Preliminary Evidence on Long COVID in Children

Introduction

Since the beginning of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, approximately 646,700,000 confirmed cases have been reported. The paediatric population has been estimated to represent 8.5% of the total cases, reaching higher percentages in some countries such as the United States of America with 18.2% of cumulative cases. The adoption of various strategies for Coronavirus Infection Disease 2019 (COVID-19) containment has helped to reduce the viral shedding and the pressure on the healthcare systems. Vaccines against SARS-CoV-2 and its most important variants have significantly reduced mortality, rate of hospital admissions and disease severity. Despite these advancements, many patients complain of long-lasting symptoms after recovery from COVID-19, typically involving different organs, with a waxing and waning presentation. This clinical manifestation following SARS-CoV-2 infection with no other medical explanation has been called Long COVID syndrome or Post-Acute Sequelae of COVID-19 syndrome.

Long COVID syndrome has emerged as a long-lasting consequence of acute SARS-CoV-2 infection in adults. In addition, children may be affected by Long COVID, with potential clinical issues in different fields, including problems in school performance and daily activities. Yet, the pathophysiologic bases of Long COVID in children are largely unknown, and it is difficult to predict who will develop the syndrome. Children have been mostly overlooked during this pandemic, since the clinical course of COVID‐19 in this group is much milder than in adults. However, there is an increasing evidence that restrictive measures aimed at limiting the pandemic are having a significant impact on child’s mental health. Childhood is a delicate and fundamental period of life, critical for acquisition of social, behavioral and educational development. The evidence that COVID‐19 can have long‐term impact on children as well, including those with asymptomatic/paucisymptomatic COVID‐19, highlight the need for paediatricians, mental health experts and policymakers of implementing measures to reduce impact of the pandemic on child’s health. Importantly, further prospective studies, not only based on surveys but with objective clinical assessment and including healthy controls that never had COVID‐19, are needed to better understand the burden of Long COVID in children.

There is a need to assess the long-term consequences of Covid-19 in paediatric populations, to inform clinicians, researchers and public health experts and address the impacts of this condition on those affected and their families and to inform discussions on vaccination of children. This cohort study aimed to investigate the incidence of and risk factors for long-term Covid-19 outcomes in children post-hospital discharge.
Several research investigations have examined the long-term Covid-19 outcomes in children with laboratory confirmed SARS-CoV-2 infection post hospital discharge. We found that a quarter of children had persistent symptoms at the time of the follow-up with fatigue, sleep disturbance and sensory problems being the most common. Almost one in ten reported multi-system impacts with two or more categories of persistent symptoms at the time of the follow-up. Children in mid-childhoods were at higher risk of persistent symptoms at the time of the follow-up. Although prevalence of symptoms declined over time, a substantial proportion experienced problems many months after discharge.

Therefore that almost one in ten children had multisystem impacts with two or more categories of persistent symptoms present at the time of the follow-up. Similar numbers were previously reported in the Russian adult population and patients with clusters of different symptoms were described in the UK. Patients with multisystem involvement will represent the primary target for the future research and intervention strategies development. The study showed that Age was significantly associated with persistent symptom presence at the time of the follow-up, with children above 6 years of age being at higher risk. To our knowledge, risk factors for long Covid in children have not been investigated in previous studies, so we may draw comparisons with the data from adult cohorts only. Previous data suggest that long Covid is prevalent in adults and that age is associated with a higher risk of long Covid. An Australian follow-up study of 151 children (median 3 years) who had predominantly mild acute covid-19 infection [8] found only 8% with on-going long-covid symptoms. As acknowledged by the authors the low median age may be the main reason for the low long-covid prevalence and our study substantiates this. We also found that in children of six years of age and above, severe acute Covid-19 was associated with persistent symptoms and excessive weight and obesity with multisystem involvement. That allergic diseases in long COVID in children were also associated with a higher risk of long Covid. Perhaps connected to reporting asthma to be associated with development of long Covid. Recent data suggested that COVID-19 consequences may be linked with the mast cell activation syndrome and the Th-2 biased immunological response in children with allergic diseases may be responsible for an increased risk of long-term consequences from the infection.

