key: cord-0955060-9456f33m
authors: Chen, Jiankun; Liu, Yuntao; Qin, Jinying; Ruan, Chunyan; Zeng, Xianghui; Xu, Aiting; Yang, Rongyuan; Li, Jiqiang; Cai, Huayang; Zhang, Zhongde
title: Hypertension as an independent risk factor for severity and mortality in patients with COVID-19: a retrospective study
date: 2021-10-05
journal: Postgrad Med J
DOI: 10.1136/postgradmedj-2021-140674
sha: 05de2750d939c8df58736bea16f5726b270c2b7a
doc_id: 955060
cord_uid: 9456f33m

PURPOSE OF THE STUDY: Hypertension is one of the most common comorbidities in COVID-19 pneumonia. However, whether it is an independent factor on the severity and mortality of COVID-19 has not been studied. STUDY DESIGN: In this study, 736 patients with a PCR-confirmed diagnosis of COVID-19 were included from 12 January 2020 to 25 March 2020. All patients were divided into two groups according to whether or not they were hypertensive. After propensity score matching (PSM) to remove the interference of mismatches in the baseline data, the clinical characteristics and outcomes of angiotensin II receptor blocker (ARB)/ACE inhibitors application were analysed. RESULTS: A total of 220 (29.9%) patients were hypertensive, and 516 (70.1%) patients were not hypertensive. PSM eliminated demographic and comorbidity differences between the two groups. Of all participants, 32 patients died (4.3% mortality), including 17 out of 220 in the hypertension group (7.7%) and 15 out of 516 in the non-hypertension group (2.9%). The incidence of intensive care unit (ICU) stay in the hypertension group (12.8%) was higher than in the non-hypertension group (5.3%) (p<0.05). Logistic regression analysis showed that hypertension was an independent risk factor for death, not other comorbidities. Kaplan-Meier analysis showed that mortality was higher in the hypertension group than in the non-hypertension group before and after PSM (p<0.05). There was no statistically significant difference in ICU therapy, mortality and hospitalisation time between hypertensive patients with or without ARBs/ACE inhibitors (p>0.05). CONCLUSION: Hypertension was an independent risk factor for the severity and mortality of patients with COVID-19. ARBs/ACE inhibitors should not be discontinued in hypertensive patients with COVID-19.

As of 27 April 2021, a cumulative total of 147 539 302 cases and 3116 444 deaths have been caused by COVID-19 since the start of the outbreak. 1 Although its mortality rate has been decreasing by 3% per week until now, its incidence rate continues to increase by 1% in the number of cases per week. COVID-19 poses a great challenge to public health and the global economy.

It was estimated that almost 1.39 billion adults worldwide were hypertensive. 2 Hypertension causes a variety of diseases that greatly increase the mortality rate in the population. Although there is no direct evidence that hypertension increases the risk of new infections, several recent clinical studies have shown that hypertension is one of the most prevalent comorbidities of COVID-19 and a risk factor for severe COVID-19 infection. [3] [4] [5] Another major concern between hypertension and COVID-19 is the viral invasion pathway. The COVID-19 virus belongs to the β genus coronavirus, and the first step of human infection with coronavirus is the contact of the virus with ACE2 on the cell surface. 6 ACE2, one of the components of the renin-angiotensin system, on the other hand, is one of the targets of antihypertensive drugs. Many patients with COVID-19 are hypertensive, which has caused a lot of discussion on the treatment of hypertensive patients. The use of angiotensin II receptor blocker (ARB)/ACE inhibitors has also become a hot topic in patients with To date, studies on the systematic and comprehensive epidemiology and clinical features of hypertensive patients with COVID-19 are still lacking. More evidence for the epidemiology and clinical information should be collected and analysed. In addition, investigating whether hypertension affects the clinical outcomes of patients with COVID-19 deserves further attention. This study aimed to investigate the clinical characteristics and outcomes of hypertensive and non-hypertensive patients with COVID-19. Furthermore, the relationship between ARBs/ACE inhibitors and clinical outcomes in patients with COVID-19 was analysed to provide clinical evidence to address the question of whether or not ARBs/ACE inhibitors should be discontinued during COVID-19 infection.

