Abstract
It is widely recognized that hypertension is one of the major risk factor for disease severity and mortality in patients with coronavirus disease 2019 (COVID‐19). However, type 2 diabetes mellitus (T2DM) and hypertension are frequent comorbid conditions, complicating the assessment of hypertension's individual contribution to the risk. The aims of this study were to evaluate the contributions of hypertension alone, T2DM alone, or their combination to the risk of death, acute respiratory distress syndrome (ARDS)/respiratory failure, and severe COVID‐19 infection. Additionally, we assessed risks associated with elevated blood pressure and fasting blood glucose on the same three clinical outcomes. Multivariate logistic models were used for these analyses. Among the 3400 patients, 3327(97.9%) survived and 73(2.1%) died. Compared to patients having neither hypertension nor T2DM (n = 1392), the risk of mortality was significantly higher in patients with T2DM alone (n = 226, OR 5.26 [95% CI: 2.39–11.58]) or with T2DM in combination with hypertension (n = 507, OR 3.02, [95% CI: 1.48–6.15]). Similarly, T2DM was a risk factor for development of ARDS/respiratory failure and severe infection. Hypertension alone (n = 1275) only conferred additional risk for the development of severe infection (OR 1.22 [95% CI: 1.00–1.51]). In conclusion, neither hypertension nor elevated blood pressure was independent risk factors for death or ARDS/respiratory failure but hypertension marginally increased the risk of severe COVID‐19 infection. The risk associated with hypertension is accentuated through its confounding effect on T2DM.
Keywords: blood glucose, blood pressure, COVID‐19, hypertension, type 2 diabetes mellitus
1. INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) emerged in Wuhan, China, in December 2019 and has subsequently spread worldwide, causing a pandemic of coronavirus disease 2019 (COVID‐19). Recent studies have suggested that hypertension and type 2 diabetes mellitus (T2DM) were the most frequent comorbidities in infected patients and are also considered independent risk factors for disease severity and mortality. 1 , 2 , 3 , 4 However, hypertension and T2DM are commonly encountered together. Epidemiological studies have indicated that ~40% of patients with T2DM also have hypertension. 5 , 6 Conversely, hypertension is reported to occur in over two‐thirds of patients with T2DM. 7 Yet, no study has thus far addressed the individual effects of hypertension alone, T2DM alone, or their combination on the risk of mortality and morbidity in patients with COVID‐19.
Furthermore, several hypotheses regarding independent mechanistic roles of hypertension and T2DM in worsening outcomes have been advanced. Among those, viral tropism for pancreatic β‐cells and pulmonary vascular endothelial cells and how those are potentially modified in patients with preexisting conditions, and treatments for those conditions, have been discussed. For example, similar to prior infection disease epidemics, it has been hypothesized that hyperglycemia at the time of hospital admission, even in the absence of a history of T2DM, was associated with worse clinical outcomes. 8 , 9 , 10 Whether comparable associations exist for admission blood pressure, history of hypertension, and outcomes has not been explored.
Accordingly, the primary purpose of this study was to determine the impact of hypertension alone, T2DM alone, or their combination, on mortality and disease severity in patients hospitalized with COVID‐19. Secondarily, we more specifically evaluated the impact of elevated blood pressure and elevated fasting blood glucose, individually and in combination, on clinical outcomes.
2. METHODS
2.1. Study population
This study included patients who were hospitalized with COVID‐19 infection at either the Huoshen Mountain Hospital or the Guanggu Fangcang Shelter Hospital, Wuhan, China between January and April 2020. All original clinical data, including epidemiological, demographic, clinical, laboratory, radiology, treatment, and outcome data from these patients were entered and housed in the Chinese PLA General Hospital electronic medical records system from where data were extracted.
For inclusion in these study it was required that: (1) the patient was hospitalized and had laboratory‐confirmed COVID‐19 infection defined as a positive real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) assay or high‐throughput sequencing of nasal and pharyngeal swab specimens for SARS‐CoV‐2 virus; and (2) the patient be ≥18 years. The exclusion criteria were as follows: (1) lack of data concerning blood pressure; (2) lack of fasting blood glucose results; and (3) subjects was diagnosed with type 1 diabetes mellitus.
2.2. Patient subgroups
For the main analysis, to specifically address the risks associated with hypertension and T2DM, patients were grouped by comorbid condition as follows: (1) neither hypertension nor T2DM; (2) hypertension alone; (3) T2DM alone; and (4) both hypertension and T2DM. To further isolate the effects of hypertension and T2DM, we also identified a subgroup of patients who did not have any known comorbid conditions other than hypertension or T2DM.
Patients were designated as having hypertension if he/she was prescribed antihypertensive treatments or if mean systolic blood pressure was ≥140 mmHg or mean diastolic blood pressure was ≥90 mmHg based on at least two measurements within the first 2 days of admission; patients meeting these criteria without known history of hypertension were considered to have new‐onset hypertension. Subjects with a history of T2DM and taking oral antidiabetic agents or insulin starting at age ≥40 years were considered to have T2DM. Additionally, patients were designated as having T2DM if fasting blood glucose concentration was ≥7 mmol/L on the first available test within the first 2 days of admission; patients with elevated fasting blood glucose without prior history of T2DM were considered to have new‐onset diabetes. 11
To specifically assess the effects of blood pressure and fasting blood glucose, we also grouped patients as follows: (1) blood pressure <140/90 mmHg and fasting blood glucose <7 mmol/L; (2) blood pressure ≥140/90 mmHg and fasting blood glucose <7 mmol/L; (3) blood pressure <140/90 mmHg and fasting blood glucose ≥7 mmol/L; and (4) blood pressure ≥140/90 mmHg and fasting blood glucose ≥7 mmol/L. Values for blood pressure and fasting blood glucose were the same as those defined above. Patients' history of prior hypertension or T2DM did not factor into this grouping.
2.3. Study outcomes and definitions
The primary outcome measures were death or hospital discharge. Importantly, the following standardized criteria were used for hospital discharge: (1) absence of fever for at least 3 days; (2) substantial improvement of chest x‐ray appearance of both lungs; (3) remission of respiratory symptoms; and (4) two negative SARS‐CoV‐2 RT‐PCR obtained at least 24 h apart. 12
The secondary outcome measures were severe COVID‐19 infection and ARDS/respiratory failure. COVID‐19 illness severity (non‐severe vs. severe) was assessed at the time of hospital admission using the American Thoracic Society guidelines for community‐acquired pneumonia and Chinese management guidelines for COVID‐19. 12 , 13 Patients were designated as having non‐severe COVID‐19 if he/she with mild upper respiratory tract symptoms and/or mild chest x‐ray changes. 12 Subjects with any of the following conditions: (1) respiration rate ≥30 times/min; (2) resting blood oxygen saturation ≤93%; (3) partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ≤300 mmHg; (4) with respiratory or other organ failure that requires intensive care; or (5) shock were considered to have severe COVID‐19. 12
Acute respiratory distress syndrome was defined according to the guidance of World Health Organization for COVID‐19 and respiratory failure was defined as impairment of respiratory function requiring intubation or mechanical ventilation, with severity graded according to the maximum respiratory support received at any time point during hospitalization. 14
2.4. Data completeness and review
All patients had a definite clinical outcome (discharge or death), since Huoshen Mountain Hospital (built new) and Guanggu Fangcang Shelter Hospital (completely transformed) were designated as emergency specialty field hospitals that were established in January 2020 in Wuhan in response to the COVID‐19 pandemic and were fully closed on April 14, 2020. All clinical data were reviewed by two senior physicians (XZ Guan and LJ Jia) and two senior radiologists (N Xing and LQ Cheng) and were finally reviewed by the primary author (YH Sun) to confirm the final disposition.
