COVID-19 is more severe in patients with hypertension; ACEI/ARB treatment does not influence clinical severity and outcome.

Dear Editor

A number of pneumonia cases of unknown causes have emerged in Wuhan, Hubei, China since December 2019. After sequencing analysis of samples from the lower respiratory tract, a coronavirus, which was last named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), 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). 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. Decreased ACE2 expression is a cause of hypertension because ACE2 is identified as a major angiotensin 1-7 (Ang1-7)-forming enzyme. Based on studies of COVID-19, we found that hypertension initially occurs in many complications in COVID-19 patients. 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. , 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 guidance 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 1

Clinical characteristics of COVID-19 patients with and without hypertension

	With 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%)	0.588	367 (49.93%)	0.042
Age (years)	57.00 (49.50-66.00)	56.00 (48.00-64.00)	58.00 (52.00-67.00)	0.043	43.00 (34.00-54.00)	0.000
≥60 yr	65 (43.62%)	25 (38.46%)	40 (47.62%)	0.264	102 (13.88%)	0.000
Coexisting Condition
Diabetes	30 (20.13%)	16 (24.62%)	14 (16.67%)	0.230	35 (4.76%)	0.000
Heart disease	7 (4.70%)	2 (3.08%)	5 (5.95%)	0.469	8 (1.09%)	0.006
COPD	2 (1.34%)	1 (1.54%)	1 (1.19%)	1.000	3 (0.41%)	0.200
Chronic liver disease	9 (6.04%)	5 (7.69%)	4 (4.76%)	0.691	26 (3.54%)	0.153
Chronic renal disease	6 (4.03%)	4 (6.15%)	2 (2.38%)	0.404	2 (0.27%)	0.000
Cancer	3 (2.01%)	0 (0.00%)	3 (3.57%)	0.257	6 (0.82%)	0.379
Clinical Type
Mild Type	88 (59.06%)	37 (56.92%)	51 (60.71%)	0.641	635 (86.39%)	0.000
Severe Type	39 (26.17%)	20 (30.77%)	19 (22.62%)	0.262	84 (11.43%)	0.000
Critical Type	22 (14.77%)	8 (12.31%)	14 (16.67%)	0.457	15 (2.04%)	0.000
General symptoms
Fever	127 (85.23%)	58 (89.23%)	69 (82.14%)	0.226	587 (79.86%)	0.129
Fatigue	32 (21.48%)	17 (26.15%)	15 (17.86%)	0.221	126 (17.14%)	0.208
headache	7 (4.70%)	4 (6.15%)	3 (3.57%)	0.699	74 (10.07%)	0.038
Muscle ache	22 (14.77%)	11 (16.92%)	11 (13.10%)	0.514	77 (10.48%)	0.130
Respiratory symptoms
Nasal obstruction	3 (2.01%)	1 (1.54%)	2 (2.38%)	1.000	48 (6.53%)	0.031
Sore throat	20 (13.42%)	11 (16.92%)	9 (10.71%)	0.270	103 (14.01%)	0.849
Cough	100 (67.11%)	47 (72.31%)	53 (63.10%)	0.235	471 (64.08%)	0.480
Sputum production	56 (37.58%)	26 (40.00%)	30 (35.71%)	0.592	245 (33.33%)	0.318
Hemoptysis	7 (4.70%)	5 (7.69%)	2 (2.38%)	0.240	7 (0.95%)	0.003
Shortness of breath	21 (14.09%)	10 (15.38%)	11 (13.10%)	0.690	20 (2.72%)	0.000
Gastrointestinal symptoms
Nausea and vomiting	7 (4.70%)	4 (6.15%)	3 (3.57%)	0.699	24 (3.27%)	0.386
Diarrhea	12 (8.05%)	7 (10.77%)	5 (5.95%)	0.284	59 (8.03%)	0.991
Complications
Acute respiratory distress syndrome	36 (24.16%)	16 (24.62%)	20 (23.81%)	0.909	49 (6.67%)	0.000
Shock	2 (1.34%)	1 (1.54%)	1 (1.19%)	1.000	2 (0.27%)	0.134
Treatment
Glucocorticoids	47 (31.54%)	19 (29.23%)	28 (33.33%)	0.559	94 (12.79%)	0.000
Antibiotic treatment	75 (50.33%)	31 (47.69%)	44 (52.38%)	0.570	289 (39.32%)	0.013
