COVID-19 is more severe in patients with hypertension; ACEI/ARB treatment does not influence clinical severity and outcome
Authors: Jianhua Hu, Xiaoli Zhang, Xuan Zhang, Hong Zhao, Jiangshan Lian, Shaorui Hao, Hongyu Jia, Meifang Yang, Yingfeng Lu, Dairong Xiang, Huan Cai, Shanyan Zhang, Jueqing Gu, Chanyuan Ye, Guodong Yu, Ciliang Jin, Lin Zheng, Yida Yang, Jifang Sheng
Journal: Journal of Infection (2020)

A number of pneumonia cases of unknown causes have emerged in Wuhan, Hubei, China since December 2019.1Wang W Tang J Wei F Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan, China.Journal of medical virology. 2020; (2020-Jan-29. PubMed PMID: MEDLINE:31994742)Google Scholar After sequencing analysis of samples from the lower respiratory tract, a coronavirus,2Zhu N Zhang D Wang W Li X Yang B Song J et al.A Novel Coronavirus from Patients with Pneumonia in China, 2019.The New England journal of medicine. 2020 Feb 20; 382 (PubMed PMID: 31978945. Pubmed Central PMCID: 7092803): 727-733Crossref PubMed Scopus (18380) Google Scholar which was last named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),3Alexander E. Gorbalenya SCB, Ralph S. Baric, Raoul J. de Groot, Christian Drosten, Anastasia A. Gulyaeva, Bart L. Haagmans, Chris Lauber, Andrey M. Leontovich, Benjamin W. Neuman, Dmitry Penzar, Stanley Perlman, Leo L.M. Poon, Dmitry Samborskiy, Igor A. Sidorov, Isabel Sola, John Ziebuhr. Severe acute respiratory syndrome-related coronavirus: The species and its viruses - a statement of the Coronavirus Study Group. 2020.Google Scholar was newly discovered. On February 11, 2020, the World Health Organization (WHO) announced a new name for the disease caused by 2019-nCoV: coronavirus disease 2019 (COVID-19).4Lai CC Shih TP Ko WC Tang HJ Hsueh PR Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): the epidemic and the challenges.Int J Antimicrob Agents. 2020 Feb 17; (105924. PubMed PMID: 32081636. eng)Crossref Scopus (3834) Google Scholar With the arrival of the Spring Festival, an epidemic SARS-CoV-2 infection has spread rapidly. It has swept across China and all over the world, and became a major global health concern. Chinese scientists found that SARS-CoV-2, like the SARS virus in 2003, enters human cells by recognizing angiotensin-converting enzyme 2 (ACE2) protein, which is the key to the invasion of the "new coronavirus" into the body.5Zhou P Yang XL Wang XG Hu B Zhang L Zhang W et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020 Feb 3; (PubMed PMID: 32015507)Crossref Scopus (14264) Google Scholar Decreased ACE2 expression is a cause of hypertension because ACE2 is identified as a major angiotensin 1-7 (Ang1-7)-forming enzyme.6Kuba K Imai Y Penninger JM Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases.Circ J. 2013; 77 (PubMed PMID: 23328447): 301-308Crossref PubMed Scopus (149) Google Scholar Based on studies of COVID-19, we found that hypertension initially occurs in many complications in COVID-19 patients.7Huang C Wang Y Li X Ren L Zhao J Hu Y et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020 Feb 15; 395 (PubMed PMID: 31986264. Pubmed Central PMCID: 7159299): 497-506Abstract Full Text Full Text PDF PubMed Scopus (32462) Google Scholar However, limited reports on COVID-19 patients with hypertension are available in literature. Whether patients with hypertension who undergo angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) therapy are more likely to suffer SARS-CoV-2 infection and whether ACEI/ARB therapy would have an influence on the clinical outcomes of patients with COVID-19 are controversy.8Zhang P Zhu L Cai J Lei F Qin JJ Xie J et al.Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19.Circulation research. 2020 Apr 17; (PubMed PMID: 32302265)Crossref Scopus (856) Google Scholar, 9Sunden-Cullberg J. Chronic Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Is High Among Intensive Care Unit Patients With Non-COVID-19 Sepsis but Carry a Moderately Increased Risk of Death.Hypertension (Dallas, Tex: 1979). 2020 Apr 10; (HYPERTENSIONAHA12015178. PubMed PMID: 32275190. Epub 2020/04/11. eng.)Crossref PubMed Scopus (14) Google Scholar Moreover, the epidemiologic and clinical features of COVID-19 patients with hypertension are also not completely elucidated. Thus, in this study, we describe the demographic, epidemiologic, and clinical characteristics of COVID-19 patients with hypertension. And we also attempted to analyze whether ACEI/ARB treatment would have an influence on the clinical severity and outcomes of COVID-19 patients. Altogether, 884 COVID-19 patients between January 17, 2020 and February 8, 2020, who confirmed with SARS-CoV-2 infection in Zhejiang Province, diagnosed as having COVID-19 according to WHO interim guidance10WHO. Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) infection is suspected: interim guidance. Jan 11, 2020. https://wwwwhoint/internal-publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected(accessed Jan 30,2020) 2020.Google Scholar were enrolled in this study. Among various coexisting conditions, the proportion of patients with hypertension (149 patients, 16.86%) was higher than that of others. Compared with COVID-19 patients without hypertension, those patients with hypertension had a higher percentage of male sex (59.06% vs 49.93%, P=0.042), were older (57.00 years vs 43.00 years, P=0.000) and had a higher percentage of age ≥60 years (43.62% vs 13.88%, P=0.000). In this study, 723 patients were diagnosed to have a mild type; 123 patients, severe type; and 37 patients, critical type. Patients with hypertension had a lower rate of mild type (59.06% vs 86.39%, P=0.000), but had a higher rate of severe (26.17% vs 11.43%, P=0.001) and critical types (14.77% vs 2.04%, P=0.000) than patients without hypertension. Compared with patients without hypertension, patients with hypertension had a higher incidence of acute respiratory distress syndrome(ARDS) (24.16% vs 6.67%, P=0.000), were more likely to use glucocorticoids (31.54% vs 12.79%, P=0.000), antibiotic (50.33% vs 39.32%, P=0.013), and intravenous immune globulin therapy (21.48% vs 6.67%, P=0.000) and more likely to need mechanical ventilation (14.77% vs 2.04%, P=0.000) and intensive care unit (ICU) admission (16.11% vs 2.31%, P=0.000), extracorporeal membrane oxygenation (ECMO) (4.03% vs 0.82%, P=0.007) and continuous renal replacement therapy (CRRT) (2.01%vs 0.14%, P=0.016) therapy. The time intervals from