2.5. Statistical analysis
Patients characteristics are summarized with descriptive statistics (median [IQR] for continuous variables and N [%] for categorical variables). Comparisons of proportions between study groups were made using the chi‐square tests or fisher's exact tests for categorical variables and Kruskal‐Wallis test for continuous variables. Bonferroni corrections were performed for Kruskal‐Wallis analyses with multiple comparisons.
Multivariate logistic models were used to estimate the effect of hypertension, T2DM and their combination on the odds of developing: (1) death (primary outcome); (2) ARDS/respiratory failure; and (3) severe COVID‐19 infection. Similarly, multivariate logistic models were also used to estimate the effect of elevated blood pressure alone, elevated fasting blood glucose alone or in combination on the same three clinical outcomes. Other factors associated with clinical outcomes of COVID‐19 were evaluated using multivariate logistic model as covariables. The following variables were considered: age, sex, other comorbid conditions (cardiovascular disease, cerebrovascular disease, chronic lung disease, chronic liver disease, chronic kidney disease, endocrine/Immune system disease, or tumor), and ACEIs/ARBs treatments. The unadjusted risk values for all variables included in the multivariate logistic models were evaluated with binary logistic regression.
For all analyses, aside from hypertension, other types of cardiovascular diseases (eg, coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, and abdominal aortic aneurysm) were grouped together into one category.
All p values reported are two‐sided, with the significance level set to .05. Statistical analyses were performed using SAS (version 9.4; SAS Institute) and R (version 3.6.1; R Foundation for Statistical Computing).
3. RESULTS
3.1. Study population and primary outcome
Between February 4, 2020 and April 14, 2020, 4961 patients were admitted to the Huoshen Mountain Hospital or Guanggu Fangcang Shelter Hospital for suspected COVID‐19 infection. As detailed in Figure S1A in Appendix S1, from among these 4961 patients, 3400 were ≥18 years old without type 1 diabetes mellitus and with required core test information were confirmed to have COVID‐19; definitive outcomes were available for all patients.
Overall patient characteristics are summarized in Table 1, along with a comparison of characteristics of survivors versus non‐survivors. A total of 3400 patients were included in this study. The median age was 61 years (IQR, 50–68 years), and 1751 (51.5%) were female. 2361 (69.4%) patients had comorbidities, including hypertension (n = 1782 [52.4%]), T2DM (n = 733 [21.6%]), cardiovascular disease (n = 343 [10.1%]), cerebrovascular disease (n = 161 [4.7%]), chronic kidney disease (n = 75 [2.2%]), chronic liver disease (n = 132 [3.9%]), chronic lung disease (n = 111 [3.3%]), endocrine/Immune system disease not including diabetes (n = 148 [4.4%]), and tumors (n = 99 [2.9%]). 3327 (97.9%) patients survived to discharge and 73 (2.1%) patients died. Patients who died were significantly older, more likely male, had greater prevalence of T2DM, cardiovascular disease, cerebrovascular disease, chronic kidney disease, and tumors. Fasting blood glucose levels at the beginning of hospitalization were also higher in patients who died. Additionally, the prevalence of ACEI and ARB use not differs between survivors and non‐survivors. However, the prevalence of beta‐blockers, diuretics, and insulin use was higher in patients who died.
TABLE 1.
Demographic characteristics of all patients, and a comparison broken down by survivors and non‐survivors
| Characteristic | All patients (N = 3400) |
Survivors n = 3327 (97.9%) |
Non‐survivors n = 73 (2.1%) |
p value |
|---|---|---|---|---|
| Age, years, median [IQR] | 61 (50, 68) | 60 (50, 68) | 75 (67, 82) | <.001 |
| Age group, No. (%) | ||||
| 18–65 | 2103 (61.9%) | 2089 (62.8%) | 14 (19.2%) | <.001 |
| ≥65 | 1297 (38.2%) | 1238 (37.2%) | 59 (80.8%) | |
| Sex, No. (%) | ||||
| Female | 1751 (51.5%) | 1729 (52.0%) | 22 (30.1%) | <.001 |
| Male | 1649 (48.5%) | 1598 (48.0%) | 51 (69.9%) | |
| Hypertension (total), No. (%) | 1782 (52.4%) | 1737 (52.2%) | 45 (61.6%) | .110 |
| Systolic blood pressure, median [IQR] | 130 (120, 140) | 130 (120, 140) | 130 (120, 146) | .111 |
| Diastolic blood pressure, median [IQR] | 80 (74, 89) | 80 (74, 89) | 79 (68, 85) | <.001 |
| Type 2 diabetes mellitus (total), No. (%) | 733 (21.6%) | 687 (20.6%) | 46 (63.0%) | <.001 |
| Fasting plasma glucose, median [IQR] | 4.9 (4.5, 5.8) | 4.9 (4.5, 5.7) | 7.5 (5.7, 9.7) | <.001 |
| Other comorbid conditions, No. (%) | ||||
| Cardiovascular disease | 343 (10.1%) | 314 (9.4%) | 29 (39.7%) | <.001 |
| Cerebrovascular disease | 161 (4.7%) | 148 (4.5%) | 13 (17.8%) | <.001 |
| Chronic kidney disease | 75 (2.2%) | 67 (2.0%) | 8 (11.0%) | <.001 |
| Chronic liver disease | 132 (3.9%) | 131 (3.9%) | 1 (1.4%) | .261 |
| Chronic lung disease | 111 (3.3%) | 106 (3.2%) | 5 (6.9%) | .082 |
| Endocrine/Immune system disease | 148 (4.4%) | 143 (4.3%) | 5 (6.9%) | .291 |
| Tumor | 99 (2.9%) | 92 (2.8%) | 7 (9.6%) | <.001 |
| Antihypertensive treatment, No. (%) | ||||
| ACE inhibitors | 43 (1.3%) | 42 (1.3%) | 1 (1.3%) | .935 |
| ARBs | 264 (7.8%) | 257 (7.7%) | 7 (9.6%) | .556 |
| Calcium‐channel blockers | 1054 (31.0%) | 1025 (30.8%) | 29 (39.7%) | .103 |
| Beta‐blockers | 525 (15.4%) | 507 (15.2%) | 18 (24.7%) | .028 |
| Diuretics | 260 (7.7%) | 207 (6.2%) | 53 (72.6%) | <.001 |
| Antidiabetic treatment, No. (%) | ||||
| Insulin | 327 (9.6%) | 274 (8.2%) | 53 (72.6%) | <.001 |
| Other hypoglycemic agents | 447 (13.2%) | 443 (13.3%) | 4 (5.5%) | .05 |
When patients were grouped into four subgroups: (1) neither hypertension nor T2DM; (2) hypertension alone, (3) T2DM alone; and (4) both hypertension and T2DM (Table 2), there were significant differences noted among these subgroups in age, sex, blood pressure at hospital admission, fasting blood glucose at hospital admission, cardiovascular disease, cerebrovascular disease, chronic kidney disease, and tumors. Multivariable analysis showed that compared to patients without hypertension or T2DM, the risk of mortality was significantly higher in patients with T2DM alone (OR 5.26 [95% CI: 2.39–11.58]) or with T2DM in combination with hypertension (OR 3.02 [95% CI: 1.48–6.15]) (details in Table 3a). Hypertension alone did not confer additional risk (OR 0.73 [95% CI: 0.33–1.61]). As further summarized in Table 3a, older age, male sex, and a history of cardiovascular disease, chronic kidney disease, or tumor (benign or malignant) also inferred independent risk of mortality. However, ACEI and/or ARB use did not increase the risk of death. Additional analysis comparing the odds ratio of death between hypertension alone vs T2DM alone, hypertension alone vs hypertension plus T2DM, and T2DM alone vs hypertension plus T2DM confirmed that hypertension did not increase the risk of mortality (Table S1A in Appendix S1).
