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Infectious Diseases
A structural analysis of the range of drugs and treatment strategies in the context of etiotropic, pathogenetic, and symptomatic therapy has shown that in the global context and in real clinical practice, the etiotropic-pathogenetic approach based on information about the effectiveness of individual medical technologies prevails today. It has been established that eight international nonproprietary/grouping names are present in international practice as means of etiotropic therapy for pediatric patients with COVID-19, and 18 positions are used for pathogenetic therapy. In terms of frequency of occurrence, the leading positions are occupied by remdesivir and the combination of nirmatrelvir with ritonavir, as well as dexamethasone and tocilizumab.
- COVID-19
- pediatrics
- drug provision
- treatment
1. Introduction
The coronavirus infection caused by SARS-CoV2 marked another milestone in healthcare and a new stage in improving medical care in pediatrics. In observations conducted in different countries in the first months of the pandemic, children usually accounted for up to 2% of laboratory-confirmed cases of SARS-CoV-2 infection, at least in the early stages of the COVID-19 pandemic [1,2,3,4,5].
WHO data indicate that children under the age of 18 account for approximately 8.5% of reported cases, usually with a mild form of the disease [5,6,7]. Among the age-disaggregated cases reported to WHO from 30 December 2019 to 13 September 2021, cases among children under the age of 5 years accounted for 1.8% of cases and 0.1% of deaths worldwide. Cases among children aged 5 to 14 years accounted for 6.3% of cases and 0.1% of deaths worldwide, and cases among older adolescents and young people aged 15 to 24 years accounted for 14.5% of cases and caused 0.4% of deaths worldwide [8,9].
Most studies show that the COVID-19 pandemic affects slightly more boys than girls; however, there are no significant differences in gender. With the accumulation of scientific data and the formation of an evidence base, the health systems of individual States have introduced and periodically reviewed clinical recommendations and improved treatment strategies. The versatility of pharmacotherapy approaches, as well as the diversity of the portfolio of medicines used in the treatment of pediatric patients with COVID-19 in conditions of high virulence of SARS-CoV-2, emphasize the relevance and timeliness of research in the field of medical technology expertise and the improvement of drug provision for children with the indicated infectious pathology [5,10].
2. Clinical Manifestations, Risk Factors and Features of the Course of COVID-19 in Pediatric Patients
The clinical picture of the course of pathology under the conditions of exposure to the virus in the child’s body has its own characteristics, both in terms of symptoms and in terms of assessing potential risks.
The first severe case of childhood infection reported in Wuhan, China, started with gastrointestinal symptoms, had no obvious early respiratory manifestations, but rapidly progressed to acute respiratory distress syndrome [11,12].
Cases of the disease in children after the appearance of the Omicron variant increased significantly (from <2% at the beginning of the pandemic to 25% from 27 January to 3 February 2022) [13]. In Sweden, in the first week of January 2022, four children with COVID-19 were hospitalized with seizures in the pediatric department in Örebro. At that time, the Omicron variant accounted for more than 98% of COVID-19 cases in the country. Three children tested positive for the virus, and one had a clinical form of COVID-19. None of the four children had a history of epilepsy or febrile seizures. J.F. Ludvigsson believes that seizures may be a sign of the Omicron variant in children [13,14,15].
The most common symptoms in children are fever, an unproductive cough, and possible signs of intoxication (myalgia, nausea, and weakness). Some patients have a sore throat, nasal congestion, and symptoms of gastrointestinal tract damage (abdominal pain, diarrhea, and vomiting) [16,17]. Thus, in the ISARIC-WHO-CCP study conducted on 651 patients under the age of 19 with laboratory-confirmed SARS-CoV-2 who were registered in the period from 17 January to 3 July 2020 in 138 hospitals in England, Scotland, and Wales, three clusters of signs were identified [18,19]:
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Respiratory cluster, in which children show separate respiratory episodes of coughing, other symptoms from the upper and lower respiratory tract, and fever;
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Systemic muco-cutaneous-intestinal clusters are manifested by headache, myalgia, gastrointestinal symptoms, lymphadenopathy, fatigue, rash, and conjunctivitis;
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A rarer cluster of neurological signs, especially seizures and confusion.
Typical signs of the disease have evolved over time as new variants of the virus have emerged. Of the symptoms described later, one can note such things as a spotted rash (as with chickenpox), neurological complications (Guillain–Barre syndrome, strokes, polyneuropathies, including rapidly transient ones), as well as psychiatric complications (delirium, followed by depression, increased anxiety, insomnia, and long-term consequences of post-traumatic stress) [20,21,22,23].
