Cryoglobulins, Cryofibrinogens, and Cold Agglutinins in Cold Urticaria: Literature Review, Retrospective Patient Analysis, and Observational Study in 49 Patients.

Katharina Ginter,Dalia Melina Ahsan,Marcus Maurer,Dorothea Terhorst-Molawi,Sabine Altrichter,Karoline Krause,Mojca Bizjak

doi:10.3389/fimmu.2021.675451

Abstract

IntroductionCryoproteins, 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.MethodsWe conducted 3 analyses: i) a systematic review and meta-analysis of published data using an adapted version of the Joanna Briggs Institute’s 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.ResultsOur 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).ConclusionOur 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.

Highlights

Cryoproteins, such as cryoglobulins, cryofibrinogens and cold agglutinins, precipitate at low temperatures or agglutinate erythrocytes and dissolve again when warmed
Secondary acquired Cold urticaria (ColdU) can be caused by hematologic diseases, infections, malignancies, cryoproteins (CPs) or other diseases [4]
CPs had been determined in all 14 studies in patient cohorts ranging from 9 to 208 ColdU patients

Summary

Introduction

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. Two different classification approaches can be found in the published literature. The classification of ColdU based on CSTs differentiates between typical ColdU, with wheals in the CSTs, and atypical ColdU, without wheals or atypical wheals in the CSTs [3]. The etiology-based classification, a hereditary and an acquired form are distinguished, the latter being further subdivided into primary and secondary. Secondary acquired ColdU can be caused by hematologic diseases, infections, malignancies, cryoproteins (CPs) or other diseases [4]. The pathophysiology of ColdU is not well understood, and autoallergic and autoimmune mechanisms, temperaturesensitive receptors, neurogenic signals, and CPs have been speculated to play a role [5, 6]

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