key: cord-0690169-nqjgcfwg
authors: Fagyas, Miklós; Fejes, Zsolt; Sütő, Renáta; Nagy, Zsuzsanna; Székely, Borbála; Pócsi, Marianna; Ivády, Gergely; Bíró, Edina; Bekő, Gabriella; Nagy, Attila; Kerekes, György; Szentkereszty, Zoltán; Papp, Zoltán; Tóth, Attila; Kappelmayer, János; Nagy, Béla
title: Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients
date: 2021-11-25
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.11.028
sha: 306bfff5f559258246593305b8c82e592f2982aa
doc_id: 690169
cord_uid: nqjgcfwg

Objectives Angiotensin-converting enzyme 2 (ACE2) represents the main receptor for SARS-CoV-2 to enter endothelial cells. Here we investigated circulating ACE2 activity to predict the severity and mortality of COVID-19. Methods Serum ACE2 activity was measured in COVID-19 (110 critically ill and 66 severely ill subjects at hospital admission and in 106 follow-up samples) and in 32 non-COVID-19 severe sepsis patients. Associations between ACE2, inflammation-dependent biomarkers, pre-existing comorbidities and clinical outcome were studied. Results Initial ACE2 activity was significantly higher in critically ill COVID-19 patients (54.4 [36.7-90.8] mU/L) than in severe COVID-19 (34.5 [25.2-48.7] mU/L; P<0.0001) and non-COVID-19 sepsis patients (40.9 [21.4-65.7] mU/L; P=0.0260) regardless of comorbidities. Circulating ACE2 activity correlated with inflammatory biomarkers and was further elevated during hospital stay in critically ill patients. Based on ROC-curve analysis and logistic regression test, baseline ACE2 independently indicated the severity of COVID-19 with an AUC value of 0.701 (95% CI [0.621-0.781], P<0.0001). Furthermore, non-survivors showed higher serum ACE2 activity vs survivors at hospital admission (P<0.0001). Finally, high ACE2 activity (≥45.4 mU/L) predicted a higher risk (65 vs 37%) for 30-day mortality (Log-Rank P<0.0001). Conclusions Serum ACE2 activity correlates with COVID-19 severity and predicts mortality.

Coronavirus disease 2019 has been associated with significant morbidity and 55 mortality worldwide in the last 1.5 years. This disease is caused by severe acute respiratory 56 syndrome coronavirus 2 (SARS-CoV-2) infection and represents a mild course in the majority 57 of cases, but about one-fifth of the patients develop severe clinical complications, such as 58 acute respiratory distress syndrome (ARDS), systemic hyperinflammatory response and 59 death (Huang et al. 2020 , Martincic et al. 2020 ). There are several risk factors for fatal 60 infection, e.g. increasing age, male sex, smoking, history of hypertension, heart, lung and 61 kidney disorders (Zhou et al. 2020 , Kaur et al. 2021 . 62

Endothelial cells express angiotensin converting enzyme 2 (ACE2) on their surface, 63 which is the main receptor for SARS-CoV-2 (Hoffmann et al. 2020) . ACE2 mediates the 64 infection of endothelial cells, which induces endothelial activation and damage resulting in 65 substantial release of von Willebrand factor (Escher et al. 2020 ) and enhanced levels of 66 soluble E-selectin (Nagy et al. 2021) . In parallel, bronchoalveolar lavage fluid samples from 67 COVID-19 subjects showed a critical imbalance in the renin-angiotensin-aldosterone system 68 (RAAS) with upregulated expression of ACE2, renin and kallikrein enzymes (Garvin et al. 69 2020) . Due to the cleavage of angiotensin II (Ang II) into Ang-1-7 by the zinc-metalloprotease 70 ACE2 (Paz Ocaranza et al. 2020) , decreased Ang II level and enhanced Ang-1-7 formation 71 were determined in the presence of increased ACE2 function in severe COVID -19 compared 72 to healthy controls (van Lier et al. 2021) . Nonetheless, their impact on clinical outcome is not 73 clearly understood. However, ACE2 has been implicated in the pathomechanism of various 74 cardiovascular diseases, which represent a risk for COVID-19 mortality. In particular, 75 elevated circulating ACE2 levels were reported in heart failure (Úri et al. 2014 (Úri et al. , Úri et al. 76 2016 (Úri et al. , Fagyas et al. 2021 ) and hypertension (Úri et al. 2016) . It was hypothesized, that 77 secretion of ACE2 from cardiovascular tissues contributes to the elevation of circulating 78 ACE2 and results in a dysregulation of ACE/ACE2 balance in the tissues of cardiovascular 79 patients (Úri et al. 2016) , similarly being implicated in severe COVID-19 (Garvin et al. 2020 , 80 van Lier et al. 2021 . 81

