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      Increased platelet activating factor levels in chronic spontaneous urticaria predicts refractoriness to antihistamine treatment: an observational study

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          Abstract

          Background

          Platelet activating factor (PAF) is an endogenous, active phospholipid released from inflammatory cells, platelets, and endothelial cells, and is involved in the regulation of immune responses. Degradation of PAF by PAF acetylhydrolase (PAF-AH) has been shown to be associated with anaphylaxis, asthma, and peanut allergy. The purpose of this study was to investigate relationships among clinical parameters, including urticaria severity and treatment responsiveness, and PAF and PAF-AH levels in sera from patients with chronic spontaneous urticaria (CSU).

          Methods

          Serum PAF and PAF-AH levels were measured by enzyme-linked immunosorbent assay in 283 CSU patients and 111 age- and sex-matched, healthy normal controls (NCs). Urticaria severity was evaluated by urticaria activity score over 7 days (UAS7). Within 3 months after measuring PAF levels, patients whose urticaria was not controlled by antihistamine treatment were classified as histamine receptor 1 antagonist (H1RA) non-responders.

          Results

          Serum PAF levels were significantly higher in CSU patients than in NCs (median 4368.9 vs. 3256.4 pg/ml, p = 0.015), while serum PAF-AH levels were significantly lower in CSU patients (105.6 vs. 125.7 ng/ml, p = 0.001). H1RA non-responders had higher levels of PAF in their sera than H1RA responders. A generalized linear model revealed that a higher UAS7 score (odds ratio 1.023, p = 0.024) and a PAF level ≥ 5000 pg/ml (1.409, p < 0.001) were significant predictors of a poor response to H1RA treatment.

          Conclusions

          Compared with NCs, CSU patients, particularly those with H1RA refractoriness, showed significant increases in serum PAF levels and decreases in PAF-AH. Therapies modulating PAF and PAF-AH levels could be effective in patients with CSU refractory to antihistamines.

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          Most cited references37

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          The EAACI/GA²LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update

          This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
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            Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis.

            Platelet-activating factor (PAF) is an important mediator of anaphylaxis in animals, and interventions that block PAF prevent fatal anaphylaxis. The roles of PAF and PAF acetylhydrolase, the enzyme that inactivates PAF, in anaphylaxis in humans have not been reported. We measured serum PAF levels and PAF acetylhydrolase activity in 41 patients with anaphylaxis and in 23 control patients. Serum PAF acetylhydrolase activity was also measured in 9 patients with peanut allergy who had fatal anaphylaxis and compared with that in 26 nonallergic pediatric control patients, 49 nonallergic adult control patients, 63 children with mild peanut allergy, 24 patients with nonfatal anaphylaxis, 10 children who died of nonanaphylactic causes, 15 children with life-threatening asthma, and 19 children with non-life-threatening asthma. Mean (+/-SD) serum PAF levels were significantly higher in patients with anaphylaxis (805+/-595 pg per milliliter) than in patients in the control groups (127+/-104 pg per milliliter, P<0.001 after log transformation) and were correlated with the severity of anaphylaxis. The proportion of subjects with elevated PAF levels increased from 4% in the control groups to 20% in the group with grade 1 anaphylaxis, 71% in the group with grade 2 anaphylaxis, and 100% in the group with grade 3 anaphylaxis (P<0.001). There was an inverse correlation between PAF levels and PAF acetylhydrolase activity (P<0.001). The proportion of patients with low PAF acetylhydrolase values increased with the severity of anaphylaxis (P<0.001 for all comparisons). Serum PAF acetylhydrolase activity was significantly lower in patients with fatal peanut anaphylaxis than in control patients (P values <0.001 for all comparisons). Serum PAF levels were directly correlated and serum PAF acetylhydrolase activity was inversely correlated with the severity of anaphylaxis. PAF acetylhydrolase activity was significantly lower in patients with fatal anaphylactic reactions to peanuts than in patients in any of the control groups. Failure of PAF acetylhydrolase to inactivate PAF may contribute to the severity of anaphylaxis. Copyright 2008 Massachusetts Medical Society.
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              EAACI/GA(2)LEN task force consensus report: the autologous serum skin test in urticaria.

              Injection of autologous serum collected during disease activity from some patients with chronic spontaneous urticaria (CU) into clinically normal skin elicits an immediate weal and flare response. This observation provides a convincing demonstration of a circulating factor or factors that may be relevant to the understanding of the pathogenesis and management of the disease. This test has become known as the autologous serum skin test (ASST) and is now widely practised despite incomplete agreement about its value and meaning, the methodology and the definition of a positive response. It should be regarded as a test for autoreactivity rather than a specific test for autoimmune urticaria. It has only moderate specificity as a marker for functional autoantibodies against IgE or the high affinity IgE receptor (FcepsilonRI), detected by the basophil histamine release assay, but high negative predictive value for CU patients without them. It is usually negative in other patterns of CU, including those that are physically induced. Positive ASSTs have been reported in some subjects without CU, including those with multiple drug intolerance, patients with respiratory allergy and healthy controls, although the clinical implications of this are uncertain. It is essential that failsafe precautions are taken to ensure that the patient's own serum is used for skin testing and aseptic procedures are followed for sample preparation and handling. CU patients with a positive ASST (ASST(+)) are more likely to be associated with HLADR4, to have autoimmune thyroid disease, a more prolonged disease course and may be less responsive to H1-antihistamine treatment than those with a negative ASST (ASST(-)) although more evidence is needed to confirm these observations conclusively.
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                Author and article information

                Contributors
                bastsetseg0413@gmail.com
                eun-1210@hanmail.net
                9801645@daum.net
                drsys93@naver.com
                hspark@ajou.ac.kr
                +82-31-219-5155 , ye9007@ajou.ac.kr
                Journal
                Clin Transl Allergy
                Clin Transl Allergy
                Clinical and Translational Allergy
                BioMed Central (London )
                2045-7022
                17 July 2019
                17 July 2019
                2019
                : 9
                : 33
                Affiliations
                ISNI 0000 0004 0532 3933, GRID grid.251916.8, Department of Allergy and Clinical Immunology, , Ajou University School of Medicine, ; 164 Worldcup-ro, Yeongtong-gu, Suwon, 443-721 Korea
                Author information
                http://orcid.org/0000-0002-7517-1715
                Article
                275
                10.1186/s13601-019-0275-6
                6636088
                31346408
                e927681f-2669-4c1a-8743-a01a3f76de3b
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 March 2019
                : 28 June 2019
                Funding
                Funded by: National Research Foundation of Korea
                Award ID: NRF-2018R1A2B6006199
                Award Recipient :
                Funded by: Ahn-Gook Pharmaceutical Co, Ltd.
                Award ID: 2018-2019
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Immunology
                platelet activating factor,platelet activating factor acetylhydrolase,chronic spontaneous urticaria

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