TABLE 2.
Demographic characteristics with patients grouped according to whether they have hypertension (HTN) alone, type 2 diabetes mellitus (T2DM) alone, or in combination
| Characteristic | All patients (N = 3400) |
Neither HTN nor T2DM n = 1392 (40.9%) |
HTN alone n = 1275 (37.5%) |
T2DM alone n = 226 (6.7%) |
HTN + T2DM n = 226 (6.7%) |
p value | Multiple comparisons |
|---|---|---|---|---|---|---|---|
| Age, years, median [IQR] | 61 (50, 68) | 55 (43, 65) | 63 (54, 70) | 61.5 (55, 68) | 66 (58, 72) | <.001 | *, † , ‡ , § , ¶ |
| Age group, No. (%) | |||||||
| 18–65 | 2103 (61.9%) | 1025 (73.6%) | 713 (55.9%) | 146 (64.6%) | 219 (43.2%) | <.001 | *, † , ‡ , **, § , ¶ |
| ≥65 | 1297 (38.2%) | 367 (26.4%) | 562 (44.1%) | 80 (35.4%) | 288 (56.8%) | ||
| Sex, No. (%) | |||||||
| Female | 1751 (51.5%) | 782 (56.2%) | 614 (48.2%) | 103 (45.6%) | 252 (49.7%) | <.001 | *, † , ‡ |
| Male | 1649 (48.5%) | 610 (43.8%) | 661 (51.8%) | 123 (54.4%) | 255 (50.3%) | ||
| Systolic blood pressure, median [IQR] | 130 (120, 140) | 122 (115, 130) | 140 (129, 148) | 121 (114, 130) | 140 (129, 151) | <.001 | *, ‡ , **, ¶ |
| Diastolic blood pressure, median [IQR] | 80 (74, 89) | 77 (70, 81) | 89 (80, 95) | 76 (70, 80) | 85 (78, 93) | <.001 | *, ‡ , **, § , ¶ |
| Fasting plasma glucose, median [IQR] | 4.9 (4.5, 5.8) | 4.6 (4.3, 5.1) | 4.8 (4.4, 5.3) | 7.9 (6.8, 10.3) | 7.7 (6.0, 9.7) | <.001 | *, † , ‡ , **, § |
| Other comorbid conditions, No. (%) | |||||||
| Cardiovascular disease | 343 (10.1%) | 69 (5.0%) | 147 (11.5%) | 23 (10.2%) | 104 (20.5%) | <.001 | *, † , ‡ , § , ¶ |
| Cerebrovascular disease | 161 (4.7%) | 22 (1.6%) | 73 (5.7%) | 9 (4.0%) | 57 (11.2%) | <.001 | *, † , ‡ , § , ¶ |
| Chronic kidney disease | 75 (2.2%) | 16 (1.2%) | 30 (2.4%) | 5 (2.2%) | 24 (4.7%) | <.001 | *, ‡ , § |
| Chronic liver disease | 132 (3.9%) | 53 (3.8%) | 60 (4.7%) | 7 (3.1%) | 12 (2.4%) | .120 | § |
| Chronic lung disease | 111 (3.3%) | 51 (3.7%) | 38 (3.0%) | 10 (4.4%) | 12 (2.4%) | .350 | |
| Endocrine/Immune system disease | 148 (4.4%) | 46 (3.3%) | 67 (5.3%) | 8 (3.5%) | 27 (5.3%) | .053 | *, ‡ |
| Tumor | 99 (2.9%) | 31 (2.2%) | 36 (2.8%) | 13 (5.8%) | 19 (3.8%) | .018 | † , ** |
| Antihypertensive treatment, No. (%) | |||||||
| ACE inhibitors | 43 (1.3%) | 2 (0.1%) | 23 (1.8%) | 0 | 18 (3.6%) | <.001 | *, ‡ , **, § , ¶ |
| ARBs | 264 (7.8%) | 10 (0.7%) | 172 (13.5%) | 3 (1.3%) | 79 (15.6%) | <.001 | *, ‡ , **, ¶ |
| Calcium‐channel blockers | 1054 (31.0%) | 66 (4.7%) | 650 (51.0%) | 21 (9.3%) | 317 (62.5%) | <.001 | *, † , ‡ , **, § , ¶ |
| Beta‐blockers | 525 (15.4%) | 128 (9.2%) | 249 (19.5%) | 30 (13.3%) | 118 (23.3%) | <.001 | *, ‡ , **, ¶ |
| Diuretics | 260 (7.7%) | 45 (3.2%) | 107 (8.4%) | 25 (11.1%) | 83 (13.4%) | <.001 | *, † , ‡ , § |
| Antidiabetic treatment, No. (%) | |||||||
| Insulin | 327 (9.6%) | 34 (2.4%) | 38 (3.0%) | 76 (33.6%) | 179 (35.3%) | <.001 | † , ‡ , **, § |
| Other hypoglycemic agents | 447 (13.2%) | 4 (0.3%) | 14 (1.1%) | 113 (50%) | 316 (62.3%) | <.001 | *, † , ‡ , **, § , ¶ |
Significantly (p < .05):
None vs HTN;
None vs DM;
None vs DM + HTN;
HTN vs DM + HTN;
DM vs DM + HTN;
HTN vs DM.
TABLE 3a.
Risk factors associated with death in patients with confirmed COVID‐19 infection (primary outcome)
| Covariate | Survivors, % | Non‐survivors, % | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||
| Comorbid conditions * | ||||||
| Neither hypertension nor T2DM | 1379 (41.5%) | 13 (17.8%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Hypertension alone | 1261 (37.9%) | 14 (19.2%) | 1.18 (0.55, 2.52) | 0.73 (0.33, 1.61) | ||
| T2DM alone | 211 (6.3%) | 15 (20.6%) | 7.54 (3.54, 16.08) | 5.26 (2.39, 11.58) | ||
| Hypertension and T2DM | 476 (14.3%) | 31 (42.5%) | 6.91 (3.59, 13.31) | 3.02 (1.48, 6.15) | ||
| Age group | ||||||
| 18–65 | 2089 (62.8%) | 14 (19.2%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≥65 | 1238 (37.2%) | 59 (80.8%) | 7.11 (3.95, 12.79) | 4.76 (2.56, 8.87) | ||
| Sex | ||||||
| Female | 1729 (52.0%) | 22 (30.1%) | 1 [Reference] | <.001 | 1 [Reference] | .003 |
| Male | 1598 (48.0%) | 51 (69.9%) | 2.51 (1.51, 4.15) | 2.20 (1.30, 3.73) | ||
| Cardiovascular disease | ||||||
| No | 3013 (90.6%) | 44 (60.3%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Yes | 314 (9.4%) | 29 (39.7%) | 6.32 (3.90, 10.25) | 2.85 (1.65, 4.94) | ||
| Cerebrovascular disease | ||||||
| No | 3179 (95.5%) | 60 (82.2%) | 1 [Reference] | <.001 | 1 [Reference] | .127 |
| Yes | 148 (4.5%) | 13 (17.8%) | 4.65 (2.50, 8.67) | 1.72 (0.86, 3.44) | ||
| Chronic kidney disease | ||||||
| No | 3260 (98.0%) | 65 (89.0%) | 1 [Reference] | <.001 | 1 [Reference] | .030 |
| Yes | 67 (2.0%) | 8 (11.0%) | 5.99 (2.76, 12.98) | 2.71 (1.10, 6.68) | ||
| Chronic liver disease | ||||||
| No | 3196 (96.1%) | 72 (98.6%) | 1 [Reference] | .284 | 1 [Reference] | .276 |
| Yes | 131 (3.9%) | 1 (1.4%) | 0.34 (0.05, 2.46) | 0.33 (0.04, 2.45) | ||
| Chronic lung disease | ||||||
| No | 3221 (96.8%) | 68 (93.2%) | 1 [Reference] | .090 | 1 [Reference] | .976 |
| Yes | 106 (3.2%) | 5 (6.8%) | 2.23 (0.88, 5.66) | 0.99 (0.36, 2.71) | ||
| Endocrine/Immune system disease | ||||||
| No | 3184 (95.7%) | 68 (93.2%) | 1 [Reference] | .295 | 1 [Reference] | .924 |
| Yes | 143 (4.3%) | 5 (6.8%) | 1.64 (0.65, 4.12) | 1.05 (0.37, 2.98) | ||
| Tumor | ||||||
| No | 3235 (97.2%) | 66 (90.4%) | 1 [Reference] | .001 | 1 [Reference] | .041 |
| Yes | 92 (2.8%) | 7 (9.6%) | 3.73 (1.67, 8.35) | 2.55 (1.04, 6.25) | ||
| ACEIs/ARBs treatment | ||||||
| No | 3033 (91.2%) | 65 (89.0%) | 1 [Reference] | .529 | 1 [Reference] | .425 |
| Yes | 294 (8.8%) | 8 (11.0%) | 1.27 (0.60, 2.67) | 0.72 (0.32, 1.63) | ||
Patients grouped according to the diagnosis of hypertension and type 2 diabetes mellitus (T2DM).
