By Feb 21st, 2020, 55 confirmed cases of COVID-19 were included in this study. All of them had data on plasma AngII, renin and aldosterone in the lying position without sodium restriction. 34(61.8%) cases had an increased level of AngII while most patients had normal levels of renin and aldosterone (showed in Table 1). The critically ill patients had higher level of AngII than the non-critically ill patients (showed in Table 2).
Table 1
the baseline value of RAS system in COVID-19 patients
RAS system parameter | Normal Range | Total (N = 55) | Abnormality, N(%) |
---|
AngII(pg/ml, IQR) | 25–129 | 134.2(117.8,155.3) | 34(61.8) |
Renin(pg/ml, IQR) | 4–24 | 10.9(6.3,16.9) | 11 (20) |
ALD(pg/ml, IQR) | 10–160 | 129.5(112,149.8) | 9(16.4) |
AARR(IQR) | / | 12.3(7.6,19.2) | / |
Legend: Ang II: angiotensin II, ALD: aldosterone, AARR: aldosterone/ Renin ratio |
Table 2
Comparison of RAS system between non-critically ill and critically ill patients with COVID-19
RAS system | Normal Range | Total (N = 55) | Non-critically ill group(n = 32) | critically ill group(n = 23) | P value |
---|
AngII(pg/ml, IQR) | 25–129 | 134.2(117.8,155.3) | 127.4(93.5,145.6) | 147.4(131.5,169.5) | 0.009* |
Renin(pg/ml, IQR) | 4–24 | 10.9(6.3,16.9) | 10.2(5.8,16.2) | 14.7(6.5,19.7) | 0.232 |
ALD(pg/ml, IQR) | 10–160 | 129.5(112,149.8) | 133.4(115.1,168.1) | 115.9(104.8,135.7) | 0.050 |
AARR(IQR) | / | 12.3(7.6,19.2) | 14.1(10.1,21.5) | 9.1(6.2,18.7) | 0.028* |
Legend- Ang II: angiotensin II, ALD: aldosterone, AARR: aldosterone/ Renin ratio |
To further analyze the demographic, clinical and laboratory characteristics of the patients with increased AngII level, we divided the patients into the AngII increased group and the AngII normal group. No difference was seen in renin and aldosterone values between the two groups (showed in Table 3). To our interest, as shown in Table 4, the patients with increased level of AngII were more severe than those with normal level of AngII [18(52.9%)vs5(23.8%), p = 0.033]. Significant gender differences were found between the two groups. In addition, there was no significant difference in the history of hypertension and the use of vasoactive drugs such as norepinephrine and dopamine in the two groups.
Table 3
Comparison of RAS system between COVID-19 patients grouped by Ang II level
RAS system | Normal Range | Total (N = 55) | Ang II increased group(n = 34) | Ang II normal group(n = 21) | P value |
---|
AngII(pg/ml, IQR) | 25–129 | 134.2(117.8,155.3) | 149.7(137.8,165.1) | 99.4(84.5,119.1) | 0.000 |
Renin(pg/ml, IQR) | 4–24 | 10.9(6.3,16.9) | 11.1(6.0,19.5) | 10(6.5,16.9) | 0.842 |
ALD(pg/ml, IQR) | 10–160 | 129.5(112,149.8) | 133.4(112.4,142.1) | 121.8(106.9,163.5) | 0.591 |
AARR(IQR) | / | 12.3(7.6,19.2) | 12.3(7.0,19.9) | 12.4(9.3,19.5) | 0.665 |
Legend- Ang II: angiotensin II, ALD: aldosterone, AARR: aldosterone/ Renin ratio |
Table 4
Comparison of Demographic and clinical characteristic between COVID-19 patients grouped by Ang II level
Demographic and clinical characteristics | Total (N = 55) | Ang II increased group(n = 34) | Ang II normal group(n = 21) | P value |
---|
Gender female, n(%) | 20(36.4) | 7(12.7) | 13(21.7) | 0.002* |
Age(year, IQR) | 53(45,66) | 56(44.75,66.5) | 52(45.5,67) | 0.0822 |
