Abstract

Cold urticaria (ColdU) represents a peculiar subset of chronic inducible urticaria (CINDU) that poses significant risks of systemic reactions. While IgE-mediated autoimmunity is known as the primary relevant driver, studies on adults suggest that the presence of cryoproteins, such as cryoglobulins (CGs), cryofibrinogens (CFs), and cold agglutinins (CAs), may radically complicate the clinical picture modifying the disease. This review explores ColdU pathophysiology and diagnostic workup focusing on whether these proteins act merely as bystanders or as key players in driving pediatric disease severity and distinct clinical phenotypes.

References

  1. Ginter K., Ahsan DM, Bizjak M, et al. Cryoglobulins, Cryofibrinogens, and Cold Agglutinins in Cold Urticaria: Literature Review, Retrospective Patient Analysis, and Observational Study in 49 Patients. Front immunol 2021;12:675451. https://doi.org/10.3389/fimmu.2021.675451.
  2. Bizjak M, Košnik M, Terhorst-Molawi D, et al. Cold Agglutinins and Cryoglobulins Associate With Clinical and Laboratory Parameters of Cold Urticaria. Front immunol 2021;12:12:665491. https://doi.org/10.3389/fimmu.2021.665491.
  3. Church MK, Kolkhir P, Metz M, et al. The role and relevance of mast cells in urticaria. Immunol Rev 2018;282:232–247. https://doi.org/10.1111/imr.12632.
  4. Maltseva N, Borzova E, Fomina D, et al., Cold urticaria - What we know and what we do not know. Allergy 2020;76:1077-1094. https://doi.org/https://doi.org/10.1111/all.14674.
  5. Maurer M, Fluhr JW, Khan DA. How to Approach Chronic Inducible Urticaria. J Allergy Clin Immunol Pract 2018;6:1119-1130. https://doi.org/10.1016/j.jaip.2018.03.007.
  6. Trejo O, Ramos-Casals M, García-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine 2001;80:252-262. https://doi.org/10.1097/00005792-200107000-00004.
  7. Damoiseaux J. The diagnosis and classification of the cryoglobulinemic syndrome. Autoimmun Rev 2014;13:359-362. https://doi.org/10.1016/j.autrev.2014.01.027.
  8. Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers 2018;4:11. https://doi.org/10.1038/s41572-018-0009-4.
  9. Kolopp-Sarda MN, Miossec P. Cryoglobulins: An update on detection, mechanisms and clinical contribution. Autoimmun Rev 2018;17:457-464. https://doi.org/10.1016/j.autrev.2017.11.035.
  10. Brouet, J. C., Clauvel, J. P., Danon, F., Klein, M., & Seligmann, M. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 1974;57:775-788. https://doi.org/10.1016/0002-9343(74)90852-3.
  11. Moiseev S, Luqmani R, Novikov P, et al. Cryofibrinogenaemia-a neglected disease. Rheumatology Oxford 2017;56:1445-1451. https://doi.org/10.1093/rheumatology/kew379.
  12. Michaud M, Pourrat J. Cryofibrinogenemia. J Clin Rheumatol 2013;19:142-148. https://doi.org/10.1097/RHU.0b013e318289e06e.
  13. Maire MA, Mittey M, Lambert PH. The presence of cryoprecipitable immunoglobulins in normal human sera may reflect specific molecular interactions. Autoimmunity 1989;2:155-164. https://doi.org/10.3109/08916938909019952.
  14. Holm JG, Agner T, Thomsen SF. (2017). Diagnostic properties of provocation tests for cold, heat, and delayed-pressure urticaria. Eur J Dermatol 2017;27:406-408. https://doi.org/10.1684/ejd.2017.3014.
  15. Siebenhaar F, Staubach P, Metz M, et al. Peltier effect-based temperature challenge: an improved method for diagnosing cold urticaria. J Allergy Clin Immunol 2004;114:1224-1225. https://doi.org/10.1016/j.jaci.2004.07.018.
  16. Wassef C, Laureano A, Schwartz RA. Aquagenic Urticaria: A Perplexing Physical Phenomenon. Acta Dermatovenerol Croat 2017;25:234-237.
  17. Magerl M, Abajian M, Krause K, et al. An improved Peltier effect-based instrument for critical temperature threshold measurement in cold- and heat-induced urticaria. J. Eur Acad Dermatol Venereol 2015;29:2043-2045. https://doi.org/10.1111/jdv.12739.
  18. Wanderer AA, Grandel KE, Wasserman SI, et al. 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. J Allergy Clin Immunol 1986;78:417-423. https://doi.org/10.1016/0091-6749(86)90027-8.
  19. Magerl M, Altrichter S, Borzova E, et al. The definition, diagnostic testing, and management of chronic inducible urticarias - The EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy 2016;71:780-802. https://doi.org/10.1111/all.12884.
  20. Młynek A, Magerl M, Siebenhaar F, et al.. Results and relevance of critical temperature threshold testing in patients with acquired cold urticaria.. Br J Dermatol Suppl 2010;162:198-200. https://doi.org/10.1111/j.1365-2133.2009.09441.x.
  21. Magerl M, Pisarevskaja D, Staubach P, et al. Critical temperature threshold measurement for cold urticaria: a randomized controlled trial of H(1) -antihistamine dose escalation. Br J Dermatol Suppl 2012;166:1095-1099. https://doi.org/10.1111/j.1365-2133.2012.10822.x.
  22. Maltseva NP, Riabova KA, Zhernov YV. Cold and Cholinergic Urticaria: Predictors of Anaphylaxis and Therapeutic Approaches—What We Know and What We Do Not Know? Immuno 2025;5:44. https://doi.org/10.3390/immuno5040044.
  23. Deza G, Brasileiro A, Bertolín-Colilla M, et al. Acquired cold urticaria: Clinical features, particular phenotypes, and disease course in a tertiary care center cohort. J Am Acad Dermatol 2016;75:918-924.e2. https://doi.org/10.1016/j.jaad.2016.06.017.
  24. Shaker MS, Wallace DV, Golden DBK., et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol 2020;145:1082–1123. https://doi.org/10.1016/j.jaci.2020.01.017.
  25. Kolopp-Sarda MN, Miossec P. Cryoglobulins: An update on detection, mechanisms and clinical contribution. Autoimmun Rev 2018;17:457-464. https://doi.org/10.1016/j.autrev.2017.11.035.
  26. Cutts L, Parslew R, Eustace K. Neonatal urticaria: Could it be CAPS?. Pediatr Dermatol 2018;35:e420–e421. https://doi.org/10.1111/pde.13660.
  27. Ombrello MJ, Remmers E.F, Sun G, et al. (2012). Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions N Engl J Med 2012;366:330-338. https://doi.org/10.1056/NEJMoa1102140.
  28. Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 2001;108:615-620. https://doi.org/10.1067/mai.2001.118790.
  29. Scheffel J, Mahnke NA, Hofman ZLM, et al. Cold-induced urticarial autoinflammatory syndrome related to factor XII activation. Nat Commun 2020;11:179. https://doi.org/10.1038/s41467-019-13984-8.
  30. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018;3:1393-1414. https://doi.org/10.1111/all.13397.
  31. Bizjak M. Cold Urticaria: From Wheals to Anaphylaxis. Allergy Asthma Immunol Res 2025;17:547-562. https://doi.org/10.4168/aair.2025.17.5.547.
  32. Abajian M, Curto-Barredo L, Krause K, et al. Rupatadine 20 mg and 40 mg are Effective in Reducing the Symptoms of Chronic Cold Urticaria. Acta Dermatovenerol 2015;96:56-59. https://doi.org/10.2340/00015555-2150.
  33. Maurer M, Metz M, Brehler R, et al. Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence. J Allergy Clin Immunol 2018;141:638-649. https://doi.org/10.1016/j.jaci.2017.06.032. https://clinicaltrials.gov/study/NCT04681729.

