{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:33:41Z","timestamp":1760236421703,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T00:00:00Z","timestamp":1637280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>To explore retinal abnormalities using spectral domain optical coherence tomography (SD-OCT) and OCT-angiography (OCT-A) in a highly selective cohort of patients with type I hereditary angioedema (HAE). This prospective case-control study included 40 type I HAE patients and 40 age-\/sex-matched healthy subjects (HC). All participants underwent SD-OCT-scanning of retinal posterior pole (PP), peripapillary retinal nerve fiber layer (pRNFL), and optic nerve head (ONH). Superficial\/deep capillary density was analyzed by OCT-A. A total of 80 eyes from 40 HAE and 40 eyes from HC were evaluated. The pRNFL was thicker in HAE than in HC in nasal superior (p &lt; 0.0001) and temporal quadrants (p = 0.0005 left, p = 0.003 right). The ONH thickness in HAE patients was greater than in HC in the nasal (p = 0.008 left, p = 0.01 right), temporal (p = 0.0005 left, p = 0.003 right), temporal inferior (p = 0.007 left, p = 0.0008 right), and global (p = 0.005 left, p = 0.007 right) scans. Compared to HC, HAE showed a lower capillary density in both superficial (p = 0.001 left, p = 0.006 right) and deep (p = 0.008 left, p = 0.004 right) whole images, and superficial (p = 0.03 left) and deep parafoveal (p = 0.007 left, p = 0.005 right) areas. Our findings documented subclinical retinal abnormalities in type I HAE, supporting a potential role of the retinal assessment by SD-OCT\/OCT-A as a useful tool in the comprehensive care of HAE patients.<\/jats:p>","DOI":"10.3390\/jcm10225415","type":"journal-article","created":{"date-parts":[[2021,11,21]],"date-time":"2021-11-21T20:58:21Z","timestamp":1637528301000},"page":"5415","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Subclinical Signs of Retinal Involvement in Hereditary Angioedema"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1954-2825","authenticated-orcid":false,"given":"Paola","family":"Triggianese","sequence":"first","affiliation":[{"name":"Rheumatology, Allergology and Clinical Immunology, Department of \u201cMedicina dei Sistemi\u201d, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6926-9655","authenticated-orcid":false,"given":"Matteo","family":"Di Marino","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Nesi","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Greco","sequence":"additional","affiliation":[{"name":"Rheumatology, Allergology and Clinical Immunology, Department of \u201cMedicina dei Sistemi\u201d, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"Modica","sequence":"additional","affiliation":[{"name":"Rheumatology, Allergology and Clinical Immunology, Department of \u201cMedicina dei Sistemi\u201d, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-1729","authenticated-orcid":false,"given":"Maria","family":"Chimenti","sequence":"additional","affiliation":[{"name":"Rheumatology, Allergology and Clinical Immunology, Department of \u201cMedicina dei Sistemi\u201d, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Conigliaro","sequence":"additional","affiliation":[{"name":"Rheumatology, Allergology and Clinical Immunology, Department of \u201cMedicina dei Sistemi\u201d, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"Mancino","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Nucci","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Cesareo","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1056\/NEJMcp0803977","article-title":"Clinical practice. Hereditary angioedema","volume":"359","author":"Zuraw","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s12016-016-8561-8","article-title":"HAE Pathophysiology and Underlying Mechanisms","volume":"51","author":"Zuraw","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.jaci.2007.05.041","article-title":"Denaturing HPLC in laboratory diagnosis of hereditary angioedema","volume":"120","author":"Guarino","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1172\/JCI98869","article-title":"Dominant negative SERPING1 variants cause intracellular retention of C1-inhibitor in hereditary angioedema","volume":"129","author":"Haslund","year":"2018","journal-title":"J. Clin. Invest."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/S0140-6736(11)60935-5","article-title":"Hereditary angio-oedema","volume":"379","author":"Longhurst","year":"2012","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000453663","article-title":"Recurrent Angioedema: Occurrence, Features, and Concomitant Diseases in an Italian Single-Center Study","volume":"172","author":"Triggianese","year":"2017","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.jaci.2017.07.012","article-title":"Cleaved kininogen as a biomarker for bradykinin release in hereditary angioedema","volume":"140","author":"Hofman","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1056\/NEJMoa1605767","article-title":"Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis","volume":"376","author":"Banerji","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.3389\/fimmu.2018.01721","article-title":"Secreted Phospholipases A2 in Hereditary Angioedema with C1-Inhibitor Deficiency","volume":"9","author":"Loffredo","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.jaci.2018.01.015","article-title":"Hereditary angioedema with normal C1 inhibitor: Four types and