illness onset to discharge and from admission to discharge in patients with hypertension (median 25.00 days and 20.00 days, respectively) were longer than those in patients without hypertension (median 22.00 days and 18.00 days, respectively) (P=0.000, P=0.002) (Table 1).Table 1Clinical characteristics of COVID-19 patients with and without hypertensionWith Hypertension (n=149)Without Hypertension (n=735)P-Value#Total (n=149)ACEI/ARB (n=65)Non-ACEI/ARB (n=84)P-Value*Sex (male)88 (59.06%)40 (61.54%)48 (57.14%)0.588367 (49.93%)0.042Age (years)57.00 (49.50-66.00)56.00 (48.00-64.00)58.00 (52.00-67.00)0.04343.00 (34.00-54.00)0.000≥60 yr65 (43.62%)25 (38.46%)40 (47.62%)0.264102 (13.88%)0.000Coexisting ConditionDiabetes30 (20.13%)16 (24.62%)14 (16.67%)0.23035 (4.76%)0.000Heart disease7 (4.70%)2 (3.08%)5 (5.95%)0.4698 (1.09%)0.006COPD2 (1.34%)1 (1.54%)1 (1.19%)1.0003 (0.41%)0.200Chronic liver disease9 (6.04%)5 (7.69%)4 (4.76%)0.69126 (3.54%)0.153Chronic renal disease6 (4.03%)4 (6.15%)2 (2.38%)0.4042 (0.27%)0.000Cancer3 (2.01%)0 (0.00%)3 (3.57%)0.2576 (0.82%)0.379Clinical TypeMild Type88 (59.06%)37 (56.92%)51 (60.71%)0.641635 (86.39%)0.000Severe Type39 (26.17%)20 (30.77%)19 (22.62%)0.26284 (11.43%)0.000Critical Type22 (14.77%)8 (12.31%)14 (16.67%)0.45715 (2.04%)0.000General symptomsFever127 (85.23%)58 (89.23%)69 (82.14%)0.226587 (79.86%)0.129Fatigue32 (21.48%)17 (26.15%)15 (17.86%)0.221126 (17.14%)0.208headache7 (4.70%)4 (6.15%)3 (3.57%)0.69974 (10.07%)0.038Muscle ache22 (14.77%)11 (16.92%)11 (13.10%)0.51477 (10.48%)0.130Respiratory symptomsNasal obstruction3 (2.01%)1 (1.54%)2 (2.38%)1.00048 (6.53%)0.031Sore throat20 (13.42%)11 (16.92%)9 (10.71%)0.270103 (14.01%)0.849Cough100 (67.11%)47 (72.31%)53 (63.10%)0.235471 (64.08%)0.480Sputum production56 (37.58%)26 (40.00%)30 (35.71%)0.592245 (33.33%)0.318Hemoptysis7 (4.70%)5 (7.69%)2 (2.38%)0.2407 (0.95%)0.003Shortness of breath21 (14.09%)10 (15.38%)11 (13.10%)0.69020 (2.72%)0.000Gastrointestinal symptomsNausea and vomiting7 (4.70%)4 (6.15%)3 (3.57%)0.69924 (3.27%)0.386Diarrhea12 (8.05%)7 (10.77%)5 (5.95%)0.28459 (8.03%)0.991ComplicationsAcute respiratory distress syndrome36 (24.16%)16 (24.62%)20 (23.81%)0.90949 (6.67%)0.000Shock2 (1.34%)1 (1.54%)1 (1.19%)1.0002 (0.27%)0.134TreatmentGlucocorticoids47 (31.54%)19 (29.23%)28 (33.33%)0.55994 (12.79%)0.000Antibiotic treatment75 (50.33%)31 (47.69%)44 (52.38%)0.570289 (39.32%)0.013Intravenous immune globulin therapy32 (21.48%)14 (21.54%)18 (21.43%)0.98749 (6.67%)0.000Admission to intensive care unit24 (16.11%)9 (13.85%)15 (17.86%)0.50917 (2.31%)0.000Mechanical ventilation22 (14.77%)8 (12.31%)14 (16.67%)0.45715 (2.04%)0.000EMCO6 (4.03%)3 (4.62%)3 (3.57%)1.0006 (0.82%)0.007CRRT3 (2.01%)1(1.54%)2 (2.38%)1.0001 (0.14%)0.016Interval between illness onset to hospital outpatient (Days)2.00(0.00-5.00)2.00(1.00-4.00)1.00(0.00-5.00)0.6882.00 (1.00-4.00)0.931Interval between illness onset to admission (Days)4.00(1.00-7.00)4.00(2.50-6.00)4.00(1.00-7.00)0.5483.00 (1.00-6.00)0.206Interval between illness onset to confirmation (Days)4.00(2.00-8.00)4.00(2.50-7.00)4.50(2.00-8.00)0.7824.00 (2.00-7.00)0.576Interval between illness onset to discharge (Days)25.00(19.00-32.00)26.00(18.25-32.00)25.00(19.00-31.50)0.95522.00(17.00-28.00)0.000Interval