Downloads

PDF
Authors

Ivan Spinelli - Department of Pediatrics, Regional Referral Center of Pediatric Pulmonology, Allergy, Immunology and Rheumatology. Pediatric Hospital Giovanni XXIII, University of Bari. Bari, Italy

Carla Mastrorilli - Department of Pediatrics, Regional Referral Center of Pediatric Pulmonology, Allergy, Immunology and Rheumatology. Pediatric Hospital Giovanni XXIII, University of Bari. Bari, Italy

Adrea Cianci - Department of Pediatrics, Regional Referral Center of Pediatric Pulmonology, Allergy, Immunology and Rheumatology. Pediatric Hospital Giovanni XXIII, University of Bari. Bari, Italy

Mariagrazia Dibenedetto - Department of Pediatrics, Regional Referral Center of Pediatric Pulmonology, Allergy, Immunology and Rheumatology. Pediatric Hospital Giovanni XXIII, University of Bari. Bari, Italy

Simona Sottili - Department of Pediatrics, Regional Referral Center of Pediatric Pulmonology, Allergy, Immunology and Rheumatology. Pediatric Hospital Giovanni XXIII, University of Bari. Bari, Italy

Fabio Cardinale - Department of Pediatrics, Regional Referral Center of Pediatric Pulmonology, Allergy, Immunology and Rheumatology. Pediatric Hospital Giovanni XXIII, University of Bari. Bari, Italy

License

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Copyright

Copyright (c) 2026 Italian Journal of Pediatric Allergy and Immunology

How to Cite
Spinelli, I., Mastrorilli, C., Cianci, A., Dibenedetto, M., Sottili, S., & Cardinale, F. (2026). Cryoglobulins, cryofibrinogens, and cold agglutinins in pediatric cold urticaria: pathophysiological insights and clinical management. Italian Journal of Pediatric Allergy and Immunology, 40(1), 31–35. https://doi.org/10.53151/2531-3916/2026-2221
  • Abstract viewed - 0 times
  • PDF downloaded - 0 times