History of chronic disease, n(%) | 25(45.5) | 18(32.7) | 7(12.7) | 0.156 |
History of hypertension, n(%) | 16(29.1) | 13(23.6) | 3(5.5) | 0.057 |
History of diabetes, n(%) | 8(14.5) | 7(12.7) | 1(1.8) | 0.136 |
Newly-onset hypertension, n(%) | 10(18.2) | 6(10.9) | 4(7.3) | 1.0 |
Systolic pressure(mmHg, IQR) | 129(122,141) | 134(122,141) | 126(123,140) | 0.640 |
Diastolic pressure(mmHg, IQR) | 81(76,90) | 80(73,91) | 83(72,96) | 0.641 |
The severity of COVID-19 | - | - | - | - |
Non-critically ill, n(%) | 32(58.2) | 16(29.1) | 16(29.1) | 0.033* |
Critically ill, n(%) | 23(41.8) | 18(32.7) | 5(9.1) | - |
Usage of vasoactive drugs, n(%) | 7(12.7) | 5(9.1) | 2(3.6) | 0.696 |
Legend- Critically ill COVID-19 was defined as meeting either one of the flowing criteria: 1) Respiratory distress with respiratory rate more than 30 times/min; 2) Oxygen saturation ≤ 93% in resting state; 3) PaO2/FiO2 ≤ 300mmHg (1mmHg = 0.133 kPa).4) Respiratory failure requires mechanical ventilation; 5) Shock; 6) Combining other organ failures requires ICU monitoring and treatment. |
Vasoactive drugs included norepinephrine, dopamine, Adrenaline and Isoproterenol. |
As presented in Tables 5–6, there were statistical difference in the level of blood lymphocyte[0.66(0.36,1.03)vs1.02(0.68,1.42),p = 0.021], PCT[0.07༈0.03༌0.12༉vs0.03༈0.02༌0.07༉, p = 0.007], CD4/CD8 cells ratio[2.35༈1.86༌3.22༉vs1.55༈1.11༌2.54༉, p = 0.015], ALT[27༈21༌44༉vs19༈13༌34༉,p = 0.03], AST[24.5(18.5,36)vs18(14,22.5),p = 0.028], CD3 + CD8 + cells [128(51,206)vs218(123,322),p = 0.016], CD3 + CD8 + cells proportion [20.1(14,25.6)vs25.4(20.9,35.7),p = 0.011], CD56 + CD16 + CD3- cells [81(56,102)/111(66,171) p = 0.031] between the AngII increased group and the AngII normal group. The rate of Lymphopenia [27(79.4%)vs11(52.4%), p = 0.035] were remarkably higher in Patients with elevated AngII level.
Table 5
Comparison of laboratory assessments between COVID-19 patients grouped by Ang II level
Laboratory assessments | Normal Range | Total (N = 55) | Ang II increased group(n = 34) | Ang II normal group(n = 21) | P value |
---|
WBC(109/L,IQR) | 3.5–9.5 | 6.76(5.25,9.36) | 6.98(4.77,10.06) | 6.67(5.67,8.23) | 0.952 |
Ly (109/L,IQR) | 1.1–3.2 | 0.74(0.49,1.19) | 0.66(0.36,1.03) | 1.02(0.68,1.42) | 0.021* |
HB(g/L,IQR) | 130–175 | 128(114,142) | 127.5(112,142.8) | 128(114,140) | 0.959 |
PLT(109/L,IQR) | 125–350 | 198(142,263) | 189(122.3,263.8) | 238(171,274) | 0.225 |
CRP(mg/L,IQR) | 0–8 | 7.73(2.88–26.36) | 11.2(3.67,44.99) | 7.03(1.53,21.20) | 0.253 |
PCT (ng/mL,IQR) | 0-0.09 | 0.06(0.03,0.1) | 0.07(0.05,0.12) | 0.03(0.02,0.07) | 0.007* |
ALT(U/L,IQR) | 9–50 | 26(18,38) | 27(21,44.3) | 19(13,34) | 0.030* |
AST (U/L,IQR) | 15–40 | 21(16,32) | 24.5(18.5,36) | 18(14,22.5) | 0.028* |
ALB(g/L,IQR) | 40–55 | 33.9(30.1,37.4) | 33.6(30.1,36.1) | 36(29.8,38.9) | 0.253 |
BUN(mmol/L,IQR) | 3.2-8.0 | 4.9(3.0,7.5) | 4.95(3.1,8.38) | 4.3(2.85,6.45) | 0.287 |
sCr(umol/L,IQR) | Male:57–97 Female:41–81 | 60(48.2,67.4) | 61.3(54.6,70.3) | 55.2(45.7,65.8) | 0.203 |
LDH(U/L,IQR) | 120–250 | 214(179,354) | 244(188.3,400) | 201(176.5,258) | 0.057 |
CK(U/L,IQR) | 50–310 | 39(26,57) | 38(26.8,59) | 40(25,59) | 0.972 |
Na(mmol/L,IQR) | 137–147 | 135(132.1,138.7) | 134.9(131.6,137.5) | 136.3(134,138.9) | 0.194 |
