International register “Dynamics analysis of comorbidities in SARS-CoV-2 survivors” (AKTIV SARS-CoV-2): analysis of 1,000 patients

we created an international with the estimated capacity of 5,000 patients — Dynamics Analysis of Comorbidities in SARS-CoV-2 Survivors which brought together professionals from the Republic of Republic of and Kyrgyz Republic. The article presents the first analysis of the register involving 1,003 patients. It was shown that the most significant difference of the Caucasian population was the higher effect of multimorbidity on the mortality risk vs other registers. More pronounced effect on mortality of such diseases as diabetes, obesity, hypertension, chronic kidney disease, and age over 60 years was also revealed.

Coronavirus disease 2019 (COVID-19) is a severe infectious disease with a high death risk. At the time of preparing article, according to the World Health Organization (October 25, 2020), the disease has spread to 235 countries and there were 42,512,186 documented cases of infection and 1,147,301 related deaths [1]. The concept of the disease is based on large registries made in the USA, Spain, Italy, and China. However, to date, there is no data on the characteristics of the disease course in Eurasian patients. In this regard, an international AKTIV SARS-CoV-2 register was created, in which specialists from the Russian Federation, the Republic of Armenia, the Republic of Kazakhstan and the Kyrgyz Republic united. The design and prerequisites for register creation are described in article [2]. The main aim of the register with estimated capacity of 5 thousand patients, in addition to assessing the influence of individual risk factors (RFs) (obesity, smoking, hypertension (HTN), age over 60 years) and chronic non-infectious diseases on the risk of severe disease course and death, was the analysis of the infection influence on the course of chronic non-communicable diseases and cancer, as well as on the incidence of new cases of heart failure (HF), diabetes, acute coronary syndrome and cerebrovascular disease within 2 years.
Comparison of survived and deceased patients is shown in  Table 2). Age 60 years and older (60+) increased the mortality risk more than 7 times (odds ratio (OR), 7,523 [95% confidence tively. The second most common RF was obesity, which was observed in 42,2% and 34,2% of in-and outpatients, respectively. Smoking was more common among outpatients (24,1%) than among hospitalized patients (3,9%). Among chronic noncommunicable diseases in patients with COVID-19, coronary artery disease (CAD) was most common, which was observed with the same frequency in in-and outpatients (21,5%). Prior myocardial infarction was noted in 7,7% of hospitalized patients and only 2,5% of outpatients. Type 2 diabetes occurred in 18,3% of inpatients and 12,7% of outpatients. Class I-II HF was observed in 12,0% and 6,3% of in-and outpatients, respectively. Class III-IV HF occurred only in hospitalized patients (2,3%). Chronic kidney disease Abbreviations: HTN -hypertension, CAD -coronary artery disease, MI -myocardial infarction, CKD -chronic kidney disease, COPD -chronic obstructive pulmonary disease, HF -heart failure. Among the deceased patients, multimorbi dity was significantly more common, which negatively affected the prognosis. Among the deceased patients, 2 or more chronic diseases were observed in 89,3% vs 46,8% among the survivors (p=0,001). The presence of 2 or more comorbidities in comparison with those with no more than 1 disease increased the risk of death by more than 9 times (OR, 9,   Abbreviations: HTN -hypertension, ARBs -angiotensin receptor blockers, ACE -angiotensin-converting enzyme, CI -confidence interval, CAD -coronary artery disease, OR -odds ratio.
Comparison of a large array of routine laboratory parameters in the population of deceased and surviving patients showed that significant differences were achieved in the levels of C-reactive protein (CRP) ( Analysis of the effect of individual drugs on the risk of death showed that: -In patients over 60 years of age who received anticoagulant therapy, the death risk was lower than in patients who did not receive it (3,0% vs 10,6%, p=0,049, OR, 0,259 [0,078-0,855]) ( Table 4).
-Statin therapy (not adjusted for dose and achievement of target low-density lipoprotein level) did not lead to a decrease in mortality, but significantly reduced the level of CRP by ≥50% at 7-12 days in 82,9%, while in patients not receiving statins, such CRP changes was observed only in 48,1% (OR, 5,205 [1,634-16,582] p=0,009).

Discussion
Comparison of AKTIV register data with large registers performed in Great Britain, China, Italy, Spain is of great interest. The analysis showed that the patients in the AKTIV register reflecting the Eurasian cohort of patients were 5-15 years younger (mean age, 58 years vs 73 (UK [3]), 64 (China [4]), 63 (USA [5]), 69 (Spain [6]), 63 (Italy [7]). The proportion of women was significantly higher.
Comparison of RFs for death in the AKTIV register with the meta-analysis by the Noor FM, et al. [20] with58 studies involving 122,191 patients and the meta-analysis by Parohan M, et al. [21], with 14 studies involving 14,909 patients ( Figure 1) found number of differences. Thus, in the AKTIV register, type 2 diabetes, obesity, HTN, CKD, age over 60 and multimorbidity had the most significant negative influence, higher than in above-mentioned meta-analyzes ( Figure 1). Multimorbidity had the most significant negative impact on the prognosis in the Eurasian population of COVID-19 patients: 2 or more chronic diseases increased the risk of death by 9,5 times, while in the meta-analysis by the Noor FM, et al. [20], only by 2,6 times.
A number of RFs (male sex, COPD, cancer, asthma, cerebrovascular diseases, chronic liver d iseases), which was associated with death in other studies [20,21], with a pronounced trend, did not achieve significance in the AKTIV register. This can be explained by different sample sizes.
In the AKTIV register, deceased patients had a higher CRP level and a lower lymphocyte count, which is consistent with other studies [22][23][24][25].
According to the AKTIV register, the mortality rate was lower in patients over 60 years old who received anticoagulant therapy than in patients who did not receive it. The positive effect of anticoagulant therapy on the severity of COVID-19 course and the death risk was also shown in the study by Paranjpe I, et al. [26]. In this study, long-term anticoagulant therapy was associated with in-hospital mortality reduction by a 14% (hazard ratio, 0,86 [95% CI, 0,82-0,89] p<0,001). According to the study by Lemos AC, et al. [27], therapeutic-dose anticoagulation has advantages over prophylactic doses. The rationale for the widespread use of anticoagulant therapy for COVID-19 patients is the high risk of thrombotic events [28,29].
According to the AKTIV register, the statin therapy in CAD patients contributed to a decrease in CRP level in comparison with patients not receiving these drugs. A similar beneficial effect of statins on inflammatory markers was demonstrated in the study by Zhang XJ, et al. [32]. It is now known that, in addition to the anti-inflammatory effect, statins can inhibit the penetration of SARS-CoV-2 into host cells. Statins, activating autophagy, can regulate viral replication or degradation, providing protective effects in COVID-19 [32,33]. According to the meta-analysis by the Kow CS and Hasan SS with 8,990 patients [34], the all-cause mortality and/ or disease severity in patients with COVID-19 was reduced by 30% in patients taking statins.

Conclusion
The Eurasian population of COVID-19 patients differs from the populations in the European, US and Chinese registers, primarily in terms of the age and sex. The population of the AKTIV register is characterized by a younger age and female predominance. HTN and HF were observed more often than in other registers.
The most significant difference of the Eurasian population was the higher effect of multimorbidity on the mortality risk vs other registers. More pronounced effect on mortality of such diseases as diabetes, obesity, hypertension, chronic kidney disease, and age over 60 years was also revealed.
The mortality rate in the AKTIV register was 3,7%, which is lower than in the Italian register and approximately corresponds to the mortality rate in the Chinese and US registers.