MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN: DIAGNOSTIC MARKERS AND FEATURES OF PHARMACOTHERAPY

Relevance. In 2020, children were hospitalized with fever and multisystem inflammation throughout the world during the COVID-19 pandemic. In the United States, this condition is called MIS-C (Multisystem Inflammatory Syndrome in Children). This syndrome is thought to be similar to the severe course of COVID-19 in adults (cytokine storm). The objective of the work is to evaluate the features of the course and pharmacotherapy of multisystem inflammatory syndrome in children. Materials and methods. The study included 17 children (10 boys and 7 girls) aged 3-16 years (on average – 9.5±3.4 years). Diagnosis of coronavirus infection was performed by polymerase chain reaction with real-time detection, determined the level of immunoglobulins M and G before coronavirus infection. Results. The duration of fever in patients was 5-21 days (average 8.1±4.0 days), the duration of inpatient treatment – 7-35 days (average 15.7±7.0 days). Blood albumin levels were reduced in 53.8% of children; the level of fibrinogen was increased in 88.2% of children, the level of C-reactive protein, ferritin and D-dimer – in all patients. 15 (88.2%) children had pathology of the digestive system, 13 (76.5%) – cardiovascular system (7 children were diagnosed with carditis, 2 – dilation of coronary arteries, 7 – cardiac arrhythmia). Acute respiratory distress -syndrome was found in a 13-year-old girl, shock in an 11-year-old boy, 11 children (64.7%) were diagnosed with pathology of the respiratory system (pleurisy, pneumonia), skin and mucous membranes, and 4 children (23.5%) there were manifestations of central nervous system disorders (meningism, decreased reflexes, ataxia), in 2 (11.8%) – renal failure. On average, each patient had lesions of 3.9 ±1.2 systems. Conclusions. MIS-C was manifested by prolonged fever, high levels of laboratory markers of inflammation, hypoalbuminemia, hypercoagulation, often – pathological manifestations of the cardiovascular, digestive, respiratory systems, skin and mucous membranes. The treatment included intravenous immunoglobulin, steroids, anticoagulant and antibacterial therapy and was effective.


Relevance.
In 2020, hospitalization of children who developed fever and multisystem inflammation during the COVID-19 pandemic was registered in different countries of the world. Although most children had a mild course of COVID-19 infection [9], some were hospitalized in critical condition with shock and multiorgan failure and required intensive care, some had symptoms similar to those seen in Kawasaki syndrome (but the disease was accompanied by shock). In the United States, this condition is called MIS-C (multisystem inflammatory syndrome in children), in the UK -PIMS-TS (pediatric inflammatory multisystem syndrome temporally associated with COVID-19) [1]. The definition states that this syndrome is associated with coronavirus infection over time. Thus, many children who developed this syndrome were found to have antibodies to SARS-CoV-2 [12], although virus tests did not always show a positive result. Some doubts about the association of this syndrome with COVID-19 infection were due to the fact that only in a small number of patients the manifestations of MIS-C were detected against the background of acute SARS-CoV-2 -this led to think that these are manifestations of various diseases [3].
Over the past six months, both individual cases of the disease [10,11] and literature reviews have been published and the results of many individual studies have been summarized. It has been proven that multisystem inflammatory syndrome often occurs in the late stages of the disease, can be observed in children who were previously completely healthy, 3-4 weeks after asymptomatic infection.
It is believed that this syndrome is analogous to the severe course of COVID-19 in adults (cytokine storm). It is caused by the body's excessive immune response to COVID-19. This develops a variant of virus-induced secondary hemophagocytic syndrome [7], which is massive, uncontrolled, often fatal activation of the immune system, the release of pro-inflammatory cytokines (TNF-alpha, IL-1, IL-2 IL-6, IL-8, IL -10, MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN: DIAGNOSTIC MARKERS AND FEATURES OF PHARMACOTHERAPY granulocyte colony-stimulating factor, monocyte chemoattractive protein-1 and markers of inflammation (C-reactive protein, serum ferritin), which can lead to the development of acute respiratory distress syndrome, multiple organ failure and can cause patient death.
Mostly MIS-C was found in children aged 3-12 years, less common in adolescents and young children, but also described in newborns [2]. There were mainly lesions of the heart, blood vessels, kidneys, digestive system, brain, skin and eyes. The following symptoms are typical: fever that lasts more than a day; feeling tired; intense abdominal pain, which may be accompanied by vomiting and/or diarrhea; chest pain; rapid heartbeat; dyspnea; lowering blood pressure; cyanosis of the lips or face; «Brain fog», skin rash; redness of the eyes; swelling of the extremities, lips and tongue. Thus, according to Indian researchers, 100% of children with this syndrome have a fever, 80% -neurological disorders, halfpathology of the lower respiratory tract, 35% -rash, 25% -acute gastroenteritis [5].
The objective of the work is to evaluate the features of the course and pharmacotherapy of multisystem inflammatory syndrome in children.