Intravenous immune globulin therapy	32 (21.48%)	14 (21.54%)	18 (21.43%)	0.987	49 (6.67%)	0.000
Admission to intensive care unit	24 (16.11%)	9 (13.85%)	15 (17.86%)	0.509	17 (2.31%)	0.000
Mechanical ventilation	22 (14.77%)	8 (12.31%)	14 (16.67%)	0.457	15 (2.04%)	0.000
EMCO	6 (4.03%)	3 (4.62%)	3 (3.57%)	1.000	6 (0.82%)	0.007
CRRT	3 (2.01%)	1(1.54%)	2 (2.38%)	1.000	1 (0.14%)	0.016
Interval 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)	0.688	2.00 (1.00-4.00)	0.931
Interval between illness onset to admission (Days)	4.00(1.00-7.00)	4.00(2.50-6.00)	4.00(1.00-7.00)	0.548	3.00 (1.00-6.00)	0.206
Interval between illness onset to confirmation (Days)	4.00(2.00-8.00)	4.00(2.50-7.00)	4.50(2.00-8.00)	0.782	4.00 (2.00-7.00)	0.576
Interval between illness onset to discharge (Days)	25.00(19.00-32.00)	26.00(18.25-32.00)	25.00(19.00-31.50)	0.955	22.00(17.00-28.00)	0.000
Interval between admission to discharge (Day)	20.00(14.00-27.00)	20.50(14.00-26.75)	20.00(14.50-27.00)	0.915	18.00(13.00-23.00)	0.002
Death	1 (0.67%)	1 (1.54%)	0 (0.00%)	0.436	0 (0.00%)	0.169
Laboratory detection
Leucocytes (× 109 /L; normal range 4-10)	5.40 (4.29-6.48)	5.30 (4.26-6.32)	5.45 (4.30-6.64)	0.749	4.70 (3.80-5.90)	0.000
Neutrophils (× 109 /L; normal range 2-7)	3.60 (2.80-4.80)	3.43 (2.92-4.95)	3.65 (2.71-4.79)	0.928	2.90 (2.20-3.83)	0.000
Lymphocyte (× 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)	0.896	1.20 (0.90-1.60)	0.000
Platelets (× 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)	0.336	183.00 (149.00-223.00)	0.095
INR(normal range 0.85-1.15)	1.02 (0.97-1.10)	1.02 (0.97-1.11)	1.02 (0.98-1.08)	0.871	1.01 (0.97-1.08)	0.190
Alb (g/L; normal range 40-55)	40.34 (36.73-42.60)	40.70 (37.2-42.89)	39.20 (36.20-42.40)	0.339	41.30 (38.50-43.80)	0.001
ALT (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)	0.375	21.00 (15.00-33.00)	0.001
AST (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)	0.857	25.00 (19.00-32.00)	0.001
TB (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)	0.716	9.50 (6.90-13.10)	0.010
Scr (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)	0.829	66.00 (55.00-76.43)	0.000
BUN (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)	0.277	3.77 (3.00-4.50)	0.000
CK (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)	0.521	69.00 (47.00-105.00)	0.003
LDH (U/L; normal range 120-250)	250.00 (194.50-315.00)	244.00 (181.00-318.00)	253.00 (204.00-311.50)	0.332	211.00 (169.00-256.00)	0.000
Serum 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)	0.576	3.85 (3.60-4.14)	0.031
Serum 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)	0.942	138.60 (136.39-140.08)	0.000
CRP (mg/L; normal range 0-8)	16.88 (7.20-44.55)	21.00 (7.29-40.90)	15.53 (6.39-51.00)	0.556	7.80 (2.30-19.00)	0.000

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 ).

Fig. 1

Clinical type, complications and outcome of COVID-19 patients with hypertension of different anti-hypertensive drugs.

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.

Funding

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).

Potential conflicts of interest

None.