The study design is an observational clinical trial. We utilized 458 medical records from COVID-19 patients who received treatment in the St. Petersburg State Budgetary Institution of Healthcare City Hospital 40 (City Hospital 40, St. Petersburg) from Apr. 18, 2020 to Nov. 21, 2020; the patients tested positive for SARS-CoV-2 RNA by polymerase chain reaction (PCR) amplification of nucleic acids from clinical material and presented clinical manifestations and symptoms (fever, general fatigue, malaise, cough, and dyspnea), features of viral pneumonia seen on unenhanced lung CT scan (noted as multiple lobular abnormalities often located in the peripheral areas of the lower lobes and manifested with predominantly perivascular bilateral disease distribution; multiple peripheral areas of ground-glass opacities with rounded morphology and variable extent; interlobular septal thickening/flattening that causes a crazy-paving pattern, areas of consolidation, air bronchogram sign, etc.) (5, 6).

Table 1 shows demographic characteristics, history, and comorbidities of the patient study cohort.

In accordance with the International and Russian Recommendations for the Prevention, Diagnosis and Treatment of New Coronavirus Infection (COVID-19), all patients were divided in two groups of comparable age (7, 8). The first group included 100 (21.8%) patients with clinical and radiological characteristics of stable, moderately severe course of disease. The criteria for an easy course were considered to be body temperature below 38°C, cough, weakness, sore throat, and the absence of criteria for moderate and severe course. The criteria for a moderate course are fever, temperature above 38°C, respiratory rate over 22/min, shortness of breath during exercise, pneumonia (exposed to CT of the lungs), and SpO₂ <95%. The second group included 358 (78.2%) patients with progressive, moderately severe, severe, and extremely severe course of disease. Clinical and radiological criteria for severe course were respiratory rate more than 30/min, SpO₂ 93%, PaO₂/FiO₂ 300 mmHg, progression of changes in the lungs typical for COVID-19 pneumonia according to CT data, including an increase in the prevalence of revealed changes by more than 25%, as well as the appearance of signs of other pathological conditions, changes in the level of consciousness, unstable hemodynamics (systolic blood pressure less than 90 mmHg or diastolic blood pressure less than 60 mmHg, urine output less than 20 ml/h), and qSOFA >2 points. The criteria for an extremely severe course were signs of ARF with the need for respiratory support (invasive ventilation), septic shock, and multiple organ failure. Thus, patients with mild and moderate and severe and extremely severe course are shown in Table 2 .

Symptoms at admission were fever in 365 (80%) patients, cough in 329 (72%) patients, dyspnea in 265 (57.86%) patients, myalgia in 43 (9.39%) patients, general fatigue in 344 (75.11%) patients, headache in 36 (7.86%) patients, a sore throat in 29 (6.33%) patients, a runny nose or rhinorrhea in 46 (10.04%) patients, chest pain in 51 (11.14%) patients, diarrhea in 34 (7.42%) patients, nausea and vomiting in 13 (2.84%) patients, and impaired taste and smell in 40 (8.73%) patients. Four hundred fifty (98.25%) reported one or more disease-specific symptoms. CT imaging manifestation of pneumonia was detected in 458 (100%) patients.

Medical examination of all patients included history taking, with a focus on the course of disease, physical examination, and assessment of hemodynamics and respiratory system (respiratory rate, heart rate, blood pressure, SpO₂, respiratory distress); calculation of the National Early Warning Score (NEWS), a recommended scoring system for use in COVID-19 patients (10, 11); computed tomography (CT) of the chest with the severity score ranking on a 4-point scale (CT-1, CT-2, CT-3, CT-4); laboratory tests (complete haemogram, basic blood chemistry panel, ferritin test, С-reactive protein, IL-6, lactate dehydrogenase test, D-dimer); ECG; and other instrumental examinations, if required.

In group 1, treatment of COVID-19 and its complications included antibacterial and antiviral drugs, prevention of hypercoagulability and disseminated intravascular coagulation, symptom-related treatment, and oxygen therapy. To prevent or treat the cytokine storm depending on the disease severity, in group 2, standard treatment was supplemented with convalescent plasma therapy, anticytokine drugs: interleukine-6 (IL-6) inhibitors (tocilizumab, olokizumab, levilimab), IL-1 inhibitors (canakinumab, RH104), JAK inhibitors (tofacitinib, ruxolitinib, baricitinib), Bcr–Abl tyrosine kinase inhibitor (radotinib), and glucocorticoids for some cases. Respiratory therapy, modified antibacterial therapy, extracorporeal membrane oxygenation, sepsis, and septic shock treatment (extracorporeal detoxication and blood purification, etc.) were performed in a stepwise fashion according to indications (5).

