International register “Dynamics analysis of comorbidities in SARS-CoV-2 survivors” (AKTIV SARS-CoV-2): analysis of predictors of short-term adverse outcomes in COVID-19

The international AKTIV register presents a detailed description of out- and inpatients with COVID-19 in the Eurasian region. It was found that hospitalized patients had more comorbidities. In addition, these patients were older and there were more men than among outpatients. Among the traditional risk factors, obesity and hypertension had a significant negative effect on prognosis, which was more significant for patients 60 years of age and older. Among comorbidities, CVDs had the maximum negative effect on prognosis, and this effect was more significant for patients 60 years of age and older. Among other comorbidities, type 2 and 1 diabetes, chronic kidney disease, chronic obstructive pulmonary disease, cancer and anemia had a negative impact on the prognosis. This effect was also more significant (with the exception of type 1 diabetes) for patients 60 years and older. The death risk in patients with COVID-19 depended on the severity and type of multimorbidity. Clusters of diseases typical for deceased patients were identified and their impact on prognosis was determined. The most unfavorable was a cluster of 4 diseases, including hypertension, coronary artery disease, heart failure, and diabetes mellitus. The data obtained should be taken into account when planning measures for prevention (vaccination priority groups), treatment and rehabilitation of COVID-19 survivors. troponin,

For more than a year, the coronavirus disease 2019 (COVID-19) pandemic continues, which has covered almost all countries of the world and claimed 2978935 lives (according to the World Health Organization as of April 16, 2021) [1]. To assess the specifics of COVID-19 in the Eurasian region, an international register "Dynamics analysis of comorbidities in SARS-CoV-2 survivors" (AKTIV) was created [2], which was attended by specialists from 7 countries: Russian Federation, Republic of Armenia, Republic of Belarus, Republic of Kazakhstan, Kyrgyz Republic, Republic of Moldova, Republic of Uzbekistan.
The central aim of the register is to assess the impact of multimorbidity, various combinations of comorbidities and risk factors (RF) (obesity, smoking, hypertension (HTN), age over 60 years) on the risk of a severe COVID-19 course and death, as well as to analyze the effect of SARS-CoV-2 infection on the course of main noncommunicable diseases and cancer.
The design and statistical analysis methods of the register, as well the first data (n=1000) were presented in detail in previous publications [3][4][5]. It should be noted that analysis of the complete cohort of patients (n=5808) confirmed the patterns that were found in the preliminary analysis [5], and new patterns were also found.
comorbidities, cardiovascular diseases (CVDs) had the maximum negative effect on prognosis, and this effect was more significant for patients aged ≥60 years. Among other comorbidities, T2D, T1D, CKD, COPD, cancer and anemia had a negative impact on the prognosis. This effect was also more significant (with the exception of T1D) for patients aged ≥60 years. One of the most significant risk factors for lethal outcomes was the multimorbidity. So, among the deceased patients, there were only 4,88% without comorbidities, while among the surviving ones -21,44% (p<0,001) ( Table 3). Four or more comorbidities were present in 52,03% and 18,09% of deceased and surviving patients, respectively (p<0,001). With age adjustment, multimorbidity as RF was most significant for patients aged 60 years and older. For such patients, the presence of 2 or more comorbidities was associated with an increased death risk by more than 4,5 times (OR, 4,608 (95% CI, 3,462-6,132) p<0,001). We analy zed the influence of the most common combinations of comorbidities on the death risk. Among the most common combinations of two diseases, the most significant negative effect on the prognosis had a combination of HTN and HF (OR, 3,963 (95% CI, 3,022-5,197) p<0,001). This combination of two diseases occurred in 43,5% of deceased patients and only in 18,9% of survivors. Among the common combinations of three diseases, the combination of HTN, CAD and HF had a great adverse effect on the prognosis (OR, 4,082 (95% CI, 3,054-5,455) p<0,001). This cluster of diseases was observed in 32,93% and 10,74% of deceased and surviving patients, respectively. Among the common combinations of four diseases, the combination of Table 3 Characteristics of survivors and deceased inpatients from the AKTIV register, depending on the degree and type of multimorbidity  The deceased patients had a higher level of C-reactive protein (CRP) (102,52 vs 54,24 mg/L, p<0,001), D-dimer (2,40 vs 1,62 µg FEU/ml, p<0,001), troponin (Tn) T (0,21 vs 0,01 ng/ml), and procalcitonin (2,09 vs 0,62 ng/ml, p<0,001). An increase in the Tn level was observed in 16,33% of deceased patients and was a RF for lethal outcome (OR, 3,665 (95% CI, 1,542-8,712) p<0,001).