Also, investigations revealed that Post–COVID-19 Condition in Children This set of patients had a 77% less likely to have symptoms resolution after COVID-19 (hazard ratio [HR], 0.23; 95% CI, 0.08-0.60; P < .05) if they had symptoms reported every 2 weeks prior to infection. The most common post–COVID-19 symptoms included rhinitis (62%), sore throat (68%), headache (52%), cough (42%), fever (41%), and fatigue (35%). Each of these symptoms resolved within 10 weeks following a positive PCR test result. The more frequent presence of rhinitis (HR, 0.08; 95% CI, 0.01-0.42; P < .01), sore throat (HR, 0.08; 95% CI, 0.01-0.53; P < .05), headache (HR, 0.05; 95% CI, 0.01-0.27; P < .001), cough (HR, 0.00; 95% CI, 0.00-0.02; P < .001), fever (HR, 0.01; 95% CI, 0.00-0.13; P < .01), and fatigue (HR, 0.00; 95% CI, 0.00-0.09; P < .001) before COVID-19 infection was significantly associated with delayed resolution of each symptom after COVID-19. Neither current nor past health conditions were associated with symptoms after COVID-19.
There is increasing evidence that children patients diagnosed with acute COVID‐19 suffer from Long COVID. As mentioned before, Although they all started after discharge and improved over time, certain Long Covid effects persist. As a result, screening for COVID symptoms in children is critical.

Recent scientific reports have raised attention to the burden of Long COVID syndrome in the paediatric population. Although the clinical characteristics and the course of this condition seem to be similar to those affecting adults, there are limited data on the pathophysiologic bases.
This analyze current evidence on Long COVID syndrome in children, focusing on a clinical multidisciplinary assessment aimed at providing practical insights.

Pathophysiology

There are several mechanisms that determine SARS-CoV-2 pathogenicity. Once inside the host cell, the viral RNA genome triggers an immune response via pathogen-associated molecular patterns (PAMPs), inducing the release of proinflammatory cytokines and an inflammatory programmed death sequence called pyroptosis. The dead cells release damage-associated molecular patterns (DAMPs) into the vascular stream, recruiting migrating immune system cells, such as macrophages, monocytes and T cells. In predisposed individuals, these events could lead to a “cytokine storm”, which is an uncontrolled release of pro-inflammatory cytokines, such as interleukine-2 (IL-2), IL-7, IL-10, granulocyte-colony-stimulating factor (G-CSF), tumour necrosis factor-α (TNF-α) and macrophage inflammatory protein 1α (MIP1α).

It has been hypothesised that sustained activation of mast cells could be at the basis of prolonged inflammatory status in Long COVID patients, as many symptoms overlap with that of mast cell activation syndrome (MCAS), but more studies are needed to confirm this pathogenic pathway.

The unbalance between pro-coagulant and anti-coagulant factors during SARS-CoV-2 infection is responsible for hypoxic tissue damage in many organs. In fact, SARS-CoV-2 dampens angiotensin-converting enzyme 2 (ACE2) protective action on endothelial cells and its anti-atherosclerotic effects and impairs the fibrinolysis of amyloid fibrinogen microclots through circulating spike proteins.

Figure 1. SARS-CoV-2 main pathogenic pathways.

The virus binds to ACE2 receptor, dampening its anti-thrombotic and anti-atherosclerotic action and inducing vascular damage. Once inside the cell it replicates and viral RNA is recognised by PAMPs (pathogen-associated molecular patterns) receptor, such as Toll-like receptors (TLRs). Activated TLRs induce pro-inflammatory cytokines release, triggering a cascade of events that leads to cell apoptosis (pyroptosis). Cellular debris and cytokines in the bloodstream induce the activation of the innate and immune system, sustaining the inflammatory process. Importantly, SARS-CoV-2 can bind to cell proteins different from ACE2 receptor, thus explaining why cells not expressing ACE2 receptor can also be infected by the virus. Abbreviations: ACE2 = angiotensin-converting enzyme 2; PAMPs = pathogen-associated molecular patterns; DAMPS = damage-associated molecular patterns; TLR = toll-like receptor; IL = interleukin; TNF-a = tumour necrosis factor α; MIP1a = macrophage inflammatory protein 1 α; G-CSF = granulocyte-colony-stimulating factor.

T- and B-cells function is fundamental to fight SARS-CoV-2 infection. Severe patients showed low levels of interferon-γ (IFN-γ) and TNF-α and high levels of perforin and granzyme B, markers of T-cell exhaustion. Antibodies production by B cells can slow down the infection by preventing S protein—ACE2 interaction or by binding to viral capsid. Surprisingly, the antibody–virus complex can also facilitate the entry and replication of the virus inside phagocytic cells, a non-well understood biological mechanism called antibody-dependent enhancement (ADE).