Recently, controversial data have been reported on soluble ACE2 levels in patients. In contrast to healthy individuals having low circulating ACE2 activity (Patel et al. 83 2021) , upregulated ACE2 protein level (van Lier et al. 2021 , Kragstrup et al. 2021 2021) and activity (Nagy et al. 2021 , Patel et al. 2021 , Kaur et al. 2021 , Reindl-Schwaighofer 85 et al. 2021 were identified. In contrast, others found no change (Rieder et al. 2020 , 86 Kintscher et al. 2020 or lower ACE2 in severe COVID-19 patients than pre-pandemic controls 87 (Rojas et al. 2021) . Furthermore, it is still not evident how circulating ACE2 level is affected 88 by SARS-CoV-2 infection and recovery. Increasing levels of ACE2 were found in the first 2 89 weeks of the acute phase of COVID-19 (Lundström et al. 2021 , Reindl-Schwaighofer et al. 90 2021 . However, soluble ACE2 levels remained increased in 1-3 months following infection 91 (Rojas et al. 2021 , Patel et al. 2021 , and showed a reduction by 4 months of the disease 92 course (Lundström et al. 2021). 93 In this study, our aims were i) to compare circulating ACE2 activity in critically ill and 94 severe COVID-19 patients; ii) contrast these values to non-COVID-19 severe septic subjects, 95 iii) to correlate serum ACE2 activity with routinely measured laboratory biomarkers and 96 clinical parameters, such as Horowitz index, and iv) to evaluate whether ACE2 activity at the 97 hospital admission predicts the severity and outcome of the severe COVID- 19 To evaluate overall lung function and oxygenation in sepsis patients suffering from acute respiratory distress syndrome (ARDS), the PaO 2 /FiO 2 137 (P/F) ratio, also known as the Horowitz index, was determined in 106 study participants. This 138 index was calculated by the clinicians as follows: PaO 2 /FiO 2 ratio (P/F, mmHg) = Partial 139 pressure of oxygen PaO 2 (mmHg) / Fraction of inspired oxygen FiO 2 (%) (Ranieri et al. 2012) . Initial characteristics of critically ill and severe In this study, 176 COVID-19 positive subjects were recruited to analyze serum ACE2 activity 151 upon hospital admission and during hospital treatment. Based on disease severity, patients 152 were divided into two (critically ill and severe) subgroups as 110 individuals were critically ill 153 patients, while 66 suffered from moderate COVID-19 symptoms (Table 1) . Critically ill 154 patients were older than those with severe disease (median IQR 67 59-76 vs 61 52-65 155 years P  0.0001), while there was no difference in sex between the two cohorts. No 156 difference was observed in the length of hospital stay between the critically ill and severe 157 groups (median IQR 10 5-19 vs 8 6-12 days P = 0.1517). Mechanical ventilation was 158 applied more frequently in critically ill than in severe COVID-19 subjects (96 vs 6 patients, 159 respectively). Out of 110 critically ill patients 86 (78.2%) died of COVID-19 disease in contrast 160 to the severe cohort with 3 non-survivors (4.5%) out of 66 patients (P  0.0001). According 161 to the routine laboratory investigation, significantly higher levels of inflammation specific 162 parameters, i.e. CRP, IL-6 and ferritin as well as WBC count, were determined among 163 critically ill than severe COVID-19 conditions. On the other hand, platelet count did not differ 164 between the two cohorts, as no severe thrombocytopenia developed in these subjects. Age-165 and sex-matched non-COVID-19 severe septic patients showed similar SOFA-scores 166 compared to severe COVID-19 subjects, however, the mortality rate was lower in these non-167 COVID-19 ICU patients (Table 1) . 168