HTN, CAD, HF and diabetes was most associated with a negative prognosis (OR, 4,215 (2,784-6,382) p<0,001). This cluster of diseases occurred in 13,41% and 3,55% of deceased and surviving patients, respectively. Thus, the death risk in patients with COVID-19 depended on the degree and type of multimorbidity; the most unfavorable factor was the presence of 4 or more comorbidities, among which the most unfavorable cluster was a combination of HTN, CAD, HF and diabetes.
[9] and significantly more common than in the registers from Italy (3,0%) [8], China (3,4%) [6] and USA (5,0%) [7], and less common more than 2 times than in the UK register (16,0%) [10]. According to the AKTIV register, the death predictors was the age ≥60 years, which increased the risk for men 3 times, and for women almost 1,5 times, which coincides with the other studies [17,[26][27][28]. Male sex also had a death risk, increasing the risk by one and a half times, which was noted in many observational studies. Thus, according to the study by Abate SM, et al., men had a 37% higher risk of death compared to women [15].
According to the AKTIV register, among the comorbidities, CVDs had the most unfavorable effect on the prognosis. Thus, HTN and CAD increased the death risk by 3 and almost 4 times, respectively. This is slightly more than in the meta-analysis by Noor FM, et al. with 58 studies (n=122191), which showed that HTN and CAD increases the risk by 2,1 and 3,6 times, respectively [29]. According to the meta-analysis by Parohan M, et al. (14 studies, n=29909), HTN and CAD increases the risk by 2,7 and 3,7 times, respectively [30]. According to the AKTIV register, HF of any functional class is associated with a poor prognosis, increasing the death risk by more than 4 times; severe class III-IV HF increased the death risk by 6 times. Similar findings were reported in the study by Tomasoni D, et al. involving 13 centers and 692 patients: HF was a strong independent predictor of increased intrahospital mortality (OR, 2,25, 95% CI 1,26-4,02, p=0,006) [31]. According to the study by Rey JR, et al., patients with HF were more likely to develop acute heart failure (11,2% vs 2,1%, p<0,001) and had a higher level of NT-proBNP. In addition, in the HF group, the mortality rate was higher (48,7% vs 19,0%, p<0,001) [32].
According to the AKTIV register, prior stroke was of great importance for the outcome, which increased the death risk by 5 times. According to the review by Trejo-Gabriel-Galán JM, prior stroke increases the death risk from COVID-19 by 3 times [33].
According to the AKTIV register, type 1 and 2 diabetes was associated with an increased risk of death by 3,8 and 2,7 times, respectively. Other researchers have also reported adverse effects of diabetes on prognosis. For example, according to the meta-analysis by Noor FM, et al. [29], diabetes increased the death risk by 1,9 times, and according to the meta-analysis by Parohan M, et al. [30] -2,4 times. According to the AKTIV register, CKD was also associated with a poor prognosis, increasing the risk by more than 3 times, and the risk was maximally increased at a GFR <45 ml/min/1,73 m 2 .
to the meta-analysis by Abate SM, et al., ARDS was diagnosed in 32% of patients [15], which indicates a more severe contingent of hospitalized patients in these studies.
The incidence of in-life diagnosed thrombotic events according to the AKTIV register was less than in other studies: PE -0,61%, stroke -0,47%, DVT -0,44%. According to the Bilaloglu S, et al., the incidence of DVT, PE, and stroke was 3,9%, 3,2%, and 1,6% [19]. According to the study by Mestre-Gómez B, et al., in-life PE was diagnosed in 6,4% of patients [20]. During lower limb deep vein ultrasound, DVT was detected in 46,1% of cases [21]. The low incidence of in-life diagnosed thrombotic events in the AKTIV register is probably due to the fact that in actual clinical practice a targeted search for these conditions was rarely carried out, and lower limb vein ultrasound and multislice computed tomography-angiopulmonography were not performed.
The incidence of coronary artery disease in hospitalized patients in the AKTIV register (23,1%) was close to the data of the Italian register (21,4%) [8], was slightly less than in the US register (27,8%) [7], and significantly more than in the register from China (14,7%) [6]. Attention was drawn to the incidence of HF in patients of the AKTIV register -16,3%, which was significantly higher than in the registers of the United States (6,9%) [7] and Spain (9,2%) [9].
