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Id Subject Object Predicate Lexical cue
T1 0-104 Sentence denotes Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension
T2 105-135 Sentence denotes Emerging Microbes & Infections
T3 136-138 Sentence denotes J.
T4 139-150 Sentence denotes Meng et al.
T5 152-160 Sentence denotes Abstract
T6 161-169 Sentence denotes ABSTRACT
T7 170-487 Sentence denotes The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown.
T8 488-579 Sentence denotes COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors.
T9 580-733 Sentence denotes We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood.
T10 734-898 Sentence denotes In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs.
T11 899-1062 Sentence denotes This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.
T12 1064-1076 Sentence denotes Introduction
T13 1077-1238 Sentence denotes The COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to endanger global health and to hamper the world economy.
T14 1239-1303 Sentence denotes This outbreak started in December 2019 in Wuhan, Hubei Province.
T15 1304-1394 Sentence denotes Unfortunately, currently, there is still no specific and effective treatment for COVID-19.
T16 1395-1553 Sentence denotes Evidence shows that elderly people with SARS-CoV-2 infections and cardiovascular diseases, including hypertension, are at risk of developing severe cases [1].
T17 1554-1751 Sentence denotes A hypertension survey from 2012 to 2015 reported that 23.2% of Chinese people ≥18 years of age had hypertension, whereas the prevalence of hypertension was >55% among citizens ≥65 years of age [2].
T18 1752-1937 Sentence denotes RAS plays an important role in regulating electrolyte balance and blood pressure and comprises two pathways: the ACE/Ang II/AT1R pathway and the ACE2/Ang (1–7)/Mas receptor pathway [3].
T19 1938-2155 Sentence denotes Under normal physiological conditions, the activity of the ACE/Ang II/AT1R axis and the ACE2/Ang (1–7)/Mas receptor axis are in a dynamic equilibrium state, maintaining the normal function of the corresponding system.
T20 2156-2256 Sentence denotes Similar to SARS, SARS-CoV-2 is believed to invade the host through the cell entry receptor ACE2 [4].
T21 2257-2405 Sentence denotes SARS-CoV infections reduce ACE2 expression, resulting in an imbalance between the ACE/Ang II/AT1R axis and the ACE2/Ang (1–7)/Mas receptor axis [5].
T22 2406-2490 Sentence denotes Targeting the ACE/Ang II/AT1R axis is a novel therapeutic strategy for hypertension.
T23 2491-2613 Sentence denotes ACEIs and ARAs not only inhibit the ACE/Ang II/AT1R pathway but also modulate the ACE2/Ang (1–7)/Mas receptor pathway [6].
T24 2614-2931 Sentence denotes The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown.
T25 2932-3047 Sentence denotes Here, we aimed to evaluate the ability of RAS inhibitors to protect against COVID-19 in patients with hypertension.
T26 3049-3056 Sentence denotes Methods
T27 3057-3139 Sentence denotes This study was approved by the Shenzhen Third People’s Hospital Ethical Committee.
T28 3140-3223 Sentence denotes Verbal informed consent was obtained from all patients or patients’ family members.
T29 3224-3405 Sentence denotes We performed a retrospective review of medical records from hospitalized patients with COVID-19 admitted to the Shenzhen Third People’s Hospital from 11 January to 23 February 2020.
T30 3406-3502 Sentence denotes The information on patients with hypertension was extracted from all enrolled COVID-19 patients.
T31 3503-3635 Sentence denotes We reviewed the clinical data extracted from electronic medical records, including clinical symptoms, signs and laboratory findings.
T32 3636-3734 Sentence denotes A commercial real-time PCR kit (GeneoDX Co., Ltd., Shanghai, China) was used to detect SARS-CoV-2.
T33 3735-3859 Sentence denotes Samples were considered positive if the cycle threshold value (Ct-value) less than 37 and negative if Ct-value more than 40.
T34 3860-3936 Sentence denotes Samples with a Ct-value between 37 and 40 require confirmation by retesting.
T35 3937-4057 Sentence denotes Samples identified as positive by the local laboratory were further validated by the key laboratory of the Shenzhen CDC.
T36 4058-4232 Sentence denotes The severity of COVID-19 wasidentified during the hospitalization according to the guidelines established by the National Health Commission of the People’s Republic of China.
T37 4233-4381 Sentence denotes Therapeutic regimens for COVID-19 patients complied with guidelines established by the National Health Commission of the People’s Republic of China.
T38 4382-4517 Sentence denotes Hypertension was classified as Grade 1, Grade 2 and Grade 3 according to 2018 guidelines of the European Society of Hypertension (ESH).
T39 4518-4628 Sentence denotes Hypertensive patients with COVID-19 were divided into two subgroups based on antihypertensive drug treatments.