In this study, we included 736 hospitalised patients with a PCR-confirmed diagnosis of COVID-19 from the Hubei Provincial Hospital of Integrated Traditional Chinese and Western Medicine between 12 January and 25 March 2020. COVID-19 was diagnosed according to the WHO's interim guidance. A total of 220 hypertensive and 516 non-hypertensive patients were randomly selected. In accordance with the guidelines for prevention and treatment of hypertension in China (2018 edition), hypertension was defined as: clinical systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg without the use of antihypertensive medications at three visits Original research on different days; with a BP <140/90 mm Hg but having hypertensive history and currently are taking antihypertensive medication.

Information on demographics, past history, symptoms and signs, laboratory data, radiological features, treatments, complications, and outcome data of admitted patients was extracted from electronic medical records. Incomplete data would be directly obtained by contacting attending doctors or other healthcare providers; finally, missing data would describe the reasons. Clinical outcomes were followed up until 25 March 2020.

Laboratory confirmation was conducted in the Hubei Provincial Hospital of Integrated Traditional Chinese and Western Medicine. The confirmation of 2019 -nCoV was done via highthroughput sequencing or real-time reverse-transcriptase PCR (RT-PCR) assay of nasal and pharyngeal swab specimens in accordance with the protocol established by WHO. Other laboratory indicators include complete blood count, coagulation testing, and kidney and liver function tests. The radiological examination results of the included patients were also collected according to documentation or description in inspection report charts.

All patients were divided into two groups according to whether or not they were hypertensive. After propensity score matching (PSM) to remove the interference of mismatches in the baseline data, their clinical characteristics and outcomes were analysed. The covariates included in the propensity score model were the patient's age, sex and past history (including diabetes, coronary heart disease, stroke, malignant tumour, chronic kidney disease, chronic obstructive pulmonary disease, asthma, heart failure, arrhythmia, bronchiectasis and systemic lupus erythematosus). Matching was performed with the use of a 1:1 matching protocol without replacement, with a calliper width equal to 0.01 of the SD of the logit of the propensity score. Logistic regression was used to clarify the effects of independent variables on mortality of patients with COVID-19. The survival rates of COVID-19positive patients during the observation period were analysed using Kaplan-Meier plots and compared using the log-rank test. In addition, the clinical outcome of ARBs/ACE inhibitors in hypertensive patients has also attracted attention. According to their antihypertensive medication, patients were retrospectively allocated to the ARBs/ACE inhibitor and non-ARBs/ACE inhibitor groups.

The Statistical Package for the Social Sciences V.26.0 software was used for statistical analyses. To reduce the effect of potential confounding factors other than hypertension, PSM was used to match hypertensive and non-hypertensive patients when we evaluated the associations between hypertension and outcome variables. The association of ARBs/ACE inhibitor exposure and clinical outcome was assessed using Kaplan-Meier regression analysis in all hypertensive patients.

Continuous variables were expressed as medians (IQRs), while categorical variables as counts and percentages. Normally distributed data were compared using t-tests or one-way analysis of variance. Non-normally distributed data were compared using the Mann-Whitney U test. Categorical variables were compared using the χ 2 test or Fisher's exact test when necessary. The threshold for significance was set at p<0.05.

