COVID-19 patients with hypertension are at potential risk of worsened organ injury

In less than 6 months, COVID-19 spread rapidly around the world and became a global health concern. Hypertension is the most common chronic disease in COVID-19 patients, but its impact on these patients has not been well described. In this retrospective study, 82 patients diagnosed with COVID-19 were enrolled, and epidemiological, demographic, clinical, laboratory, radiological and therapy-related data were analyzed and compared between COVID-19 patients with (29 cases) or without (53 cases) hypertension. The median age of the included patients was 60.5 years, and the cohort included 49 women (59.8%) and 33 (40.2%) men. Hypertension (31 [28.2%]) was the most common chronic illness, followed by diabetes (16 [19.5%]) and cardiovascular disease (15 [18.3%]). The most common symptoms were fatigue (55 [67.1%]), dry cough (46 [56.1%]) and fever ≥ 37.3 °C (46 [56.1%]). The median time from illness onset to positive RT-PCR test was 13.0 days (range 3–25 days). There were 6 deaths (20.7%) in the hypertension group and 5 deaths (9.4%) in the nonhypertension group, and more hypertensive patients with COVID-19 (8 [27.6%]) than nonhypertensive patients (2 [3.8%]) (P = 0.002) had at least one comorbid disease. Compared with nonhypertensive patients, hypertensive patients exhibited higher neutrophil counts, serum amyloid A, C-reactive protein, and NT-proBNP and lower lymphocyte counts and eGFR. Dynamic observations indicated more severe disease and poorer outcomes after hospital admission in the hypertension group. COVID-19 patients with hypertension have increased risks of severe inflammatory reactions, serious internal organ injury, and disease progression and deterioration.

and was indicated by suspected symptoms, chest CT results and SARS-CoV-2 positivity on quantitative RT-PCR. Throat-swab specimens from all patients were collected at admission and kept in virus transport medium. Briefly, SARS-CoV-2 detection in respiratory specimens was conducted by the Chinese Center for Disease Control and Prevention, the Chinese Academy of Medical Science, the Academy of Military Medical Sciences, and the Wuhan Institute of Virology, the Chinese Academy of Sciences using real-time RT-PCR or next-generation sequencing technology. Other respiratory viruses, including influenza A virus (H1N1, H3N2, H7N9), influenza B virus, respiratory syncytial virus, parainfluenza virus, adenovirus, SARS coronavirus (SARS-CoV), and MERS coronavirus (MERS-CoV), were also detected by real-time RT-PCR. Sputum or endotracheal aspirates were also examined to identify potential pathogenic bacteria or fungi. Chest computed tomographic (CT) scans were carried out at least twice for each patient.
Patients hospitalized with COVID-19 are clinically classified as having mild, moderate, or severe disease, defined as follows: mild cases: mild clinical symptoms, no manifestations of pneumonia on imaging; moderate cases: symptoms such as fever and respiratory tract symptoms and imaging showing signs of pneumonia; severe cases: respiratory distress, respiratory rate ≥ 30 breaths/min, SpO 2 ≤ 93% at rest, or PaO 2 /FIO 2 ratio ≤ 300. In addition, cases with > 50% lesions progressing within 24 to 48 h on pulmonary imaging are considered severe.

Ethical approval. The research protocol was reviewed and approved by the Ethics Committee of Hubei
No. 3 People's Hospital of Jianghan University (202004). All procedures were carried out in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki. All patients had completed treatment at the beginning of the study, and the study did not interfere with diagnosis or treatment in any case. Therefore, the need for informed consent was waived by the Ethics Committee of Hubei No. 3 People's Hospital of Jianghan University. In addition, all patient privacy and data were respected and protected. Data collection. Eighty-two patients hospitalized with COVID-19 were included in this retrospective study, and 29 of these patients also had hypertension. Epidemiological, demographic, clinical, laboratory, X-ray and chest CT scan, treatment, and outcome data were extracted from electronic medical records with data collection forms. Eight researchers, including physicians and clinical pharmacists, reviewed the data collection forms and examined the data independently three times. COVID-19 patients were divided into two groups according to the presence or absence of hypertension. Hypertension was defined as clinic systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg without the use of antihypertensive medications. Subjects with a blood pressure < 140/90 mmHg but with a history of hypertension and who were taking antihypertensive medication at the time of admission were also included in the hypertension group 10 .
