In December 2019, the outbreak of COVID-19 began in Wuhan city of Hubei Province in China. Although the epidemic has been controlled to a great extent in China, the disease is still prevalent around the world and is the focus of physicians worldwide. During the early stages of the COVID-19 outbreak, many doctors noticed that the dead victims were often elderly patients with multiple complications such as acute respiratory distress syndrome [20] and hypertension.
Some researchers have proposed that administration of hypertension medication such as ACEIs or ARBs to COVID-19 patients can aggravate the existing disease (COVID-19) [21], or increase the chances of healthy patients encountering COVID-19. Therefore, they advocated for discontinuation/cautious use of such drugs in patients with COVID-19 that down-regulate the renin-angiotensin-aldosterone system (RAAS) system. Despite some recent studies [22], there is currently no confirmatory evidence to support the use of RAS inhibitors in COVID-19 patients. ACEI/ARB drugs should be used in hypertensive patients with stable COVID-19, or hypertensive patients who are at risk of developing COVID-19, as recommended in the 2018 ESC/ESH hypertension guidelines [23]. There is a need to further assess the impact of hypertension and antihypertensive drugs, especially RAS inhibitors, on the course of COVID-19. As a result, some physicians in our hospital also stopped the use of ACEIs and/or ARBs drugs in COVID-19 patients.
Recent studies have demonstrated that classical ACE/Ang-II/AT1R and newly discovered ACE2/Ang 1-7/Mas pathways play a balancing role in the RAAS system. Some studies showed that ARBs or ACEIs induces the expression of ACE2 [15]; however, whether the upregulated expression of ACE2 causes an increased risk of infection with SARS-CoV-2 and/or a deterioration in the progression of COVID-19, is unknown. According to the results of this study and other clinical data from Wuhan [24], there is no significant difference in prevalence of hypertension between un-infected and COVID-19 infected patients. Thus, hypertension and the use of ARBs/ACEI drugs may not be the predisposing factors for COVID-19, although this statement needs further clinical or epidemiological verification. The data collected in this study were from Raytheon Mountain Hospital in Wuhan, which specializes in the treatment of COVID-19. Out of 202 patients in 4 wards, COVID-19 and hypertension were found to co-occur in 33.17% of the patients, which is close to the prevalence of hypertension in China [18].
Compared with the condition of COVID-19 patients who did not receive ACEI or ARB, condition of the patients who received ACEI or ARB did not deteriorate; no increase in death, recovery, or length of stay was observed. The patients who did not receive ACEI or ARB did not see any other therapeutic benefit in their condition of not receiving ACEI or ARB, suggesting that ACEI or ARB did not worsen the condition of COVID-19 patients. Although the pulmonary CT changes of patients in each group were not analyzed in this study, clinical prognosis suggested that the use of ACEI or ARB would not promote the secondary spread of the virus in the lungs of patients, or the possibility of secondary infection was low. Whether the use of ACEI or ARB can aggravate the pneumonia-induced damage in COVID-19 patients is a major point of contention in the use of RAS inhibitors in COVID-19 patients.
Most studies investigating whether ARBs/ACEIs aggravate COVID-19 induced pneumonia have indicated that inhibition of the RAAS system upregulates the expression of ACE2 and alleviates viral pneumonia [14]. On both axes of the RAAS system, the consequence of the ACE/Ang II/AT1R axis causes hypertension and exacerbates lung injury, while it is counteracted by the ACE2/Ang 1-7/MasR axis [12-13], protecting the lung function [25-26]. The clinical examination of patients from Wuhan with COVID-19 induced pneumonia showed that IL-1b, IFN-, IL-10, and other inflammatory factors were significantly increased when patients were admitted to the hospital, and the expression level of G-CSF, IP-10, MCP-1, and TNF were upregulated in severe COVID-19 patients. This suggests that there is a correlation between the cytokines/inflammatory factors and the severity of the disease [27]. The mechanism underlying this phenomenon is that COVID-19 downregulated the expression of ACE2, causing an imbalance of ACE/ACE2 and an absolute or a relative increase in the Ang II expression level. This not only induces cytokine storms and systemic inflammatory responses in the patients but also exacerbates inflammatory exudation in the lung [28-29]. The animal experiments have confirmed that the inflammatory response in the lung could be reversed by increasing the expression level of ACE2 and Ang 1-7 [26,30].
According to the two functional axes of the RAAS system, ARBs block the interaction of Ang II with its receptor and increase the expression of ACE2. This increases the expression level of Ang1-7 and protects the patients from hypertension and inflammatory injury. ACEI inhibitors block the conversion of Ang I to Ang II. Although the expression of ACE2 is increased, it is not sure whether the Ang1-7 expression level would be upregulated because of the insufficient substrate Ang II. Previous experiments have indicated that blocking the Ang II receptor ATIR better attenuates inflammation and acute lung injury as compared with inhibiting ACE [31]. This study enhanced the question about the application of ACEI drugs, but accurate animal experiments are required to confirm this hypothesis. Similar to the invention of anti-HIV drug Nvevir peptide [32], the discovery of ACE2/Ang 1-7/MasR axis is recognized as a major breakthrough for the discovery of antihypertensive drugs and the treatment of viral pneumonia, including COVID-19 induced pneumonia. Researchers are further investigating this axis to develop effective therapeutic solutions to treat the COVID patients [14, 33-36].
ARBs/ACEIs do not increase the risk of aggravation of COVID-19, but instead helps in treating COVID-19 induced pneumonia. We found that the ABRs/ACEI treated patients stayed shorter in the hospital than the group b during COVID-19 treatment. Although this study might suffer from the limitation of a smaller sample size number of patients, it still provides evidence that ACEs/ARBs do not increase the aggravation risk of COVID-19 pneumonia. To treat hypertension patients with COVID-19 induced pneumonia, anti-hypertensive drugs such as ACEs and ARBs may be used in accordance with the relative guidelines. The treatment regimen with these drugs does not need to be adjusted for the COVID-19 patients.
This study has some other limitations: patients who were given ARBs and ACEI were categorized into the same group because of the limited sample size and time constraints, this study is a retrospective study involving patients in a single hospital. Prospective studies with a larger sample size are warranted. Since all data were collected during the patient's hospitalization, some comorbidities may not be documented in the clinical data.