Conflicts that this editors consider relevant to the content of the manuscript have been disclosed

Conflicts that this editors consider relevant to the content of the manuscript have been disclosed. Contributor Information RCI-COVID-19 study group : br / Martin Jaeger, Helga Dijkstra, Heidi Lemmers, Liesbeth van Emst, Kiki Schraa, Cor Jacobs, Anneke Hijmans, Trees Jansen, Fieke Weren, Liz Fransman, Jelle Gerretsen, Josephine van de Maat, Gerine Nijman, Simone Moorlag, Esther Taks, Priya Debisarun, Ilse Kouijzer, Heiman Wertheim, Joost Hopman, Janette Rahamat-Langendoen, Chantal Bleeker-Rovers, Jaap ten Oever, Reinout van Crevel, Jacobien Hoogerwerf, Quirijn de Mast, Hans van der Hoeven, Peter Pickkers, Matthijs Kox, Tim Frenzel, Jeroen Schouten, Pleun Hemelaar, Remi Beunders, Sjef van der Velde, Emma Kooistra, Nicole Waalders, Wout Claassen, Hidde Heesakkers, Tirsa van Schaik, Hetty van der Eng, Noortje Rovers, and Margreet Klop-Riehl. system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is usually unknown. Methods A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. Results Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (Value (All Groups)Value (Non-ICU vs ICU)or Kruskal-Wallis assessments for continuous variables and Fisher exact or ?2 assessments for discrete variables. Kinetics of complement factors were assessed using general mixed models on log-transformed data. Correlations between inflammatory markers and complement factors were assessed using Spearman rank correlation assessments. Differences were considered statistically significant at .05 (2 tailed). RESULTS Patient Characteristics Overall, we collected plasma samples of 197 patients with confirmed COVID-19. Of these, 75 patients were admitted to the ICU, and 115 patients were admitted to the clinical ward at the time of first sampling. Seven patients were initially admitted to the clinical ward but required ICU care during admission. Baseline samples (0C3 days after admission) were available from 122 of the 197 patients (87 of 115 non-ICU and 30 of 75 ICU patients). 2,4,6-Tribromophenyl caproate Table 1 shows that the COVID-19 ICU populace had higher concentrations of inflammatory parameters (C-reactive protein [CRP], D-dimer, and IL-6) and a higher mortality rate (23% vs 9%) than the patients who did not require ICU care. Complement Activation in COVID-19 First, we investigated whether complement factor plasma concentrations differ between patients COVID-19, patients with sepsis, and healthy individuals at baseline. Activation of the complement system commences via the classical, lectin, and/or alternative pathway resulting in the formation of C3 convertase, which cleaves C3 into C3a and C3b. C3b further degrades to C3c but also activates C5 convertase, which cleaves C5 into C5a and C5b. C5b combined with other complement factors forms the TCC or membrane attack complex (MAC) (Physique 1). Because C3a, C3c, and TCC are the most stable complement factors, plasma concentrations of these complement factors were measured in healthy controls (n?=?10), patients with COVID-19 at baseline (n?=?122), and patients with sepsis (n?=?39). 2,4,6-Tribromophenyl caproate All markers were significantly elevated in patients COVID-19 compared with healthy controls at baseline (represents upper detection limit. values between all groups were? .001 for all those complement factors. *values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range. Complement Activation and Mortality Rates Subsequently, we assessed whether complement activation was correlated with mortality rates. The overall mortality rate was 14% (27 of 191), with rates of 9% in non-ICU (n?=?10) and 23% in ICU (n?=?16) patients. The available baseline samples in 107 survivors and 11 nonsurvivors showed no differences in concentrations for C3a and TCC, whereas concentrations of C3c were significantly lower in the nonsurvivors (values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range. Complement Activation in Patients With Thromboembolic Events During admission, thromboembolic events were documented in 28 patients (14%); 27 of these patients were admitted to the 2,4,6-Tribromophenyl caproate ICU. Thromboembolic events included pulmonary embolisms (n?=?26), cerebrovascular accidents (n?=?2) and deep venous thrombosis (n?