The Horowitz index -as an assessment of overall lung function and oxygenation in 169 patients suffering from life-threating pulmonary disorders -was calculated in 106 subjects in whom a greater degree of respiratory distress was indicated. Consequently, 171 critically ill COVID-19 patients (with severe ARDS) showed significantly lower values of 172

Horowitz index (103 71-160 mmHg) compared to severe cases (147 89-222 mmHg, P  173 0.0001), while non-COVID-19 septic subjects had mild/moderate pulmonary disorders based 174 on this index (243 182-384 mmHg) ( Table 1) . 175 176

First, we determined serum ACE2 activity of COVID-19 patients upon hospitalization. ACE2 178 activity was significantly higher in critically ill (54.4 36.7-90.8 mU/L) than in severe COVID-179 19 subjects (34.5 25.2-48.7 mU/L, P  0.0001) and in non-COVID-19 severe sepsis (40.9 180 21.4-65.7 mU/L; P = 0.0260) regardless of comorbidities ( Figure 1A ). The direct effect of sex 181 and age on soluble ACE2 level was investigated in the COVID-19 cohort. ACE2 was 182 significantly higher in males than females among critically ill patients (P = 0.0436), while this 183 difference could not be seen among severe subjects (P = 0.2870) ( Figure 1B ). There was a 184 tendency for higher ACE2 activity in relation to increasing age (P = 0.0134) regardless of 185 disease severity (Suppl. Figure 1B) . However, when this association was separately analyzed 186 within the two severity groups, this trend was not found in either cohort (P = 0.6841 and P = 187 0.4344, respectively) suggesting that disease severity but not age modulated serum ACE2 188 levels (Figures 1C and D) . Also, when Spearman's test was used to analyze the correlation 189 between baseline ACE2 and age, no relationship was found (r = 0.074, P = 0.3279) (data not 190 shown). We then studied the correlation between circulating ACE2 activity and the levels of 191 routinely available laboratory tests suggesting a link between the elevated expression of 192 ACE2 and systemic inflammation causing cardiac, liver and kidney disorders in (Suppl. Table 1 ). Based on these results, serum ACE2 activity is strongly associated with the 194 severity of COVID-19, although it is not specific to Changes in ACE2 activity among critically ill vs severe Serum ACE2 activities were determined not only in baseline samples but were followed in a 198 subgroup of recruited critically ill and severe patients to study the kinetics of ACE2 activity 199 depending on COVID-19 severity. We found that, when compared to baseline levels, ACE2 200 activities were further elevated during the hospital treatment of critically ill patients (P  201 0.0001), in contrast to severely ill study participants where alterations did not reach 202 statistical significance during hospital stay (P = 0.0579) ( Figure 2A ). Moreover, similarly 203 abnormal ACE2 activity values (P = 0.4165) were found at the admission and subsequent 204 time intervals ( Figure 2B ). Overall, these data imply that ACE2 expression is sustainedly 205 induced under severe COVID-19 conditions, particularly in critically ill patients. 206 207 208 Association between serum ACE2 and the outcome of Serum ACE2 was also analyzed whether this biomarker showed any association with the 210 disease outcome. Accordingly, non-survivors demonstrated significantly higher ACE2 211 activities (54.6 37.3-94.7 mU/L) at hospital admission vs survivors (35.6 25.3-58.5 mU/L 212 (P  0.0001, Figure 3A ). Then hypothetical differences in patients' ACE2 activities were 213 further contrasted between initial and follow-up serum samples depending on the outcome 214 on an individual basis. In this context, most (both critically ill and severe) patients who finally 215 died of COVID-19 showed significant ACE2 elevations (P  0.0001) before death, while no 216 significant change (P = 0.0623) in ACE2 activities were observed before discharge from the 217 hospital in survivors (Figures 3B and C) . According to these results, there is a strong 218 association between the level of ACE2 and the clinical consequences of COVID-19 disease. 219 220 Suitability of initial ACE2 to predict the severity and outcome of To further investigate initial ACE2 in the prediction of the severity and outcome of COVID-19 222 disease, ROC-curve analyses were performed. The best discriminative threshold of ACE2 at 223 admission, estimated by Youden-index, was 45.4 mU/L with a sensitivity of 60% and 224 specificity of 71.2% to estimate disease severity at an AUC value of 0.701 (95% CI 0.621-225 0.781, P  0.0001) ( Figure 4A ). Using the same cut-off value, ACE2 could predict the 226 mortality with a sensitivity of 61.8% and specificity of 65.5% at a similar AUC value of 0.679 227 (95% CI 0.600-0.759, P  0.0001) ( Figure 4B ). 228