A total of 736 patients with confirmed COVID-19 was included in this study. Among the patients, 344 (46.7%) were men and 392 (53.5%) were women (table 1). The median age was 59 years (IQR 48-69 years). A total of 220 (29.9%) of these patients had a history of hypertension (hypertension group) and 516 (70.1%) patients were without hypertension (non-hypertension group). The median ages in the hypertension and non-hypertension groups were 67 years (IQR 58-76 years) and 56 years (IQR 43-65 years) (p=0.000), respectively. The average age of the hypertensive group was higher than that of the non-hypertensive group. The number of male patients was 107 (48.6%) in the hypertension group and 237 (45.9%) in the non-hypertension group (p=0.501). There were no significant differences between the two subgroups underlying comorbidities, including cancer (p=0.327), chronic kidney disease (p=0.163), chronic kidney disease (p=0.848), asthma (p=0.280), heart failure (p=0.280), arrhythmia (p=0.059), bronchiectasis (p=0.534), systemic lupus erythematosus (p=0.513), diabetes (p=0.007), coronary heart disease (p=0.000) and stroke (p=0.000), which demonstrated that hypertensive patients had a higher comorbidity rate than non-hypertensive patients with glucolipid metabolic disease, which is consistent with the results of previous studies. 3 7 After PSM, the differences in demographic data and comorbidities between the two groups were removed (table 1) .

On admission and during hospitalisation, the body temperature of hypertensive patients was similar to that of non-hypertensive patients (p=0.396). Obviously, hypertensive patients had significantly higher BP values than non-hypertensive patients (p<0.05). The common symptoms of patients with COVID-19 were fatigue (67.3%), cough (56.0%), shortness of breath (27.2%), chest tightness (23.4%), sputum (19.4%), myalgia or arthralgia (12.5%), chills (8%), diarrhoea (7.3%), nausea or vomiting (4.3%), dyspnoea (4.3%), and headache (3.5%) (table 1). There were no statistically significant differences in any of the symptoms at baseline between the two groups (p>0.05). After PSM, there was still no significant difference in the main symptoms such as cough, fatigue, shortness of breath, chest tightness, and sputum between the two groups.

The laboratory test (including routine blood tests, blood biochemistry and coagulation markers) and radiological data of all patients and the propensity score-matched subpopulations between the two groups are shown in table 1. Of all participants, the patients in the hypertension group had a higher white cell count, aspartate aminotransferase, globulin, cystatin C, total bilirubin, creatinine and blood urea nitrogen than those in the nonhypertension group (p<0.05). On the contrary, the lymphocyte count and albumin levels were lower in the hypertension group than in the non-hypertension group (p<0.05). Leucocytosis and lymphopenia indicate different immune functions in hypertensive patients with COVID-19 and in non-hypertensive patients. However, there were no significant differences in platelet count, haemoglobin, alanine aminotransferase, prothrombin time, international normalized ratio, activated partial thromboplastin time and thrombin time levels (p>0.05). These findings indicate that hypertensive patients with COVID-19 are more likely to show abnormal liver and kidney functions in clinical practice. After PSM, there was no statistically significant difference According to radiological results, except for 49 (6.7%) cases without inspection, most patients had ground-glass opacity and bilateral patchy shadowing, accounting for 61.6% and 60.0%, respectively. Additionally, hydrothorax occurred in 34 (5.0%) patients, and 63 (9.1%) patients reported unilateral patchy shadowing. It should be noted that whether or not propensity matching was performed, the radiological data showed that the incidence of hydrothorax in the hypertension group was significantly higher than that in the non-hypertension group (p<0.05), although hydrothorax is less common in COVID-19.

The common serious complications in patients with COVID-19 included acute respiratory distress syndrome (ARDS), heart failure, septic shock and acute renal failure (table 1). No significant difference in the rate of occurrence of complications was observed between the hypertension and non-hypertension groups (p>0.05). Once diagnosed with COVID-19, all patients received standard treatments according to the Clinical Guideline for COVID-19 Diagnosis and Treatment published by the National Health Commission of China (National Health Commission of the People's Republic of China, 2020). Table 1 demonstrates that antiviral medication (74.6%), antibacterial medication (61.1%), traditional Chinese medicine (84.9%), oxygen therapy (85.7%), glucocorticoids (31.5%), immunoglobulins (24.0%) and antihypertensive medication (35.9%) were the most common treatments. There was no statistically significant difference in management between the hypertension and non-hypertension groups, except for antihypertensive therapy (p<0.05).