Specific COVID‐19 mortality attributable to hypertension or diabetes is probably underscored because of the confounding effects for cardiovascular disease, cerebrovascular disease, chronic lung disease, chronic liver disease, chronic kidney disease, endocrine/Immune system disease, or tumor (benign or malignant). To exclude possible confounding effects of comorbid conditions listed above, we assessed the risk of mortality among the 2604 patients who did not have any other identified comorbidities other than hypertension or T2DM. This analysis (detailed in Table S1B in Appendix S1) confirmed the above results that T2DM, but not hypertension, increased the risk of death.
Similarly, analyses restricted to patients with a prior history of hypertension alone to those with neither hypertension nor T2DM also confirmed a lack of increased risk associated with hypertension, independent of whether other comorbidities were or were not included in the analysis (Tables S1C and S1D in Appendix S1).
As detailed in Figure S1B in Appendix S1, patients were also grouped according to actual blood pressures (Systolic blood pressure <140 vs. ≥140 mmHg or Diastolic blood pressure <90 vs. ≥90 mmHg) and fasting blood glucose levels (<7.0 vs. ≥7.0 mmol/L). Paralleling the primary analysis, fasting blood glucose ≥7.0 mmol/L was associated with markedly increased risk of mortality, independent of blood pressure and independent of whether other comorbidities were or were not included in the analysis (Table 3b, Tables S1E and S1F in Appendix S1). Blood pressure was not a risk factor for mortality.
TABLE 3b.
Risk factors associated with death in patients with confirmed COVID‐19 infection (primary outcome)
| Covariate | Survivors, % | Non‐survivors, % | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||
| Comorbid conditions * | ||||||
| BP < 140/90 mmHg and FBG < 7 mmol/L | 1846 (55.5%) | 26 (35.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| BP ≥ 140/90 mmHg and FBG < 7 mmol/L | 1022 (30.7%) | 7 (9.6%) | 0.49 (0.21, 1.12) | 0.44 (0.19, 1.03) | ||
| BP < 140/90 mmHg and FBG ≥ 7 mmol/L | 255 (7.7%) | 23 (31.5%) | 6.40 (3.60, 11.39) | 4.61 (2.50, 8.48) | ||
| BP ≥ 140/90 mmHg and FBG ≥ 7 mmol/L | 204 (6.1%) | 17 (23.3%) | 5.92 (3.16, 11.09) | 4.22 (2.17, 8.18) | ||
| Age group | ||||||
| 18–65 | 2089 (62.8%) | 14 (19.2%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≥65 | 1238 (37.2%) | 59 (80.8%) | 7.11 (3.95, 12.79) | 4.57 (2.47, 8.47) | ||
| Sex | ||||||
| Female | 1729 (52.0%) | 22 (30.1%) | 1 [Reference] | <.001 | 1 [Reference] | .001 |
| Male | 1598 (48.0%) | 51 (69.9%) | 2.51 (1.51, 4.15) | 2.42 (1.42, 4.13) | ||
| Cardiovascular disease | ||||||
| No | 3013 (90.6%) | 44 (60.3%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Yes | 314 (9.4%) | 29 (39.7%) | 6.32 (3.90, 10.25) | 2.92 (1.68, 5.07) | ||
| Cerebrovascular disease | ||||||
| No | 3179 (95.5%) | 60 (82.2%) | 1 [Reference] | <.001 | 1 [Reference] | .152 |
| Yes | 148 (4.5%) | 13 (17.8%) | 4.65 (2.50, 8.67) | 1.66 (0.83, 3.34) | ||
| Chronic kidney disease | ||||||
| No | 3260 (98.0%) | 65 (89.0%) | 1 [Reference] | <.001 | 1 [Reference] | .008 |
| Yes | 67 (2.0%) | 8 (11.0%) | 5.99 (2.76, 12.98) | 3.41 (1.38, 8.45) | ||
| Chronic liver disease | ||||||
| No | 3196 (96.1%) | 72 (98.6%) | 1 [Reference] | .284 | 1 [Reference] | .326 |
| Yes | 131 (3.9%) | 1 (1.4%) | 0.34 (0.05, 2.46) | 0.36 (0.05, 2.74) | ||
| Chronic lung disease | ||||||
| No | 3221 (96.8%) | 68 (93.2%) | 1 [Reference] | .090 | 1 [Reference] | .718 |
| Yes | 106 (3.2%) | 5 (6.9%) | 2.23 (0.88, 5.66) | 0.83 (0.30, 2.30) | ||
| Endocrine/Immune system disease | ||||||
| No | 3184 (95.7%) | 68 (93.2%) | 1 [Reference] | .295 | 1 [Reference] | .811 |
| Yes | 143 (4.3%) | 5 (6.8%) | 1.64 (0.65, 4.12) | 1.14 (0.39, 3.29) | ||
| Tumor | ||||||
| No | 3235 (97.2%) | 66 (90.4%) | 1 [Reference] | .001 | 1 [Reference] | .067 |
| Yes | 92 (2.8%) | 7 (9.6%) | 3.73 (1.67, 8.35) | 2.37 (0.94, 5.94) | ||
| ACEIs/ARBs treatment | ||||||
| No | 3033 (91.2%) | 65 (89.0%) | 1 [Reference] | .529 | 1 [Reference] | .260 |
| Yes | 294 (8.8%) | 8 (11.0%) | 1.27 (0.60, 2.67) | 0.63 (0.28, 1.42) | ||
Patients grouped according to blood pressure (BP) and fasting blood glucose (FBG) levels.
3.2. Secondary outcome: ARDS and respiratory failure
Among 3400 patients infected and hospitalized with COVID‐19, 144 were diagnosed with ARDS/respiratory failure either at the time of hospital admission or at some point during hospitalization. As detailed in Table 4a, and similar to mortality, the results of multivariable analysis showed the T2DM alone (OR 4.38 [95% CI: 2.41–7.95]) or in combination with hypertension (OR 3.39 [95% CI: 2.04–5.64)) increased the risk of these outcomes. Older age, male sex, cardiovascular disease, and chronic kidney disease also remained significant in this model. ACEI/ARB use did not impact the odds of developing ARDS/respiratory failure. Additional analysis comparing the odds ratio of ARDS/respiratory failure between hypertension alone versus T2DM alone, hypertension alone vs hypertension plus T2DM, and T2DM alone vs hypertension plus T2DM confirmed that hypertension did not increase the risk of developing ARDS/respiratory failure (Table S2A in Appendix S1).
