{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T09:59:36Z","timestamp":1770458376492,"version":"3.49.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4\u20138 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U\/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6\u201312 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean \u00b1 SD total scores improved significantly with the Headache Impact Test (from 62.8 \u00b1 6.2 at pre-treatment to 57.7 \u00b1 9.1 after treatment; mean \u0394, \u22125.0; <jats:italic>p<\/jats:italic> = 0.02) and Modified Fatigue Impact Scale (from 59.3 \u00b1 13.1 to 51.2 \u00b1 15.4; mean \u0394, \u22128.1; <jats:italic>p<\/jats:italic> = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items (<jats:italic>p<\/jats:italic> \u2264 0.002). Mean \u00b1 SD C1-INH level increased from 26.8 \u00b1 5.9 mg\/dl after the second round of IVIG (pre-treatment) to 32.1 \u00b1 7.8 mg\/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 \u00b1 34.7% to 158.3 \u00b1 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease.<\/jats:p><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p><jats:uri>ClinicalTrials.gov<\/jats:uri>, identifier NCT03576469.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.632744","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T12:38:11Z","timestamp":1614688691000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Recombinant Human C1 Esterase Inhibitor for the Management of Adverse Events Related to Intravenous Immunoglobulin Infusion in Patients With Common Variable Immunodeficiency or Polyneuropathy: A Pilot Open-Label Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Isaac R.","family":"Melamed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holly","family":"Miranda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melinda","family":"Heffron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph R.","family":"Harper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.jaci.2016.09.023","article-title":"Update on the use of immunoglobulin in human disease: A review of evidence","volume":"139","author":"Perez","year":"2017","journal-title":"J\u00a0Allergy Clin Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1111\/j.1365-2249.2011.04387.x","article-title":"Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy","volume":"164","author":"Kaveri","year":"2011","journal-title":"Clin Exp Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1159\/000226232","article-title":"Common variable immunodeficiency: etiological and treatment issues","volume":"150","author":"Deane","year":"2009","journal-title":"Int Arch Allergy Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.jaip.2015.07.025","article-title":"International Consensus Document (ICON): common variable immunodeficiency disorders","volume":"4","author":"Bonilla","year":"2016","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B5","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.ijantimicag.2010.11.027","article-title":"Immunoglobulin treatment in primary antibody deficiency","volume":"37","author":"Maarschalk-Ellerbroek","year":"2011","journal-title":"Int J Antimicrob Agents"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01299","article-title":"Adverse effects of immunoglobulin therapy","volume":"9","author":"Guo","year":"2018","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.autrev.2015.09.002","article-title":"Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence","volume":"15","author":"Cherin","year":"2016","journal-title":"Autoimmun Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2015.04.023","article-title":"A new subset of common variable immune deficiency characterized by reduced C1 esterase inhibitor levels","volume":"115","author":"Melamed","year":"2015","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4172\/2471-9552.1000115","article-title":"Alzheimer\u2019s disease of the immune system: a new variant of immune deficiency","volume":"2","author":"Melamed","year":"2016","journal-title":"Immunother Open Acc"},{"key":"B10","volume-title":"(C1 esterase inhibitor [recombinant]) for intravenous use, lyophilized powder for reconstitution","year":"2020"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-017-0273-x","article-title":"Pharmacological management of hereditary angioedema with C1-inhibitor deficiency in pediatric patients","volume":"20","author":"Farkas","year":"2018","journal-title":"Paediatr Drugs"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp0803977","article-title":"Clinical practice. Hereditary angioedema","volume":"359","author":"Zuraw","year":"2008","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.05.019","article-title":"A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema","volume":"116","author":"van Doorn","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1016\/j.jaci.2010.07.021","article-title":"Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema","volume":"126","author":"Zuraw","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2013.12.004","article-title":"Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial","volume":"112","author":"Riedl","year":"2014","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.2012.03984.x","article-title":"Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study","volume":"42","author":"Moldovan","year":"2012","journal-title":"Clin Exp Allergy"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2013.02.007","article-title":"Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study","volume":"110","author":"Riedl","year":"2013","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2014.12.013","article-title":"Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks","volume":"3","author":"Li","year":"2015","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/pai.13065","article-title":"Recombinant human C1 esterase inhibitor treatment for hereditary angioedema attacks in children","volume":"30","author":"Reshef","year":"2019","journal-title":"Pediatr Allergy Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1023\/a:1026119331193","article-title":"A six-item short-form survey for measuring headache impact: the HIT-6","volume":"12","author":"Kosinski","year":"2003","journal-title":"Qual Life Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.56.suppl_1.s20","article-title":"Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability","volume":"56","author":"Stewart","year":"2001","journal-title":"Neurology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2013.05.023","article-title":"Psychometric properties of the Fatigue Severity Scale and the Modified Fatigue Impact Scale","volume":"331","author":"Learmonth","year":"2013","journal-title":"J Neurol Sci"},{"key":"B23","article-title":"Adverse reactions of prophylactic intravenous immunoglobulin; a 13-year experience with 3004 infusions in Iranian patients with primary immunodeficiency diseases","volume":"19","author":"Dashti-Khavidaki","year":"2009","journal-title":"J Investig Allergol Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02199.x","article-title":"Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin","volume":"133","author":"Brennan","year":"2003","journal-title":"Clin Exp Immunol"},{"key":"B25","first-page":"1000578","article-title":"Observational study of intravenous immunoglobulin 5% for alleviating adverse drug reactions in primary immunodeficiency disorders","volume":"10","author":"Melamed","year":"2019","journal-title":"J Clin Cell Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2005.09.064","article-title":"Hereditary angioedema: new findings concerning symptoms, affected organs, and course","volume":"119","author":"Bork","year":"2006","journal-title":"Am J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2012.27.1.104","article-title":"Migraine-like headache in a patient with complement 1 inhibitor deficient hereditary angioedema","volume":"27","author":"Chung","year":"2012","journal-title":"J Korean Med Sci"},{"key":"B28","article-title":"Severity of hereditary angioedema, prevalence, and diagnostic considerations","volume":"24","author":"Bernstein","year":"2018","journal-title":"Am J Manag Care"},{"key":"B29","article-title":"Benefits of Gammaplex 5% IVIG for patients experiencing adverse events on 10% IVIG","author":"Melamed","year":"2013"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.632744\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T12:38:19Z","timestamp":1614688699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.632744\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,2]]},"references-count":29,"alternative-id":["10.3389\/fimmu.2021.632744"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.632744","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,2]]},"article-number":"632744"}}