In table 2, among the 736 patients with COVID-19, a total of 32 patients died (mortality 4.3%), including 17 out of 220 in the hypertension group (7.7%) and 15 out of 516 in the nonhypertension group (2.9%, p=0.003). After PSM, there was still a statistically significant difference in mortality between the hypertension and non-hypertension groups (p=0.006). The hypertension group had a higher mortality rate than the non-hypertension group. In addition, the rate of intensive care unit(ICU) stay in the hypertension group (12.8%) was higher than that in the non-hypertension group (5.3%) (p<0.05). There was no statistically significant difference between the two groups in terms of median hospital stay (p=0.931).

Logistic regression was used to clarify the effects of independent variables on mortality of patients with COVID-19. Results showed that hypertension was an independent risk factor for death (p<0.05), not other comorbidities before and after PSM (table 3) . Kaplan-Meier plots and comparison using the log-rank test was used to analyse the influence of hypertension on survival rates. The results ( figure 1) showed that the survival rates were higher in the non-hypertension group than in the hypertension group (p<0.05). By the log-rank test, the mean survival times for patients with COVID-19 with non-hypertension were longer than for those with hypertension before (χ 2 =7.912, p=0.005) and after (χ 2 =7.228, p=0.007) PSM. In the observation period, the mean survival time for all patients with COVID-19 with or without hypertension was 80.52 days (range=78.01-83.03 days) and 87.71 days (range=86.57-88.85 days), respectively. After further adjustments for age, sex and past history (including diabetes, coronary heart disease, stroke, malignant tumour, The relationship between ARB/ACE inhibitor exposure and clinical outcomes of hypertensive patients with COVID-19 were further analysed and compared. Table 4 shows that there was no significant difference in mortality among hypertensive patients with or without ARBs/ACE inhibitors (p=0.260). Otherwise, ICU therapy and hospitalisation time were analysed and showed no statistical significance (p>0.05).

The influence of ARBs/ACE inhibitor exposure on the mortality of hypertensive patients with COVID-19 was also analysed by Kaplan-Meier regression. The results showed that the risk of mortality in the ARBs/ACE inhibitor group did not differ significantly from that in the non-ARBs/ACE inhibitor group (χ 2 =1.217, p=0.270).

In this retrospective study, we evaluated the association between hypertension and adverse clinical outcomes in patients with COVID-19. Our results showed that hypertension was associated with significantly increased mortality, and a similar association was observed in different subgroups after PSM removed the interference of mismatches in the baseline data (age, sex and comorbidities). Furthermore, ARBs/ACE inhibitor treatment had no significant effect on the severity of COVID-19 and the mortality of hypertensive patients with COVID-19.

Hypertension is the leading cause of cardiovascular disease and death worldwide. Although the global average BP has decreased due to the widespread use of antihypertensive drugs, the prevalence of hypertension is still on the rise. Hypertension is also a common comorbidity in patients with COVID-19. Clinical studies have shown that it has a high incidence (30.6%-49.6%) among patients with COVID-19. 8 9 In our study, 220 (29.9%) of these patients had a history of hypertension, which is in line with the overall trend. Although there is no reliable evidence that hypertension is associated with the risk of infection with COVID-19, several studies have suggested that it increases the risk of COVID-19 severity and COVID-19-related mortality, which is always associated with age, obesity, diabetes mellitus, cardiovascular and cerebrovascular diseases, and chronic respiratory disease. 9 10 Our results also showed that hypertension, diabetes, coronary heart disease and stroke were common comorbidities. Among the 736 patients, the prevalence of hypertension was closely related to age and other comorbidities such as diabetes, stroke and coronary heart disease (p<0.05). All of these comorbidities were found to be associated with worse clinical outcomes in patients with COVID-19, although not as independent risk factors. 11 12 To clarify the effect of hypertension as an independent factor on COVID-19-related mortality, PSM was used to eliminate age and other comorbidities from our study.

