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Management of chronic spontaneous urticaria: a worldwide perspective

Management of chronic spontaneous urticaria: a worldwide perspective Background: The approaches to the diagnosis and treatment of chronic spontaneous urticaria (CSU) differ in various parts of the world. We sought to determine the adherence to international and national urticaria guidelines as well as the motives to deviate from the guidelines among physicians worldwide. Methods: A web-based questionnaire was created and launched via e-mail by the World Allergy Organization (WAO) to representatives of all WAO Member Societies, the members of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the members of the WAO Junior Members Group (JMG), regardless of the specialty, affiliation, or nationality in March 2017. Results: We received 1140 completed surveys from participating physicians from 99 countries. Virtually all participants (96%) were aware of at least one urticaria guideline and reported that they follow a guideline. However, one in five physicians who follow a guideline (22%) reported to deviate from it. Reliance on own clinical experience is the most frequent reason for deviation from guidelines or not following them (44%). Young (< 40 years) and less experienced physicians more often follow a guideline and less often deviate than older and experienced ones. Physicians who follow a urticaria guideline showed higher rates of routinely ordering a complete blood count, the erythrocyte sedimentation rate, C-reactive protein, anti-thyroid antibodies, and thyroid-stimulating hormone and of performing the autologous serum skin test as compared to those who do not. Physicians who follow a urticaria guideline showed higher rates of using second generation antihistamines as their first-line treatment of CSU (p = 0.001) and more frequently observed higher efficacy of these drugs (or had more confidence that it would work, p < 0.019)ascomparedtothose whodonot follow the guidelines. Conclusions: Physicians’ characteristics (e.g. age, clinical experience, and specialty) and country specifics and regional features (e.g. availability of drugs for CSU treatment) importantly influence adherence to urticaria guidelines and CSU patient care and should be addressed in more detail in future research. Keywords: Chronic spontaneous urticaria, Guidelines, Worldwide, Guideline adherence, Urticaria treatment, Urticaria management, Global survey * Correspondence: pavel.kolkhir@yandex.ru Division of Immune-mediated skin diseases, I.M. Sechenov First Moscow State Medical University, 119991, Trubeckaya str., 8/2, Moscow, Russian Federation Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This 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. Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 2 of 13 Background disease, and treatment options used). There were 11 Chronic spontaneous urticaria (CSU) is a mast single-choice and 13 multiple-choice questions. cell-driven disease that is defined as the occurrence of wheals, angioedema, or both for more than 6 weeks due Recruitment and dissemination to known or unknown causes [1]. CSU affects up to 1% The survey was beta tested and approved by the WAO of the general population [2, 3]. It exerts a devastating JMG Steering Committee and WAO leadership before impact on patients’ quality of life [4, 5]. dissemination among participants. It was disseminated via The approaches to the diagnostic workup and treatment email by the WAO office to representatives of WAO of CSU patients differ in various parts of the world, and Member Societies as well as members of AAAAI and the there are discrepancies between national consensus papers WAO JMG in March 2017, with no restrictions applied to and guidelines and the international EAACI/GA LEN/ the specialty, affiliation, or nationality of the participants. EDF/WAO guideline [1, 6, 7]. The impact of guidelines on The email contained a link (Internet address) to the online the diagnostic workup and treatment strategy selection in questionnaire that was unique to each participating every day clinical practice needs further research. How member. A reminder to participate was sent in April 2017. many physicians know urticaria guidelines? How many Participants were given 30 days to reply and were guaran- physicians use them to guide their clinical practice? What teed complete anonymity. are the reasons for not following the available guidelines? What is the impact of following the guidelines on the Statistical analysis quality of care for urticaria patients? These questions need SPSS v.22 (Armonk, NY: IBM Corp, USA) was used for all to be addressed on a global level. The answers to these analyses. Analyses of the difference in frequencies across questions can be of significant value in updating and revis- groups were performed with the Pearson