Study design

This is a prospective multi-center observational cohort study with 30-day outcomes from 12,948 consecutive patients with confirmed a SARS-CoV-2 PCR-positive. Patients had first medical evaluation in the Tashkent COVID-19 distribution centers, with 30 day follow-up after treatment in 46 outpatient state clinics of Tashkent, the capital of Uzbekistan, during the period of June 1-September 30, 2020.

Study patients

In this study, 12,948 consecutive patients with baseline characteristics of all confirmed COVID-19 patients were included and data were retrieved on the day of the first visit to the Tashkent COVID-19 distribution centers after the onset of clinical symptoms. Of them, 9,531 patients were ≥ 18 years old (41.9 ± 9.7years, 49.2% male), and were included in the data analysis. Patients who were seeking medical care through emergency services and people using the private health care sector were not included in the study due to separate regulations for data availability and surveillance systems.

Study setting

Before June 1, 2020, all patients with the confirmed COVID-19 status based on RT-PCR were immediately admitted to the hospitals regardless of symptoms. Since June 1, the management of COVID-19 patients was organised at the COVID-19 distribution centers due to progressively increased number of infected patients and overload of hospitals beds allocated to treat COVID-19 patients. This was done in accordance with the Presidential Decree No. R-5537, which was aimed to combat COVID-19 in Uzbekistan [8]. After exam, CT scan, and laboratory tests, if mild COVID-19 course, patients were referred to outpatient clinics; if moderately severe, patients might stay under the supervision of medical personnel for 1–5 days; if severe, patients were admitted to the COVID-19 hospitals. ICU units had been organized at the distribution centers for patients who required critical care.

The active surveillance and follow-up response system was established on the basis of outpatient clinics to monitor patients’ conditions daily until symptoms resolved for outpatients and within at least 30 days after dispatch from distribution centers or hospitals. Management of COVID-19 patients in hospital, at the distribution centers, and outpatient clinics, including testing, exams, and medications was completely free of charge for patients and covered by the government of Uzbekistan.

Diagnosis and clinical classification of COVID-19 infection

All patients with COVID-19 infection diagnosis met the following criteria: positive SARS-COV-2 RNA by RT-PCR, plus fever, respiratory and/or other symptoms. In case of abnormal lung sounds, chest CT scan or X-ray was performed. The clinical classification of patients was based on the Interim Guidelines for the Management of Patients Infected with COVID-19 (7th ed.) developed by the Ministry of Health of Uzbekistan, adopted from the temporary guidelines of the WHO [9]. Clinical classification of the COVID-19 course was the following: 1) mild clinical symptoms; 2) moderately severe patients who had not signs of severe COVID-19; 3) severe course with signs of respiratory distress, respiratory rate ≥ 30 beats/min, mean oxygen saturation ≤ 93% at rest; 4) critically severe patients were defined if intensive or critical care treatment, e.g. mechanical ventilation, vasopressor therapy required.

Data acquisition

Baseline characteristics of confirmed COVID-19 patients were retrieved on the day of the exam at the COVID-19 distribution centers. Patient’s risk factors such as obesity, history of cardiovascular disease (CVD), history of diabetes, chronic obstructive pulmonary disease (COPD) or asthma were assessed along with socio-economic factors, lifestyle risk factors such as self-reported smoking status, physical activity, and nutrition. Diabetes was defined by a hemoglobin HbA1C ≥ 6.5%, history of physician based diagnosis, or use of anti-diabetic medications according to 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases [10]. Smoking was defined as current (tobacco products used within the last month), occasional or never [11]. Coronary artery disease was defined according to the 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes [11]. In adults (age over 18 years) obesity was defined by a BMI ≥ 30 kg/m [2, 12]. Lungs CT scan was conducted for suspected pneumonia.