To test whether ACE2 can independently predict the severity of the disease, a logistic 229 regression analysis was performed. Higher initial ACE2 activity had a significantly higher odds 230 ratio for a more severe outcome (OD: 1.032, 95% CI 1.005-1.061, P = 0.019). Also, ferritin, 231 creatinine, WBC count, lymphocyte count, hemoglobin, and MPV showed statistically 232 significant OD in the prediction of COVID-19 severity (Table 2) . Taken together, these data 233 indicate that serum ACE2 activity has a capacity to predict the development of adverse 234 clinical events in 236 Horowitz index in COVID-19 and its relationship with ACE2 levels 237

As we described above, the values of P/F ratio in patients with critically ill clinical conditions 238 were significantly lower (P = 0.0306) compared to moderate COVID-19 cases (see Table 1 ). 239

This index was also analyzed regarding the outcome of the disease, and non-survivors had a 240 significantly decreased P/F ratio vs survivors (100.5 66.3-160 vs 142 90.7-200.3 mmHg, P 241 = 0.0180). The diagnostic characteristics of P/F ratio was further studied by using ROC-curve 242 analysis. Its best discriminative threshold was 129 mmHg with a sensitivity of 66.7% and 243 specificity of 64.8% for the assessment of disease severity at an AUC value of 0.662 (95% CI 244 [0.522-0.802, P = 0.0312) ( Figure 4C ). Using the same cut-off value, ACE2 predicted the 245 outcome of the disease with a sensitivity of 65.8% and specificity of 61.5% at an AUC value 246 of 0.653 (95% CI [0.539-0.767, P = 0.0196) ( Figure 4D) . Surprisingly, when ACE2 levels were 247 correlated with the values of Horowitz index, no relationship was observed between the two 248 parameters (in the entire group: r = 0.045, P = 0.6417 within the critically ill subgroup: r = 249 0.0342, P = 0.7517). According to these preliminary results, Horowitz index is suitable to 250 monitor COVID-19 with lung function disorders although lacking a direct association with the 251 expression of ACE2. 252

Prediction of 30-day mortality by high initial ACE2 level in patients with Out of the 176 COVID-19 patients, 89 (50.6%) died during the 30-day follow-up. In Figure 3A , 255 there was a significant difference in baseline ACE2 activity between survivors and non-256 survivors, and this biomarker predicted the outcome based on ROC analysis ( Figure 4B) . 257

Using the derived cut-off value in Kaplan-Meier analysis, COVID-19 patients with highly 258 elevated ACE2 level ( 45.4 mU/L) had a larger risk for 30-day mortality when compared to 259 those with lower ACE2 activity (37.2% vs 64.7%, Log-Rank P  0.0001) ( Figure 5) Here we conducted a retrospective, dual-center clinical study to compare baseline 284 serum ACE2 activity in a large group of critically ill and severe COVID-19 patients (Table 1) . 285 There was a difference in age, as critically ill patients were older than those having moderate 286 symptoms which may be related to the fact that increasing age can predispose more severe cohort in contrast to recently reported COVID-19 cases (Lippi et al. 2020 , Martincic et al. 292 2020 . 293