These molecular strategies adopted by the virus during acute infection seem to be partially responsible for the subsequent development of Long COVID syndrome. In fact, Di Sante et al. found higher levels of IL-6 and IL-1 in children with PASC compared with those who recovered completely after acute infection. This aspect would demonstrate the persistence of inflammation in Long COVID children. And higher levels of plasmablasts, IgD-CD27+ memory and switched to IgM-IgD-B cells, all signs of B-cells activation.

Long COVID in Children: Background and Definition

A first case series of five children complaining of variable long-lasting non-specific symptoms after COVID-19 in children was described in November 2020. All the children were pauci-symptomatic during the acute infection and exhibited persistent symptoms lasting 6–8 months, and one child had comorbidities and a history of peri-myocarditis after COVID-19 diagnosis. After this publication, more attention was given to PASC in children. In an Italian study conducted on 129 children, the authors reported non-specific symptoms, such as fatigue, palpitations, muscle and joint pain, headache, insomnia and respiratory problems, in approximately 50% of patients 60 days or more after the infection. An Australian study showed an 8% prevalence of PASC in children with asymptomatic COVID-19 infection. The post-acute symptoms were mostly mild and resolved spontaneously after 8 months of follow-up.

PASC symptomatology is heterogeneous in both clinical presentation and the timing of exacerbation and resolution. The following definition was proposed through a Delphi-consensus process: “Post-COVID-19 condition occurs in young people with a history of confirmed SARS-CoV-2 infection, with one or more persisting physical symptoms for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time”.

This work, which evaluated 21 cohort studies with a total population of 80,070, determined the persistence of Long COVID symptoms in 25.2% of children affected by acute SARS-CoV-2 infection. The most common PASC-associated symptoms in children overlapped with those in adults: mood symptoms (e.g., sadness, tension, anger, depression and anxiety) (16.5%), fatigue (9.7%), sleep disorders (8.4%), headache (7.8%), respiratory symptoms (7.6%), sputum production or nasal congestion (7.5%), cognitive symptoms (e.g., less concentration, learning difficulties, confusion and memory loss) (6.3%), loss of appetite (6.1%), exercise intolerance (5.7%) and altered smell (5.6%). Symptoms appeared to resolve in 54–75% of children within 1–5 months, with 4.4% of the cases reporting persistency at >4 weeks after COVID-19 onset and 1.8% at 8 or more weeks.

Long COVID Assessment in Children

1. Respiratory Assessment
   In children and adolescents with Long COVID, the most frequently reported respiratory symptoms are persistent cough, fatigue and exertional dyspnoea.
   1.1. Pulmonary Function Tests (PFTs)
   In a study evaluating lung function impairment in a paediatric population (n = 29) affected by persisting respiratory symptoms, Leftin Dobkin et al. reported the most frequently observed abnormality to be exercise intolerance, assessed by the six-minute walking test (6MWT). Spirometry, plethysmography and diffusing capacity for CO (DLCO) were normal in most patients, with unremarkable chest-X ray findings. A Czech multicentre study conducted on 39 adolescents similarly showed a low prevalence of functional and/or structural lung anomalies at spirometry, DLCO, 6MWT, chest X-ray and D-dimer. Notably, PFTs and imaging alterations fully recovered within 1 to 8 months.
   1.2. Thoracic Imaging
   Pulmonary sequelae of COVID-19 in children have been investigated by chest X-ray and lung ultrasound (LUS). Whilst X-ray findings are mainly unremarkable, studies performed with the use of LUS identified pleural irregularities, vertical artifacts or areas of white lung and subpleural consolidations. This children with Long COVID may experiment respiratory symptoms, with a tendency towards complete recovery within six months.
2. Upper Airway Assessment
   The otorhinolaryngologic sequelae of COVID-19 in children is indeed very scant. However, the pathological long-term alterations described in other organs such as fibrotic changes due to microvascular and endothelial damage or chronic neuroinflammation are sure to be found in the Head and Neck region and may explain the vast heterogeneity of Ear, Nose and Throat (ENT) symptoms.
3. Gastrointestinal Assessment
   Data regarding gastrointestinal manifestations of Long COVID are scarce. According to the available information, Long COVID in children and young people shows a similar gastrointestinal manifestation pattern compared to acute disease, but the prevalence is lower.
4. Cardiologic Assessment
   In children with Long COVID, involvement of the cardiovascular system and clinical cardiovascular symptoms are constantly described in multiple studies. The five most prevalent clinical cardiovascular manifestations were orthostatic intolerance (6.9%), exercise intolerance (5.7%), chest pain (4.6%) and variations in heart rate (2.29%). Less frequently also palpitations (1.27%) were associated with children with Long COVID.
5. Common Motor Syndromes
   Long COVID in children commonly affects the motor system. According to several studies, fatigue is among the most common disturbances, being reported by approximately 10% of affected children, and arthralgia and muscle soreness are also frequent. Even if more rarely, dizziness and even balance problems can be found in the Long COVID syndrome.
6. Psychological Aspects
   The COVID-19 pandemic has severely threatened psychological health, as well as relational and social well-being. Despite the lower incidence of infection and mortality in children than in adults, the negative impact of the pandemic on psychological well-being has been evident. Children over the age of two were aware of the changes caused by the spread of the virus and were afraid of their health and family members. Children experienced a state of uncertainty for a prolonged period and suffered isolation due to the closure of schools and social gathering places. Several studies have shown that the psychological pressure generated by social isolation and routine derangement increased anxiety and depression symptomatology, irritability, mood instability, behavioural and emotional changes and sleep disturbances. Special attention should be paid to children who have been infected by COVID-19. These children were more susceptible to psychological difficulties due to the risks associated with infection, isolation and the experience of hospitalisation.