According to the AKTIV register, the most important risk factor of lethal outcome is multimorbidity, while a pattern is observed: the more comorbidities, the more unfavorable the prognosis in COVID-19. For patients aged ≥60 years, the presence of 2 or more comorbidities was associated with an increased death risk by more than 4,5 times. According to other studies, multimorbidity was also a predictor of an unfavorable disease course. According to the meta-analysis by Abate SM, et al., mortality among COVID-19 inpatients was 2 times higher in those with any comorbidities compared with those without comorbidities (HR, 2,20 (95% CI, 1,75-2,77) [15]. According to the Cho SI registry, et al., age-adjusted Charlson comorbidity index (CCI) correlated with patient mortality, and an ICI threshold >3,5 provided the best cut-off point for predicting mortality [40]. Analysis of the AKTIV register revealed the most common clusters of comorbidities and their influence on the patient prognosis. The clusters were dominated by CVDs in various combinations and diabetes. Four-disease cluster (HTN, CAD, HF, diabetes) had the most unfavorable effect on the prognosis. No similar data were found in the available literature.
According to the AKTIV register, patients with a poor prognosis were characterized by a complete blood count abnormalities: a decrease in hemoglobin and lymphocyte (%) levels, platelet count, as well as an increase in white blood cell count. In addition, the deceased patients had higher levels of CRP, D-dimer, AST and troponin, which is consistent with the other studies [17]. According to the AKTIV register, a troponin increase was observed in 16,33% of deceased patients, which increased the death risk by more than 3,5 times. According to the metaanalysis by Bavishi C, et al. an increase in Tn level occurs in 20% of inpatients with COVID-19 [42]. Qin JJ, et al showed that increased Tn level is a strong predictor of 28-day mortality (HR, 7,12 (95% CI, 4,60-11,03, p<0,001) [43].

Conclusion
The international AKTIV register presents a detailed description of out-and inpatients with COVID-19 The meta-analysis by Noor FM, et al. [29] also indicated a 2,1-fold increase in the death risk in patients with CKD.
According to the AKTIV register, obesity in patients aged ≥60 years was an unfavorable factor that increased the death risk by 2 times, but a significantly reduced body weight (BMI <18,5 kg/ m 2 ) was also associated with a poor prognosis. Thus, U-shaped dependence of risk on the patient's body weight. The negative impact of obesity on prognosis has been reported by many researchers [29,34]. Previously, it was also indicated that there is a U-shaped relationship between BMI and influenza pneumonia risk [35]. According to Zheng KI, et al., the association between obesity and the COVID-19 severity remained significant even after statistical adjustments for age, sex, smoking, diabetes, HTN, and dyslipidemia [36]. According to the AKTIV register, obesity posed the greatest danger for patients aged ≥60 years. In contrast, Lighter J, et al. showed that obesity was more dangerous for patients younger than 60 years old [37].
According to the AKTIV register, any type of AF increased the death risk by more than 4 times. This factor represented the greatest risk for patients over 60 years of age. The incidence of AF in this registry was less (6,78%) than on other studies, according to which, among patients with COVID-19, AF was detected from 19% to 21% of all cases and was more common in patients with a severe COVID-19 course, and in the death cohort was observed in 44% of cases [38].
As for the effect of cancer on the COVID-19 severity, the literature data are contradictory. According to the AKTIV register, active cancer is a predictor of an unfavorable outcome and increases the death risk by 2,5 times, which was most significant for patients aged ≥60 years. These data are consistent with the South Korean registry (n=7590), which showed that cancer is a predictor of a poor prognosis: among deceased patients, it was found significantly more often compared with survivors (11,9 vs 3,2%, p<0,001) [40].
According to the AKTIV register, anemia was a death predictor, increasing its risk by more than 2,5 times. The deceased patients had a lower hemoglobin level in comparison with the survivors: 127,05 (111-144) vs 134,51 (125-146) g/L (p<0,001). Similar data were found in the meta-analysis by Taneri PE, for patients 60 years and older. The death risk in patients with COVID-19 depended on the severity and type of multimorbidity. Clusters of diseases typical for deceased patients and their impact on prognosis were identified. The most unfavorable was a cluster of 4 diseases, including hypertension, coronary artery disease, heart failure, and diabetes mellitus. The data obtained should be taken into account when planning measures for prevention (vaccination priority groups), treatment and rehabilitation of COVID-19 survivors.
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in the Eurasian region. Hospitalized patients had more comorbidities and were older, as well as there were more men than among outpatients. Among the traditional risk factors, obesity and HTN had a significant negative effect on prognosis, which was more significant for patients 60 years of age and older. Among comorbidities, CVDs had the ma ximum negative effect on prognosis, and this effect was more significant for patients 60 years of age and older. Among other comorbidities, type 2 and 1 diabetes, CKD, COPD, cancer and anemia had a negative impact on the prognosis. This effect was also more significant (with the exception of T1D)