Hypertension criteria/definition

Blood pressure (BP) was measured after some rest, in sitting position, at the beginning and at the end of the healthcare providers exam in both arms, the mean of two measurements was used [3, 13, 14]. The main analysis was conducted based on BP and history of antihypertensive therapy. Patients were subdivided into six hypertension groups according to guidelines of the Eighth Joint National Committee (JNC8) [13]:

• (1) Normal: Less than 120/80 mm Hg;
• (2) Elevated: Systolic between 120–129 and diastolic less than 80;
• Stage 1: Systolic between 130–139 or diastolic between 80–89; (3) treated; (4) untreated
• Stage 2: Systolic at least 140 or diastolic at least 90 mm Hg; (5) treated; (6) untreated

Patients were considered treated if they had previously established diagnosis of arterial hypertension, and had received prescriptions of medications within 90 days before visiting the outpatient clinic due to COVID-19 symptoms. The patients’ hypertension treatment of antihypertensive medications, such as angiotensin converting enzyme inhibitors (ACEI), angiotensin receptors blockers (ARB), calcium channel blockers (CCB), beta-blockers (BB), diuretics and others were recorded. The patient was considered untreated if hypertension was not previously diagnosed (based on the patient history/charts), if the patient was aware of having hypertension but did not take prescribed medications or used ad hoc only in case of ‘emergency’. (Table 1).

Outcomes

We specified three outcomes that represented severe cases of COVID-19: 1) Hospital admission for one or more nights. 2) ICU admission for one or more nights. 3) All-cause mortality within 30 days. Patients’ survival/death was confirmed by the follow-up data of the outpatient clinics as well as with vital statistics.

Statistical analysis

Statistical analyses were performed using SPSS software (v27, IBM, Chicago, IL, USA). Descriptive statistics for studied variables are presented as mean±SD (standard deviation) for normally distributed continuous variables, median with interquartile range for non-normally distributed continuous variables and frequency with percentage for categorical variables. Variables were compared with independent Student t-tests for normally distributed continuous data, and Chi-square test for categorical data. Differences between groups were determined by a one-way analysis of variance (ANOVA), with a subsequent Tukey’s/Dunnet C post hoc test. There were no loss of follow-up unless patients death.

The association of risk factors and hospital admission as well as 30-day all-cause mortality was assessed using multivariate logistic regression to examine how variables predict an outcome in the main analysis (six hypertension groups based on the JNC8) [11]. Univariable analysis of each risk factor (group of arterial hypertension, age, sex, history of obesity, diabetes, obstructive CVD, prior cases of acute coronary syndrome, e.g. myocardial infarction (MI), history COPD or asthma) was assessed separately. In the multivariable analysis, we adjusted all selected covariates with the reference for the categorical variable as normal blood pressure, no obesity, no diabetes, no MI, etc). Variables used in the analysis did not have missing data. To bring statistical power we analyzed 3,087 patients who were 50 years old and older. The statistical test did not show any significant difference for any stage of hypertension, thus the results are presented for the entire cohort.

Sensitivity analyses

We also conducted a sensitivity analysis to show the differences on the outcomes between the presence vs. no hypertension per se (Supplement 1–3). We also tested the hypotheses whether controlled or uncontrolled hypertension compare with no hypertension were associated with severe COVID-19. Controlled means BP < 140/90 during study visit or hospitalization and irrespective of treatment. Treatment was used only within the definition of hypertension (Supplement 4–7). We also conducted additional regression analysis stratified by gender (Supplement 8). Univariable and multivariable logistic regression to examine the association between 30-day mortality and baseline characteristics in COVID-19 patients is shown in the Supplement 9.

COVID-19 Hospital Admission

During the course of COVID-19, 1,183 out of9,531 patients (12.41%) required at least one day of in-hospital treatment. Patients with stage-2 untreated hypertension had the highest hospitalization rate among all groups with 144 out of 233 (61.8%), following by stage-1 untreated with 129 out of 457 (28.2%), and stage-2 treated group with 224 out of 865 (25.9%). The hospital stay was longer in patients with stage-2 hypertension, and stage-1 treated (one-way ANOVA, was significant, F (5, 1177) = 24.3, p < 0.001, for pairwise combinations).

The multivariable logistic regression analysis was conducted to present unadjusted and the adjusted effect of confounders (six hypertension groups according to JNC8 [11], age, sex, history of myocardial infarction, type-2 diabetes, obesity) to the hospital.

In the unadjusted model, all hypertension groups had significantly increased odds to be hospitalized with COVID-19 compared to the patients with normotensives (reference group). The greatest odds were in the case of having stage-2 untreated hypertension (OR = 23.91, 95%CI [18.03–31.7]), following by stage-2 treated and stage-1 untreated.

