key: cord-0879250-0wcte77e
authors: Sun, Yuhui; Guan, Xizhou; Jia, Lijing; Xing, Ning; Cheng, Liuquan; Liu, Bo; Zhang, Sibing; He, Kunlun
title: 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
date: 2020-12-25
journal: J Clin Hypertens (Greenwich)
DOI: 10.1111/jch.14146
sha: 8ce84d3b3ea4249242c84dde8f5009989a471630
doc_id: 879250
cord_uid: 0wcte77e

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.

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.

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.

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.

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 

All patients had a definite clinical outcome (discharge or death), since

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. 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).

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 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).

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. 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.

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 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 ( 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.

As detailed in Table S3A in Appendix S1.

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).

Prior studies have shown that there is a high prevalence of hyperten- 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. 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.

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 

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.

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.

The authors declare that there is no conflict of interest.

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.

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.

The authors do hereby declare that all illustrations and figures in the manuscript are entirely original and do not require reprint permission.

Kunlun He https://orcid.org/0000-0002-3335-5700

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Additional supporting information may be found online in the Supporting Information section.