Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population

The 2019 novel coronavirus disease (COVID-19) was officially declared as a public health emergency of international concern in March 2020 [1]. Despite the implementation of preventive strategies to contain the infection, millions of people were infected by SARS-CoV-2 and millions of deaths have been recorded all over the world [2].

Most of the early published studies focused mainly on the characteristics of the disease in the adult and elderly population [3, 4], considered to be at the highest risk of severe disease and death [5]. In fact, since the beginning of the outbreak, children are seemed to have an asymptomatic or a milder clinical course compared to adults [6‐8] and the focus on them has been initially lower. Subsequently, however, numerous reports have been conducted to describe the clinical features of the infection also in pediatric age [9], the secrets of their immune response [10] and the differences with adult population [11, 12]. Researches have, also, focused the attention on the possible negative effects on mental health symptoms due to rigid measures implemented during lock down to contain the spread of the infection [13, 14].

Recently, although increasing attention has been given in adult patients to the long-term effects of COVID-19, generating another category of patients called “Long Covid” [15, 16], few data have been collected in the pediatric population [17, 18].

Therefore, we wanted to conduct a survey among all children infected with SARS-CoV-2 in Latina.

The primary aim of our study was to evaluate long-term symptoms of infection, lifestyle changes and emotional and psychological aspects of a sample of Italian children infected by SARS-CoV-2; Secondary aim was to investigate the demographic characteristics and the clinical features of infection of these children and their parents.

Following the activation of a pediatric outpatient clinic post-COVID in our hospital, we have taken charge of all children infected by SARS-CoV-2 between March 2020 and March 2021 and living at Latina Local Health Authority (ASL of Latina).

Institutional review board of Maternal and Child Health Department of the Local Health Authority of Latina approved the study protocol (protocol 02–15/03/2021).

We developed a survey with a web-form link to collect data (Google forms). The survey was conducted through a questionnaire administered by telephone by the pediatricians assigned to the management of outpatient clinic post-COVID. All families with children infected by SARS-CoV-2 between March 2020 to March 2021, were invited to participate to the survey. The questionnaire included specific questions for parent and children for participants ≥ 6 years, while only the parent’s section was required for younger kids. In particular, the questionnaire included different items about children’s demographic characteristics, clinical features of infection, long-term symptoms of infection, lifestyle changes and the main activities practiced during lock down and a final section dedicated to emotional and psychological aspects; Furthermore, the questionnaire included also a section that investigated parents’s demographic characteristics and clinical features and the course of infection. A verbal informed consent was obtained before beginning the interview. The information obtained was automatically linked to a spreadsheet and analyzed.

In relation to the post-COVID pediatric outpatient clinic of our hospital, the local protocol implemented includes: clinical examination with detailed history of previous infection and the possible presence of current symptoms, blood tests, evaluation of glomerul and tubular function and proteinuria on 24 h urine sample, electrocardiogram, spirometry, multidimensional fatigue questionnaire (Peds-QL Fatigue). Then, depending on the symptoms that emerged during the first clinical examination, our children are referred to specialist evaluations: cardiological, otolaryngology, dermatological, pneumology.

We contacted the family of 3075 children (5.7% of all children aged 0–18 years living in the ASL of Latina) who were infected with SARS-CoV-2 between March 2020 and March 2021, to invite them to come to our pediatric post-COVID outpatient clinic for a visit. Initial work consisted of a telephone interview, conducted by pediatricians assigned to manage the post COVID outpatient clinic. 10.8% (n = 333) did not answer the telephone and 43.2% (n = 1329) declined to participate; 46% (n = 1413) agreed to participate to the survey and were finally enrolled in the study.

The clinical and demographic characteristics are summarized in Table 1.

It is interesting to note that, although 49% (n = 696) of the parents of infected children was not aware of the blood group of their children, in the remaining cases, group A + prevailed in 17.3% (n = 244) of cases and group 0 + in 17.5% (n = 247).

Our findings showed that 20% of children infected with SARS-CoV-2 are at risk of experiencing persistent symptoms after the infection. Therefore, we believe that it is important to formulate an action of prevention, that should be implemented in all those areas at greater risk of contracting the infection.

Related to this, our study highlighted an interesting data, that children are infected mainly inside familial clusters [19, 20], while to a lesser extent at school or during sports activities. This finding is important and draw attention the importance of parental vaccination in limiting the spread of SARS-CoV-2.

Analyzing the children’s characteristics and clinical features of infection, our data are in line with those already present in the literature; in fact, in our children we found that the most frequent blood groups were group A and 0 Rh-positive, because seems that subjects with blood group A are more susceptible to infection [21, 22], while the group 0 is the most common in the Italian population. In addition, 27.5% of our children were asymptomatic or exhibit mild symptoms (72.5%) and could be treated at home in 99% of cases [6, 8, 23], requiring hospitalization in only 1% of cases.