It was found that the clinical picture of COVID-19 in children depends on the age group. For example, children under the age of 9 most often have fever (46%), cough (37%), headache (15%), diarrhea (14%), and a sore throat (13%). While older children aged 10–19 years are more likely to have symptoms similar to COVID-19 in adults, with headache (42%), cough (41%), fever (35%), myalgia (30%), sore throat (29%), and shortness of breath (16%) [14,15].
With the clinical manifestation of COVID-19 in children, some manifestations are significantly less common or significantly more common than in adults; some symptoms are described in adults but not in children; and others, on the contrary, are described in children but not found in adults. For example, children rarely have such clinical symptoms as rhinorrhea, wheezing, and general malaise. However, diarrhea in pediatric patients with COVID-19 infection is more common than in adults [24,25,26].
To date, very little data has been recorded on the presence in children with the disease of such common symptoms in adults as anosmia/hyposmia (in adults, it is attributed to pathognomonic symptoms), conjunctivitis, and acute kidney damage. At the same time, there are specific manifestations of the disease in children, namely “COVID Fingers”. Against the background of the absence of other symptoms of the disease in children in Spain and the USA, cases of soreness of the fingers or individual phalanges with signs of cutaneous vasculitis, superficially similar to frostbite, have been described. In May 2020, new publications appeared on the presence of this sign in Italy and Spain, and systematic data in the USA allow this symptom to be recommended as pathognomonic for the diagnosis of COVID-19 in children, even in laboratory-unconfirmed cases [24,27,28].
It is generally recognized that concomitant pathology increases the risk of hospitalization or severe manifestations of the disease. British scientists conducted a meta-analysis of data on children hospitalized with COVID-19 for the period from 1 January 2020 to 21 May 2021. The risk of hospitalization in the intensive care unit (ICU) is higher for children with one chronic disease than for children without concomitant pathology. At the same time, the risk increases significantly as the number of chronic diseases increases [29].
To date, a list of conditions has been formed that are considered risk factors for severe COVID-19 in children:
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High body mass index (obesity);
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Severe pre-existing respiratory disease (asthma, COPD);
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Complex genetic or metabolic conditions associated with concomitant diseases (diabetes mellitus and impaired glucose tolerance, heart and vascular diseases);
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Clinicians also include age (up to 1 year and 10–14 years) and non-European races as risk factors [30].
In pediatric practice, there are three stages of COVID-19 that characterize clinical manifestations at different periods of time after infection. At the first stage of the disease, which lasts for 3–7 days, the virus replicates. The SARS-CoV-2 virus can initiate a pathological response of the immune system, which in some patients reaches the level of a cytokine storm. Inadequate responses of the immune system lead to pathological activation of the hemostasis system. This is the second stage of COVID-19, which lasts about 7 days. The third stage of COVID-19 occurs approximately 14–15 days after the onset of the disease. This stage is characterized either by the patient’s recovery with a favorable course of the disease or by the development of complications with an unfavorable course [16].
It is worth noting that some children who have undergone a new coronavirus infection, COVID-19, may develop multisystem inflammatory syndrome (MIS-C). This syndrome is also called pediatric multisystem inflammatory syndrome and is temporarily associated with SARS-CoV-2. The syndrome was first described in healthy children with severe inflammation and signs of Kawasaki disease who were identified as having had a current or recent SARS-CoV-2 infection [31]. MIS-C corresponds to the postinfectious inflammatory syndrome associated with SARS-CoV-2. Most patients with MIS-C have serological signs of previous SARS-CoV-2 infection, but only some patients showed a positive result for SARS-CoV-2 upon admission [33,34,35,36].
The peak of the population incidence of MIS-C is about 4 weeks behind the peak of acute pediatric hospitalizations associated with COVID-19 [32,37,38]. MIS-C is caused by metabolic disorders in conditions of prolonged persistence of the virus in the body.
MIS-C is manifested by fever (>38.0 °C for ≥24 h), laboratory signs of inflammation (more than one violation in the following indicators: increased levels of C-reactive protein, fibrinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase, or interleukin (IL)-6; increased erythrocyte sedimentation rate or the number of neutrophils; or decrease in the number of lymphocytes or albumin level) and clinical signs of a serious disease requiring hospitalization, with multisystem (i.e., >2) organ damage (heart, kidneys, respiratory organs, blood changes, gastrointestinal tract, skin, central nervous system) [32,39].