Common symptoms of COVID-19 include fever, cough, fatigue, sputum, myalgia, headache, haemoptysis, vomiting and diarrhoea. 13 Except for BP, there were no clinical symptoms to distinguish between hypertensive patients and non-hypertensive patients among the participants. Consistent with the report, patients with COVID-19 usually experience immune function and abnormal coagulation function imbalances. 14 15 Compared with the non-hypertension group, impaired liver and kidney functions in the hypertension group may indicate severity and poor clinical outcomes. Studies have shown that the imaging features of COVID-19 could help in the initial diagnosis of highly suspicious cases by supplementing the results of RT-PCR. However, radiological characteristics could be used as the basis for determining the severity of pneumonia. 16 Previous chest CT studies have shown typical features of pneumonia, such as peripheral ground-glass opacity, usually bilateral, with adjacent and multilobed expansion, depending on the severity of the disease. [17] [18] [19] Our results also stated that ground-glass opacity and bilateral patchy shadowing were prevalent in radiological studies of COVID-19.

The lungs are in direct contact with the external environment, so they are the main hosts of many airborne pathogens, including coronaviruses. ARDS is the most common and severe complication of COVID-19. Mechanical ventilation (invasive or non-invasive) is a suitable management method for respiratory failure and provides an opportunity for the treatment of critically ill patients. All patients received standard treatment according to the clinical guidelines once diagnosed with COVID-19. Traditional Chinese medicine has been widely used in SARS-CoV-2 (COVID-19) as in SARS-CoV-1 and has been reported to inhibit the replication, transcription, and invasion of viruses and attenuate cytokine storms and the immune deficiency caused by infection with the virus. 20 21 In terms of complications and treatment, there was no significant difference between the hypertension and non-hypertension groups, except for antihypertensive treatment.

To identify and treat critically ill patients as soon as possible, the factors associated with the COVID-19 severity and COVID-19-related mortality in clinical practice are of great importance. Advanced age, high sequential organ failure assessment score, medical comorbidities (hypertension, diabetes, cardiovascular disease and so on), morbid obesity, and abnormally elevated D-dimer levels were reported to help clinicians identify patients with poor prognoses at an early stage. [22] [23] [24] To some extent, most risk factors have a combined effect on the adverse outcomes of COVID-19 rather than independent risk factors. This study aimed to analyse the role of hypertension as an independent factor in the clinical process and outcome of COVID-19. In view of the poorer baseline well-being in patients with coexisting comorbidities, it is necessary to balance the baseline data (including age and major comorbidities) of hypertensive and non-hypertensive patients. PSM reduced the effects of the potential confounding factors. Our results demonstrated that hypertension was an independent risk factor for severity and increased mortality due to pneumonia.

In addition, the administration of ARBs/ACE inhibitors to patients with COVID-19 has become an issue that requires attention. SARS-CoV-2 binds to the ACE2 receptor, which is highly expressed in lung epithelial cells and other tissues. 25 26 Increased expression of ACE2 can facilitate viral infection and pathological inflammation. ARBs/ACE inhibitors, extensively used in hypertensive patients and patients with other cardiovascular conditions, were found to upregulate the expression of ACE2. 27 The continued use of ARBs/ACE inhibitors in hypertensive patients with COVID-19 has become a hot topic. Our results indicated that ARBs/ACE inhibitors had no effect on the severity and clinical outcome of patients with COVID-19, indicating that patients with COVID-19 should not discontinue ARBs/ACE inhibitors.