TABLE 4a.
Risk factors associated with development of acute respiratory distress syndrome (ARDS) and/or respiratory failure (RF) in patients with confirmed COVID‐19 infection (secondary outcome)
| Covariate | Non‐ARDS/RF, % | ARDS/RF, % | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||
| Comorbid conditions * | ||||||
| Neither hypertension nor T2DM | 1364 (41.9%) | 28 (19.4%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Hypertension alone | 1234 (37.9%) | 41 (28.5%) | 1.62 (0.995, 2.63) | 1.19 (0.72, 1.98) | ||
| T2DM alone | 204 (6.3%) | 22 (15.3%) | 5.25 (2.95, 9.36) | 4.38 (2.41, 7.95) | ||
| Hypertension and T2DM | 454 (13.9%) | 53 (36.8%) | 5.69 (3.55, 9.10) | 3.39 (2.04, 5.64) | ||
| Age group | ||||||
| 18–65 | 2062 (63.3%) | 41 (28.5%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≥65 | 1194 (36.7%) | 103 (71.5%) | 4.34 (3.00, 6.27) | 3.14 (2.12, 4.65) | ||
| Sex | ||||||
| Female | 1695 (52.1%) | 56 (38.9%) | 1 [Reference] | .002 | 1 [Reference] | .042 |
| Male | 1561 (41.9%) | 88 (61.1%) | 1.71 (1.21, 2.40) | 1.45 (1.01, 2.08) | ||
| Cardiovascular disease | ||||||
| No | 2952 (90.7%) | 105 (72.9%) | 1 [Reference] | <.001 | 1 [Reference] | .026 |
| Yes | 304 (9.3%) | 39 (27.1%) | 3.61 (2.45, 5.31) | 1.64 (1.06, 2.53) | ||
| Cerebrovascular disease | ||||||
| No | 3115 (95.7%) | 124 (86.1%) | 1 [Reference] | <.001 | 1 [Reference] | .132 |
| Yes | 141 (4.3%) | 20 (13.9%) | 3.56 (2.16, 5.88) | 1.52 (0.88, 2.62) | ||
| Chronic kidney disease | ||||||
| No | 3196 (98.2%) | 129 (89.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Yes | 60 (1.8%) | 15 (10.4%) | 6.19 (3.43, 11.20) | 3.53 (1.80, 6.91) | ||
| Chronic liver disease | ||||||
| No | 3132 (96.2%) | 136 (94.4%) | 1 [Reference] | .291 | 1 [Reference] | .316 |
| Yes | 124 (3.8%) | 8 (5.6%) | 1.49 (0.71, 3.10) | 1.48 (0.69, 3.21) | ||
| Chronic lung disease | ||||||
| No | 3157 (97.0%) | 132 (91.7%) | 1 [Reference] | <.001 | 1 [Reference] | .088 |
| Yes | 99 (3.0%) | 12 (8.3%) | 2.90 (1.55, 5.41) | 1.81 (0.92, 3.59) | ||
| Endocrine/Immune system disease | ||||||
| No | 3117 (95.7%) | 135 (93.8%) | 1 [Reference] | .257 | 1 [Reference] | .820 |
| Yes | 139 (4.3%) | 9 (6.3%) | 1.50 (0.75, 3.00) | 0.91 (0.42, 1.98) | ||
| Tumor | ||||||
| No | 3167 (97.3%) | 134 (93.1%) | 1 [Reference] | .005 | 1 [Reference] | .134 |
| Yes | 89 (2.7%) | 10 (6.9%) | 2.66 (1.35, 5.22) | 1.75 (0.84, 3.62) | ||
| ACEIs/ARBs treatment | ||||||
| No | 2973 (91.3%) | 125 (86.8%) | 1 [Reference] | .065 | 1 [Reference] | .996 |
| Yes | 283 (8.7%) | 19 (13.2%) | 1.60 (0.97, 2.63) | 1.00 (0.58, 1.73) | ||
Patients grouped according to the diagnosis of hypertension and type 2 diabetes mellitus (T2DM).
Similar to the primary outcome analysis, to exclude possible confounding effects of comorbid conditions, a sensitivity analysis that included only the 2604 patients who did not have any comorbidities (cardiovascular disease, cerebrovascular disease, chronic lung disease, chronic liver disease, chronic kidney disease, endocrine/Immune system disease, or tumor) other than hypertension or T2DM confirmed the above results for this outcome (Table S2B in Appendix S1).
Comparing patients with prior hypertension alone vs those having neither hypertension nor T2DM also confirmed that hypertension did not increases the risk of developing ARDS/respiratory failure, independent of whether other comorbidities were or were not included in the analysis (Tables S2C and S2D in Appendix S1).
Grouping patients by blood pressures and fasting blood glucose levels yielded similar results: patients with increased fasting blood glucose levels were at increased risk of ARDS/respiratory failure independent of blood pressure, and independent of whether patients with or without other comorbidities were included in the analysis (Table 4b, Tables S2E and S2F in Appendix S1). Elevated blood pressure did not increase the risk of ARDS/respiratory failure.
TABLE 4b.
Risk factors associated with development of acute respiratory distress syndrome (ARDS) and/or respiratory failure (RF) in patients with confirmed COVID‐19 infection (secondary outcome)
| Covariate | Non‐ARDS/RF, % | ARDS/RF, % | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||
| Comorbid conditions * | ||||||
| BP < 140/90 mmHg and FBG < 7 mmol/L | 1819 55.9% | 53 36.8% | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| BP ≥ 140/90 mmHg and FBG < 7 mmol/L | 1004 30.8% | 25 17.4% | 0.86 (0.53, 1.38) | 0.79 (0.48, 1.29) | ||
| BP < 140/90 mmHg and FBG ≥ 7 mmol/L | 242 7.4% | 36 25.0% | 5.11 (3.28, 7.96) | 4.19 (2.63, 6.68) | ||
| BP ≥ 140/90 mmHg and FBG ≥ 7 mmol/L | 191 5.9% | 30 20.8% | 5.39 (3.36, 8.64) | 4.38 (2.66, 7.20) | ||
| Age group | ||||||
| 18–65 | 2062 63.3% | 41 28.5% | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≥65 | 1194 36.7% | 103 71.5% | 4.34 (3.00, 6.27) | 3.12 (2.11, 4.62) | ||
| Sex | ||||||
| Female | 1695 52.1% | 56 38.9% | 1 [Reference] | .002 | 1 [Reference] | .016 |
| Male | 1561 41.9% | 88 61.1% | 1.71 (1.21, 2.40) | 1.56 (1.09, 2.25) | ||
| Cardiovascular disease | ||||||
| No | 2952 90.7% | 105 72.9% | 1 [Reference] | <.001 | 1 [Reference] | .019 |
| Yes | 304 9.3% | 39 27.1% | 3.61 (2.45, 5.31) | 1.69 (1.09, 2.25) | ||
| Cerebrovascular disease | ||||||
| No | 3115 (95.7%) | 124 (86.1%) | 1 [Reference] | <.001 | 1 [Reference] | .132 |
| Yes | 141 (4.3%) | 20 (13.9%) | 3.56 (2.16, 5.88) | 1.53 (0.88, 2.64) | ||
| Chronic kidney disease | ||||||
| No | 3196 (98.2%) | 129 (89.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Yes | 60 (1.8%) | 15 (10.4%) | 6.19 (3.43, 11.20) | 4.24 (2.14, 8.41) | ||
| Chronic liver disease | ||||||
| No | 3132 (96.2%) | 136 (94.4%) | 1 [Reference] | .291 | 1 [Reference] | .237 |
| Yes | 124 (3.8%) | 8 (5.6%) | 1.49 (0.71, 3.10) | 1.60 (0.73, 3.50) | ||
| Chronic lung disease | ||||||
| No | 3157 (97.0%) | 132 (91.7%) | 1 [Reference] | <.001 | 1 [Reference] | .205 |
| Yes | 99 (3.0%) | 12 (8.3%) | 2.90 (1.55, 5.41) | 1.57 (0.78, 3.13) | ||
| Endocrine/Immune system disease | ||||||
| No | 3117 (95.7%) | 135 (93.8%) | 1 [Reference] | .257 | 1 [Reference] | .931 |
| Yes | 139 (4.3%) | 9 (6.3%) | 1.50 (0.75, 3.00) | 0.97 (0.44, 2.12) | ||
| Tumor | ||||||
| No | 3167 (97.3%) | 134 (93.1%) | 1 [Reference] | .005 | 1 [Reference] | .190 |
| Yes | 89 (2.7%) | 10 (6.9%) | 2.66 (1.35, 5.22) | 1.65 (0.78, 3.46) | ||
| ACEIs/ARBs treatment | ||||||
| No | 2973 (91.3%) | 125 (86.8%) | 1 [Reference] | .065 | 1 [Reference] | .960 |
| Yes | 283 (8.7%) | 19 (13.2%) | 1.60 (0.97, 2.63) | 0.99 (0.57, 1.70) | ||
Patients grouped according to blood pressure (BP) and fasting blood glucose (FBG) levels.
