In this retrospective study, we found that few patients (11.76%) with COVID-19 were severe. They were older, had higher BMI and proportion of hypertension, and accompanied by a huge change in peripheral immune-inflammatory parameters. It was demonstrated that fibrinogen, neutrophil%, NLR, SA, CRP were increased, and platelet count, lymphocyte% and lymphocyte count were decreased in the severe cases when compared with the non-severe cases and normal controls. It was similar to our previous report [12], although we enlarged sample size in this study. We also found that the baseline serum ACE activity in the severe group and non-severe group were both decreased, with the lowest level in the severe group. Moreover, serum ACE activity at baseline was significant correlated with most of the immune-inflammatory parameters, and it increases with the remission of the disease. Meanwhile, no significant difference was found among the severe group, non-severe group and normal controls in the recovery phase. However, it could not severe as an independent risk factor for the severity of COVID-19.
Previous studies have revealed that serum ACE can be a marker to monitor the condition of ARDS. ARDS is the most severe form of acute lung injury (ALI) [8], which could be caused by various pathogenic conditions like influenza, SARS-CoV and SARS-CoV-2 [1, 13, 14], and characterized by pulmonary endothelium cell damage and capillary permeability increased. Decrease serum ACE activity has been found in the patients with ARDS [9, 10], closely correlated with the severity of lung injury, and increased in the recovery phase [10]. However, ACE activity in the bronchoalveolar lavage fluid was increased in patients and animal models with ARDS [15, 16], as well as a high expression in the bronchoalveolar lavage fluid and lung tissue of ARDS animal model [16, 17]. Apart from a reducing synthesis by an injured vascular endothelium resulted in decreased serum ACE activity, circulating ACE inhibitors and proteolytic enzymes generated in critical illness may also played an role [9, 15].
In consistent with the previous studies performed in ARDS [9, 10], our study also found that serum ACE activity was lowest in the severe group on admission, and raised after treatment. In recovery phase, no significant differences could be found among severe group, non-severe group and normal controls. Immune-inflammatory reaction played a key role in the progression of COVID-19 [12, 18], Therefore, we performed correlation analyses to found that serum ACE was significantly correlated with most of immune-inflammatory parameters in this study. Additionally, we performed multiple linear regression to find only neutrophil%, age and diastolic blood pressure had negative correlations with serum ACE activity after adjusting for other confounders. It was just fit our findings that severe cases are old and hypertensive, which further support its role in the development of COVID-19.
Serum ACE activity was always increased in patients with hypertension revealed by previous studies [19, 20], which was different from our results. As far as we are concerned, hypertension resulted in worse deterioration of lung tissue, thus offsetting the originally increased serum ACE activity. On the other hand, ACE inhibitors (ACEI) would affect the serum ACE activity. However, only one patient with hypertension was treated with ACEI in our study, which would have little bearing on the overall result.
Serum ACE activity was detected by a kinetic spectrophotometric assay in this study. Kinetic spectrophotometric assay using FAPGG as substrate was first introduced by Holmquist et al. in 1979 [21], and soon widely used on automated biochemical analyzers [22]. Similarly, we used ADVIA 2400 Chemistry System, an advanced high-speed automated clinical chemistry analyzer to test ACE activity.
Interestingly, some studies have reported that the ACE gene insertion/deletion (I/D) polymorphism of the 287 bp in the intron16 is associated with the incidence and consequence of the patients of ARDS [23, 24], as well as related to the hypoxemia of SARS cases revealed by Itoyama et al. in Vietnamese [25]. However, another study performed in Hongkong did not discover a relationship between the ACE I/D polymorphism and the susceptibility of SARS-CoV infection and the outcome of SARS-CoV infected patients [14]. A vary recent report have indicated that ACE I/D polymorphism may affected the spread and outcome of COVID-19 [26]. Additionally, an earlier study found that the circulating ACE is influenced by ACE I/D polymorphism [27]. Therefore, the relationship between ACE I/D polymorphism, serum ACE activity and the outcome of patients with COVID-19 is need to be explored in future.
To our own knowledge, this is the first study to investigate the role of serum ACE activity in the progression of COVID-19. However, this study has some limitations. First, the ACE activity in the bronchoalveolar lavage and the ACE protein expression in lung tissue, along with ACE2 and angiotensin Ⅱ etc. did not tested. To better understand the RAS role in the pathogenesis of COVID-19, the above markers should be investigated. Second, serum ACE activity could not severe as an independent risk factor for the severity of COVID-19 revealed by us. Third, few patients did not test serum ACE activity at recovery phase. Forth, it was a single-center retrospective study with a relatively small sample size. These limitations must be considered when using this marker, and a e multicenter, prospective cohort study with a larger sample size is needed to validate its role in the COVID-19.