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

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.

Cold Agglutinins and Cryoglobulins Associate With Clinical and Laboratory Parameters of Cold Urticaria

Mast cell-activating signals in cold urticaria are not yet well defined and are likely to be heterogeneous. Cold agglutinins and cryoglobulins have been described as factors possibly associated with cold urticaria, but their relevance has not been explained. We performed a single-center prospective cohort study of 35 cold urticaria patients. Cold agglutinin and cryoglobulin test results, demographics, detailed history data, cold stimulation test results, complete blood count values, C-reactive protein, total immunoglobulin E levels, and basal serum tryptase levels were analyzed. Forty six percent (n = 16) of 35 tested patients had a positive cold agglutinin test and 27% (n = 9) of 33 tested patients had a positive cryoglobulin test. Cold agglutinin positive patients, when compared to cold agglutinin negative ones, were mainly female (P = 0.030). No gender-association was found for cryoglobulins. A positive cold agglutinin test, but not a positive cryoglobulin test, was associated with a higher rate of reactions triggered by cold ambient air (P = 0.009) or immersion in cold water (P = 0.041), and aggravated by increased summer humidity (P = 0.007). Additionally, patients with a positive cold agglutinin test had a higher frequency of angioedema triggered by ingestion of cold foods or drinks (P = 0.043), and lower disease control based on Urticaria Control Test (P = 0.023). Cold agglutinin levels correlated with erythrocyte counts (r = −0.372, P = 0.028) and monocyte counts (r = −0.425, P = 0.011). Cryoglobulin concentrations correlated with basal serum tryptase levels (r = 0.733, P = 0.025) and cold urticaria duration (r = 0.683, P = 0.042). Results of our study suggest that cold agglutinins and cryoglobulins, in a subpopulation of cold urticaria patients, are linked to the course and possibly the pathogenesis of their disease.

A case of hemolytic anemia associated with interstitial lung disease, arthralgia and fever caused by Mycoplasma pneumoniae

Pulmonary interstitiopathies have become the most diagnosed forms of pneumonia in 2020 due to the COVID-19 pandemic. The spectrum of interstitiopathies is broad and includes idiopathic diseases and secondary forms. In April 2020, a 36-year-old man admitted to our department for arthralgias, fever, asthenia, cough, and dyspnea. In January 2020 fever, cough, arthralgias and asthenia appeared. In April, his general condition worsened with development of macrohematuria, malaise, and intense asthenia. On admission, the patient presented pale, asthenic and symptomatic for dyspnea and arthralgias. There was objective joint pain in the small joints of the hands, elbow, and knees with morning stiffness and decreased strength. CT of the chest documented ground-glass opacities in both lung fields. He performed 2 swabs for SARS-CoV2, which were negative. On hematochemical examination: IgM 332 mg/dL and ferritin 700.2 ng/ml. At venous blood smear peripheral venous blood, agglutination of erythrocytes. The serology (IgM) for M. Pneumoniae was positive with agglutinins in the serum; Doxaciclina was started. There was a progressive normalization of hemoglobin levels and cold agglutinins were gradually reduced and were no longer detected at 15 days after the start of treatment. At one month after discharge, pulmonary function had fully recovered and the picture of hemolytic anemia was resolved.