After adjusting for covariates, having stage-2 untreated hypertension remained significant and increased the odds of hospitalization 4.51-fold vs. normotensive patients (OR = 4.51, 95% CI [3.21–6.32], p < 0.001), stage-1 untreated hypertension (OR = 1.97, 95%CI [1.52–2.56]), and elevated BP group (OR = 1.82, 95%CI [1.42–2.34]) (Table 3). Stage 1 and 2 treated hypertension did not show statistically significant effect on hospitalization after adjusting for the confounders (Table 3). The greater odds of hospital admission in patients with untreated hypertension may be explained by greater prevalence of obesity, symptomatic CAD, and diabetes, as well as the fact that the patient who were aware of having hypertension but did not take prescribed medications or used ad hoc only in case of ‘emergency’ were included as untreated patients.

The adjusted effect of age to increase chances of COVID-19 hospitalization remained statistically significant (OR = 1.03, 95%CI [1.03–1.04]). Obesity (having BMI > 30) increased odds for being hospitalized 5.54-fold (OR = 5.54, 95%CI [4.78–6.45]), type-2 diabetes 3.35-fold (OR = 3.35, 95% CI [2.77–4.05]), and history of myocardial infarction 1.28-fold (OR = 1.28, 95%CI [0.98–1.3]).

COVID-19 ICU Admission

In the whole cohort 132 patients (1.38%) required at least 1 day of stay in the ICU. After adjusting for age, sex, history of myocardial infarction, type 2 diabetes, obesity, COPD/asthma, only having stage 2 untreated hypertension increased the odds of hospitalization (OR = 3.05, 95%CI [1.57–5.93]). Neither stage 1 or 2 treated hypertension patients or stage 1 untreated were at statistically significant increased risk for ICU admission after adjusting for confounders (Table 4). The adjusted effect of covariates on ICU admission remained significant: age (OR = 1.07, 95%CI [1.05–1.09]), obesity (OR = 5.61, 95%CI [3.55–8.88]), diabetes (OR = 4.19, 95% CI [2.74–6.40]), and history of myocardial infarction (OR1.76-fold (95%CI [1.11–2.79]).

Thirty-day All-cause Mortality

In the whole cohort, all-cause mortality was 1.18% (112 out of 9,531). In the JNC8 stages mortality was 0.19% (n = 13) in normotensives, 1.41% (n = 8) in stage elevated, zero in stage-1 untreated, 2.53% (n = 18) in stage-1 treated, 6.01% (n = 14) in stage-2 untreated and 6.82% (n = 59) in stage-2 treated (Chi-square = 356.75; p < 0,001). After adjusting for age, sex, history of MI, type-2 diabetes, obesity, none of six JNC8 groups showed any significant difference in 30-day all-cause mortality (Table 4). However, age was associated with an increased risk of 30-day all-cause mortality (OR = 1.09, 95%CI [1.07–1.12], p < 0.001), obesity (OR = 7.18, 95%CI [4.18–12.44], p < 0.001), diabetes (OR 4.18, 95%CI [2.58–6.76], p < 0.001), and history of MI (OR = 2.68, 95%CI [1.67–4.31], p < 0.001). In the sensitivity test, being ≥ 65 years old increased mortality 10.56-fold (OR = 10.56, 95%CI [5.89–18.92], p < 0.001) (Table 5).

Univariable and multivariable logistic regression to examine the association between 30-day all-cause mortality and baseline characteristics in COVID-19 patients stepwise is shown in the Supplement 9. After adjusting for age and obesity, only stage-2 untreated and treated hypertension significantly increased odds of 30-day all-cause mortality, (OR = 2.64, 95%CI [1.18–5.90], p = 0.019) and (OR = 2.06, 95%CI (1.06–4.01), p = 0.034); respectively. If adjusting only for age and diabetes, only stage-2 untreated hypertension remained significant (OR = 2.39, 95%CI [1.05–5.46], p = 0.037). However, after adjustment for age, diabetes and obesity none of six JNC8 groups showed any significant difference in 30-day all-cause mortality (Supplement 9).