Statistical analysis. Categorical variables are reported as frequencies and percentages. Continuous variables are reported as mean (SD), median, and interquartile range (IQR) values. Comparisons of quantitative variables between groups were performed by the Wilcoxon rank sum test. Categorical variables are expressed as numbers (%) and were compared between groups using χ 2 or Fisher's exact tests. A two-sided p-value less than 0.05 was considered statistically significant. Statistical analysis was performed in SPSS (version 21.0). Figure 1 shows the flow chart for participant inclusion. Briefly, 295 cases with dates from Dec 31, 2019, to Feb 28, 2020, in the medical record system were initially screened, of which 213 were considered ineligible, including 73 cases admitted after 01 Feb, 23 cases without confirmed COVID-19 diagnosis, 22 duplicate records, 43 cases without available medical information, and 52 cases with missing core examination or therapy information. Ultimately, 82 patients were included in this study. The median age of the included patients was 60.5 years, and 49 (59.8%) were women ( 1%]) were the most common symptoms. The median time from illness onset to positive RT-PCR test was 13.0 days (range 3-25 days). A significant difference in clinical types on admission was observed (P < 0.001) between the two groups. There was no significant difference in mortality rate between the hypertension group (6 [20.7%]) and the nonhypertension group (5 [9.4%]). Furthermore, no significant difference between the two groups was observed in the survival analysis (Fig. 2 Table 2). There were no significant differences in routine blood analysis parameters between the hypertension and nonhypertension groups. However, the hypertension group exhibited higher white blood cell counts (4.9 × 10 9 /L), neutrophil counts (3.9 × 10 9 /L), and neutrophil percentages (79.3%) and lower lymphocyte counts (0.72 × 10 9 /L) and lymphocyte percentages (12.5%). Moreover, the median SAA in the hypertension group reached 630.1 mg/L, which was approximately double that (373.5 mg/L) in the nonhypertension group. Similarly, the median CRP level (79.2 mg/L) also exceeded that of the nonhypertension group (57.8 mg/L). In blood chemistry assays, no significant changes were found in AST (32. Imaging findings. Of all 82 nonmedical COVID-19 patients on admission ( Dynamic characteristics of laboratory parameters in COVID-19 patients with or without hypertension. The dynamic laboratory features of COVID-19 patients, including 8 clinical parameters related to hematology, infection, coagulation function, and internal organ injury, were traced from hospital admission to 20 days in the hospital at a 2-day interval on the basis of no significant difference observed at hospital admission between the two groups ( Table 1). As shown in Fig. 3A and B, white blood cell and neutrophil counts were higher in the hypertension group than in the nonhypertension group for almost the whole duration of hospitalization. Most patients had notable lymphopenia, with a 2-day delay in lymphocyte count increasing to the normal range compared to the nonhypertension group (Fig. 3C). Both CRP and SAA were higher in the hypertension group until 10 days after admission ( Fig. 3D and E). The eGFR of patients with hypertension was markedly lower than that of nonhypertensive patients, maintaining an overall slow increase from the day of admission but a slight decrease from its peak on day 10; by contrast, there was a reduction of approximately 30 mL/min/1.73 m 2 in the   www.nature.com/scientificreports/ eGFR of the nonhypertension group from days 8 to 14 (Fig. 3F). The creatine kinase level in the hypertension group was higher on admission, increased to approximately 400 U/L on day 2, and then decreased (Fig. 3H). Similarly, the level of D-dimer in the hypertension group continued to increase until day 4 after admission or day 11 from onset and then declined after day 6 ( Fig. 3G).

Discussion
In this investigation, we studied the epidemiology, clinical characteristics, and treatment of COVID-19, with a particular focus on potential differences in the disease course in the hypertensive population. Among the 82 included COVID-19 patients, there were 11 deaths (13.4%), which was consistent with the overall COVID-19 mortality rate at Jinyintan Hospital during the same period 8 . Nevertheless, national data showed that the case fatality had dropped to 2.3% by February 11 11 , suggesting that SARS-CoV-2 was more lethal at the early stage of the outbreak in January 12 .
Previously, hypertension has been identified as the most common chronic illness in more COVID-19 patients 4,5,13,14 . ACE2 is the receptor that mediates SARS-CoV-2 invasion in COVID-19, identical to SARS-CoV transmission, via the spike (S) glycoprotein-ACE2 binding pathway [15][16][17][18] . After infection, the ACE2 level was found to be reduced due to binding with the spike protein of SARS-CoV 19 , suggesting that SARS-CoV-2 may also reduce the level of ACE2 in infected cells, resulting in an imbalance between ACE1 and ACE2. Second, the renin-angiotensin II-aldosterone axis has been traditionally recognized as a key regulator of blood pressure in the development of hypertension, with AngII levels regulated by ACE. The balance between ACE1 and ACE2 is crucial for controlling the level of AngII. Thus, due to the imbalance of ACE1 and ACE2 induced by virus infection, the hypertensive population may tend to experience more serious organ injury.
In hypertensive COVID-19 patients, more severe clinical types or mortality were observed, suggesting that hypertension might be associated with the clinical outcomes of COVID-19. Our study also found that 31.0% of hypertensive patients also had other forms of cardiovascular disease, which has been associated with an increased risk of death in COVID-19 patients 13,20 . However, hypertension remains the most important risk factor leading to cardiovascular disease 21 . Accordingly, preexisting hypertension, rather than cardiovascular disease, might be the underlying cause of increased susceptibility to rapid disease progression and more severe COVID-19.
