Epidemiological and clinical and laboratory features of COVID-19 in pediatric patients

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Over the past 20 years, humanity has faced three epidemics caused by coronaviruses, namely, severe acute respiratory syndrome (SARS-2003), Middle East respiratory syndrome (MERS, 2012), and a new coronavirus infection (nCoV) [33]. In early January 2020, a new type of coronavirus (CoV) was detected in a bronchoalveolar lavage sample from a patient with pneumonia of unknown origin in China, which was provisionally named novel coronavirus (2019-nCoV) to distinguish it from SARS-CoV and MERS-CoV which caused previous outbreaks. Subsequently, the International Committee on Taxonomy of Viruses identified it as SARS-CoV 2, and the disease associated with it was named coronavirus disease 2019 (COVID-19) [11].

SARS-CoV-2 spread quickly worldwide; therefore, on January 30, 2020, the World Health Organization declared an outbreak of a disease caused by a new coronavirus as a public health emergency of international concern [50].

The first confirmed case of SARS-CoV-2 infection in children was reported in Shenzhen (a province in southern China) on January 20, 2020 [10]. As early as February 10, 2020, 398 cases of COVID-19 in children were reported in China, except the Hubei province where initially children were very rarely tested for SARS-CoV-2. In an analysis of 44,672 laboratory-confirmed cases of COVID-19 from all over China, as of February 11, 2020, 0.9% of the patients were children aged <10 years, and 1.2% of these patients were aged 10–20 years [37]. To date, we know that children get sick much less often with the clinical forms of this infection, especially with its severe course, compared with adults. However, data on the epidemiological characteristics and clinical aspects of the course of COVID-19 in children are still scarce. A Chinese Center for Disease Control and Prevention (CDC) report of 72,314 cases indicates that approximately 2% of all patients were patients aged <19 years [51]. In Italy, one of the first countries affected by the COVID-19 pandemic, 1.2% of all patients were children [29]. In the USA, as of October 22, 2020, there were 7,207,186 cases of COVID-19, and 11% of them occurred in children (1,053 cases per 100,000 pediatric population). Moreover, 0.6%–6.9% of patients with identified cases of infection requiring hospitalization, which accounted for 1%–3.6% of all patients hospitalized. The rate of lethal outcomes among hospitalized children was 0.23% [6, 15].

In China, 94% of children had asymptomatic or mild/moderate disease, approximately 5% of the pediatric patients had a severe course, and 1% had an extremely severe disease [36]. Most often, COVID-19 was detected in the group aged up to 5 years and older than 10 years; however, severe COVID-19 was more common in children aged 5–10 years. Boys were sick slightly more often than girls (52% versus 48%). The majority of confirmed cases (68.6%) had contact with family members with COVID-19. More than 90% of the patients had an asymptomatic, mild, or moderate course. A severe course was recorded in 10.6% of children aged <1 year, 7.3% of children aged 1–5 years, 4.2% of children aged 6–10 years, 4.1% of children aged 11–15 years, and 3.0% of children aged ≥16 years [17].

According to the Russian Federal State Agency for Health and Consumer Rights, more than 3,159 million cases of COVID-19 were detected in 85 regions of the Russian Federation in 2020. The incidence rate was 2152.63 per 100 thousand populations. Changes in the number of COVID-19 cases in Russia in 2020 were characterized by two increases in incidence. Among all COVID-19 cases, 5.1% were recorded in schoolchildren and 1.8% in students, and 3.3% in preschool children. Severe forms of COVID-19 were mostly registered in the group aged >55 years (77.6%) [2].