Data were analyzed using STATISTICA for Windows (version 10, license No. BXXR310F964808FA-V) software. Since all data (except age) did not follow a normal distribution, we applied the Mann-Whitney, Kolmogorov-Smirnov, median Chi-square, and ANOVA tests to evaluate between-group differences in quantitative parameters (age, NEWS score, D-dimer, C-reactive protein (CRP), IL-6, etc.) and normality of sampling distribution. We used Pearson’s Chi-squared and Fischer’s exact nonparametric tests to assess the frequencies of qualitative data (gender, disease manifestations and severity, complaints). Classification Trees were utilized to identify cutoff thresholds for age, NEWS score, and lab test values. The odds ratio (OR) for developing the CS—the ratio of probabilities of a certain event for different groups—was calculated for a 2 × 2 contingency table using a standard formula and the associated confidence interval. We applied the Haldane’s correction, if the 2 × 2 table contained a zero cell.

At admission, group 1 patients showed a reliably higher frequency of chest CT score 1, whereas group 2 patients were admitted with more extensive lung involvement (CT score ranging from 2 to 4). Although moderately severe lung involvement (CT score 2) prevailed in group 2, at admission, these patients reported manifestations of progressive respiratory failure and fever ( Table 3 ). There is a reliable difference in the NEWS score: group 1 had the average admission NEWS score of 2 and the average hospital stay of 11 days; group 2 had the average NEWS score of 4 at admission which exacerbated to 5 at the start of treatment, including anticytokine drugs, anti-COVID-19 convalescent plasma, and hemoadsorbtion; the average hospital stay in group 2 was 12 days. The death rate due to comorbidities was highest in group 2 patients with severe and extremely severe course of disease (28.8% in group 2 and 22.5% in the total cohort). At baseline, such patients had an unfavorable forecast due to age, comorbidity, clinical severity of acute respiratory failure, a high NEWS score, dynamic evaluation of extensive lung involvement, and exacerbation of lung injury based on chest CT ( Table 3 ). The virus-induced infection elicits inflammatory manifestations (absolute lymphocyte count and levels of LDG, CRP, ferritin, D-dimer, and IL-6) that correlate with a CS scenario (lymphocytopenia, hypercytokinemia, hyperinflammation) (12).

In addition, prevalence of comorbidities in our cohort was greater than reported by other authors for adult patients with COVID-19 (31%) (13). The high rate of comorbidities in our patients is due to the specific profile of our department, which focuses on patients with a severe and extremely severe course of disease. Two hundred twenty-one (48%) patients were admitted to ICU from other departments or hospitals due to COVID-19 progression.

Comparative analysis of clinical, imaging, and lab characteristics in recruited cohorts of patients has revealed most critical CS-related variables ( Table 4 ).

The NEWS score dynamics across different patient groups exhibits qualitative differences: the NEWS score decreased from baseline in group 1 (by −1 [−2; 0] points) and increased in group 2 with progressive course of disease (by +1 [0; 2] points) (р < 0.001). There are reliable between-group differences in lab variables (absolute lymphocyte count, CRP, ferritin, D-dimer, IL-6), which correlate with the NEWS score dynamics at admission until the start of CS treatment.

Classification Trees were utilized to identify cutoffs for CS-associated risk factors ( Table 5 ).

Group 2 patients showed a reliably higher frequency of prognostic variables exceeding CS-associated cutoff values ( Table 6 ).

This was followed by a comprehensive evaluation of CS-associated risk based on the ranking of variables obtained at admission. These variables were ranked by prognostic relevance in accordance with Classification Trees by using CART-style method for Split selection and included the following: NEWS score dynamics, serum IL-6 greater than 23 pg/ml, serum CRP 50 mg/l and greater, absolute lymphocyte count less than 0.72 × 10⁹/L, positive test for replicative SARS-CoV-2 RNA, and age 40 years and over. An assessment of the effectiveness of the obtained criteria was carried out, which confirmed the possibility of their application in clinical practice. These biomarkers can be used as predictive criteria to determine the CS risk. We should note that there are no meaningful gender-related differences in the comprehensive examination of CS-related risk.

Figure 1 shows incremental CS-associated risk (OR) and its correlation with lab test values.

Increased CS incidence is associated with a larger number of risk factors (correlation coefficient Rg = +0.91, р < 0.001) ( Table 6 ; Figure 2 ). Each of these factors, if combined with the largest number of other risk factors, exacerbated the CS-associated risk.

We outlined the following risk categories of patients to enhance clinical relevance of our prognostic model: category 1 (0 to 1 risk factors) = CS-associated risk is near zero; category 2 (two to three risk factors) = CS-associated risk escalates dramatically to 55%, augmenting 35.5-fold vs. category 1; category 3 (four and more risk factors) = CS-associated risk exacerbates to 96%, augmenting 718-fold vs. category 1. The obtained results are consistent with findings by other authors on the evaluation of risk factors for COVID-19-associated CS (14, 15). Our results provide a justification for a treatment strategy with an early onset of proactive anti-inflammatory therapy and anti-COVID-19 convalescent plasma in patients at a high risk for CS development.