=?1). Baseline samples showed higher concentrations of C3a and TCC in patients who experienced thromboembolic complications (values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range. Correlation Between Complement Activation and Other Inflammatory Markers in Patients With COVID-19 Next, we investigated the relationship between complement factors and inflammatory parameters measured within 3 days after admission. Overall, a trend toward a positive correlation between complement factors and inflammatory markers was observed. However, not all correlations were statistically significant (Figure 6). The strongest correlation was found for CRP (statistically significant for C3a 2,4,6-Tribromophenyl caproate and TCC). The single correlation plots are shown in Supplementary Figures 6, 7, and 8. Open in a separate window Figure 6. Correlation of complement activation with inflammatory markers in patients with coronavirus disease 2019.. Correlation coefficients (values, shown in the figure) and values were calculated using the Spearman rank correlation test. *online. Consisting of data provided by the authors to benefit the reader, the.Data are presented as medians with interquartile range. Complement Activation and Mortality Rates Subsequently, we assessed whether complement activation was correlated with mortality rates. and can stimulate inflammation, but its role in COVID-19 is unknown. Methods A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. Results Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (Value (All Groups)Value (Non-ICU vs ICU)or Kruskal-Wallis tests for continuous variables and Fisher exact or ?2 tests for discrete variables. Kinetics of complement factors were assessed using general mixed models on log-transformed data. Correlations between inflammatory markers and complement factors were assessed using Spearman rank correlation tests. Differences were considered statistically significant at .05 (2 tailed). RESULTS Patient Characteristics Overall, we collected plasma samples of 197 patients with confirmed COVID-19. Of these, 75 patients were admitted to the ICU, and 115 patients were admitted to the clinical ward at the time of first sampling. Seven patients were initially admitted to the clinical ward but required ICU care during admission. Baseline samples (0C3 days after admission) were available from 122 of the 197 patients (87 of 115 non-ICU and 30 of 75 ICU patients). Table 1 shows that the COVID-19 ICU population had higher concentrations of inflammatory parameters (C-reactive protein [CRP], D-dimer, and IL-6) and a higher mortality rate (23% vs 9%) than the patients who did not require ICU care. Complement Activation in COVID-19 First, we investigated whether complement factor plasma concentrations differ between patients COVID-19, patients with sepsis, and healthy individuals at baseline. Activation of the complement system commences via the classical, lectin, and/or alternative pathway resulting in the formation of C3 convertase, which cleaves C3 into C3a and C3b. C3b further degrades to C3c but also activates C5 convertase, which cleaves C5 into C5a and C5b. C5b combined with other complement factors forms the TCC or membrane attack complex (MAC) (Figure 1). Because C3a, C3c, and TCC are the most stable complement factors, plasma concentrations of these complement factors were measured in healthy controls (n?=?10), patients with COVID-19 at baseline (n?=?122), and patients with 2,4,6-Tribromophenyl caproate sepsis (n?=?39). All markers were significantly elevated in patients COVID-19 compared with healthy controls at baseline (represents upper detection limit. values between all groups were? .001 for all complement factors. *values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range. Complement Activation and Mortality Rates Subsequently, we assessed whether complement activation was correlated with mortality rates. The overall mortality rate was 14% (27 of 191), with rates of 9% in non-ICU (n?=?10) and 23% in ICU (n?=?16) patients. The available baseline samples in 107 survivors and 11 nonsurvivors showed no differences in concentrations for C3a and TCC, whereas concentrations of C3c were significantly lower in the nonsurvivors (values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with interquartile range. Complement Activation in Patients With Thromboembolic Events During admission, thromboembolic events were documented in 28 patients (14%); 27 of these patients were admitted to the ICU. Thromboembolic events included pulmonary embolisms (n?=?26), cerebrovascular accidents (n?=?2) and deep venous thrombosis (n?=?1). Baseline samples showed higher concentrations of C3a and TCC in patients who experienced thromboembolic complications (values were calculated with general mixed model analyses on log-transformed data. Data are presented as medians with LEPR interquartile range. Correlation Between Complement Activation and Other Inflammatory Markers in Patients With COVID-19 Next, we investigated the relationship between complement factors and inflammatory parameters measured within 3 days after admission. Overall, a trend toward a positive correlation between complement factors and inflammatory markers was observed. However, not all correlations were statistically significant (Figure 6). The strongest correlation was found for CRP (statistically significant for C3a and TCC). The single correlation plots are shown in Supplementary Figures 6, 7, and 8. Open in a separate window Figure 6. Correlation of complement activation with inflammatory markers in patients with coronavirus disease 2019.. Correlation coefficients (values, demonstrated in the number) and ideals were determined using the Spearman rank correlation test. *on-line. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the.