Our study has several limitations. As a retrospective study, it was a single-centre study, and all patients were from a hospital in Wuhan, which might have produced sample bias and narrowed down the interpretation of the conclusion. To reduce this bias, we included as many eligible cases as possible. In addition, we hope to conduct larger cohort studies or prospective randomised controlled trials to further verify our conclusions. Based on only 220 hypertensive patients among the participants, the sample size of the study on the effect of ARBs/ACE inhibitors in patients with COVID-19 was limited. Therefore, the results require further verification through future large-sample studies. Much information 

about inflammatory factors and immune function was incomplete, so we could not explore the mechanism of adverse prognosis in hypertensive patients with COVID-19. Although the mechanism is still unclear, our study provides an important cautionary note for clinicians. In conclusion, apart from age and other comorbidities, hypertension was an independent risk factor for severity and mortality in patients with COVID-19. ARBs/ACE inhibitors do not increase the risk of severity and mortality in patients with COVID-19; thus, the drugs should not be discontinued.

► Hypertension was an independent risk factor for the severity and mortality of patients with COVID-19. ► Angiotensin II receptor blockers (ARBs)/ACE inhibitors should not be discontinued in hypertensive patients with COVID-19.

► Is hypertension an independent factor for the severity and mortality of COVID-19? ► Do ARBs/ACE inhibitors increase the risk of severity and mortality in patients with COVID-19?

What is already known on the subject ► In our study, the hypertensive patients with COVID-19 had a higher mortality rate than the non-hypertensive patients with COVID-19. ► The incidence of intensive care unit stay in the hypertensive patients with COVID-19 (12.8%) was higher than in the nonhypertensive patients with COVID-19 (5.3%). ► There was no significant difference in the mortality rate among hypertensive patients with COVID-19 with or without ARBs/ACE inhibitors.

WHO. WHO coronavirus disease (COVID-19) dashboard, 2020

The global epidemiology of hypertension

Clinical characteristics and outcomes of type 2 diabetes patients infected with COVID-19: a retrospective study

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

SARS-CoV-2 infection in patients with autoimmune hepatitis

Angiotensin-Converting enzyme 2 is a functional receptor for the SARS coronavirus

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a casepopulation study

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

High prevalence of obesity in severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation

COVID-19 and hypertension-evidence and practical management: guidance from the HOPE Asia network

Hypertension and related diseases in the era of COVID-19: a report from the Japanese Society of hypertension Task force on COVID-19

COVID-19: current knowledge in clinical features, immunological responses, and vaccine development

Immunology of COVID-19: current state of the science

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

Deep COVID DeteCT: an international experience on COVID-19 lung detection and prognosis using chest CT

Emerging 2019 novel coronavirus (2019-nCoV) pneumonia

CT imaging features of 2019 novel coronavirus (2019-nCoV)

High resolution computed tomography for the diagnosis of 2019 novel coronavirus (2019-nCoV) pneumonia: a study from multiple medical centers in Western China

The direct evidence and mechanism of traditional Chinese medicine treatment of COVID-19

Chinese therapeutic strategy for fighting COVID-19 and potential small-molecule inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state

Coronavirus disease 2019 (COVID-19) in Italy

Single-Cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

At2 receptors: potential therapeutic targets for hypertension

The authors thank the Hubei Provincial Integrated Chinese and Western Medicine Hospital for their assistance.Contributors CHY, LJQ, YRY and XAT planned and designed the research. CJK, LYT, QJY, RCY and ZXH executed the research and analysed the data. CJK and LYT drafted the main manuscript. All the authors participated in the manuscript review and vouch for the accuracy and completeness of the data and the study's adherence to the protocol. 

Competing interests None declared.

Ethics approval This study was carried out in accordance with the recommendations of the Chinese National Guidelines and Ethics Branch of the Biomedical Ethics Committee of Guangzhou University of Chinese Medicine (ZE2020-049-01).Provenance and peer review Not commissioned; externally peer reviewed.Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

Jiankun Chen http:// orcid. org/ 0000-0002-4417-3048