The pathogenesis of COVID-19 has already been sufficiently studied to date. A phylogenetic analysis revealed that the genetic code of SARS-CoV-2 is 70% similar to SARS-CoV; accordingly, the virus can use the same receptor to enter the cell. However, the affinity of the S-peptide for human angiotensin-converting enzyme 2 (ACE2) in SARS-CoV-2 is 10–20 times higher than that of the SARS-CoV spike, which facilitates its transmission from person to person [56]. Coronavirus susceptibility is associated with the presence of dipeptidyl peptidase 4 and ACE2 receptors in the lower respiratory tract, which are the main receptors for the SARS-CoV S-peptide [33]. Evidence shows that ACE2 expression is the highest in children, adolescents, and young women and lowest in older men. ACE2 is a part of the ACE2/angiotensin-(1–7)/MAS system that counteracts the pro-inflammatory effects of the ACE/angiotensin II axis. It catalyzes the conversion of angiotensin II to angiotensin I, 3–7, which modulates vasoconstriction, leukocyte migration, inflammatory cytokine expression, and fibrinogen activation [26]. That is, a high expression of ACE2 may be beneficial, as virions compete for receptor binding to angiotensin II. Children can maintain sufficiently high levels of angiotensin I, 3–7, to counterbalance the pro-inflammatory effects of angiotensin II. Thus, variable expression of ACE2 across age groups may explain why most children and young adults shake off SARS-CoV-2 infection without developing severe symptoms or complications and disprove the hypothesis that children are not the source of infection because they have no severe disease symptoms.

Several immune defense mechanisms are capable of eliminating viruses from the host organism. Antigen-presenting cells, such as dendritic cells and macrophages, phagocytize antigens and cleave them into fragments using lysosomes. These fragments are loaded onto major class I or class II histocompatibility complex molecules and transported to the cell surface for antigen presentation. Toll-like receptors (TLRs) on T cells, together with co-receptors, bind to the presented antigen. Helper T cells secrete cytokines that activate cytotoxic T cells (T_Cs) and B cells. T_Cs destroy infected cells through cell-mediated immunity, and antibody-secreting B cells mediate humoral immunity. According to Li et al. [26], the human innate immune system detects viral pathogen-associated molecular patterns using pattern-recognition receptors represented by TLR, RIG-I-like (RLR), NOD-like (NLR), cytoplasmic, and type C lectin-like receptors (CLmin). Moreover, TLRs, having recognized the S-protein of SARS-CoV-2, activate the production of numerous pro-inflammatory cytokines by epithelial cells and macrophages. The release of active mature interleukin 1, beta (IL-1β) recruits neutrophils to the lung tissue, increases heat production, and activates the production of type I interferon (IFN-I). Airway epithelial cells also secrete various cytokines, chemokines, antimicrobial peptides, and other factors in response to viral infection [26, 54].

COVID-19 is accompanied by an extremely high production of pro-inflammatory cytokines (IFN-α, IFN-γ, IL 1β, IL-6, IL-12, IL-18, IL-33, tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor, etc.) and chemokines; therefore, the cytokine reaction in patients with infection was called cytokine storm syndrome (CSS). These cytokines and chemokines recruit effector immunocytes, causing the development of local inflammatory response. CSS underlies the development of acute respiratory distress syndrome (ARDS) and multiple organ failure, which are fatal in severe cases [54]. The lethality of COVID-19 is associated precisely with a high level of IL-6 and a decrease in IL-10 in the blood serum [39]. SARS-CoV-2 is highly sensitive to the action of IFN but encodes proteins that counteract innate immune defenses, including suppressing the activity of IFN-I production (immune evasion mechanism). The absence of IFN-I leads to a defect in antibody production [46].

The development of COVID-19 is accompanied by excessive activation of cellular immunity, as evidenced by a sharp increase in the representativeness of cells expressing human leukocyte antigen-DR and CD38, associated with a significant decrease in the population of CD4⁺ and NK cells in the peripheral blood. Cytotoxic CD8⁺ T cells in COVID-19 produce large amounts of granzymes A and B and perforin. Patients have a high level of pro-inflammatory CCR6⁺-Th17 cells. Excessive Th17 cell activation and extremely high levels of CD8⁺ T cell cytotoxicity are believed to underlie the severity of immune damage to the lung tissue. With COVID-19, depletion of the pool of regulatory T cells (Treg cells) is also registered, which predetermines the unlimited activation of inflammation mechanisms and delays the process of resolving the inflammatory process [54]. The activation of virus-specific B cells leads to their differentiation into the plasma cells, which sequentially produce specific antibodies of the IgM and IgG classes. Antibody-producing cells with COVID-19 appear in the peripheral bloodstream on day 7. A gradual increase in the concentration of antibodies of the IgM and IgG class in the blood serum is noted from day 7 to day 20 of the disease. Specific IgM disappears at the end of week 12 from disease onset, and IgG persists for a long period, indicating the level of protection against re-infection [1, 54].