Laboratory results provided some evidence for this hypothesis. Hypertensive COVID-19 patients presented elevated levels of serum urea nitrogen, serum creatinine, lactate dehydrogenase, creatine kinase, and NT-proBNP and markedly reduced eGFR at admission. These altered parameters indicate that internal organs with high levels of ACE2 protein expression, such as the lung, kidney, and heart 3,22 , are more vulnerable to invasion and injury by SARS-COV-2. Simultaneously, SAA and CRP, which reflect systemic inflammation throughout the body, were also elevated. These results indicate that hypertensive patients tended to develop more severe COVID-19 not only through serious cytokine storms but also through reduced protection against organ injury due to imbalances in the ACE system [23][24][25] . Thus, the delay from illness onset to hospital admission could result in an increased risk of severe illness or death in hypertensive patients with COVID-19.
More dynamic changes were observed in hypertensive COVID-19 patients. White blood cell and neutrophil counts remained higher in the hypertension group than in the nonhypertension group for almost the entire period of hospitalization; SAA and CRP continued to increase until approximately 10 days after admission. In contrast with the nonhypertension group, in the hypertension group, lymphocyte counts continued to decline until 10 days after admission and returned to the normal range 2 days later. These findings suggested that more serious cytokine storms occurred in hypertensive COVID-19 patients.
Notably, in addition to ACE2, other receptors on the surface of human cells can facilitate the entry of SARS-COV-2, including TMPRSS2 26 , sialic acid receptors 27 , and CD147 28 . Intriguingly, all of these factors are expressed by endothelial cells. Therefore, the endothelium, as one of the largest organs in the human body, is a key target organ in COVID-19 29 . Impairment of endothelium function can promote vasodilation, fibrinolysis, www.nature.com/scientificreports/ and antiaggregation [30][31][32] . Simultaneously, for hypertensive populations, endothelial dysfunction is also a key determinant of hypertension development and progression 33,34 . Therefore, hypertensive patients infected by SARS-COV-2 are vulnerable to more serious endothelial dysfunction and thus tend to develop a more severe COVID-19 phenotype, leading to a higher mortality rate. In this study, 76.8% of patients were given antiviral agents based on previous experience in treating other coronavirus infections, such as SARS and MERS. Anti-influenza drugs, including oseltamivir and arbidol, were Table 2. Laboratory findings of patients infected with COVID-19 on admission. Data are expressed as the median (IQR) or n/N (%), where N is the total number of patients with available data. p values comparing patients with or without hypertension are from χ 2 , Fisher's exact, or Wilcoxon rank sum tests. COVID-19 coronavirus disease 2019, IQR interquartile range, WBC white blood cell, PCT procalcitonin, SAA serum amyloid A, CRP C-reactive protein, ESR erythrocyte sedimentation rate, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT glutamine transpeptidase, eGFR estimated glomerular filtration rate, NT-proBNP N-terminal pro-brain natriuretic peptide. www.nature.com/scientificreports/ also used for empirical treatment during this unusual period. However, there are currently no agents proven to be an effective therapy for COVID-19 35,36 . Glucocorticoid therapy was also empirically used for severe complications in nearly 90% of patients. Nevertheless, the efficacy of glucocorticoids remains controversial because of their adverse effects 37 and lack of consistently positive outcomes 4,38 . Recently, evidence from a randomized controlled trial showed that treatment with dexamethasone resulted in lowered mortality in COVID-19 patients 39 . Therefore, more reasonable glucocorticoid administration is still needed for COVID-19 treatment. Antibacterial therapy was also used in over 50% of patients to prevent or treat bacterial infections. Combined with the dynamic laboratory outcomes, parameters related to inflammation or organ function tended to improve 8-10 days after admission. However, these improvements could not be attributed to medication treatments alone. This study had several limitations. First, only 82 patients with confirmed COVID-19 were included in the full analysis. A larger study population size would be helpful to more deeply understand the role of hypertension in the progression of COVID-19. Second, due to the retrospective study design, some information was unavailable, particularly the time from illness onset to the signs and symptoms in electronic medical records. Third, the positive rate of SARS-CoV-2 RNA detection in throat swabs is lower than that of other methods, and antibody assays were not available to assist in diagnosis by the end of January, resulting in the exclusion of suspected but unconfirmed cases from our analysis. Moreover, there are other potential risk factors, including age, chronic lung disease, cardiovascular disease, and even liver disease, that could lead to more severe disease and increased in-hospital death. However, this study initially identified hypertension as an important factor for the clinical outcomes of COVID-19. Further investigations of the mechanism in hypertensive populations are needed.