Of the 144 patients diagnosed with ARDS/respiratory failure, 69 (47.9%) died in hospital. Multivariable analysis odds ratios for death were 0.47 [95% CI: 0.17–1.35], 1.80 [95% CI: 0.54–5.95], and 1.66 [95% CI: 0.61–4.53], respectively, among patients with hypertension alone, T2DM alone, and combined hypertension and T2DM compared with patients having neither hypertension nor T2DM; older age and male sex also remained significant in this analysis. A sensitivity analysis that included 75 of the ARDS/respiratory failure patients without any comorbidities other than hypertension or T2DM confirmed the above results (detailed further in Table S2G in Appendix S1). Thus, the presence of hypertension or T2DM did not increase the risk of death in patients once they experienced ARDS/respiratory failure.
3.3. Secondary outcome: severe COVID‐19 infection
As detailed in Table 5a, and similar to mortality, the results of multivariable analysis showed the T2DM alone (OR 2.21 [95% CI: 1.60–3.06]) or in combination with hypertension (OR 1.95 [95% CI: 1.51–2.50]) increased the risk of severe infection; however, in this case, hypertension alone also conferred a mild increase of risk (OR 1.22 [95% CI: 1.00–1.50]), though less so than T2DM. Older age, male sex, cardiovascular disease, and chronic lung disease were also associated with additional risk. However, ACEI/ARB use did not impact the odds of developing severe COVID‐19 infection. Additional odds ratios for developing severe COVID‐19 infection based on hypertension and T2DM profiles are further summarized in Table S3A in Appendix S1.
TABLE 5a.
Risk factors associated with development of severe infection in patients with confirmed COVID‐19 infection (secondary outcome)
| Covariate | Non‐severe COVID‐19 infection , % | Severe COVID‐19 infection , % | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||
| Comorbid conditions * | ||||||
| Neither hypertension nor T2DM | 1168 (44.1%) | 224 (29.8%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Hypertension alone | 990 (37.4%) | 285 (37.9%) | 1.50 (1.24, 1.82) | 1.22 (1.00, 1.51) | ||
| T2DM alone | 154 (5.8%) | 72 (9.6%) | 2.44 (1.78, 3.34) | 2.21 (1.60, 3.06) | ||
| Hypertension and T2DM | 336 (12.7%) | 171 (22.7%) | 2.65 (2.10, 3.35) | 1.95 (1.51, 2.50) | ||
| Age group | ||||||
| 18–65 | 1760 (66.5%) | 334 (45.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≥65 | 888 (33.5%) | 409 (54.4%) | 2.36 (2.01, 2.79) | 1.94 (1.62, 2.31) | ||
| Sex | ||||||
| Female | 1416 (53.5%) | 335 (44.6%) | 1 [Reference] | <.001 | 1 [Reference] | .002 |
| Male | 1232 (46.5%) | 417 (55.4%) | 1.43 (1.22, 1.68) | 1.30 (1.10, 1.54) | ||
| Cardiovascular disease | ||||||
| No | 2437 (92.0%) | 620 (82.5%) | 1 [Reference] | <.001 | 1 [Reference] | .002 |
| Yes | 211 (8.0%) | 132 (17.5%) | 2.46 (1.95, 3.11) | 1.50 (1.16, 1.93) | ||
| Cerebrovascular disease | ||||||
| No | 2547 (96.2%) | 692 (92.0%) | 1 [Reference] | <.001 | 1 [Reference] | .247 |
| Yes | 101 (3.8%) | 60 (8.0%) | 2.19 (1.57, 3.04) | 1.23 (0.87, 1.75) | ||
| Chronic kidney disease | ||||||
| No | 2603 (98.3%) | 722 (96.0%) | 1 [Reference] | <.001 | 1 [Reference] | .184 |
| Yes | 45 (1.7%) | 30 (4.0%) | 2.40 (1.50, 3.84) | 1.41 (0.85, 2.34) | ||
| Chronic liver disease | ||||||
| No | 2552 (96.4%) | 716 (95.2%) | 1 [Reference] | .147 | 1 [Reference] | .300 |
| Yes | 96 (3.6%) | 36 (4.8%) | 1.34 (0.90, 1.98) | 1.24 (0.82, 1.88) | ||
| Chronic lung disease | ||||||
| No | 2585 (97.6%) | 704 (93.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Yes | 63 (2.4%) | 48 (6.4%) | 2.80 (1.90, 4.11) | 2.09 (1.39, 3.15) | ||
| Endocrine/Immune system disease | ||||||
| No | 2546 (96.2%) | 706 (93.9%) | 1 [Reference] | .008 | 1 [Reference] | .118 |
| Yes | 102 (3.9%) | 46 (6.1%) | 1.63 (1.14, 2.33) | 1.36 (0.93, 2.00) | ||
| Tumor | ||||||
| No | 2577 (97.3%) | 724 (96.3%) | 1 [Reference] | .135 | 1 [Reference] | .647 |
| Yes | 71 (2.7%) | 28 (3.7%) | 1.40 (0.90, 2.19) | 1.12 (0.70, 1.78) | ||
| ACEIs/ARBs treatment | ||||||
| No | 2437 (92.0%) | 661 (87.9%) | 1 [Reference] | <.001 | 1 [Reference] | .221 |
| Yes | 211 (8.0%) | 91 (12.1%) | 1.59 (1.23, 2.06) | 1.19 (0.90, 1.58) | ||
Patients grouped according to the diagnosis of hypertension and type 2 diabetes mellitus (T2DM).
To exclude possible confounding effects of comorbid conditions, a sensitivity analysis that included only the 2604 patients who did not have any other comorbidities (cardiovascular disease, cerebrovascular disease, chronic lung disease, chronic liver disease, chronic kidney disease, endocrine/Immune system disease, or tumor) confirmed that hypertension alone, T2DM alone, and hypertension plus T2DM were each associated with an increased risk of developing severe COVID‐19 infection (Table S3B in Appendix S1).
However, when patients were grouped according to blood pressure and fasting blood glucose, elevated fasting blood glucose but not elevated blood pressure was a risk factor for developing severe infection and this was independent of whether patients did or did not have other comorbid conditions (Table 5b, Tables S3C and S3D in Appendix S1).