While, related to comorbidities, we found that 15,3% of our infected children were allergic subjects; however, the role of atopy as risk factor for COVID-19 is very debated [24‐27]

In children who performed serologic tests for anti-SARS-CoV-2 IgM and IgG 3 months after infection, we observed a negative response in a small percentage of patients (16.7% of cases). These data confirm our previous study in which we observed that antibody responses against SARS-CoV-2 can wane also in pediatric age [10], suggesting other possible mechanism underlying immunological memory. In line with this concept none of our children, who experienced a new contact with an infected subject, then tested positive to the control swab/then developed further episodes of COVID-19.

Furthermore, we found that children, like the adult population [15, 16, 28], may also experience persistent symptoms but with a lower prevalence. In our report 20% experienced persistent symptoms after the primary infection. This percentage is lower than that described by Buonsenso et al. [18], moreover the most common symptoms referred (fatigue, insomnia, difficulty in concentration and memory, muscle and joint pain, respiratory problems and palpitations), are in line with those described in other pediatric reports [17, 18, 29, 30].

Interestingly, persistent symptoms occurred predominantly in children with a longer duration of SARS-CoV-2 infection, older in age, and with a higher body mass index.

The older age as a risk factor for persistent symptoms after SARS-CoV-2 infection in children has already been demonstrated in other studies [31‐33].

Other risk factors described for persistent symptoms after infection include: allergic diseases [31], muscle pain on admission and intensive care unit admission [33].

Related to a higher body mass index, it is known that overweight is characterized by a condition of chronic inflammation [34] and reduced immune function [35, 36] that could therefore predispose to the development of the long COVID syndrome. In fact, the proposed pathophysiological mechanisms underlying long COVID remain unclear and include: hyperinflammatory state, inadequate immune response, virus persistence and organ damage [37].

Overall, our data confirm the risk of persistent symptoms after infection even in pediatric age and highlight the need for a multidisciplinary follow-up, regardless of the severity of the initial symptoms, also in view of recent evidence of possible organ damage induced by the inflammatory process in different areas: brain [38], lung [39], heart [40].

Some of the data from our survey on the analysis of lifestyle changes and psychological impact during the period of illness are worrying. In particular, we showed that during the period of illness the most time spent by children was in front of the tv-video and social media and with phone cell. This effect was particularly evident in middle and high school children. These data need to be evaluated carefully, considering the negative effects related to prolonged use of electronic media on children. In fact, these negative effects concern not only the cognitive aspects, as difficulties with language acquisition, learning and poorer school results [41, 42] but especially physical effect [43‐45], as the relationships between screen media exposure and the increased risks of overweight /obesity in pediatric age. In fact, we found that about 30% of children interviewed presented an increase in body weight compared to the period prior to the illness and only 14% of children practiced physical activity.

On the other hand, although the hours spent studying showed an upward trend among age groups, the average number of hours was about 3.5, which is low when considering the hours that a student normally spends studying between school and home; this consideration is even more worrisome if we look at the prolonged periods of lockdown, periods of illness related to the first infection and periods of convalescence related to long covid symptomatology..

In fact, our survey showed that more than half of parents believe that this type of teaching has a negative influence on their child's learning and educational growth. In favor of the re-opening of schools, we must consider what we have pointed out, in agreement with Munro et al. [46], that school is not one of the most dangerous places for the spread of coronavirus. We think that it is important to ensure school attendance in presence, not only because the school represents a place of education, of passing on knowledge and notions, but especially for the psychophysical and relational development of children and adolescents. Not surprisingly, the same children in our survey reported that attending school was the second most missed activity.

Furthermore, school closures could have a long-term negative economic impact, as well as amplify and worsen gender and social class inequalities to the disadvantage of the poorest (in terms of access to food with the development of severe nutritional deficiencies or inability to follow distance learning) and children with severe cognitive and physical disabilities; in addition, spending more time at home in a condition of severe socioeconomic stress could lead to an increase in cases of child abuse, as already described during this pandemic [47, 48].

Certainly, we think that the return of children to school or other extracurricular activities in person should be done safely, through the implementation of prevention strategies such as distancing, hand washing and use of the mask even in pediatric age [49‐51]

This could have many advantages in pediatric care, as the significant reduction of pediatric infectious diseases disseminated through droplet and contact with the consequent drastic decrease of admissions, outpatient visits and emergency room accesses, as observed from the onset of pandemic with the diffusion of containment measures [52‐55].

This study has some limitations: primarily, we have considered all persistent symptoms after resolution of infection, regardless of distance from infection although the definition of “long covid” is still much debated; secondary we also acknowledge that symptoms were only reported through online survey rather than directly ascertained and are related to a single-centre of study.

We believe it is important to highlight from our survey that children at risk for persistent symptoms after infection are primarily those who are older, have higher weight, and have a longer duration of primary infection. In particular, increased body weight associated with greater susceptibility to infection and longer duration illnesses, that promote sedentary activities, are associated with greater psychological impact of COVID-19, and these could be among the main causes of increased susceptibility of some children to developpersistent symptoms after SARS-CoV-2 infection.