In the early phase of the disease, which generally is mild, the main role is played by nonspecific defense mechanisms and specific adaptive immune response that allows the elimination of coronavirus from the body [1]. However, if the immune response is ineffective, a late phase develops, which is based on the SARS-CoV-2 super-replication and CSS. Large-scale viral replication is accompanied by the generation of numerous virions, which leads to massive damage to target body tissues, including the lungs. Damaged ACE2-expressing cells produce pro-inflammatory cytokines that recruit effector cells (i.e., macrophages and neutrophils), release even more pro-inflammatory cytokines, and induce CSS development. If the immune function of patients in the acute phase is effective, there are no comorbid diseases, and optimal treatment is performed, the virus can be eliminated with the transition to the recovery phase [46].

Lung damage in COVID-19 is the main cause of severe disease and lethal outcomes [54]. After the penetration of SARS-CoV-2 into the body, the production of the ACE2 protein is inhibited, which leads to a decrease in the level of its representativeness, especially in lung tissues, increase in the concentration of angiotensin II, increase in capillary permeability, development of pulmonary edema, activation of apoptosis, and development of an inflammatory response in the lung tissue. A decrease in ACE2 concentration also leads to the activation of signaling pathways associated with the inducible B1 receptor Des-Arg9 bradykinin, which further increases inflammation and contributes to lung tissue damage. At the first stage of lung damage, alveolar macrophages, having recognized SARS-CoV-2, begin to produce pro-inflammatory ILs and chemokines that recruit effector T-lymphocytes. In the late period, an extremely high production level of IL-6, IL-1β, TNF-α, and other pro-inflammatory cytokines causes an influx of numerous monocytes and neutrophils, which enhance inflammation and contribute to the development of pulmonary edema. IL-1β and TNF-α induce hyaluronan synthase 2 activity in endothelial cells, lung alveolar epithelial cells, and fibroblasts, resulting in excess hyaluronic acid production and fluid accumulation in the alveolar space [23, 24].

With COVID-19, other organs and systems are also affected. SARS-CoV-2 infection, by suppressing ACE2 expression, can lead to excessive accumulation of angiotensin II, which causes the development of fulminant myocarditis and ARDS. Two-thirds of patients who died from COVID-19 had a history of arterial hypertension, cardiovascular disease, or diabetes mellitus [1, 20]. It is assumed that the COVID-19 course associated with cardiovascular diseases is predetermined by the state of the renin–angiotensin system. The mechanism of acute myocardial injury caused by SARS-CoV-2 is perhaps associated with increased expression of the ACE2 protein, CSS, and hypoxemia [55]. Two competing hypotheses are put forward: First, the blockade of the renin–angiotensin system reduces the pro-inflammatory activity of angiotensin II, reducing the risk of ARDS, myocarditis, or mortality. Second, the blockade of the renin-angiotensin system increases the expression of ACE2, contributing to the internalization of SARS-CoV-2 into lung and heart cells, which leads to ARDS, myocarditis, and death [20].

The kidneys also become a specific target for SARS-CoV-2, since ACE2 is actively expressed in the epithelial cells of the proximal tubules [52]. With COVID-19, pro-inflammatory macrophages are recruited into the tubulointerstitium, and a pronounced deposition of complement C5b-9 in the renal tubules occurs, which can cause acute renal failure. In addition, 78%–88% of patients with severe COVID-19 have signs of damage to the central nervous system, such as impaired consciousness, cerebrovascular disorders, reduced taste (hypogeusia), and olfactory sensitivity (hyposmia) [31]. It is assumed that SARS-CoV-2, like other coronaviruses, initially infects peripheral nerve endings and then, using the mechanism of transsynaptic transfer, penetrates the tissue of the central nervous system, mainly affecting the cells of the thalamus and brainstem [27].

