Initial reports of long-COVID were described in Italian adults during August of 2020 , with the first five children suffering from this syndrome identified by Ludvigsson in Sweden in November of 2020 . According to his observations of these five children, the most common symptoms were fatigue, dyspnea, palpitations, chest pain, headache, concentration difficulties, and muscle weakness. Following the publication of this information, Ludvigsson was contacted by parents of a further 35 Swedish children with similar complications , and similar reports began to quickly emerge from other parts of the world. The second such report of these symptoms in children were described by Buensenso et al., from Rome. This report described 123 children whose parents had been surveyed around five months after diagnosis of COVID-19. Symptoms were reported to persist in 58 % of the children, the most common of which were insomnia, fatigue, nasal congestion, headache, muscle pain and difficulty concentrating . Subsequent studies reported similar symptoms, although the prevalence of long-COVID varied widely (4 – 66 %) . A larger prospective controlled study, which included a cohort of 1734 children who had tested positive for SARS-CoV-2, was published in August of 2021. The authors, Molteni et al., observed that children most often displayed symptoms of fatigue, headache and anosmia. However, they did not report impaired concentration, anxiety, or memory disturbances. Moreover, they estimated the prevalence of post-COVID symptoms to be only 4.4 % on day 28 following a positive test and 1.8 % on day 56. Nonetheless, this percentage was significantly higher than in the control group, whilst the authors also suggested that older children (> 12 years of age) experienced a higher incidence of symptoms than younger .
Unfortunately, the prevalence of symptoms in the immunodeficient children cannot be compared as no similar studies have been conducted yet, to our knowledge. Therefore, we can only compare our control group, in which the prevalence of long-COVID was relatively high (60.0 %) and increased with age. Moreover, the most frequently reported symptoms described by us were consistent with those obtained by previous researcher. Like others, we did not find a relationship between long-COVID and the presence of allergic diseases. However, we have demonstrated that the syndrome affects immunocompromised children less often. Why immunodeficient children are spared from the development of long-COVID is unclear, though mechanisms underlying this complication can be investigated. Although the underlying cause of long-COVID has yet to be established, there are several possible theories that do not exclude one another [11,12].
One of the possible causes may be the higher frequency of asymptomatic SARS-CoV-2 infection in this group. Although it has been suggested that the severity of COVID-19 does not correlate with the presence or severity of long-COVID [13,14], it is currently postulated that this relationship is dependent on the type of symptoms. Organ or tissue damage caused by SARS-CoV-2, such as fibrosis and scarring, as well as inflammation, may lead to long-term consequences , such as severe pneumonia, chronic cough or breathing difficulties. . This would explain the presence of chronic respiratory symptoms and persistent declines in blood oxygen saturation in several of our patients after severe COVID pneumonia requiring intensive treatment. However, this pathomechanism does not explain the presence of the general and neurocognitive symptoms of long-COVID.
As for the symptoms that affect the central nervous system, such as concentration and sleep disorders, fatigue, and irritability, the pathomechanisms seem to be at least partially understood. Recent reports have suggested that the spike protein of the virus can cross the blood-brain barrier and cause perivascular inflammation [16,17]. Moreover, molecular mimicry between the spike protein and human proteins contributes to autoimmunity and activates toll-like receptors (TLRs), leading to the release of inflammatory cytokines . Various researchers have linked this phenomena to neuroinflammation that may damage brain blood vessels and brain cells, contributing to long-COVID [19,19-21]. Additionally, mast cells may also contribute, as they have been shown to be activated by SARS-CoV-2 and release numerous chemokines and cytokines that may promote inflammatory symptoms [11,22]. Therefore, we propose that the state of reduced immunity may constitute a protective factor against this inflammatory reaction and, thus, protect against the symptoms of long-COVID.
Another possible pathomechanism of long-COVID is the persistence of SARS-CoV-2 reservoirs in specific tissues, with some patients infected with the virus not able to clear it for a long period. Therefore, they are characterized by viral ribonucleic acid (RNA) and proteins in nasopharyngeal swabs and samples of feces [23,24]. Moreover, immunosuppression seems to facilitate SARS-CoV-2 persistence [11,25,26], which leads to mutations in the virus that confer resistance to a typical class of neutralizing antibodies. It is possible that SARS-CoV-2 evades the immune response and thus causes persistent symptoms . Among several of our immunocompromised patients, we observed the persistence of SARS-CoV-2 for up to 3 months, however, this did not lead to the symptoms of long-COVID. Nevertheless, it was a significant inconvenience, as parents reported that it hindered the treatment of underlying diseases.
Another reason for the persistence of post-COVID symptoms is the reactivation of previously harbored pathogens, due to dysregulation of the host immune response by SARS-CoV-2. It is well known that during their lifetime people accumulate persistent viruses in their bodies, mainly herpesviruses. When the host is in a state of good health these pathogens do not cause any symptoms, however they can reactivate under conditions of reduced immunity or stress. It has been shown that SARS-CoV-2 can dysregulate the immune response that keeps these viruses latent, a process regulated by host interferons, leading to a change in their gene expression or protein production that generate persistent symptoms [11,27]. Various researchers have reported the reactivation of Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and human herpesviruses 6 and 7, during COVID-19 [28-30]. These viruses can infect new organs or tissues, generate new symptoms, or induce neuroinflammatory processes in the central nervous system . It appears that this reactivation should be better promoted in children with immunodeficiency. However, we observe a more intense immune response to the viral infection among immunocompetent children, which may play a significant role in its interaction with herpesviruses. Further research is needed to clarify this issue.