between admission to discharge (Day)20.00(14.00-27.00)20.50(14.00-26.75)20.00(14.50-27.00)0.91518.00(13.00-23.00)0.002Death1 (0.67%)1 (1.54%)0 (0.00%)0.4360 (0.00%)0.169Laboratory detectionLeucocytes (× 109 /L; normal range 4-10)5.40 (4.29-6.48)5.30 (4.26-6.32)5.45 (4.30-6.64)0.7494.70 (3.80-5.90)0.000Neutrophils (× 109 /L; normal range 2-7)3.60 (2.80-4.80)3.43 (2.92-4.95)3.65 (2.71-4.79)0.9282.90 (2.20-3.83)0.000Lymphocyte (× 109 /L; normal range 0.8-4.0)1.00 (0.71-1.37)0.96 (0.70-1.40)1.04 (0.77-1.33)0.8961.20 (0.90-1.60)0.000Platelets (× 109 per L; normal range 83-303(Male), 101-320 (female)171.00 (138.00-220.50)166.00 (140.00-196.50)179.00 (137.00-225.50)0.336183.00 (149.00-223.00)0.095INR(normal range 0.85-1.15)1.02 (0.97-1.10)1.02 (0.97-1.11)1.02 (0.98-1.08)0.8711.01 (0.97-1.08)0.190Alb (g/L; normal range 40-55)40.34 (36.73-42.60)40.70 (37.2-42.89)39.20 (36.20-42.40)0.33941.30 (38.50-43.80)0.001ALT (U/L; normal range 9-50 (Male), 7-40 (Female))25.00 (18.20-39.00)26.00 (19.00-41.00)25.00 (17.00-32.75)0.37521.00 (15.00-33.00)0.001AST (U/L; normal range 15-40 (Male),13-35 (Female))28.00 (21.50-40.00)27.00 (19.95-40.10)28.00 (22.00-39.75)0.85725.00 (19.00-32.00)0.001TB (umol/L; normal range 0-26 (Male), 0-21 (Female))10.60 (7.70-14.95)11.40 (7.50-16.95)10.25 (7.73-14.40)0.7169.50 (6.90-13.10)0.010Scr (µmol/L; normal range: 57-97(Male), 41-73 (Female))72.00 (58.00-85.00)71.00 (57.00-85.25)73.00 (58.30-85.00)0.82966.00 (55.00-76.43)0.000BUN (mmol/L; normal range 3.1-8.0 (Male), 2.6-7.5 (Female)4.30(3.50-5.93)4.20 (3.31-5.71)4.33 (3.56-6.15)0.2773.77 (3.00-4.50)0.000CK (U/L; normal range 50-310 (Male), 40-200 (Female)83.00 (53.5-130.50)72.00 (49.50-131.00)90.00 (55.00-129.75)0.52169.00 (47.00-105.00)0.003LDH (U/L; normal range 120-250)250.00 (194.50-315.00)244.00 (181.00-318.00)253.00 (204.00-311.50)0.332211.00 (169.00-256.00)0.000Serum potassium (mmol/L; normal range 3.5-5.3)3.80 (3.50-4.05)3.84 (3.49-4.03)3.79 (3.50-4.06)0.5763.85 (3.60-4.14)0.031Serum sodium (mmol/L; normal range 137-147)137.00 (135.00-139.90)137.00 (135.14-139.85)137.15 (135.00-139.90)0.942138.60 (136.39-140.08)0.000CRP (mg/L; normal range 0-8)16.88 (7.20-44.55)21.00 (7.29-40.90)15.53 (6.39-51.00)0.5567.80 (2.30-19.00)0.000Note 1: *, P value of comparison between ACEI/ARB and non- ACEI/ARB; #, P value of comparison between with and withour hypertention.Note 2: Alb, Albumin; ALT, Alanine aminotransferase; AST: Aspartate aminotransferase; BUN, Blood urea nitrogen; CK, Creatine kinase; COPD, Chronic obstructive pulmonary disease; CRP, CRRT: Continuous renal replacement therapy;C-reactive protein; ECMO, Extracorporeal membrane oxygenation; INR: International normalized ratio; LDH: Lactate dehydrogenase; Scr, Serum creatinine; TB,Total bilirubin. Open table in a new tab Note 1: *, P value of comparison between ACEI/ARB and non- ACEI/ARB; #, P value of comparison between with and withour hypertention. Note 2: Alb, Albumin; ALT, Alanine aminotransferase; AST: Aspartate aminotransferase; BUN, Blood urea nitrogen; CK, Creatine kinase; COPD, Chronic obstructive pulmonary disease; CRP, CRRT: Continuous renal replacement therapy;C-reactive protein; ECMO, Extracorporeal membrane oxygenation; INR: International normalized ratio; LDH: Lactate dehydrogenase; Scr, Serum creatinine; TB,Total bilirubin. We found that the level of leukocyte count (median 5.40 × 109/L vs 4.70 × 109/L, P=0.000) and neutrophil count (median 3.60 × 109/L vs 2.90 × 109/L, P=0.000) was higher, but the level of lymphocyte count (median 1.00 × 109/L vs 1.20 × 109/L, P=0.000) was lower in patients with hypertension than in patients without hypertension. In terms of liver function, patients with hypertension had a lower level of albumin (median 40.34 vs 41.30, P=0.001), but a higher level of alanine aminotransferase (ALT)(median 25.00 vs 21.00, P=0.001), aspartate aminotransferase (AST) (median 28.00 vs 25.00, P=0.001), and total bilirubin (TB)(median 10.60 vs 9.50, P=0.010). As for renal function, patients with hypertension had a higher level of serum creatinine (Scr)(median 72.00 µmol/L vs 66.00µmol/L, P=0.000) and blood urea nitrogen (BUN) (median 4.30 mmol/L vs 3.77 mmol/L, P=0.000) . In addition, patients with hypertension had a higher level of creatine kinase (CK) (median 83.00 U/L vs 69 U/L, P=0.003), lactate dehydrogenase (LDH) (median 250.00 U/L vs 211 U/L, P=0.000), and C-reactive protein(CRP) (median 16.88 mg/L vs 7.80 mg/L, P=0.000), but lower level of serum potassium (median 3.80 mmol/L vs 3.85 mmol/L, P=0.031) and serum sodium (median 137.00 mmol/L vs 138.60 mmol/L, P=0.000). (Table 1) Among the 149 patients with hypertension, most patients (102 patients) treated with CCB including 62 patients used CCB alone. 149 patients were divided into two groups according to whether or not ACEI or ARB included in the antihypertensive drug regimen, 65 patients in ACEI/ARB group and 84 patients in non-ACEI/ARB group. Compared with patients treated without ACEI/ARB, the clinical presentations and laboratory results between the two groups did not reach significant difference (all P>0.05). No difference was found in severe/critical cases between patients with and those without ACEI/ARB treatment (all P>0.05). There were no significant differences of the complication (Shock, ARDS), the treatments, including anti-coronavirus treatment, glucocorticoids treatment, antibiotic treatment, mechanical ventilation, ECMO, CRRT and so on (all P>0.05). In addition, no difference was found in the rate of death, admission to ICU, interval between illness onset to discharge and the time of hospitalization (all P>0.05). (Table 1, Fig. 1). In summary, we reported the largest cases of COVID-19 patients with hypertension. This study showed that patients with hypertension might have more severe respiratory symptoms, more abnormality laboratory indication, and more proportion of severe/critical type of COVID-19. Moreover, they may need more antibiotic, hormone, and intravenous immune globulin therapy and intensive care unit admission and have a longer hospital stay. Treatment with ACEI/ARB have no influence on the severity and the clinical outcome of COVID-19 patients with hypertention. This study was supported by the Medical Science and Technology Project of Zhejiang Province (2020KY550), the national S&T major project (2017ZX10202202, 2017ZX10204401-001-002), the Zhejiang Provincial Natural Science Foundation (LQ19H190001).