In children, the disease is usually mild/moderate, and only in rare cases, CSS occurs. There are suggestions on various factors contributing to these aspects, as children travel less, which reduces the risk of communication, and this may have played a role in the beginning of the pandemic; in adults, especially in risk groups (elderly patients), the clearance of the pathogen may be reduced [1]. Children have a lower burden of comorbid pathology. Some authors also indicated the characteristics of the immune response in children compared with adults, including the presence of strong innate and weaker adaptive immune responses. These aspects contribute to a more effective containment of the virus and/or reduction of lymphocyte-mediated secondary inflammation. The role of the local microbiome and presence of concomitant viral infections (including joint sanitation), which contribute to a milder COVID-19 course in children, has been discussed [15, 17].

The protective role of routine vaccination against bacterial and viral infections in the formation of resistance against SARS-CoV-2 is also considered. Live-attenuated vaccines (e.g., against measles or Calmette–Guerin bacillus (BCG)) provide protection beyond the intended target antigen. This heterologous immune response is probably mediated by changes in innate immune mechanisms. Thus, according to some data, in individuals who received the BCG vaccine, the production of IL-1β and TNF-α increases in response to the invasion of Staphylococcus aureus or Candida spp. In addition, a decrease in mortality from sepsis is registered among children vaccinated with BCG [13]. Thus, recent vaccinations in children may protect against COVID-19, and immune aging and associated decline in T cell clonality in the elderly predispose to severe disease. Given the structural similarities between coronaviruses and SARS-CoV-2 (e.g., common viral S proteins), an adaptive immune response against coronaviruses may also provide protection against SARS-CoV-2 [19]. That is, the high recurrence rate of respiratory tract infections in children, combined with the nonspecific effects of mandatory vaccinations, may also protect against SARS-CoV-2.

Other possible protective mechanisms are differences in endothelial damage due to age-related changes in protein concentration in the blood coagulation system. In addition, quantitative and almost certainly qualitative differences occur in the hemostasis system with age. Finally, children, especially younger children, have healthier airways than older people and are not affected by cigarette smoke and pollution, which may reduce the risk of severe COVID-19. The question of whether the geographical location of the regions affects the incidence rate remains debatable, as there are many other factors including migration, population density, etc.

The role of children in infection transmission at home and in organized settings is still at the center of debates. Possible explanations for conflicting reports on the incidence and prevalence of SARS-CoV-2 infection among children and adolescents are caused by the use of various testing methods (polymerase chain reaction (PCR) and serology). According to Stringhini et al. [43], home contact with patients with SARS-CoV-2 infection results in seroconversion in 17.9% of children, which is comparable with adults, and lower seropositivity rates are detected in young children (0.8%) and elderly (4.1%), with the highest seroconversion rates in middle-aged people (9.9%).

The routes of SARS-CoV-2 transmission in the pediatric population are similar to those in adults, namely, airborne droplets, airborne aerosols, fecal–oral, and household contact. The virus can persist in aerosol form for up to 2 h and 6–8 hours on plastic/metal surfaces, 3 days on hair, and several days in the room where the patient stayed [3].

According to different authors, 7.5%–86.4% of children with COVID-19 had close contact with patients in intrafamilial foci [16]. The most common source of infection for children and adolescents was a parent or a sibling, followed by contact with a person outside the family or an unknown person. Posfay-Barbe et al. [34] reported that in 40 children with COVID-19, the onset of the disease clinical presentation occurs after or simultaneously with the disease of adult family members and suggested that children were probably not the source of infection. Moreover, adult patients remain PCR-positive for a longer time than children [42]. Close contact (e.g., sleeping in the same room with the patient) or even casual contact (eating in the same room with the patient) increases the risk of transmission. The shedding of the virus may precede the onset of symptoms, which facilitates the spread of the infection. Given that not all family members coughed, most of the viruses were possibly transmitted via the saliva, as SARS-CoV-2 was also found in saliva [45]. To date, repeated cases of diagnosing the disease in children have been described, which preceded the onset of symptoms in parents on days 6–8 [7, 57]. This raises the question, is the incubation period in children shorter than that in adults? Did the parents develop an infection following contact with the child? A German study reported that the viral load in children aged <6 years did not differ significantly from that in adults [38]. This means that even if children exhibit fewer symptoms, they can still infect others, just like adults.

