{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:23:10Z","timestamp":1790270590396,"version":"4.1.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T00:00:00Z","timestamp":1621900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002839","name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002839","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cryoproteins, such as cryoglobulins, cryofibrinogens and cold agglutinins, precipitate at low temperatures or agglutinate erythrocytes and dissolve again when warmed. Their pathogenetic and diagnostic importance in cold urticaria (ColdU) is unclear. In this study, we aimed to characterize the prevalence of cryoproteins in patients with ColdU.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted 3 analyses: i) a systematic review and meta-analysis of published data using an adapted version of the Joanna Briggs Institute\u2019s critical appraisal tool for case series, ii) a retrospective analysis of 293 ColdU patients treated at our Urticaria Center of Reference and Excellence (UCARE) from 2014 to 2019, and iii) a prospective observational study, from July 2019 to July 2020, with 49 ColdU patients as defined by the EAACI\/GA2LEN\/EDF\/UNEV consensus recommendations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our systematic review identified 14 relevant studies with a total of 1151 ColdU patients. The meta-analyses showed that 3.0% (19\/628), 1.1% (4\/357) and 0.7% (2\/283) of patients had elevated levels of cryoglobulins, cryofibrinogens and cold agglutinins, respectively. Our retrospective analyses showed that cryoproteins were assessed in 4.1% (12\/293) of ColdU patients. None of 9 ColdU patients had cryoglobulins, and one of 5 had cold agglutinins. In our prospective study, none of our patients had detectable cryoglobulins (0\/48) or cryofibrinogens (0\/48), but 4.3% (2\/46) of patients had cold agglutinins (without any known underlying autoimmune or hematological disorder).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our investigation suggests that only very few ColdU patients exhibit cryoproteins and that the pathogenesis of ColdU is driven by other mechanisms, which remain to be identified and characterized in detail.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.675451","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T13:54:12Z","timestamp":1621950852000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Cryoglobulins, Cryofibrinogens, and Cold Agglutinins in Cold Urticaria: Literature Review, Retrospective Patient Analysis, and Observational Study in 49 Patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Katharina","family":"Ginter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia Melina","family":"Ahsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojca","family":"Bizjak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Maurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Altrichter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea","family":"Terhorst-Molawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/all.13397","article-title":"The EAACI\/GA2LEN\/EDF\/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria","volume":"73","author":"Zuberbier","year":"2018","journal-title":"Allergy"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2230.2007.02376.x","article-title":"Acquired Cold Urticaria: Clinical Picture and Update on Diagnosis and Treatment","volume":"32","author":"Siebenhaar","year":"2007","journal-title":"Clin Exp Dermatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/all.14674","article-title":"Cold Urticaria - What We Know and What We do Not Know","author":"Maltseva","year":"2020","journal-title":"Allergy"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(86)90027-8","article-title":"Clinical Characteristics of Cold-Induced Systemic Reactions in Acquired Cold Urticaria Syndromes: Recommendations for Prevention of This Complication and a Proposal for a Diagnostic Classification of Cold Urticaria","volume":"78","author":"Wanderer","year":"1986","journal-title":"J Allergy Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.1975.tb01051.x","article-title":"Lymphosarcoma, Cold Urticaria, IgG1 Monoclonal Cryoglobulin and Complement Abnormalities","volume":"15","author":"Hauptmann","year":"1975","journal-title":"Scand J Haematol"},{"key":"B6","article-title":"Kappa Chain Cold Precipitable Immunoglobulin G (Igg) Associated With Cold Urticaria. I. Clinical Observations","volume":"2","author":"Costanzi","year":"1967","journal-title":"Clin Exp Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2017.11.035","article-title":"Cryoglobulins: An Update on Detection, Mechanisms and Clinical Contribution","volume":"17","author":"Kolopp-Sarda","year":"2018","journal-title":"Autoimmun Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(74)90852-3","article-title":"Biologic and Clinical Significance of Cryoglobulins: A Report of 86 Cases","volume":"57","author":"Brouet","year":"1974","journal-title":"Am J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-200107000-00004","article-title":"Cryoglobulinemia: Study of Etiologic Factors and Clinical and Immunologic Features in 443 Patients From a Single Center","volume":"80","author":"Trejo","year":"2001","journal-title":"Med (Baltimore)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1136\/jcp.55.1.4","article-title":"Cryoglobulins","volume":"55","author":"Ferri","year":"2002","journal-title":"J Clin Pathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/RHU.0b013e318289e06e","article-title":"Cryofibrinogenemia","volume":"19","author":"Michaud","year":"2013","journal-title":"J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew379","article-title":"Cryofibrinogenaemia-a Neglected Disease","volume":"56","author":"Moiseev","year":"2017","journal-title":"Rheumatol Oxf Engl"},{"key":"B13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41572-018-0009-4","article-title":"Cryoglobulinaemia","volume":"4","author":"Roccatello","year":"2018","journal-title":"Nat Rev Dis Primer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3109\/08916938909019952","article-title":"The Presence of Cryoprecipitable Immunoglobulins in Normal Human Sera may Reflect Specific Molecular Interactions","volume":"2","author":"Maire","year":"1989","journal-title":"Autoimmunity"},{"key":"B15","article-title":"[Detection and Analysis of Cryoglobulins: Comparative Study of a Population of Patients and One of Healthy Controls]","volume":"41","author":"Romaszko","year":"1993","journal-title":"Pathol Biol (Paris)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/00325481.1976.11714476","article-title":"Cold Agglutinin Disease","volume":"60","author":"Felber","year":"1976","journal-title":"Postgrad Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/all.12901","article-title":"Definition, Aims, and Implementation of GA(2) Len Urticaria Centers of Reference and Excellence","volume":"71","author":"Maurer","year":"2016","journal-title":"Allergy"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2009.06.005","article-title":"Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"62","author":"Moher","year":"2009","journal-title":"J Clin Epidemiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.02.005","article-title":"Treatments of Cold Urticaria: A\u00a0systematic Review","volume":"143","author":"Kulthanan","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-202x.2001.00028.x","article-title":"Cold Urticaria","volume":"6","author":"Claudy","year":"2001","journal-title":"J Investig Dermatol Symp Proc"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.01.031","article-title":"Chronic Inducible Urticaria: A\u00a0systematic Review of Treatment Options","volume":"141","author":"Dressler","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.46658\/JBIRM-17-06","article-title":"Chapter 7: Systematic Reviews of Etiology and Risk","volume-title":"Joanna Briggs Institute Reviewer\u2019s Manual","author":"Moola","year":""},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/s0190-9622(85)70208-3","article-title":"Cold Urticaria. Clinical Findings in 220 Patients","volume":"13","author":"Neittaanm\u00e4ki","year":"1985","journal-title":"J Am Acad Dermatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1986.tb02822.x","article-title":"Cold Urticaria and Virus Infections: A Clinical and Serological Study in 39 Patients","volume":"114","author":"Doeglas","year":"1986","journal-title":"Br J Dermatol"},{"key":"B25","article-title":"Cold Urticaria : A Clinico-Therapeutic Study in 30 Patients; With Special Emphasis on Cold Desensitization","volume":"2","author":"Henquet","year":"1992","journal-title":"Cold Urticaria Clin-Ther Study 30 Patients Spec Emphas Cold Desensitization"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-4362.1994.tb04956.x","article-title":"Treatment of Cold Urticaria","volume":"33","author":"Husz","year":"1994","journal-title":"Int J Dermatol"},{"key":"B27","article-title":"[Urticaria Caused by Cold. 104 Cases]","volume":"123","author":"Koeppel","year":"1996","journal-title":"Ann Dermatol Venereol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s001050050461","article-title":"[Epidemiology and Clinical Aspects of Cold Urticaria]","volume":"47","author":"M\u00f6ller","year":"1996","journal-title":"Hautarzt Z Dermatol Venerol Verwandte Geb"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/s0301-0546(02)79134-9","article-title":"[Cold Urticaria: Review of 12 Cases]","volume":"30","author":"Santaolalla Montoya","year":"2002","journal-title":"Allergol Immunopathol (Madr)"},{"key":"B30","article-title":"Cinnarizine is a Useful and Well-Tolerated Drug in the Treatment of Acquired Cold Urticaria (Acu)","volume":"13","author":"Tosoni","year":"2003","journal-title":"Eur J Dermatol EJD"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1542\/peds.113.4.e313","article-title":"Clinical Features and Anaphylaxis in Children With Cold Urticaria","volume":"113","author":"Alangari","year":"2004","journal-title":"Pediatrics"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-3083.2008.02840.x","article-title":"Clinical Features and Natural History of Acquired Cold Urticaria in a Tertiary Referral Hospital: A 10-Year Prospective Study","volume":"22","author":"Katsarou-Katsari","year":"2008","journal-title":"J Eur Acad Dermatol Venereol JEADV"},{"key":"B33","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s13223-018-0310-5","article-title":"Review of Cold-Induced Urticaria Characteristics, Diagnosis and Management in a Western Canadian Allergy Practice","volume":"14","author":"Stepaniuk","year":"2018","journal-title":"Allergy Asthma Clin Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1016\/j.jaip.2018.10.025","article-title":"Acquired Cold-Induced Urticaria in Pediatric Patients: A 22-Year Experience in a Tertiary Care Center (1996-2017)","volume":"7","author":"Yee","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4168\/aair.2019.11.4.538","article-title":"Cold Urticaria: Clinical Features and Natural Course in a Tropical Country","volume":"11","author":"Kulthanan","year":"2019","journal-title":"Allergy Asthma Immunol Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/j.1365-2133.2009.09441.x","article-title":"Results and Relevance of Critical Temperature Threshold Testing in Patients With Acquired Cold Urticaria","volume":"162","author":"M\u0142ynek","year":"2010","journal-title":"Br J Dermatol"},{"key":"B37","article-title":"R: A Language and Environment for Statistical Computing","year":"2018"},{"key":"B38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/s0002-9343(70)80110-3","article-title":"Cold Urticaria. Immunologic Studies","volume":"49","author":"Houser","year":"1970","journal-title":"Am J Med"},{"key":"B39","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-70313-3","volume-title":"Urticaria","author":"Czarnetzki","year":"1986"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.22023","article-title":"Laboratory Testing for Cryoglobulins","volume":"86","author":"Motyckova","year":"2011","journal-title":"Am J Hematol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1373\/clinchem.2007.090134","article-title":"A Critical Appraisal of Current Practice in the Detection, Analysis, and Reporting of Cryoglobulins","volume":"54","author":"Vermeersch","year":"2008","journal-title":"Clin Chem"},{"key":"B42","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.jaci.2006.10.041","article-title":"A Potential New Therapy for Cold Urticaria and Chronic Idiopathic Urticaria","volume":"119","author":"Wanderer","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2018.06.056","article-title":"Post-Infectious Sensory Neuropathy With anti-GT1a and GQ1b Antibodies Associated With Cold Urticaria","volume":"56","author":"Zucchi","year":"2018","journal-title":"J Clin Neurosci Off J Neurosurg Soc Australas"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1157\/13075702","article-title":"Cold Urticaria Associated With Acute Serologic Toxoplasmosis","volume":"33","author":"Miralles L\u00f3pez","year":"2005","journal-title":"Allergol Immunopathol (Madr)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/s0301-0546(04)79270-8","article-title":"Cold Urticaria and Infectious Mononucleosis in Children","volume":"32","author":"Morais-Almeida","year":"2004","journal-title":"Allergol Immunopathol (Madr)"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2003.tb00394.x","article-title":"Purpura With Cold Urticaria in a Patient With Hepatitis C Virus Infection-Associated Mixed Cryoglobulinemia Type III: Successful Treatment With Interferon-Beta","volume":"30","author":"Ito","year":"2003","journal-title":"J Dermatol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1993.tb03179.x","article-title":"Cold Urticaria and HIV Infection","volume":"129","author":"Lin","year":"1993","journal-title":"Br J Dermatol"},{"key":"B48","article-title":"[Cold Urticaria Associated With Serologic Markers of Hepatitis B and Cryoglobulinemia]","volume":"15","author":"Barranco Sanz","year":"1987","journal-title":"Allergol Immunopathol (Madr)"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.5694\/j.1326-5377.1981.tb135285.x","article-title":"Cold-Induced Urticaria in Infectious Mononucleosis","volume":"1","author":"Tyson","year":"1981","journal-title":"Med J Aust"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(76)90436-8","article-title":"Circulating Immune Complexes and Complement Sequence Activation in Infectious Mononucleosis","volume":"60","author":"Wands","year":"1976","journal-title":"Am J Med"},{"key":"B51","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1111\/j.1365-2133.1977.tb15435.x","article-title":"Erythema Elevatum Diutinum, Cryoglobulinaemia, and Fixed Urticaria on Cooling","volume":"97","author":"Morrison","year":"1977","journal-title":"Br J Dermatol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.98.1.12","article-title":"Cold Urticaria With Cryoglobulinemia in a Patient With Chronic Lymphocytic Leukemia","volume":"98","author":"Rawnsley","year":"1968","journal-title":"Arch Dermatol"},{"key":"B53","article-title":"Urticaria Caused by Cold and Cryoglobulinemia Revealing a Myeloma","volume":"76","author":"Thiers","year":"1969","journal-title":"Bull Soc Fr Dermatol Syphiligr"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(85)90681-5","article-title":"Angioimmunoblastic Lymphadenopathy in a Child With Unusual Clinical and Immunologic Features","volume":"76","author":"Chodirker","year":"1985","journal-title":"J Allergy Clin Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2230.1993.tb02188.x","article-title":"Waldenstr\u00f6m\u2019s Macroglobulinaemia Presenting With Cold Urticaria and Cold Purpura","volume":"18","author":"T\u00f6r\u00f6k","year":"1993","journal-title":"Clin Exp Dermatol"},{"key":"B56","article-title":"Autoimmunity and Auto-Immune Syndromes Associated With and Preceding the Development of Lymphoproliferative Disorders","volume":"6","author":"Polliack","year":"1992","journal-title":"Leukemia"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.675451\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T14:05:48Z","timestamp":1672236348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.675451\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,25]]},"references-count":56,"alternative-id":["10.3389\/fimmu.2021.675451"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.675451","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,25]]},"article-number":"675451"}}