T40 4629-4710 Sentence denotes Detailed information on the enrolled patients is shown in supplementary Table S1.
T41 4711-4776 Sentence denotes The SPSS 18.0 software package was used for statistical analysis.
T42 4777-4922 Sentence denotes Measurement data are expressed as the median and interquartile range (IQR), and the difference between groups was compared by an unpaired t test.
T43 4923-5032 Sentence denotes Count data are expressed as percentages, and the difference between groups was tested by the Chi-square test.
T44 5033-5083 Sentence denotes P < 0.05 was considered statistically significant.
T45 5085-5092 Sentence denotes Results
T46 5093-5203 Sentence denotes A total of 417 COVID-19 patients were admitted to the Shenzhen Third People’s Hospital as of 23 February 2020.
T47 5204-5255 Sentence denotes Among these patients, 51 (12.23%) had hypertension.
T48 5256-5413 Sentence denotes Nine patients (17.6%) with Grade 1hypertension did not take any antihypertensive drugs during hospitalization and were excluded from the subsequent analysis.
T49 5414-5512 Sentence denotes The other 42 patients (82.4%) receiving antihypertensive therapy were included in further studies.
T50 5513-5857 Sentence denotes The 42 analyzed patients were divided into two groups based on antihypertensive therapies: the ACEI/ARB group (17 patients) included patients treated with ACEI or ARB drugs, and the non-ACEI/ARB group (25 patients) included patients treated with other antihypertensive drugs, including calcium channel blockers (CCBs), β-blockers and diuretics.
T51 5858-6038 Sentence denotes Eight patients (32%) in the non-ACEI/ARB group and 5 patients (29.41%)in the ACEI/ARB group had other comorbidities, such as type 2 diabetes (T2D) and coronary heart disease (CHD).
T52 6039-6178 Sentence denotes The vast majority of hypertensive patients had received the current therapeutic regimens shown in supplementary Table S1 for over one year.
T53 6179-6289 Sentence denotes The blood pressure of patients was well-controlled with the above therapeutic regimens during hospitalization.
T54 6290-6396 Sentence denotes The comparison of baseline characteristics between the two groups is summarized in supplementary Table S2.
T55 6397-6505 Sentence denotes The median age of the analyzed subjects was 64.5 years (IQR, 55.8–69.0 years), and 57.1% of them were males.
T56 6506-6624 Sentence denotes No significant differences in hypertension grades were observed between the ACEI/ARB group and the non-ACEI/ARB group.
T57 6625-6671 Sentence denotes Both groups showed similar signs and symptoms.
T58 6672-6811 Sentence denotes The median number of days from the onset of symptoms to hospital admission was 2.0 in the non-ACEI/ARB group and 3.0 in the ACEI/ARB group.
T59 6812-6966 Sentence denotes Meanwhile, the median number of days from symptom onset to hospital discharge was 16.5 days in the non-ACEI/ARB group and 20.0 days in the ACEI/ARB group.
T60 6967-7075 Sentence denotes The median heart rate and respiratory rate from the non-ACEI/ARB group were 90.5 bpm and 20.0, respectively.
T61 7076-7199 Sentence denotes In comparison, the median heart rate and respiratory rate from the non-ACEI/ARB group were 80.0 bmp and 20.0, respectively.
T62 7200-7303 Sentence denotes All baseline characteristics shown in Table S2 were not significantly different between the two groups.
T63 7304-7432 Sentence denotes During hospitalization, 12 patients in the non-ACEI/ARB group (48%) were categorized into severe subgroups and one patient died.
T64 7433-7567 Sentence denotes In contrast, in the ACEI/ARB group, only 4 patients (23.5%) were categorized into severe subgroups and no patients died (Figure 1(A)).
T65 7568-7761 Sentence denotes The percentage of severe cases in the ACEI/ARB group was higher than that in the non-ACEI/ARB group, but this difference was not significant, possibly due to the small number of clinical cases.
T66 7762-7881 Sentence denotes We next examined the effects of taking ACEI or ARB drugs on laboratory findings of COVID-19 patients with hypertension.
T67 7882-7986 Sentence denotes As shown in Figure 1(B), there was a trend toward lower IL-6 levels in patients from the ACEI/ARB group.
T68 7987-8085 Sentence denotes No marked variation in C-reactive protein (CRP) was observed between the two groups (Figure 1(B)).
T69 8086-8214 Sentence denotes The absolute number of CD3+ and CD8+ T cells in the ACEI/ARB group was significantly higher than that in the non-ACEI/ARB group.
T70 8215-8308 Sentence denotes There were no significant changes in CD4+ T cell counts between the two groups (Figure 1(C)).
