Identification of novel biomarkers to distinguish bradykinin‐mediated angioedema from mast cell‐/histamine‐mediated angioedema

• Published in: Allergy (Copenhagen) Vol. 77; no. 3; pp. 946 - 955
• Main Authors: Bindke, Gesa, Gehring, Manuela, Wieczorek, Dorothea, Kapp, Alexander, Buhl, Timo, Wedi, Bettina
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.03.2022
• Subjects: Angioedema; Angioedema - diagnosis; Angioedemas, Hereditary - diagnosis; biomarker; Biomarkers; Bradykinin; Bradykinin - metabolism; Cadherins; Chronic Urticaria; Complement C1 Inhibitor Protein; Edema; Endothelial cells; Endothelial Cells - metabolism; hereditary angioedema; Histamine; Histamine - metabolism; Humans; Mast Cells - metabolism; Pentraxins; Permeability; Selectins - metabolism; Serine proteinase; Serum levels; Thrombolytic drugs; Tie‐2; Transcription Factors - metabolism; Urticaria; bradykinin; angioedema; hereditary angioedema; biomarker; Tie-2
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15013

Background The pathophysiology of the underlying paroxysmal permeability disturbances in angioedema (AE) is not well understood. Methods To identify clinical and laboratory parameters specific for a certain AE subtype, 40 AE patients were prospectively enrolled: 15 hereditary (HAE), 13 ACE‐inhibitor induced (ACE‐AE), and 12 mast cell‐mediated without wheals in chronic spontaneous urticaria (CSU‐AE). Ten healthy subjects served as controls. Serum levels of markers indicating activation of the ficolin‐lectin pathway, of endothelial cells, or those indicating impairment of vascular integrity or inflammation were assessed by enzyme‐linked immunosorbent assay. Results New routine clinical diagnostic criteria could not be identified, not even for distinguishing bradykinin‐mediated (BK‐) AE (ie, HAE and ACE‐AE) from mast cell‐/histamine‐mediated CSU‐AE. However, FAP‐α and tPA were significantly increased in all AE compared to controls. In HAE, FAP‐ α, tPA, uPAR, pentraxin‐3, Tie‐2, sE‐selectin, and VE‐cadherin were significantly increased compared to controls. In HAE compared to CSU‐AE and ACE‐AE, sE‐Selectin, Tie‐2, and VE‐Cadherin were significantly increased, whereas for Ang‐2 the difference was significant compared to CSU‐AE only. Tie‐2 correlated strongly negatively with C4, C1‐INH activity, and C1‐INH function. Conclusions This study is the first to compare HAE, ACE‐AE, and CSU‐AE. Although significance is limited by small sample size, Tie‐2 was identified as a new promising biomarker candidate for HAE. FAP‐ α and tPA might serve as a marker for AE in general, whereas sE‐selectin and Ang‐2 were increased in BK‐AE only. Our results add information to the role of endothelial dysfunction and serine proteases in different AE subtypes. Biomarker candidates for angioedema in general are FAP‐ α and tPA and for BK‐AE Ang‐2 and sE‐Selectin. In HAE compared to CSU‐AE and compared to ACE‐AE, sE‐Selectin, Tie‐2, and VE‐Cadherin were significantly increased, whereas for Ang‐2 the difference was significant compared to CSU‐AE only. Tie‐2 is a biomarker candidate for HAE and correlated significantly negative with C4, C1‐INH activity, and C1‐INH function. Abbreviations: AE, angioedema; ACE‐AE, angiotensin‐converting enzyme inhibitor induced AE; Ang‐2, angiopoietin 2; BK‐AE, bradykinin AE; C1‐INH, C1 inhibitor; C4, C4 complement; CSU‐AE, AE in chronic spontaneous urticaria without wheals; FAP‐a, fibroblast activation protein alpha; HAE, hereditary AE; MC/Hist‐AE, mast cell‐/histamine AE; sE‐Selectin, serum endothelial‐Selectin; Tie‐2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2; tPA, tissue‐type plasminogen activator; VE‐cadherin, vascular endothelial‐cadherin.