Children with COVID-19 usually have typical symptoms of acute respiratory infections, such as fever (95%), headache (60.3%), and asthenia (57.8%). Cough, tachypnea, hypoxia, and diarrhea were registered in 39%, 41.7%, 34.2%, and 34.7% of cases, respectively, whereas rhinorrhea and sore throat were detected in 18.3% of cases [21]. The severity of clinical symptoms in children with COVID-19 depended on the age of the child and the presence of risk factors, such as unfavorable premorbid background, comorbid pathology (lung and cardiovascular diseases, neuromuscular pathology, anemia, and type 1 diabetes mellitus), immunodeficiency states of various origins, and co-infection with respiratory syncytial and other viruses at the time of infection or in presence of infection with SARS-CoV-2 [30].

In the USA, the incidence of severe COVID-19 in children has been low. An analysis of the medical records of 177 children and adolescents with COVID-19 treated between March 15 and April 30, 2020, at a medical center in Washington, D.C., reported that 25% of the patients were hospitalized among those who fell ill, and 20.5% of them required emergency care (89% of patients required respiratory support, and one child developed Kawasaki-like syndrome) [14]. Among children admitted to the New York City Children’s Hospital, 80% had fever, 64% had respiratory symptoms, and 6% had only gastrointestinal symptoms. The most common comorbidity was obesity (22%). Moreover, the authors note that obesity was associated with the need for artificial lung ventilation in children aged >2 years. Patients with severe COVID-19 had significantly higher levels of C-reactive protein, procalcitonin, IL-6, ferritin, and D-dimer. Lymphopenia was usually noted at admission, but the indicators did not depend on the severity of the disease course. A long-term positive PCR test result (maximum 27 days) was registered in 8% of the patients [55].

In Egypt, 25.9% of 398 children hospitalized with COVID-19 had a severe disease course. Furthermore, 41.7% of children with severe disease required mechanical lung ventilation, and 20.4% of these patients died. Atypical manifestations were registered in 3.5% of children, including acute pancreatitis, deep-vein thrombosis, and multisystem inflammatory syndrome in children (MIS-C) [40]. The authors stated that COVID-19 was significantly severe in patients with high D-dimer levels, hypoxia, shock, and mechanical lung ventilation.

Approximately from day 7 to day 14 of infection, COVID-19 begins to affect the lungs, heart, and gastrointestinal tract with typical clinical symptoms and increased levels of inflammatory mediators and cytokines [26]. At this disease stage, hematological changes develop particularly significant lymphopenia. This can be due to several mechanisms: (a) exposure to SARS-CoV-2 causing lysis of lymphocytes, since lymphocytes have ACE2 receptors on their surface; (b) apoptosis of lymphocytes caused by a systemic inflammatory process with subsequent production of cytokines; and (c) atrophy of lymphoid organs, such as the spleen, which impairs the circulation of lymphocytes [35].

In 28.9% of pediatric patients with COVID-19, hematological changes occurred, such as leukopenia/lymphopenia [16, 22] and increased levels of C-reactive protein [40], erythrocyte sedimentation rate, and D-dimer in children with severe disease [35, 44]. Moreover, the erythrocyte sedimentation rate and D-dimer levels correlated directly with the severity of the patient’s condition [35].

Chest computed tomography (CT) changes in children with COVID-19 are recorded with varying frequency depending on the severity of the lesion. Children with severe disease with lung involvement had ground-glass changes in CT (68%) and crazy paving (ground-glass combinations with thickened interlobular septa, and crazy paving patterns) (16.5%) [40]. In asymptomatic COVID-19, no changes on CT scan were noted in more than 1/3 of children; in 50% of children with moderate or severe COVID-19, bilateral multilobular diffuse ground-glass opacities, crazy paving patterns, and lung tissue induration were noted (consolidation, a symptom of halo). Lung consolidation results from the combination of numerous desquamated and exudate cells and proteins that fill lung tissues to form hyaline membranes in the alveoli. A systematic review study of 674 children with COVID-19 demonstrated abnormalities in 50% of the patients. Among 605 children who underwent chest CT, 29% had ground-glass opacities, 27% had nonspecific unilateral lesions, and 23% of had bilateral lesions [59].