T71 8309-8549 Sentence denotes In addition, although the viral load was not different between the two groups at hospital admission, the peak viral load during hospitalization in the ACEI/ARB group was significantly lower than that in the non-ACEI/ARB group (Figure 1(D)).
T72 8550-8778 Sentence denotes Other laboratory findings, such as white blood cell counts, neutrophil counts, platelet counts, and lactate dehydrogenase, are shown in supplementary Table S3, and no significant differences were observed between the two groups.
T73 8779-8788 Sentence denotes Figure 1.
T74 8789-9191 Sentence denotes Summarized clinical, inflammatory, immunological, and viral findings in the non-ACEI/ARB group and the ACE/ARB group. (A) The disease severity distribution of the two groups during hospitalization. (B) The levels of IL-6 and CRP in peripheral blood. (C) Absolute numbers of CD3+, CD4+, and CD8+ T cells in peripheral blood. (D) Viral load on hospital admission and maximum value during hospitalization.
T75 9192-9237 Sentence denotes The data are expressed as the median and IQR.
T76 9238-9307 Sentence denotes An unpaired t test was used, and P < 0.05 was considered significant.
T77 9309-9319 Sentence denotes Discussion
T78 9320-9467 Sentence denotes It was reported that the RAS plays a critical role in regulating hypertension and acute lung injury caused by viruses, such as SARS and H7N9 [5,7].
T79 9468-9570 Sentence denotes Changes in RAS activity are related to the pathogenesis of hypertension and inflammatory lung disease.
T80 9571-9639 Sentence denotes Targeting RAS is an effective antihypertension therapeutic strategy.
T81 9640-9747 Sentence denotes ACEIs and ARB, which inhibit the ACE/Ang II/AT1R system, are commonly used drugs for hypertensive patients.
T82 9748-9853 Sentence denotes Recent evidence suggests that hypertensive COVID-19 patients are predisposed to develop severe cases [1].
T83 9854-9957 Sentence denotes Thus, it is important to determine the effect of RAS inhibitors on COVID-19 patients with hypertension.
T84 9958-10065 Sentence denotes Studies have suggested that COVID-19 patients have increased Angiotensin II compared to healthy people [8].
T85 10066-10151 Sentence denotes The abnormal increase in Angiotensin II was related to hypertension and lung failure.
T86 10152-10264 Sentence denotes In addition, RAS inhibitors have been shown to be associated with reduced mortality in patients with sepsis [9].
T87 10265-10378 Sentence denotes Angiotensin II positively regulates the expression of inflammatory cytokines through the activation of AT1R [10].
T88 10379-10478 Sentence denotes Excessively high levels of inflammatory cytokines are harmful to the outcomes of COVID-19 patients.
T89 10479-10583 Sentence denotes Thus, it was suggested that it is beneficial for COVID-19 patients to use ACEIs/ARBs to inhibit the RAS.
T90 10584-10654 Sentence denotes However, until now, no confirmed clinical evidence has been available.
T91 10655-10954 Sentence denotes In this study, COVID-19 patients with hypertension were enrolled, and we found that ACEI/ARB therapy attenuated the inflammatory response, potentially through the inhibition of IL-6 levels, which is consistent with the findings that ACEI and ARB therapy alleviated LPS-induced pneumonic injury [11].
T92 10955-11129 Sentence denotes For patients with chronic heart failure, it has been proven that ACEI therapy was associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine production [12].
T93 11130-11262 Sentence denotes This study also suggests that ACEI/ARB therapy had a beneficial effect on the immune system by avoiding peripheral T cell depletion.
T94 11263-11356 Sentence denotes Furthermore, the viral load was reported to be highly correlated with severe lung injury [8].
T95 11357-11712 Sentence denotes It was also observed that ACEI/ARB therapy decreased the viral load, but we hypothesize that RAS inhibitors do not directly inhibit viral replication; rather, they play an indirect antiviral role by regulating immune function and inhibiting inflammatory responses, and the mechanism needs to be clarified through in vitro and in vivostudies in the future.
T96 11713-11999 Sentence denotes Taken together, this is the first clinical evidence demonstrating that RAS inhibitors improve the clinical outcomes of COVID-19 patients with hypertension, suggesting that these patients could benefit from the persistent or preferential usage of ACEI/ARB for antihypertensive treatment.
T97 12001-12023 Sentence denotes Supplementary Material
T98 12024-12045 Sentence denotes Supplemental Material
T99 12047-12067 Sentence denotes Disclosure statement
T100 12068-12132 Sentence denotes No potential conflict of interest was reported by the author(s).
T101 12134-12139 Sentence denotes ORCID
T102 12140-12191 Sentence denotes Guoliang Zhang http://orcid.org/0000-0002-3617-5449