counting","volume":"141","author":"Zuraw","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0140-6736(00)02483-1","article-title":"Hereditary angioedema with normal C1-inhibitor activity in women","volume":"356","author":"Bork","year":"2000","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jaci.2011.02.017","article-title":"Hereditary angioedema: Key role for kallikrein and bradykinin in vascular endothelial-cadherin cleavage and edema formation","volume":"128","author":"Bouillet","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1016\/j.jaci.2016.02.021","article-title":"Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations","volume":"138","author":"Suffritti","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.3389\/fimmu.2018.02183","article-title":"Comparing Pathways of Bradykinin Formation in Whole Blood from Healthy Volunteers and Patients with Hereditary Angioedema Due to C1 Inhibitor Deficiency","volume":"9","author":"Rivard","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1056\/NEJMoa1716995","article-title":"Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema","volume":"379","author":"Bygum","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1111\/all.12862","article-title":"Elevated plasma levels of vascular permeability factors in C1 inhibitor-deficient hereditary angioedema","volume":"71","author":"Loffredo","year":"2016","journal-title":"Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.jaci.2018.03.016","article-title":"A transcriptomics study of hereditary angioedema attacks","volume":"142","author":"Castellano","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fmed.2018.00111","article-title":"The Role of Failing Autonomic Nervous System on Life-Threatening Idiopathic Systemic Capillary Leak Syndrome","volume":"5","author":"Colombo","year":"2018","journal-title":"Front. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1182\/blood-2011-08-375816","article-title":"Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)","volume":"119","author":"Xie","year":"2012","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3109\/08820538.2015.1114829","article-title":"The Role of Plasma Kallikrein-Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches","volume":"31","author":"Abdulaal","year":"2016","journal-title":"Semin. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"606","DOI":"10.3129\/i09-105","article-title":"Central serous chorioretinopathy and idiopathic nonhistaminergic angioedema","volume":"44","author":"Edalati","year":"2009","journal-title":"Can. J. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.bcp.2015.07.034","article-title":"Enhanced Ca(2+) response and stimulation of prostaglandin release by the bradykinin B2 receptor in human retinal pigment epithelial cells primed with proinflammatory cytokines","volume":"97","author":"Catalioto","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cai, W., Wei, Q., Liu, Q., Ren, C., Liu, J., Zhang, R., He, M., Wang, Q., Du, Y., and Yu, J. (2016). Effect of bradykinin on TGF-\u03b21-induced retinal pigment epithelial cell proliferation and extracellular matrix secretion. BMC Ophthalmol., 16.","DOI":"10.1186\/s12886-016-0373-3"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"483960","DOI":"10.1155\/2014\/483960","article-title":"Complement system in pathogenesis of AMD: Dual player in degeneration and protection of retinal tissue","volume":"2014","author":"Kawa","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/eye.2016.328","article-title":"Local complement activation in aqueous humor in patients with age-related macular degeneration","volume":"31","author":"Schick","year":"2017","journal-title":"Eye"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fnagi.2018.00015","article-title":"The Complement System Is Critical in Maintaining Retinal Integrity during Aging","volume":"10","author":"Mukai","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.18632\/aging.101474","article-title":"The expression of C1 inhibitor (C1INH) in macrophages is upregulated by retinal pigment epithelial cells - implication in subretinal immune privilege in the aging eye","volume":"10","author":"Luo","year":"2018","journal-title":"Aging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/ICO.0b013e318033b4cb","article-title":"Unilateral lacrimal gland atrophy in a patient with hereditary angioedema","volume":"26","author":"Dollin","year":"2007","journal-title":"Cornea"},{"key":"ref_29","first-page":"422","article-title":"Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations","volume":"21","author":"Caballero","year":"2011","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13023-019-1263-6","article-title":"Evaluation of retinal microvascular perfusion in hereditary angioedema: A case-control study","volume":"15","author":"Triggianese","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ophtha.2016.10.008","article-title":"Quantification of Diabetic Macular Ischemia Using Optical Coherence Tomography Angiography and Its Relationship with Visual Acuity","volume":"124","author":"Samara","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1136\/annrheumdis-2018-214235","article-title":"Evaluation of retinal microvascular density in patients affected by systemic lupus erythematosus: An optical coherence tomography angiography study","volume":"78","author":"Conigliaro","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cesareo, M., Ciuffoletti, E., Martucci, A., Sebastiani, J., Sorge, R.P., Lamantea, E., Garavaglia, B., Ricci, F., Cusumano, A., and Nucci, C. (2017). Assessment of the retinal posterior pole in dominant optic atrophy by spectral-domain optical coherence tomography and microperimetry. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174560"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1159\/000488950","article-title":"Evidence for the Detection of Subclinical Retinal Involvement in Systemic Lupus Erythematosus and Sj\u00f6gren Syndrome: A Potential Association with Therapies","volume":"177","author":"Conigliaro","year":"2018","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.autrev.2015.03.006","article-title":"The autoimmune side of hereditary angioedema: Insights on the pathogenesis","volume":"14","author":"Triggianese","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"ref_36","first-page":"1764","article-title":"Ranking of optic disc variables for detection of glaucomatous optic nerve damage","volume":"41","author":"Jonas","year":"2000","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/S0161-6420(97)30173-0","article-title":"Analysis of reliability indices from Humphrey visual field tests in an urban glaucoma population","volume":"104","author":"Birt","year":"1997","journal-title":"Ophthalmology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3389\/fnins.2015.00479","article-title":"Association Between Alzheimer\u2019s Disease and Glaucoma: A Study Based on Heidelberg Retinal Tomography and Frequency Doubling Technology Perimetry","volume":"9","author":"Cesareo","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_39","first-page":"1111","article-title":"Optical coherence tomography angiography in the multimodal assessment of the retinal posterior pole in autosomal dominant optic atrophy","volume":"10","author":"Cesareo","year":"2021","journal-title":"Acta Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/tvst.9.9.5","article-title":"Retinal and Choroidal Vasculature in Patients with Marfan Syndrome","volume":"9","author":"Cesareo","year":"2020","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.jaci.2016.10.042","article-title":"Idiopathic systemic capillary leak syndrome (Clarkson disease)","volume":"140","author":"Druey","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jaci.2014.04.016","article-title":"VE-cadherin, a potential marker for endothelial cell activation during hereditary angioedema attacks","volume":"134","author":"Bouillet","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000455265","article-title":"Mechanisms of Retinal Fluid Accumulation and Blood-Retinal Barrier Breakdown","volume":"58","year":"2017","journal-title":"Dev. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6581846","DOI":"10.1155\/2018\/6581846","article-title":"Spectral Domain Optical Coherence Tomography Assessment of Macular and Optic Nerve Alterations in Patients with Glaucoma and Correlation with Visual Field Index","volume":"2018","author":"Martucci","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref_45","first-page":"95","article-title":"Correlating RNFL thickness by OCT with perimetric sensitivity in glaucoma patients","volume":"21","author":"Wheat","year":"2012","journal-title":"J. Glaucoma"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2147\/EB.S139417","article-title":"Retinal imaging with optical coherence tomography: A biomarker in multiple sclerosis?","volume":"10","author":"Costello","year":"2018","journal-title":"Eye Brain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ajo.2016.05.005","article-title":"Vascular Density in Retina and Choriocapillaris as Measured by Optical Coherence Tomography Angiography","volume":"168","author":"Wang","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0002-9394(89)90206-7","article-title":"Pseudotumor cerebri induced by danazol","volume":"107","author":"Hamed","year":"1989","journal-title":"Am. J. Ophthalmol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1080\/01658107.2017.1316744","article-title":"What Do Transgender Patients Teach Us About Idiopathic Intracranial Hypertension?","volume":"41","author":"Hornby","year":"2017","journal-title":"Neuroophthalmology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s00592-017-0996-8","article-title":"Optical coherence tomography angiography analysis of retinal vascular plexuses and choriocapillaris in patients with type 1 diabetes without diabetic retinopathy","volume":"54","author":"Carnevali","year":"2017","journal-title":"Acta Diabetol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1016\/j.ophtha.2013.01.069","article-title":"Fluorescein angiography versus optical coherence tomography for diagnosis of uveitic macular edema","volume":"120","author":"Kempen","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3986","DOI":"10.1167\/iovs.17-21510","article-title":"The Distribution of Leakage on Fluorescein Angiography in Diabetic Macular Edema: A New Approach to Its Etiology","volume":"58","author":"Najeeb","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/22\/5415\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:33:01Z","timestamp":1760167981000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/22\/5415"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,19]]},"references-count":52,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jcm10225415"],"URL":"https:\/\/doi.org\/10.3390\/jcm10225415","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2021,11,19]]}}}