Unlike adults, children more often have extrarespiratory symptoms, with diarrhea (9.4%) and vomiting (7.3%) as the most frequently reported, usually preceding the onset of typical respiratory symptoms [59]. Previous studies have demonstrated the presence of the virus in intestinal and stool biopsy samples of recovered patients, indicating a possible tropism of SARS-CoV for gastrointestinal tract cell receptors [25]. This partly explains the extrarespiratory symptoms and persistent fecal viral shedding [54]. At present, increasing evidence reveals that this isolation mechanism may be characteristic of SARS-CoV-2. In 10 children with COVID-19, SARS-CoV-2 was detected in rectal swabs after a negative nasopharyngeal PCR test [32, 53].

Some researchers have noted abdominal pain and loss of appetite in children with COVID-19. Cases of necrotizing pancreatitis have been reported, including in a 7-year-old girl, when, in addition to respiratory symptoms, the child had anorexia, abdominal pain, fever, and high serum lipase levels (1,672 U/L) [4]. This was probably due to the pathophysiology of the SARS-CoV-2 pancreatic lesion as a result of ACE2 expression in both islet and exocrine cells. Pancreatic injury in COVID-19 is secondary to an immune-mediated process.

While most children and young people have mild or asymptomatic COVID-19, more recently, severe cases have also been reported. In the literature, pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV2 (PIMS-TS) and MIS-C are used to describe the phenotypes of hyperinflammatory diseases associated with SARS-CoV-2 infections in children [12]. Manifestations of PIMS-TS/MIS-C vary considerably and include clinical and laboratory evidence of systemic inflammation. A wide range of symptoms vary from fever and systemic inflammation to myocardial lesion, leading to tissue damage and shock and, in some patients, to the development of coronary artery dilatation/aneurysm [32]. However, it is still unclear whether excessive inflammatory manifestations in children are directly related to active SARS-CoV-2 infection or whether they result from immune activation to the presence of the virus. Some authors support the hypothesis that PIMS-TS/MIS-C is caused not by the pathogen itself but by host immune mechanisms in the context of infection control [38]. Arguments in favor of this hypothesis include the finding that PIMS-TS/MIS-C first appears several weeks after the first peak of COVID-19 in adults and that the majority of patients with PIMS-TS/MIS-C have negative PCR tests when testing nasopharyngeal and/or fecal samples. A significant proportion of children and young adults with PIMS-TS/MIS-C have gastrointestinal symptoms. IgG antibodies against SARS-CoV-2 are found in a significant proportion of patients with PIMS-TS/MIS-C at the time of diagnosis. Since seroconversion usually occurs approximately 14 days after infection, this is indicative of a para-/post-infection immune activation underlying PIMS-TS/MIS-C [18]. Another possible explanation for the development of PIMS-TS/MIS-C is closely related to the presence of laboratory signs of CSS. Unhindered viral replication in the early stages of the disease, for example, in the respiratory epithelium, leads to cell death and the release of the virus and intracellular components into the extracellular space. This activates the complement system and leads to the mobilization of immune cells to the infection site, their activation, local inflammation, tissue damage, and finally systemic inflammatory reactions. Variable T cell activation and response contribute to various disease outcomes [38]. The temporal–spatial composition of immune responses is likely to play a key role in determining the disease progression and outcomes [31]. The hyperinflammatory syndrome in children is possibly due to uncontrolled viral replication in the presence of an impaired antiviral response (PIMS-TS/MIS-C), for example, as a result of a decrease in INF-I production, which may contribute to the development of CSS. Most likely, the mechanisms that play a key role in determining disease susceptibility and severity, including an increased risk of adverse outcomes, are not yet recognized.

Extensive venous thrombosis and severe venous outflow obstruction with COVID-19-associated limb gangrene were described in a 12-year-old girl [47], although it was previously believed that venous thromboembolism occurs only in adults with COVID-19 [48].