Patients with MIS-C are often in critical condition, and up to 80% of children need hospitalization in the ICU. The registered mortality rate in the USA for hospitalized children with MSW ranges from 1% to 2%. Currently, studies are continuing to study the long-term consequences of this syndrome [39,40].
The literature also describes such a course of SARS-CoV-2 infection in children as prolonged COVID-19. Italian scientists equate it with MIS-C; however, these conditions presumably have different etiologies. Studies concerning this manifestation are quite heterogeneous; they depend on the level of childhood morbidity in the country and on the symptoms described by parents. In official international sources, the protracted COVID-19 is not described, but there is such a thing as post-COVID. Long-term COVID includes both post-acute COVID-19 and post-ovoid syndrome. According to an international study, the duration of prolonged COVID with the preservation of some symptoms is possible up to 6–7 months [41,42].
A review of clinical practice in the field of the problem under study gives grounds to conclude that the severity of the patient’s condition is determined by the severity of clinical symptoms. To date, it has been established that a severe course is observed on average in 1% of cases. More than 95% of all cases of the disease vary from an asymptomatic course to clinical manifestations of mild and moderate severity [17,17,22,32].
WHO identifies three forms of the disease (mild, severe, and critical) [32]. The critical form of COVID-19 is determined by the criteria of acute respiratory distress syndrome (ARDS), sepsis, septic shock, or other conditions that usually require life-sustaining therapy, such as artificial ventilation (invasive or non-invasive) or vasopressor therapy. Indicators of the severe form of COVID-19 are:
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Oxygen saturation < 90% in room air;
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Signs of pneumonia;
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The non-severe form of COVID-19 is identified as the absence of any criteria for the severe or critical course of COVID-19.
In Russia, they focus on five working criteria for the severity of the COVID-19 course (asymptomatic course, mild course, moderate course, severe course, and critical course) [31,53].
The critical form of COVID-19 (extremely severe course) is determined by the occurrence of acute respiratory distress syndrome (ARDS), multisystem inflammatory syndrome (develops against the background of COVID-19 or after 3–4 weeks), hypercoagulation, DIC syndrome, and hemophagocytic syndrome (HFS).
Severe form of COVID-19 ARVI (fever, cough) at the beginning of the disease, which may be accompanied by symptoms from the gastrointestinal tract (diarrhea). The disease usually progresses within 7 days; there are signs of respiratory failure (shortness of breath with central cyanosis) and oxygen saturation of the blood <93%. On the X-ray and computed tomography (CT) of the chest organs, there are signs of lung damage typical of severe or critical viral interstitial lung damage (CT3-4).
The moderate form differs from the severe one by the absence of obvious signs of respiratory insufficiency (shortness of breath) and hypoxemia; blood oxygen saturation is >93%. A chest CT shows minor changes in the lungs, typical of mild or moderate viral lung damage (CT1-2). Also, the symptoms of a moderate form of the severity of the disease are fever >38.0 °C and cough (mainly dry, unproductive).
With a mild form of COVID-19 and an increase in body temperature of less than 38.0 °C, symptoms of intoxication (weakness, myalgia) and damage to the upper respiratory tract (cough, sore throat, nasal congestion) are usually observed. During examination, changes in the oropharynx are noted; there are no auscultative changes in the lungs. In some cases, there may be no fever, only gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea), or only skin rashes observed. The oxygen saturation of the blood is greater than 95%.
In the asymptomatic form, clinical manifestations of the disease are completely absent, and only SARSCoV-2 RNA is detected in the laboratory.
The analysis of approaches to the gradation of the severity of pathology in children makes it possible to differentiate the features of international and national practices. It is worth noting that the classifications do not contradict each other. At the same time, WHO offers a single classification for children and adults. In the Russian recommendations for pediatrics, the classification of the severity of COVID-19 in children is highlighted separately (Table 1).
| No | WHO Approaches | Approaches in Russian Practice |
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| 1. | Unified classification of forms and severity of the disease for all ages. | Different classifications for children and adults. |
| 2. | 3–4 forms of gravity. | 5 forms of gravity. |
| 3. | The classification does not provide. specific criteria by which the patient should be assigned to a particular form of severity. | The classification details the symptoms and results of examinations that allow the patient to be attributed to one form or another of severity. |
| 4. | Oxygen saturation of the blood in severe form should be less than 90%. | Oxygen saturation of the blood in severe form should be less than 93%. |
| 5. | The critical form includes “sepsis, septic shock”. | “Sepsis” and “septic shock” are prescribed as complications. |
This entry is adapted from the peer-reviewed paper 10.3390/jcm12144731
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