MATERIALS AND METHODS
The study included 17 children (10 boys and 7 girls) aged 3-16 years (on average -9.5±3.4 years). All patients were of normal physical development (average body mass index was 18.8±2.8 kg/m2).
The examination plan included a general clinical study, also determined the levels of albumin, C-reactive protein, ferritin, fibrinogen, procalcitonin, D-dimer in plasma. Ultrasound examination was performed using a MyLab X6 device according to a standard protocol. General clinical blood test was performed on an automatic hematological analyzer SwelabAlfa, MedonicM-series, Quintus.
Diagnosis of coronavirus infection was performed by polymerase chain reaction with real-time detection using a test system for COVID-19 (Korea). Determination of immunoglobulins M and G for coronavirus infection, D-dimer was performed on an automatic immunofluorescence analyzer miniVIDAS, coagulogram -on a semi-automatic hematological coagulometer CA52.
Statistical processing of the research results was carried out using a licensed office suite Microsoft Excel 2010 and SPSS 22.3. The results were considered reliable at p<0.05.
On average, each patient had lesions of 3.9±1.2 systems, often with a combination of lesions of the digestive tract, skin and mucous membranes, cardiovascular and respiratory disorders.
Generally, the level of fibrinogen was increased in 88.2% of children, the level of C-reactive protein, ferritin and D-dimer was increased in all patients. The average values of laboratory parameters are shown in table 3. The average level of ferritin was 403,0±314,3 ng/ml, C-reactive protein -75,4±56,7 mg/l, D-dimer -3033,1±2395,0 ng/ml, Albumin -36,0±4,4 g/l, Fibrinogen -4,9±1,7 g/l, Procalcitonin -2,6±4,5 ng/ml. The level of blood albumin was reduced in 53.8% of children and was at the level of 27-37 g/l, while in other patients the level of albumin, although within the age limit, but close to the lower limit (38-43 g/l), a significant (р<0.05) negative correlation was found between the level of albumin in the blood and the duration of the fever period (r=-0.71).
The duration of fever in the examined patients was 5-21 days (average 8.1±4.0 days the length of stay in hospital was 7-35 days (on average 15.7±7.0 days).
Thus, we considered the course of a new disease in children associated with the SARS-CoV-2 virus. The syndrome involves many organs: the heart, lungs, gastrointestinal tract, nervous system, skin and mucous membranes. The results of our study coincide with those previously described in the literature [8]. We confirmed that this condition is mainly observed in children aged 3-12 years (76.5%) and in all patients laboratory manifestations of inflammation and hypercoagulation (sharply elevated levels of C-reactive protein, ferritin, fibrinogen and D-dimer). We found a close inverse correlation between the length of the fever and the blood albumin levels of children with MIS-C. Other researchers have also found low albumin levels in MIS-C [6].
It should be noted that in clinics abroad, the complex treatment of MIS-C patients included an interleukin-1 receptor antagonist anakinra [4], interleukin-6 receptor blockers (example tocilizumab) and a tumor necrotic factor antagonist (example infliximab). Our experience has confirmed the effectiveness of intravenous immunoglobulin, dexamethasone, anticoagulant therapy in the treatment of children with multisystem inflammatory syndrome.

CONCLUSIONS
Multisystem inflammatory syndrome in children is an analogue of the cytokine storm in COVID-19 infection in adults. The disease is manifested by prolonged fever, high levels of laboratory markers of inflammation, hypoalbuminemia, hypercoagulation, often pathological manifestations of the cardiovascular, digestive and respiratory systems, skin and mucous membranes. The complex of treatment, which included intravenous immunoglobulin, steroids, anticoagulant and antibacterial therapy, proved to be effective.