K(mmol/L,IQR) | 3.5–5.3 | 4.01(3.70,4.61) | 3.99(3.64,4.62) | 4.2(3.82,4.63) | 0.550 |
DD(mg/L,IQR) | 0.01–0.55 | 1.96(0.69,4.92) | 3.46(0.82,6.56) | 1.2(0.63,30.2) | 0.121 |
APTT(s,IQR) | 25-31.3 | 26.5(23.8,29.1) | 26.1(24.0,28.1) | 26.8(23.5,30.2) | 0.808 |
Urine protein positive, n(%) | / | 7(12.7) | 6(10.9) | 1(1.8) | 0.232 |
Urine RBC positive, n(%) | / | 3(5.35) | 2(3.64) | 1(1.8) | 1.0 |
Ly < 1.1, n(%) | / | 38(69.1) | 27(49.1) | 11(20) | 0.035* |
PCT > 0.09, n(%) | / | 15(27.3) | 12(21.8) | 3(5.5) | 0.123 |
Legend: Ly: Lymphocyte, HB: Hemoglobin, PLT: Platelet count, CRP: C-reactive protein, PCT: Procalcitonin,BUN: Blood urea nitrogen, sCr: serum creatinine, ALT :Aspartate aminotransferase, AST: Alanine aminotransferase, ALB: albumin, LDH༚lactate dehydrogenase, CK:Creatinine kinase, DD:D-dimer, APTT: Activated partial thromboplastin time |
Table 6
Comparison of Lymphocyte classification between COVID-19 patients grouped by Ang II level
Lymphocyte marker | Normal Range | Total (N = 46) | Ang II increased group(n = 27) | Ang II normal group(n = 19) | P value |
---|
CD3 + count (/uL,IQR) | 1185–1901 | 561(274.3,776.3) | 439(178,741) | 669(448,841) | 0.073 |
CD3+ (%,IQR) | 64.19–75.77 | 68.9(60.75,77.93) | 69.1(55.5,82.1) | 68.7(66.4,77.6) | 0.510 |
CD3 + CD4 + count (/uL,IQR) | 561–1137 | 335.5(157.8,488.3) | 298(122,488) | 390(234,504) | 0.160 |
CD3 + CD4+ (%,IQR) | 30.09–40.41 | 44.9(34.4,51.1) | 47.4(34.5,56.2) | 41.2(34,47.9) | 0.212 |
CD3 + CD8 + count (/uL,IQR) | 404–754 | 163(74.8,243.5) | 128(51,206) | 218(123,322) | 0.016* |
CD3 + CD8+ (%,IQR) | 20.74–29.42 | 23.0(17.1,29.3) | 20.1(14,25.6) | 25.4(20.9,35.7) | 0.011* |
CD4+/CD8+ | 1.36–2.61 | 2.05(1.47,2.55) | 2.35(1.86,3.22) | 1.55(1.11,2.54) | 0.015* |
CD56 + CD16 + CD3- count (/uL,IQR) | 175–567 | 86.5(62.8,125.5) | 81(56,102) | 111(66,171) | 0.031* |
CD56 + CD16 + CD3- (%,IQR) | 10.04–19.78 | 13.75(7.95,20.73) | 12.9(7,24) | 13.8(8.3,18.9) | 0.832 |
CD19 + CD3- count (/uL,IQR) | 180–324 | 91(55.8,155.8) | 73(46,131) | 134(59,170) | 0.072 |
CD19 + CD3- (%,IQR) | 10.12–15.42 | 13.8(8.5,21.7) | 14.1(5.7,24.4) | 13.5(9.6,19.5) | 0.422 |
Legend: CD: cluster of differentiation, CD3 + count: CD3 positive cells count, CD3 + CD4 + count: CD3 positive CD4 positive cells count, CD3 + CD8 + count: CD3 positive CD8 positive cells count, CD4+/CD8+: CD4+/CD8 + ratio, CD56 + CD16 + CD3- count: CD56 positive CD16 positive CD3 negtive cells count, CD19 + CD3- count: CD19 positive CD3 negtive cells count. |
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Furthermore, we evaluated the effect of various clinical and laboratory indicators on elevated AngII level with binary regression analysis. During the analysis, we applied AngII elevated or not as dependent variables, while applying the severity of COVID-19, gender, lymphocyte, PCT,CD4/CD8 cells ratio,CD3 + CD8 + cells count, CD3 + CD8 + cells proportion, CD56 + CD16 + CD3- cells count as independent variables, among these independent variables. The results showed that the severity of COVID-19 [OR = 4.123, 95%CI(1.07-15.877)༌p = 0.040] and CD4/CD8 ratio[OR = 4.050, 95%CI(1.207–13.588),p = 0.024]was the co-directional impact factor while female[OR = 0.146,95%CI(0.035–0.603)༌p = 0.008] were reverse impact factor of elevated AngII level(depicted in Fig. 1).