To evaluate overall lung function and oxygenation, the Horowitz index was 294 determined in 106 patients by the clinicians. The P/F ratio drew the attention to a greater 295 degree of respiratory distress via significantly lower values in the participants of severe 296 group compared to moderate clinical cases (Table 1) . To the best of our knowledge, there is 297 only one publication where P/F ratio has been analyzed in combination with other variables 298 in COVID-19 patients to develop a rapid clinical indicator of adverse outcomes in making 299 decision (Lagolio et al. 2021 ). In our study, the Horowitz index was associated with the 300 outcome of COVID-19 as significantly lower values were found in non-survivors than 301 survivors (Table 1) . Surprisingly, pulmonary performance did not correlate with circulating 302 ACE2 activity. disease specific marker for COVID-19. However, its level strongly correlates with COVID-19 317 severity and predicts disease prognosis and mortality. 318

The impact of age and sex was investigated on circulating ACE2, and there was a 319 tendency for increasing ACE2 activity in relation to increasing age. However, when this 320 association was separately analyzed within the two severity groups, this trend was not found 321 in either cohort. Hence, disease severity but not age directly modulated serum ACE2 levels. 322

In contrast, others found a strong relationship between ACE2 and age (Kragstrup et al. 323 2021) . Male patients demonstrated higher baseline ACE2 levels than females in the entire 324 study cohort, predominately in the critically ill group in this study. This is in agreement with 325 recent findings with lower ACE2 activity in females than males (Kaur et al. 2021 , Reindl-326 Schwaighofer et al. 2021 . The relationship between initial ACE2 and pre-existing 327 cardiovascular or other comorbidities was then studied, and surprisingly, no significant 328 association was shown in COVID-19 patients with hypertension, atrial fibrillation and cardiac 329 decompensation as well as renal disorder, diabetes mellitus and COPD. In contrast, Kragstup 330 et al. found an elevation in ACE2 level in those who previously suffered from hypertension, 331 heart and renal disorders (Kragstrup et al. 2021) , and diabetes was also associated with 332 higher ACE2 concentrations (Reindl-Schwaighofer et al. 2021) . Others reported higher ACE2 333 activity in smokers than non-smokers (Kaur et al. 2021) . Initial ACE2 moderately correlated 334 with inflammation dependent parameters, such as CRP, IL-6, ferritin and WBC count in this 335 study. Similarly, IL-6 concentrations were correlated with ACE2 levels (Reindl-Schwaighofer 336 et al. 2021), whilst PAI-1 and tPA were associated with inflammatory markers with identical 337 AUC values to ours in COVID-19 (Henry et al. 2021 ). On the other hand, ACE2 was not 338 correlating with IL-6 and TNF- in another study (Lundström et al. 2021) . 339

Next, serum ACE2 activity in follow-up blood samples were determined to study the 340 kinetics of ACE2 activity depending on COVID-19 severity. Initial serum ACE2 activity was 341 further elevated in the follow-up samples, especially in critically ill patients. Based on the 342 timing of the follow-up sampling, no marked difference was observed in ACE2 activity at 343 early and subsequent time points. Our data are in accordance with a recent study showing 344 persisted ACE2 activity following SARS-CoV-2 infection (Patel et al. 2021) . In contrast, acute 345 phase soluble ACE2 levels increased with symptom duration but reduced by 4 months of 346 clinical course (Lundström et al. 2021) . 347

Finally, initial ACE2 was analyzed if it showed any association with the disease 348 outcome. Accordingly, non-survivors demonstrated significantly higher ACE2 activity prior to 349 any treatment vs survivors based on the data of all patients. Also, ACE2 could predict the 350 outcome of the disease at an AUC value of 0.679 (95% CI 0.600-0.759). Comparable AUC 351 value was seen for initial ACE2 to indicate clinical outcome (Kragstrup et al. 2021). 352 Furthermore, most patients who finally died of COVID-19 still showed significant ACE2 353 elevation before death, while no significant increase in ACE2 was observed before discharge 354 in survivors. Notably, COVID-19 patients with  45.4 mU/L ACE2 level had a larger risk for 30-355 day mortality when compared to those with lower ACE2 activity. Likewise, elevated plasma 356 ACE2 was associated with the maximal severity in COVID-19 positive individuals during the 357 28-day period (Kragstrup et al. 2021) . Increased complement activation was also associated 358 with advanced COVID-19 disease severity. Patients with SARS-CoV-2 infection died more 359 likely when the disease was accompanied by overactivation and consumption of C3 360 (Sinkovits et al. 2021) . 361

