At the present time, the new laboratory diagnostic markers are required which may predict complications over the post-COVID period, as well as improve diagnostics of post-COVID syndrome in the patients who underwent COVID-19. Despite the fact that changes in respiratory system are the most common manifestations of COVID-19, extrapulmonary manifestations followed by the wide range of persistent symptoms and/or delayed complications may lead to multiple organ lesions of varying severity: from symptomless to fatal forms. A number of symptoms in the developed post-COVID syndrome may persist for 3 weeks, or to be prolonged up to 6 months and later. The purpose of the study was to investigate the informativity of an early integrative diagnostic index developed by us, enabling prediction of the COVID-19 outcome, and potential development of early post-COVID syndrome. Peripheral blood samples were examined in 60 patients (38-82 years old) diagnosed with COVID-19 of moderate severity (CT-2.3) during their inpatient treatment; 30 patients (38-62 years old) in the early post-COVID period and 34 patients (38-65 years old) with early post-COVID syndrome. The comparison group consisted of 100 healthy sex- and age-matched volunteers. The IDP, an integrative diagnostic index, was calculated as a marker including the ratio of the relative neutrophil-to-lymphocyte numbers, as well as the levels of C-reactive protein (CRP), by the following formule: IDP = (% neutrophilic granulocytes CRP) / % lymphocytes. We have found that, during the inpatient treatment, upon acute clinical manifestations, IDP in study group 1 was increased 12.5 times against the comparison group. It should be noted that all patients were discharged from the hospital in compliance with official criteria, according to Temporary Guidelines. In the study group 2, during early postcovid period, IDP remained 3.4-fold elevated against the comparison group. According to the chest CT data, the patients had signs of a fibrous component, organizing stage of pneumonia and consolidation foci in the lung tissue. Among the group 3 patients (early post-COVID syndrome), IDP was increased three-fold against the comparison group, accompanied by the documented signs of chronic fatigue syndrome and cognitive impairment. The IDP can be used as a marker for the prognosis of clinical outcome and a predictor of the evolving complications during the early post-COVID period and upon development of early post-COVID syndrome in the patients who have undergone COVID-19.

The role of neutrophil granulocytes (NG) in the pathogenesis of COVID-19 is associated with the recruitment of NG into inflammatory foci, activation of their functions and enhanced formation of neutrophil extracellular networks (NETs). In this review, we analyzed a fairly large volume of scientific literature devoted to the peculiarities of the formation of NETs, their role in the pathogenesis of COVID-19, participation in the occurrence of immunothrombosis, vasculitis, acute respiratory distress syndrome, cytokine storm syndrome, multi-organ lesions. Convincing data are presented that clearly indicate the significant involvement of NETs in the immunopathogenesis of COVID-19 and the associated severe complications resulting from the intensification of the inflammation process, which is key for the course of infection caused by the SARS-CoV-2 virus. The presented role of NG and NETs, along with the role of other immune system cells and pro-inflammatory cytokines, is extremely important in understanding the development of an overactive immune response in severe COVID-19. The obtained scientific results, available today, allow identifying the possibilities of regulatory effects on hyperactivated NG, on the formation of NETs at various stages and on limiting the negative impact of already formed NETs on various tissues and organs. All of the above should help in the creation of new, specialized immunotherapy strategies designed to increase the chances of survival, reduce the severity of clinical manifestations in patients with COVID-19, as well as significantly reduce mortality rates. Currently, it is possible to use existing drugs and a number of new drugs are being developed, the action of which can regulate the amount of NG, positively affect the functions of NG and limit the intensity of NETs formation. Continuing research on the role of hyperactive NG and netosis, as well as understanding the mechanisms of regulation of the phenomenon of formation and restriction of NETs activity in severe COVID-19, apparently, are a priority, since in the future the new data obtained could become the basis for the development of targeted approaches not only to immunotherapy aimed at limiting education and blocking negative effects already formed NETs in severe COVID-19, but also to immunotherapy, which could be used in the complex treatment of other netopathies, first of all, autoimmune diseases, auto-inflammatory syndromes, severe purulent-inflammatory processes, including bacterial sepsis and hematogenous osteomyelitis.

Патофизиология тяжелой формы COVID-19 характеризуется изменением количества, фенотипа и функций нейтрофильных гранулоцитов (НГ). Среди эффекторных противовирусных механизмов НГ одними из наиболее важных являются нейтрофильные внеклеточные ловушки (NETs), но чрезмерное их образование усугубляет воспаление при остром респираторном дистресс-синдроме и способствует тромбозу микрососудов. Их обнаружение и количественная оценка могут иметь важное значение при различных формах течения COVID-19 для определения корреляции с исходом заболевания, оценки риска развития постковидного синдрома и, возможно, мониторинга будущей целевой терапии. Цель исследования: разработать новый диагностический интеграционный критерий, позволяющий оценить тяжесть течения COVID-19  и риск развития осложнений в постковидном периоде, в т.ч. постковидного синдрома в периферической крови.Материалы и методы: Исследованы образцы периферической крови (ПК)  31 пациента  с острым течением COVID-19 (среднетяжелого течения (n=15) и тяжелого течения (n=16)), 52 пациентов, выписанных из стационара после лечения COVID-19 тяжелой степени тяжести, в сроки от 30 до 60 дней, имеющие постковидный синдром (ПКС) и 100 условно-здоровых добровольцев. Оценивались показатели общеклинического анализа крови (MicroCC-20Plus), в мазках ПК проводился подсчет лейкоцитарной формулы с учетом количества образованных NET и НГ, ушедших в патологический апоптоз. На основе полученных результатах рассчитывался интеграционный диагностический критерий по формуле: ИДК= .Результаты. Показано снижение ИДК при среднетяжелом течении заболевания в 8,5 раз (p<0,05), а при тяжелом течении в 30 раз (p<0,05) по сравнению со значениями в группе условно-здоровых лиц. Также установлено, что у 88,5 % пациентов с ПКС перенесших SARS-CoV-2 в ПК не выявлено морфологически патологических измененных НГ. В тоже время у 11,5 % пациентов с ПКС отмечено появление NETs и клеток с патологическим апоптозом, при этом ИДК  НГ-ПКС был в  8 раз меньше (p<0,05), чем в группе сравнения и не отличался от показателей пациентов со среднетяжелым течением COVID-19 (p>0,05), что диктует необходимость дальнейшего диспансерного наблюдения таких пациентов.Заключение. Полученные в настоящем исследовании данные свидетельствуют о том, что  разработанный интеграционный диагностический критерий позволяет оценить как тяжесть  течения COVID-19  в острый период, так и риск возникновения  постковидного синдрома.  Следует подчеркнуть, что выявленные при COVID-19 характерные изменения НГ можно легко идентифицировать в ПК и последовательно отслеживать по расчетному интегральному диагностическому критерию. Значительное снижение ИДК свидетельствует о сохраняющейся гиперактивации НГ и необходимости проведения таргетной иммунотерапии, направленной на модулирование дисфункций НГ.