconditions [20] have been identified as potential risk factors for long COVID [20, 21].

Overweight has been described as a risk factor for long COVID in adults [17] . Among the studies included in this review, there is no significant statistical difference in terms of body mass index (BMI) between children reporting persistent symptoms and controls [17, 31]. Recently, Bloise and colleagues described obesity as a potential risk factor for long COVID syndrome also in pediatric age [41].

No correlation was noted between the severity of acute illness and the duration of symptoms [27, 31], except in one study comprising only hospitalized patients in which admission to the intensive care unit (ICU) was associated with long COVID [29].

> Management and monitoring of children with prolonged COVID-19

The need for rehabilitation plans for patients with long Covid in adults is claimed [42], while the effects of this syndrome in children are unclear and data on monitoring and management are scarce. However, according to Dutch paediatricians, 29% of children with suspected long COVID required a multidisciplinary approach comprising physiotherapy and support from psychologists [28]. In Italy, 86% of pediatricians stated that, in their area, no reference center dedicated to helping children recovering from COVID was available [30].

Seven studies [13, 17, 23, 25, 31, 34, 35] with clinical data (including 549 children with a history of SARS-CoV-2 infection) and 15 studies [10, 14, 18–22, 24, 26–30, 32, 33] based on interviews or questionnaires (including 28,227 children with a history of SARSCoV-2 infection). Data are difficult to compare due to large variability between studies in terms of study design, follow-up time, and definitions of long COVID resulting in different inclusion criteria.

The final picture is a wide discrepancy in prevalence for both symptoms and long COVID in general. The considerable variability in prevalence and symptom burden could indicate that studies are evaluating different diseases, suggesting a harmonized case definition is urgently needed. Fatigue, headache, arthralgia, shortness of breath, and altered smell or taste appear to be the most common symptoms.

According to the WHO definition, the impact on daily functioning is crucial in defining long COVID.

Interestingly, most studies were based solely on symptom persistence and only 5 studies reported a limitation in daily function attributable to long COVID [14, 17, 28, 29, 32]. It is important to emphasize that most studies were based on information reported by proxy while data provided by clinicians were scarce.

Adolescent age, pre-existing chronic pathologies and allergic disease have been identified as potential risk factors for persistent symptoms after acute illness [17, 19–24, 26, 29, 32]. However, critical evaluation is necessary to understand these findings; as an example, younger children are less likely to be able to consistently report relevant symptoms and these could lead to an underestimation of symptom prevalence at this age. Since most data are derived from online surveys, recall bias and selection bias must be considered, as symptomatic people may be more likely to participate and responses may not be accurate.

Interestingly, persistent symptoms were also described in children with previous mild or asymptomatic COVID-19 and there is no correlation between acute disease severity and long COVID [27, 31].

Furthermore, it is unclear whether persistent symptoms are related to the viral infection itself or express the effects of the pandemic, isolation and school suspension in children.

Isolation and social limitation negatively affect the mental health of children and adolescents [43]. This fact may explain why no statistically significant difference was found between seropositive and seronegative populations in neurocognitive, pain, and mood symptoms [44]. Two studies reported better quality of life in SARS-Cov-2-infected children than in controls, and the lower sense of well-being in uninfected children could reflect the psychological implications of the pandemic [24, 32]. For this reason, it is mandatory to have a control group to understand the results to the fullest.

When a control group was provided, patients with a history of SARS-CoV-2 infection were more likely to show a higher prevalence of symptom persistence [19, 20, 24, 26, 32, 33, 37], except in one study based on a small sample [18]. In particular, the prevalence of symptoms decreased over time, with headache and sleep disorders having the slowest decline, which could be driven by a psychological mechanism [21]. Since the outbreak of the SARS-CoV-2 pandemic, several variants of concern have been identified. It appears that omicron cases are less likely to experience long COVID compared to adult delta cases [45]. Currently, data on children and young people is lacking.

The symptoms observed affect the cardio-respiratory, gastrointestinal and neurological systems, and rehabilitation and psychological support are needed [28]. Therefore, a multidisciplinary approach appears to be necessary to support children and adolescents. NICE guidelines recommend an investigation in people who present with new or ongoing symptoms 4 weeks or more after acute COVID-19, and these include a complete blood count, kidney and liver function tests, C-reactive protein and a blood test. exercise tolerance [3]. Currently, no structured follow-up has been established and there is a lack of reference centers for the pediatric population [30].

The mechanisms underlying the post-COVID condition are not clearly defined; However, several models of pathogenesis were presented. One of the most supported hypotheses is based on the persistence of the virus or a component of the virus [46]. Several studies demonstrated prolonged shedding of SARS-CoV-2 in the respiratory tract, feces, and intestinal biopsies, even in asymptomatic patients [47, 48]. This could lead to an exacerbated immune response resulting in increased levels of proinflammatory cytokines, including interleukin (IL)-6, IL-1β, and TNF [49, 50].

A persistent pro-inflammatory state could explain organ damage and prolonged symptoms, such as fatigue, headache, and impaired smell [46, 48].

Furthermore, several types of autoantibodies are produced during SARS-CoV-2 infection due to a molecular mimicry mechanism between autoantigens and spike epitopes [51]. Autoantibodies against G protein-coupled receptors (GPCRs) were associated with post-COVID-19 condition. Because GPCRs can alter neuronal and vascular processing, the production of autoantibodies could explain some of the neurological and cardiovascular symptoms in patients with long COVID [48].

The authors’ review may have limitations, including that some articles may have been missed. Considering that the literature regarding long COVID is increasing rapidly, continuous updating of evidence is mandatory.

Methodological problems were common among the included studies: matched cohort studies were limited, a comparison with other viral diseases was rarely provided, and most data were based on questionnaire-based studies.

Symptom prevalence is primarily based on self-report and online surveys; therefore, recall and selection biases must be considered. Furthermore, most of the studies included in this review were published before the WHO published the definition of post-COVID-19, leading to a heterogeneous delineation of the condition among studies.

Finally, excluding children with PIMS-TS, who generally complain of more severe and persistent symptoms could have an impact on the estimation of the prevalence of long COVID.

The evidence of long COVID in children is limited, heterogeneous and based on low-quality studies. Since the precise prevalence of the condition remains undefined, it is difficult to distinguish between functional complaints of post-acute COVID syndrome and the effects of social isolation.

Further high-quality studies are required to define the optimal management of this emerging condition and to establish what resources are needed to address long COVID and the general lifelong negative effects of the SARSCoV-2 pandemic in children and adolescents.

Since the WHO provided a research definition of long COVID, its use should be promoted in future studies to harmonize data.

Controlled clinical studies using questionnaires should be encouraged to ensure an objective analysis of the true prevalence and characteristics of long COVID in children. Furthermore, the impact of new variants on the prevalence of long COVID must be investigated to ensure healthcare systems and appropriately allocate their resources.

Long COVID syndrome in children and adolescents is an entity with limited evidence, which is highlighted in the present review.

Symptoms such as fatigue, headache, arthralgia, myalgia, chest pain and dyspnea are reported in the literature with different and wide prevalences.

On the other hand, older age, female sex, and previous chronic conditions are associated with more persistent symptoms.

More controlled, methodologically more robust studies with universal definitions of long COVID should be carried out to support the data detailed in this review work.