Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally asymptomatic or have mild coronavirus disease (COVID) with low rates of hospitalization (<2%) or death (<0.03%) . 1-9
Reported hospitalization rates could overestimate severity, as many studies do not specify whether children are hospitalized with COVID or due to COVID.10 The disease burden is greatest in adolescents, who are more frequently infected and hospitalized than older children. small.9
Despite the low risk that acute COVID represents in children in the short term, there are two long-term consequences of SARS-CoV-2 infection that are of concern. The first is "pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (SIMP-AT)" or "multisystem inflammatory syndrome in children (SIM-N)", an immune-mediated disease that occurs in a small proportion (< 0.1%) of children 2 to 6 weeks after being infected with SARS-CoV-2.11–20
The second is “long COVID,” also called “post-COVID syndrome” or “post-acute sequelae of SARS-CoV-2 (PACS).” These terms describe persistent symptoms after COVID, mainly described in adults, affecting the sensory, neurological and cardiorespiratory systems, as well as mental health.21-23
To date, there is no clear definition for this syndrome and there is no agreement on the duration of symptoms that justify the diagnosis, which varies from 4 to 12 weeks after acute infection. More than 200 symptoms have been attributed to long COVID, many of them non-specific and highly prevalent in the general population, such as fatigue, sleep disturbances, difficulty concentrating, loss of appetite, and muscle or joint pain.24-26
In adults, risk factors for long COVID have been reported including female sex, middle age, white ethnicity, and comorbidities, especially asthma.27-29 There is much less data on long COVID in children and adolescents.
The low risk posed by acute illness means that one of the key benefits of the COVID vaccine in children and adolescents could be protecting them from long COVID.
Therefore, an accurate determination of the risk of long COVID is crucial in the debate about the risks and benefits of vaccination in this age group. Here, the authors reviewed and summarized studies that reported on long COVID symptoms in children and adolescents.
| Long Covid studies in children and adolescents |
The authors identified 14 studies (4 cross-sectional studies, 26,30–32 9 prospective cohort studies, 33-41 1 retrospective cohort study42) that investigated long COVID symptoms in a total of 19,426 children and adolescents.
The number of children and adolescents in each study ranged from 16 to 6804 (median 330, interquartile range 89-1533). All studies were conducted in high-income countries. Case reports, studies that followed children after SARS-CoV-2 infection but did not assess long COVID symptoms, or studies that did not predominantly address children and adolescents were not included.43-50
There is marked heterogeneity between studies, including differences in design, inclusion criteria, results, and follow-up time. Children were evaluated for persistent symptoms for different durations: more than 4 weeks (2 studies), 31,36 more than 4 and 8 weeks (1 study), 35 more than 4 and 12 weeks (2 studies), 34,41 more 12 weeks (1 study), 37 more than 5 months (2 studies), 33,40 and at arbitrary times (6 studies). 26,30,32,38,39,42
In 7 studies, symptom assessment was performed only through internet questionnaires or telephone interviews, 26,31,32,34–36,40 while 5 studies included study visits.30,33,39,41, 42
| Results of long Covid studies in children and adolescents |
The prevalence of long COVID symptoms varied considerably across studies from 4 to 66%.26,33–38,40–42 There was also wide variation in the reported frequency of long-term symptoms.
The most common reported symptoms were headache (3 to 80%), fatigue (3 to 87%), sleep disturbances (2 to 63%), difficulty concentrating (2 to 81%), abdominal pain (1 to 76%). %), myalgia or arthralgia (1 to 61%), stuffy or runny nose (1 to 12%), cough (1 to 30%), chest tightness or pain (1 to 31%), loss of appetite or weight (2 to 50%), altered smell or anosmia (3 to 26%), and rash (2 to 52%).26,30–42
Four studies reported much higher prevalence of symptoms compared to the other studies.26,30-32 Of these studies, 3 were conducted at arbitrary times after SARS-CoV-2 infection.26,30,32
Six studies reported a positive correlation with increasing age, 30,35-37,39,40 3 among females30,36,37 and 1 between allergic diseases40 or worse pre-infection physical and mental health37 and the prevalence of persistent symptoms.40 Additionally, one study found an association between longer hospitalization and more severe persistent symptoms, and between SIMP-AT and a higher prevalence of persistent symptoms.38
A control group was included in only 5 of the 14 studies. These 5 studies reported symptoms in children and adolescents without evidence of SARS-CoV-2 infection as a comparison group. 30,34-37 Three of these studies found that persistent symptoms were more prevalent in children and adolescents with evidence of SARS-CoV-2 infection.35–37
| Strengths and limitations of the studies |
Almost all studies to date on long COVID in children and adolescents have major limitations.