TABLE 5b.
Risk factors associated with development of severe infection in patients with confirmed COVID‐19 infection (secondary outcome)
| Covariate | Non‐severe COVID‐19 infection, % | Severe COVID‐19 infection, % | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||
| Comorbid conditions * | ||||||
| BP < 140/90 mmHg and FBG < 7 mmol/L | 1504 56.8% | 368 48.9% | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| BP ≥ 140/90 mmHg and FBG < 7 mmol/L | 819 30.9% | 210 27.9% | 1.05 (0.87, 1.27) | 0.98 (0.80, 1.19) | ||
| BP < 140/90 mmHg and FBG ≥ 7 mmol/L | 180 6.8% | 98 13.0% | 2.23 (1.70, 2.92) | 1.92 (1.45, 2.54) | ||
| BP ≥ 140/90 mmHg and FBG ≥ 7 mmol/L | 145 5.5% | 76 10.1% | 2.14 (1.59, 2.89) | 1.82 (1.33, 2.48) | ||
| Age group | ||||||
| 18–65 | 1760 (66.5%) | 334 (45.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| ≥65 | 888 (33.5%) | 409 (54.4%) | 2.36 (2.01, 2.79) | 1.98 (1.67, 2.36) | ||
| Sex | ||||||
| Female | 1416 (53.5%) | 335 (44.6%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Male | 1232 (46.5%) | 417 (55.4%) | 1.43 (1.22, 1.68) | 1.34 (1.13, 1.58) | ||
| Cardiovascular disease | ||||||
| No | 2437 (92.0%) | 620 (82.5%) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Yes | 211 (8.0%) | 132 (17.5%) | 2.46 (1.95, 3.11) | 1.56 (1.21, 2.01) | ||
| Cerebrovascular disease | ||||||
| No | 2547 (96.2%) | 692 (92.0%) | 1 [Reference] | <.001 | 1 [Reference] | .196 |
| Yes | 101 (3.8%) | 60 (8.0%) | 2.19 (1.57, 3.04) | 1.26 (0.89, 1.79) | ||
| Chronic kidney disease | ||||||
| No | 2603 (98.3%) | 722 (96.0%) | 1 [Reference] | <.001 | 1 [Reference] | .111 |
| Yes | 45 (1.7%) | 30 (4.0%) | 2.40 (1.50, 3.84) | 1.51 (0.91, 2.51) | ||
| Chronic liver disease | ||||||
| No | 2552 (96.4%) | 716 (95.2%) | 1 [Reference] | .147 | 1 [Reference] | .267 |
| Yes | 96 (3.6%) | 36 (4.8%) | 1.34 (0.90, 1.98) | 1.26 (0.84, 1.91) | ||
| Chronic lung disease | ||||||
| No | 2585 (97.6%) | 704 (93.6%) | 1 [Reference] | <.001 | 1 [Reference] | .001 |
| Yes | 63 (2.4%) | 48 (6.4%) | 2.80 (1.90, 4.11) | 1.96 (1.30, 2.94) | ||
| Endocrine/Immune system disease | ||||||
| No | 2546 (96.2%) | 706 (93.9%) | 1 [Reference] | .008 | 1 [Reference] | .094 |
| Yes | 102 (3.9%) | 46 (6.1%) | 1.63 (1.14, 2.33) | 1.39 (0.95, 2.04) | ||
| Tumor | ||||||
| No | 2577 (97.3%) | 724 (96.3%) | 1 [Reference] | .135 | 1 [Reference] | .663 |
| Yes | 71 (2.7%) | 28 (3.7%) | 1.40 (0.90, 2.19) | 1.11 (0.70, 1.77) | ||
| ACEIs/ARBs treatment | ||||||
| No | 2437 (92.0%) | 661 (87.9%) | 1 [Reference] | <.001 | 1 [Reference] | .104 |
| Yes | 211 (8.0%) | 91 (12.1%) | 1.59 (1.23, 2.06) | 1.26 (0.95, 1.66) | ||
Patients grouped according to blood pressure (BP) and fasting blood glucose (FBG) levels.
4. DISCUSSION
Prior studies have shown that there is a high prevalence of hypertension and T2DM in patients infected with COVID‐19, which have both been associated with increased risk of death, ARDS/respiratory failure and severe COVID‐19 infection. However, because hypertension and T2DM commonly occur together, their independent contributions have not been clearly defined.
An outstanding clinical research that included 2877 confirmed COVID‐19 patients, 15 Gao and colleagues demonstrated that after adjusted for confounders and compared with non‐hypertensive patients, the hypertensive patients indicated a significant increase in the risk of mortality from COVID‐19. However, this study did not address the contributions of diabetes. Even in the latest review, hypertension is considered an independent major factor for worse clinical outcomes. 4 In our large patient cohort with well‐defined characteristics and outcomes, we have demonstrated that T2DM is a major independent risk factor for adverse outcomes associated with COVID‐19; hypertension itself contributed only to a relatively small degree to the development of severe infection, but not to death nor development of ARDS/respiratory failure. These findings were robust in that they survived adjustment for other comorbid conditions and that they survived multiple sensitivity analyses. It should be noted that the risk associated with hypertension is accentuated through its confounding effect on T2DM. Also, once ARDS/respiratory failure was established, neither hypertension nor T2DM increased the risk of death. Very significantly, elevated fasting blood glucose more so than a history of T2DM was the major driver of increased risk of all adverse outcomes, whereas elevated blood pressure was noncontributory. Regarding other comorbidities, we also identified advanced age, male sex, history of other cardiovascular diseases, chronic kidney disease and tumors as risk factors for adverse outcomes. Chronic lung disease emerged only as a risk factor for development of severe infection, but not mortality, ARDS or respiratory failure. Finally, our results further confirmed prior findings that under all circumstances investigated, ACEI/ARB use did not contribute to disease severity or final clinical outcome. 16 , 17
A recent meta‐analysis 18 that included outcomes from 3994 COVID‐19 positive patients derived from 16 publications, all from China and published between December 2019 and February 2020, 1 , 32 identified hypertension, T2DM, a history of cardiovascular diseases, chronic obstructive pulmonary disease and chronic kidney disease as having significant associations with the development of serious events (including ICU admission, ARDS, and mechanical ventilation). 18 However, only the presence of T2DM had a significant impact on death. Since this was not a patient‐level meta‐analysis, the study was not able to identify the independent contributions of hypertension and T2DM. A more recent study and meta‐analysis 11 that included some of the same references and additional small reports (several nonpeer‐reviewed) specifically identified T2DM as a risk factor for death, based on univariate analysis. Additionally, that study did not address the contributions of hypertension. Accordingly, our study presents the first, largest, and most comprehensive analysis providing direct evidence of the primary importance of T2DM and lack of impact of hypertension in determining outcomes after accounting for other comorbid conditions. It is also noteworthy that consistent with the prior study 28 that a history of tumors increased the risk of mortality, though not specifically of severe infection, ARDS, or respiratory failure.
As reviewed in detail by Apicella and colleagues, 4 a few recent studies have specifically identified the increased risks associated with hyperglycemia upon hospital admission independent of a prior history of T2DM. 8 , 9 , 10 Whether admission hyperglycemia identifies a population of undiagnosed T2DM patients, reflects direct effects on pancreatic β‐cell function by the SARS‐CoV‐2, or a more general reaction to the proinflammatory state is not yet identified. Also unknown is if tighter glycemic control following admission results in better outcomes 33 and, if so, which drugs provide better or worse outcomes. 4 Careful prospective studies will be required before specific treatment guidelines can be provided.
