Circulating angiotensin converting enzyme 2 and COVID-19

Table 1 Circulating angiotensin converting enzyme 2 in coronavirus disease 2019 patients

Ref.	Country	Study design	No. of Participants COVID-19 +ve/ COVID-19-ve	Association with disease severity	Conclusion
Kragstrup et al[49]	Denmark	Longitudinal	306/78	Yes	High admission cACE2 was associated with increased maximal disease severity within 28 d in COVID-19 participants
Reindl-Schwaighofer et al[50]	Austria	Retrospective cohort	126/27	Yes	When compared to non-severe patients, cACE2 in COVID-19 patients increased throughout time, peaking at 15.1 ng/mL in the late time period (days 9-11), notably in the more severe patients
Osman et al[51]	France	Prospective cohort	44/15	Yes	cACE2 levels were not statistically different in the short viral shedders (22141 pg/mL), but they were considerably lower in the prolonged viral shedders (19396 pg/mL) than in the healthy volunteer group (22600 pg/mL)
Gerard et al[52]	Belgium	Retrospective and prospective	15/28 (Retrospective); 84/42 (Prospective)	Yes	In contrast to patients with ARDS who do not have COVID-19 and control subjects, ACE2 is raised in lung tissue and blood from both COVID-19-related and unrelated ARDS, but AT2 cell loss is only observed in COVID-19-related ARDS
Fagyas et al[53]	Hungary	Retrospective cohort	188/0	N/A	Severe COVID-19 is distinguished by a decreased proportion of the TMPRSS2 rs2070788 AA genotype, increased renin and cACE2, lower aldosterone levels, an aldosterone/renin ratio, and lower aldosterone levels
Lundström et al[54]	Sweden	Retrospective cohort	114/10	Yes	COVID-19 patients had greater levels of cACE2 than healthy controls (median 5.0 (2.8-11.8) ng/mL vs 1.4 (1.1-1.6) ng/mL). cACE2 levels were greater in males than in females, but were unaffected by other risk factors for severe COVID-19
Maza et al[55]	Spain	Retrospective	147/30	Yes	cACE2 levels were considerably greater in infected individuals who had cutaneous symptoms rather than respiratory symptoms, and cACE2 levels were similarly higher in patients with milder symptoms
Elrayess et al[56]	Qatar	Cross-sectional	200/0	N/A	Patients with severe COVID-19 condition had greater levels of cACE2 than those with mild or moderate disease. There is a link between cACE2 levels and length of hospital stay
Elemam et al[57]	United Arab Emirates	Retrospective cohort	59/60	Yes	In COVID-19 patients, cACE2 and its regulatory miRNAs were shown to be increased and associated to laboratory results, suggesting their clinical use as biomarkers for SARS-CoV-2 infection
Zhang et al[58]	China	Prospective cohort	245/404	Yes	The use of hypoglycemic drugs was associated with significantly lower cACE2 concentrations in COVID-19 diabetics with chronic disease (2973.83 ± 2196.79 pg/mL) than in control patients (4308.21 ± 2352.42 pg/mL)
Silva et al[60]	Argentina	Prospective cohort	93/40	Yes	Hospitalized COVID-19 patients showed lower circulating Ang-(1-7) and Ang II levels, as well as increased cACE2 enzymatic activity and protein levels, with no difference between normotensive and hypertensive COVID-19 patients
Daniell et al[61]	United States	Retrospective	59/27	Yes	COVID-19 patient plasma had significantly lower cACE2 activity than controls. Regardless of patient age, demographic variations, or comorbidity, nadir cACE2 activity in early hospitalization was regained after disease recovery
Mariappan et al[62]	India	Prospective cohort	42/10	Yes	When compared to healthy controls, SARS-CoV-2 infected patients showed noticeably greater cACE2 at the time of admission. In addition, in severe cases compared to moderate cases of infection, there was a significant increase in cACE2. Cases with both diabetes and hypertension had significant increases in cACE2

Ang-(1-7); Angiotensin-(1-7); Ang II; Angiotensin II; ARDS: Acute respiratory distress syndrome; cACE2; Circulating angiotensin converting enzyme 2; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.