In Bergamo, the province of Italy most affected by the epidemic, from February 18 to April 20, 2020, 10 children with Kawasaki-like syndrome were admitted to the intensive care unit of the city hospital. Moreover, five children had the classic form of Kawasaki disease, and five had MIS-C with non-exudative bulbar conjunctivitis, changes in the lips and/or oral cavity, polymorphic rash, and electrocardiogram changes [47]. In the UK, during the COVID-19 outbreak, eight children with hyperinflammatory shock were admitted to the clinic within 10 days alone, although the usual hospitalization rate for such patients is 1–2 people per week. Among the patients, boys predominated (5 of 8), 7 of 8 children were overweight, but none of the children had lung lesions. In addition, in all patients, the primary PCR test for SARS-CoV-2 was negative, the repeated test was positive in 2 of 8 cases, but a week later, antibodies to SARS-CoV-2 were detected in all patients. One Afro-Caribbean patient aged 15 years who was obese died of acute heart failure despite therapy [47].

In India, among children admitted to the intensive care unit, 7 (36.8%) patients were in a critical condition, 4 (21%) required mechanical lung ventilation with a mean duration of 14.1 days, and 1 had a lethal outcome [5]. The authors note that older children, African Americans or Hispanics, as well as boys are at risk for severe COVID-19, and signs such as hypoxia, thrombocytopenia, and elevated C-reactive protein levels may be useful markers for predicting a severe disease course.

To date, the role of intrauterine infection of the fetus in pregnant women with COVID-19 is still discussed. A study of nine infants born to women with laboratory-confirmed COVID-19 by cesarean section revealed that all newborns later had negative PCR results for COVID-19 [41]. However, the authors suggested that newborns born through vaginal delivery from infected mothers may still be at risk of infection because of close contact during childbirth. SARS-CoV-2 test results on amniotic fluid, cord blood, nasopharynx swabs from newborns, and colostrum samples from infected mothers were negative. According to some researchers, SARS-CoV-2 can be transmitted vertically from an infected mother to her infant, although very rarely. However, this issue remains debatable, since IgM antibodies are found in newborns born to mothers with COVID-19 [9]. Of 91 newborns born to mothers with SARS-CoV-2 infection, 3 had elevated serum IgM levels at birth. A systematic review of 65 articles suggests that the clinical presentation in newborns may be somewhat different from that in older children, with 12% experiencing severe COVID-19 [28]. To minimize infection during the neonatal period, in China, all children are separated from mothers with SARS-CoV-2 infection for at least 14 days [37, 49]. However, the CDC in the USA recommends that the issue of temporary separation of an infected mother from her child should be resolved in each case [8].

Thus, nowadays, a severe COVID-19 course is known to develop in children less often than in adults, and 95% of all cases vary from asymptomatic to clinical manifestations of mild-to-moderate severity. By contrast, approximately 2% of pediatric patients require hospitalization in the resuscitation and intensive care unit or mechanical lung ventilation. Understanding the role of the pediatric population in the rate of infection transmission is important, as children influence significantly the spread of infection. The reaction of the innate immune system in patients remains insufficiently studied. Therefore, more extensive epidemiological and clinical cohort studies are required to understand better the course and possible consequences of COVID-19 in children.

ADDITIONAL INFORMATION

Author contributions. All authors confirm that their authorship complies with the ICMJE criteria. All authors have made a significant contribution to the development of the concept, research, and preparation of the article and have read and approved the final version before its publication.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study had no external funding.

About the authors

Natalya A. Belykh

I.P. Pavlov Ryazan State Medical University

Author for correspondence.
Email: nbelyh68@mail.ru

MD, PhD, Dr. Sci. (Med), Professor, Head, Department of Faculty and Polyclinic Pediatrics with the Course of Pediatric of Postgraduate Education

Russian Federation, Ryazan

Olga A. Solovyova

I.P. Pavlov Ryazan State Medical University

Email: olgasolovejka@yandex.ru

Postgraduate Student, Department of Faculty and Polyclinic Pediatrics with the Course of Pediatric of Postgraduate Education

Russian Federation, Ryazan

Natalya A. Anikeeva

I.P. Pavlov Ryazan State Medical University

Email: natasha782@inbox.ru

MD, PhD, Associate Professor Department of Faculty and Polyclinic Pediatrics with the Course of Pediatric of Postgraduate Education

Russian Federation, Ryazan

References

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