4.1. Limitations
The main limitation of the study is that it is based on a retrospective analysis. However, because of the unique nature of the two primary hospitals from which data were derived, there were defined start and end dates for hospital admissions and every patient was accounted for with regard to primary and secondary outcomes and clinical characteristics including admission blood pressures and fasting blood glucose levels. Concerns about the retrospective nature of the analysis were further minimized by the fact that this was an observational study of patients receiving standard of care treatment and no intervention was being evaluated.
Our study also has limitations in classifying new‐onset hypertensive or new‐onset diabetic cases. Although patients with elevated blood pressure on admission without a history of hypertension showed symptoms and other indices similar to those of patients with a history of hypertension, we cannot rule out the possible existence of truly non‐hypertensive patients with elevated blood pressure at admission among the new‐onset hypertension. It is for this reason that the analysis of risk associated with elevated blood pressure independent of hypertensive history is so important and informative. Similarly, patients with hyperglycemia on admission showed symptoms and biochemical indices similar to those of patients with history of diabetes, as in other prior studies, we cannot rule out the possible existence of truly non‐diabetic patients with hyperglycemia at admission among those considered to have new‐onset diabetes.
5. CONCLUSION
In this large retrospective study, we show that neither hypertension nor elevated blood pressure were independent risk factors for death or ARDS/respiratory failure but hypertension did confer a slightly increased risk of developing severe COVID‐19 infection. In contrast, T2DM was an independent and strong risk factor for death, ARDS/respiratory failure, and severe COVID‐19 infection. Hyperglycemia on admission, regardless of diabetic history, was similarly a strong risk factor for adverse outcome. Once ARDS/respiratory failure occurred, neither hypertension nor T2DM increased the risk of death; however, advanced age and male sex were risk factors for death in the setting of ARDS/respiratory failure. ACEI and/or ARB use did not impact the odds of death, developing ARDS/respiratory failure, or severe COVID‐19 infection. Nor did ACEI and/or ARB use increase the risk of death once ARDS/respiratory failure had developed.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
AUTHOR CONTRIBUTIONS
YH Sun performed study design, statistical analysis, data interpretation, and manuscript writing. XZ Guan, LJ Jia, N Xing, LQ Cheng, B Liu, and SB Zhang performed data collection and manuscript revision. KL He administrated and supervised the study. All authors read and approved the final manuscript.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The study was approved by the institutional ethics committee of the Chinese PLA General Hospital, and a waiver of the requirement for patient consent was obtained. All patients included in this study did not receive financial compensation.
PERMISSIONS
The authors do hereby declare that all illustrations and figures in the manuscript are entirely original and do not require reprint permission.
Supporting information
Appendix S1
ACKNOWLEDGEMENTS
We acknowledge all health care workers involved in the diagnosis and treatment of patients at Huoshen Mountain Hospital and Guanggu Fangcang Shelter Hospital. We thank Dr Daniel Burkhoff (from Cardiovascular Research Foundation) for help editing the paper. We thank Hui Chen (from Huoshen Mountain Hospital) and Mingchao Liu (from Chinese PLA General Hospital) for assisting with data collection.
Sun Y, Guan X, Jia L, et al. Independent and combined effects of hypertension and diabetes on clinical outcomes in patients with COVID‐19: A retrospective cohort study of Huoshen Mountain Hospital and Guanggu Fangcang Shelter Hospital. J Clin Hypertens.2021;23:218–231. 10.1111/jch.14146
REFERENCES
- 1. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708‐1720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID‐19 in the New York City area. JAMA. 2020;323(20):2052‐2059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):1‐11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID‐19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 2020;8(9):782–792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Arauz‐Pacheco C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl 1):S80‐S82. [DOI] [PubMed] [Google Scholar]
- 6. Hu G, Jousilahti P, Barengo NC, Qiao Q, Lakka TA, Tuomilehto J. Physical activity, cardiovascular risk factors, and mortality among Finnish adults with diabetes. Diabetes Care. 2005;28(4):799‐805. [DOI] [PubMed] [Google Scholar]
- 7. Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet. 2012;380(9841):601‐610. [DOI] [PubMed] [Google Scholar]
- 8. Wang F, Yang Y, Dong K, et al. Clinical characteristics of 28 patients with diabetes and covid‐19 in Wuhan, China. Endocr Pract. 2020;26(6):668‐674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Bode B, Garrett V, Messler J, et al. Glycemic characteristics and clinical outcomes of COVID‐19 patients hospitalized in the United States. J Diabetes Sci Technol. 2020;14(4):813‐821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID‐19 inpatients in Wuhan. J Allergy Clin Immunol. 2020;146(1):110‐118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Wu J, Zhang J, Sun X, et al. Influence of diabetes mellitus on the severity and fatality of SARS‐CoV‐2 (COVID‐19) infection. Diabetes Obes Metab. 2020;22(10):1907–1914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. National Health Commission of the People's Republic of China . Handbook of prevention and treatment of the pneumonia caused by the novel coronavirus (2019‐nCoV) (in Chinese) 2020. http://en.nhc.gov.cn/2020‐02/06/c_76295.htm. Accessed July 14, 2020.
- 13. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community‐acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45‐e67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Clinical management of COVID‐19. 2020. https://www.who.int/publications/i/item/clinical‐management‐of‐severe‐acute‐respiratory‐infection‐when‐novel‐coronavirus‐(ncov)‐infection‐is‐suspected. Accessed July 14, 2020.
- 15. Gao C, Cai Y, Zhang K, et al. Association of hypertension and antihypertensive treatment with COVID‐19 mortality: a retrospective observational study. Eur Heart J. 2020;41(22):2058‐2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin‐angiotensin‐aldosterone system inhibitors and risk of COVID‐19. N Engl J Med. 2020;382(25):2441‐2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Fosbøl EL, Butt JH, Østergaard L, et al. Association of angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker use with COVID‐19 diagnosis and mortality. JAMA. 2020;324(2):168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Nandy K, Salunke A, Pathak SK, et al. Coronavirus disease (COVID‐19): a systematic review and meta‐analysis to evaluate the impact of various comorbidities on serious events. Diabetes Metab Syndr. 2020;14(5):1017‐1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507‐513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497‐506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Liu K, Fang Y‐Y, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J. 2020;133(9):1025‐1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID‐19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425‐434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS‐CoV‐2 pneumonia in Wuhan, China: a single‐centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475‐481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus‐infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061‐1069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054‐1062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Zhu W, Xie K, Lu H, Xu L, Zhou S, Fang S. Initial clinical features of suspected coronavirus disease 2019 in two emergency departments outside of Hubei, China. J Med Virol. 2020;92(9):1525‐1532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Wu J, Liu J, Zhao X, et al. Clinical characteristics of imported cases of COVID‐19 in Jiangsu Province: a multicenter descriptive study. Clin Infect Dis. 2020;71(15):706‐712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Liang W, Guan W, Chen R, et al. Cancer patients in SARS‐CoV‐2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335‐337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Lei S, Jiang F, Su W, et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID‐19 infection. EClinicalMedicine. 2020;21:100331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Li J, Li S, Cai Y, et al. Epidemiological and clinical characteristics of 17 hospitalized patients with 2019 novel coronavirus infections outside Wuhan, China. medRxiv. 2020;2020.02.11.20022053. [Google Scholar]
- 31. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS‐Cov‐2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:m606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China. Allergy. 2020;75(7):1730‐1741. [DOI] [PubMed] [Google Scholar]
- 33. Zhu L, She ZG, Cheng X, et al. Association of blood glucose control and outcomes in patients with COVID‐19 and pre‐existing type 2 diabetes. Cell Metab. 2020;31(6):1068‐1077.e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Supplementary Materials
Appendix S1