The first major limitation is the lack of a clear case definition which means that studies have used variable inclusion criteria and follow-up times. Some studies included children with self-reported SARSCoV-2 infection without laboratory confirmation.31,32 In addition to heterogeneity in inclusion criteria, studies followed children at arbitrary times and the method of assessment varied.
Most studies were based on self-reported or parent-reported symptoms from questionnaires without clinical evaluation or objective parameters such as lung function tests or imaging.26,30–32,34–38,40 When using apps, it is likely that online questionnaires select participants from higher socioeconomic levels, who have a lower risk of unfavorable outcomes after SARS-CoV-2 infection.51
A second important limitation is the lack of a control group in most studies. In the absence of a control group, it is impossible to distinguish long COVID symptoms from symptoms attributable to the pandemic, such as lockdown measures (school closures, deprivation of seeing friends or not being able to do sports and other activities) or seeing others. family and friends suffering or even dying from COVID. The results of the studies to date suggest that the symptoms associated with the infection are not necessarily more common or severe than those associated with the pandemic. 30,34
The prevalence of symptoms consistent with long COVID, including psychosomatic symptoms, has been considerably higher in children and adolescents since the start of the pandemic, and lockdown measures have been shown to have negative effects on the well-being and mental health of children and adolescents.52,53
While lockdown measures including school closures decrease SARS-CoV-2 transmission and prevent late COVID manifestations, these actions restrict social contact, self-determination and education and therefore amplify symptoms associated with the pandemic.
A third important limitation is selection bias as many studies have a low response rate (13% in a recent study).37 As people with persistent symptoms are more likely to respond to surveys, this may lead to overestimation. substantial prevalence of long COVID. Furthermore, as children and adolescents with mild symptoms may not be tested, selection bias and misclassification could also lead to overestimation.
Another limitation is that almost all studies include a wide range of age groups. The incidence and characteristics of long COVID are likely to vary among adolescents and younger children.
Since the risks and benefits of COVID vaccines differ between these age groups, more studies are needed that provide age-specific data. Furthermore, neither study investigated the impact of initial disease severity on the risk of long COVID. Finally, all of the studies were likely done before the delta variant became dominant, which may have a different risk for long COVID.
Adding to the confusion, the term long COVID was used to encompass those with objective complications of COVID (such as pulmonary fibrosis or myocardial dysfunction), those with mental health problems, 21,22 and those with more subjective and nonspecific symptoms reminiscent of symptoms of postviral chronic fatigue syndrome or myalgic encephalomyelitis. A separation of post-intensive care syndrome, post-viral fatigue syndrome and long-term COVID syndrome was suggested for the adult population and could be adopted for children.54
| Conclusions |
In summary, the evidence for long COVID in children and adolescents is limited, and all studies to date have substantial limitations or do not show a difference between children who have been infected by SARS-CoV-2 and those who have not. The absence of a control group in most studies makes it difficult to separate symptoms attributable to long COVID from symptoms associated with the pandemic.30,34,36
Given the large number of children and adolescents infected with SARS-CoV-2, the impact of even a low prevalence of persistent symptoms will be considerable. However, in most studies, symptoms did not persist for more than 12 weeks.33-35,41
Consistent with this, a study that found a difference between cases and controls in persistent symptoms (at 4 weeks post-COVID) reported that by 8 weeks, most symptoms had resolved, suggesting that Long COVID may be less worrying in children and adolescents than in adults.35
Interestingly, in one study, more than half of adolescents in the uninfected control group reported symptoms at 12 weeks even though only 8% reported symptoms at the time of SARS-CoV-2 testing.37
The relative paucity of long COVID studies and the limitations of those reported to date mean that the true incidence of this syndrome in children and adolescents remains uncertain. The impact of age, severity and duration of illness, virus strain and other factors on the risk of long COVID in this age group also remains to be determined.
In light of the importance of long COVID in the risk-benefit equation for policy decisions on COVID vaccines for children and adolescents, more studies are urgently needed to accurately determine the risk of long COVID.55 These should include groups rigorous monitoring procedures, including children with other infections and those admitted to hospital or intensive care for other reasons.
Longitudinal cohort studies should include regular testing for SARS-CoV-2 to confirm infection, meticulous recognition of symptoms, consistent and sufficiently long follow-up times to account for intermittent symptoms, and recording of pre-existing medical conditions. More research is also needed to identify the underlying immunological mechanisms of long COVID.