In conclusion, serum ACE2 activity at hospital admission correlates with COVID-19 362 severity and predicts mortality, independently of the pulmonary function (Horowitz index). It 363 appears that serum ACE2 is a non-specific biomarker in systemic inflammation, since it is 364 also elevated in severe sepsis. significantly lower values were found in subjects with non-COVID-19 sepsis (n = 32) than 576 critically ill COVID-19 (A). There were higher ACE2 levels in severe male than female subjects, 577 however, sex did not influence ACE2 in the non-severe cohort (B) . Age affected ACE2 activity 578 in neither critically ill (C) nor severe COVID-19 (D) . Dots represent single results, while bars 579 indicate median with IQR. To compare the data of two groups, Mann-Whitney U test was 580 applied, while more than two subcohorts were analyzed by Kruskal-Wallis test. 581 582 583 Figure 2 . Kinetics in serum ACE2 activity between baseline and follow-up sample in critically 584 ill and severe COVID-19 patients. Compared to baseline levels, ACE2 activity was further 585 elevated in the follow-up samples (n = 106), especially in critically ill patients compared to 586 non-severe study participants (A). Based on the time point of the follow-up sampling, 587 similarly abnormal ACE2 activity values were analyzed in the early (1-7 days) and subsequent 588 time intervals (8-13 days and  14 days, respectively) (B) . Dots represent single results, while 589 bars indicate median with IQR. To compare the data of two groups, Mann-Whitney U test 590 was applied, while ACE2 values in baseline and follow-up samples were analyzed with each 591 other by Wilcoxon matched-pairs signed rank test. 592 593 Figure 3 . The association between baseline ACE2 and the outcome of COVID-19. There was a 594 significant difference in ACE2 activity between the groups of survivors (n = 87) and non-595 survivors (n = 89) (A). When alteration in ACE2 was selectively studied during the follow-up 596 regarding the outcome of these cases (n = 106), a significant increment in ACE2 between the 597 baseline and follow-up sample was detected in those who died of COVID-19 (n = 68) (B) 598 compared to those with only a modest ACE2 change who recovered after treatment (n = 38) 599 (C). Dots represent single results, while bars indicate median with IQR. In parts B and C, lines 600 connect ACE2 values measured in baseline and follow-up samples. To compare the data of 601 two groups, Mann-Whitney U test was applied. 602 603 Figure 4 . ROC-curve analysis for serum ACE2 levels (A, B) and Horowitz index (C, D) for the 604 prediction of the severity and outcome of COVID-19 disease. The best discriminative cut-off 605 value of ACE2 at admission was 45.4 mU/L with a sensitivity of 60% and specificity of 71.2% 606 to estimate disease severity (A). Using the same cut-off value, ACE2 could predict the 607 outcome of the disease with a sensitivity of 61.8% and specificity of 65.5% (B) . In parallel, 608 the F/P ratio was analyzed for these aspects, and 129 mmHg was the cut-off value of 609

Horowitz index that could be used for the assessment of disease severity (C) and to predict 610 the outcome of the disease with a sensitivity of 65.8% and specificity of 61.5% (D) . ROC-AUC 611 values with P-values were determined during all calculations. 612 613 614 Figure 5 . Kaplan-Meier analysis indicates that highly elevated ACE2 levels were related to a 615 higher rate of short-term mortality. Cut-off value ( 45.4 mU/L) was determined by the ROC-616 curve analysis. There is a lower risk of death for those COVID-19 subjects who had less than 617 45.4 mU/L of ACE2 level before any treatment. Number of patients at risk are displayed at 618 given days. Log Rank P value was determined. 619 620

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