Clinical Approach: From Diagnosis to Follow-Up

Currently, there are no guidelines for Long COVID syndrome management in children. In a recent publication, Fainardi et al. [26] proposed a schematic approach to paediatric Long COVID divided into different steps.

The first one is represented by comprehensive medical history and physical examination. Paediatricians should actively search for Long COVID symptoms, particularly among at-risk patients, such as adolescent females and children with comorbidities. Specific symptom-based questionnaires for Long COVID may help to investigate the presence of long-lasting symptoms and their impact on everyday life. Validated scales have been proposed for adult patients, such as the symptom burden questionnaire for Long COVID (SBQ-LC) and the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS). Unfortunately, these items require to be fulfilled directly by the patients and are not suitable for children. Other psychometric scales have been adopted to measure specific aspects of Long COVID impact on the paediatric population, most of all the psychological health status. Though useful in terms of follow-up and guidance of therapeutic interventions, none of the scales currently available are validated for assessing children.

Secondly, the appropriate diagnostic test should be chosen on the basis of symptoms and clinical signs Figure 2). Non-invasive diagnostic tests, such as blood exams, PFTs, ECG, sniffing tests, audiometry and 6MWT, may be helpful to exclude the alternative diagnosis, but it should be reminded that currently there is no single diagnostic test for Long COVID. Moreover, mild abnormalities may persist also in healthy children with past SARS-CoV-2 infection and should be carefully evaluated on the basis of clinical presentation and past medical history. Non-invasive tests could be adopted for children monitoring and follow-up, as Long-COVID-related findings seem to be time-limited and generally resolve in a few months. During the third step, the monitoring phase, symptoms’ trend should be checked. Taking into account the actual knowledge, it seems reasonably advisable to leave more invasive tests (e.g., computed tomography or lung MRI) to selected cases that show persistent, atypical or worsening symptoms.

Figure 2. Clinical approach to paediatric Long COVID. Abbreviations: 6MWT = six-minute walking test; DLCO = diffusion lung capacity for carbon monoxide; LUS = lung ultrasound; CT = computed tomography; EMG = electromyography; CPK = creatine phosphokinase; EEG = electroencephalogram; MRI = magnetic resonance; ECG = electrocardiograph; TTE = transthoracic echocardiography; BNP = brain-derived natriuretic peptide; US = ultrasound; AST = aspartate aminotransferase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transpeptidase.

Regarding Long COVID management, non-pharmaceutical interventions such as physical rehabilitation have been proposed to treat Long COVID symptoms in the adult population. The only available randomised control trial present in the literature found that light aerobic and breath exercises improved lung function, exercise tolerance, quality of life and anxiety in a group of 72 elderly COVID-19 survivors. Common analgesics, such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), may help to control symptoms, but there is no current effective pharmaceutical treatment for Long COVID syndrome. To date, there are no available data regarding Long COVID treatment in the paediatric population. Anyway, it should be noted that this condition has a limited time course and symptoms are generally mild.