Chi-squared test ing the current guidelines and improving patient care. and a p value ≤0.05 was considered significant. The World Allergy Organization (WAO) Junior Mem- bers Group (JMG) Steering Committee developed a ques- Results tionnaire to survey the opinions on a whole variety of Demographics of study participants questions regarding CSU management and the use of A total of 32,356 individuals from 149 countries were guidelines. The questionnaire targeted the WAO members, invited to take part in the survey. We received 1140 including, but not limited to the representatives of the con- (3.5%) completed surveys from participating physicians stituent national societies of WAO, having the authority to from 99 countries, with most residing in Europe (33.2%) vote on their behalf, the WAO JMG and the American and North America (28.9%) (Table 1). Most of the Academy of Allergy, Asthma & Immunology (AAAAI) respondents were allergists/clinical immunologists members. We sought to determine, in physicians from (88.7%), followed by pediatricians (16.5%), dermatolo- around the world, the knowledge of and adherence to inter- gists (4.5%) and general practitioners (2.2%) (Table 2). national and national urticaria guidelines as well as the mo- One hundred and fifty-seven participants had more than tives to deviate from them. one specialty. The majority of participants were ≥ 40 years old (74.8%) and almost half of respondents had clinical experience of > 19 years (43.9%). Two thirds and Methods half of the participants worked in academic institutions Study survey and/or had a private practice. Most participants (88.9%) A web-based questionnaire (Additional file 1:FigureS1) reported to see primarily outpatients, both adults and was created and circulated among the members of the children with CSU (53.7%). Only 22% of physicians WAO JMG Steering Committee for revisions (July–Sep- reported to see ≥10 CSU patients per week. tember 2016). The protocol was approved by the WAO Executive Committee and Board of Directors (25 October More than 90% of physicians follow the urticaria 2016). The questionnaire was created de novo and has not guidelines, but almost one-fourth of them deviate been previously validated. The final version consisted of 24 Virtually all participants (1086 of 1126, 96%) were aware questions including survey participant demographic infor- of one or more urticaria guidelines, and almost all of them mation (country of residence, gender, age, specialty, clinical reported to follow a guideline (n = 1038 of 1086, 96%) experience and type of practice) and those concerning CSU (Fig. 1). The most widely used guideline was the inter- management (patients’ age, number of CSU patients seen national EAACI/GA LEN/EDF/WAO urticaria guideline per week, number of CSU patients with angioedema, [1] (58.9%), followed by the American AAAAI/ACAAI awareness, adherence and/or deviation of current guide- Joint Task Force practice parameters for the diagnosis and lines, examination of a CSU patient, including general management of acute and chronic urticaria [7](38.1%) laboratory work-up and targeted search for the cause of the and national guidelines (22.7%). Expectedly, the US Joint Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 3 of 13 Table 1 A geographical distribution of the respondents participating in the survey (n = 1140) North America Latin America Europe Africa/Middle-East Asia-Pacific (n = 330, 28.9%) (n = 193, 16.9%) (n = 379, 33.2%) (n = 64, 5.6%) (n = 174, 15.3%) Canada Argentina Albania Algeria Australia United States Bolivia Armenia Cyprus Bangladesh US Virgin Islands Brazil Austria Egypt Cambodia Chile Azerbaijan Ethiopia Hong Kong Colombia Belarus Iran India Costa Rica Belgium Israel Indonesia Cuba Bulgaria Kenya Japan Dominican Republic Croatia Lebanon Jordan Ecuador Czech Republic Oman Korea El Salvador Denmark Qatar Kuwait Guatemala Estonia South Africa Malaysia Honduras Finland Tunisia Mongolia Mexico France Nepal Panama Georgia New Zealand Paraguay Germany Pakistan Peru Greece Peoples Republic of China Uruguay Guernsey Philippines Venezuela Hungary Saudi Arabia Iceland Singapore Ireland Sri Lanka Italy Taiwan Kosovo Thailand Latvia United Arab Emirates Lithuania Uzbekistan Macedonia Viet Nam Moldova Montenegro Netherlands Poland Portugal Romania Russia Serbia Slovakia Slovenia Spain Sweden Switzerland Turkey Ukraine United Kingdom Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 4 of 13 Table 2 Characteristics of survey respondents (n = 1140) Characteristics of respondents Geographical regions Total % (n) NA LA EU AME AP % (n/total) % (n/total) % (n/total) % (n/total) % (n/total) Specialty (n = 1138) Allergists/ Clinical Immunologists 98.2 (324/330) 97.4 (187/192) 83.1 (315/379) 79.7 (51/64) 76.9 (133/173) 88.7 (1010) Dermatologists 0.3 (1/330) 0.5 (1/192) 9.8 (37/379) 0 6.9 (12/173) 4.5 (51) Pediatricians 4.2 (14/330) 25.5 (49/192) 17.4 (66/379) 23.4 (15/64) 25.4 (44/173) 16.5 (188) General Practitioners 0.6 (2/330) 3.1 (6/192) 1.6 (6/379) 6.2 (4/64) 4 (7/173) 2.2 (25) Gender (n = 1117) Male 58.5 (189/323) 55.1 (102/185) 43.7 (163/373) 57.1 (36/63) 58.4 (101/173) 53.0 (591) Female 41.5 (134/323) 44.9 (83/185) 56.3 (210/373) 42.9 (27/63) 41.6 (72/173) 47.0 (526) Age, years (n = 1132) < 40 22.9 (75/327) 27.6 (53/192) 28.2 (106/376) 17.2 (11/64) 23.1 (133/173) 25.2 (285) ≥40 77.1 (252/327) 72.4 (139/192) 71.8 (270/376) 82.8 (53/64) 76.9 (133/173) 74.8 (847) Clinical experience, years (n = 1130) ≤19 50.3 (164/326) 53.9 (104/193) 58.2 (217/373) 60.9 (39/64) 63.2 (110/174) 56.1 (634) Over 19 49.7 (162/326) 46.1 (89/193) 41.8 (156/373) 39.1 (25/64) 36.8 (64/174) 43.9 (496) Place of work (n = 1140) Private practice 63.9 (211/330) 82.4 (159/193) 34.6 (131/379) 54.7 (35/64) 46.0 (80/174) 54.0 (616) University clinic 70.3 (232/330) 68.4 (132/193) 57.5 (218/379) 59.4 (38/64) 71.8 (125/174) 65.3 (745) Hospital 11.8 (39/330) 39.4 (76/193) 43.3 (164/379) 42.2 (27/64) 58.6 (102/174) 35.8 (408) Specialized urticaria centre 0.9 (3/330) 4.7 (9/193) 2.9 (11/379) 3.1 (2/64) 0.3 (3/174) 2.4 (28) Department (n = 1140) Outpatients 97.3 (321/330) 89.6 (173/193) 82.3 (312/379) 81.3 (52/64) 89.1 (155/174) 88.9 (1013) Inpatients 0.9 (3/330) 8.8 (17/193) 12.4 (47/379) 10.9 (7/64) 6.9 (12/174) 7.5 (86) Outpatients and inpatients 1.8 (6/330) 1.6 (3/193) 5.3 (20/379) 7.8 (5/64) 4.0 (7/174) 3.6 (41) Age of patients (n = 1131) Adults 16.5 (54/327) 17.2 (33/192) 42.0 (158/376) 10.9 (7/64) 30.8 (53/172) 27.0 (305) Children 9.5 (31/327) 16.7 (32/192) 19.4 (73/376) 18.8 (12/64) 27.9 (71/172) 19.3 (219) Adults and children 74.0 (242/327) 66.1 (127/192) 38.6 (145/376) 70.3 (45/64) 41.3 (48/172) 53.7 (607) Number of CSU patients per week (n = 1127) < 10 75.5 (247/327) 78.8 (152/193) 80.7 (302/374) 71.0 (44/62) 78.4 (134/171) 78.0 (879) ≥10 24.5 (80/327) 21.2 (41/193) 19.3 (72/374) 29.0 (18/62) 21.6 (37/171) 22.0 (248) Patients with angioedema, % from the total number of CSU patients (n = 1131) ≤20 37.7 (123/326) 58.5 (113/193) 51.7 (195/377) 55.6 (35/63) 66.3 (114/172) 51.3 (580) > 20 62.3 (203/326) 41.5 (80/193) 48.3 (182/377) 44.4 (28/63) 33.7 (58/172) 48.7 (551) Adherence to the urticaria guidelines (n = 1126) Follow the guidelines Any of three below 88.0 (286/325) 93.8 (180/192) 97.3 (365/375) 85.7 (54/63) 89.5 (153/171) 92.2 (1038) EAACI/WAO/GA LEN/EDF 16.3 (53/325) 78.1 (150/192) 82.4 (309/375) 68.3 (43/63) 63.2 (108/171) 58.9 (663) US practice parameters 81.2 (264/325) 32.3 (62/192) 9.1 (34/375) 28.6 (18/63) 29.8 (51/171) 38.1 (429) National 7.1 (23/325) 26.0 (50/192) 32.5 (122/375) 14.3 (9/63) 30.4 (52/171) 22.7 (256) Follow any but deviate 40.0 (80/200) 28.1 (25/89) 49.4 (79/160) 58.1 (18/31) 53.8 (49/91) 22.3 (251) Do not follow 12.0 (39/325) 6.3 (12/192) 2.7 (10/375) 14.3 (9/63) 10.5 (18/171) 7.8 (88) AME Africa/Middle-East, AP Asia-Pacific, EU Europe, LA Latin America, NA North America. respondents could choose more than one option Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 5 of 13 Latin America, where the most common reason, pro- vided by 14.3% of respondents, was that some of the guidelines’ recommendations cannot be implemented in their country of residence. The second most preva- lent reason for deviating from guideline recommenda- tions (29.8%) was that the approach to CSU management recommended by the guidelines was seen as overly simplified and not reflecting the com- plexity of the disease. The least frequent reasons were the discrepancy and/or disagreement between the guidelines (3.8%) and a negative experience with following the guidelines in clinical practice (3.2%). Nine percent of participants did not agree with the Fig. 1 Adherence to the urticaria guidelines. Physicians were asked if guidelines’ recommendations and/or conclusions. they know and follow the current guidelines for management of urticaria. Results are expressed as percentage of participants who Young and less experienced physicians more often follow chose the corresponding guidelines (one respondent could choose several answers) a guideline and less often deviate than older and experienced ones Physicians who are less than 40 years of age more Task Force practice parameters are used more often often reported that they adhere to urticaria guidelines and in North America and the EAACI/GA LEN/EDF/ less often deviate as compared to responding physicians of WAO urticaria guidelines are more known in other ≥40 years of age (p = 0.001 and p = 0.023, respectively). countries of the world. One in five physicians who Responding physicians with clinical experience of > 19 follow a guideline (22%) reported to deviate from it. years statistically more often deviate from the guide- lines and less frequently follow them as compared to Reliance on own clinical experience is the most frequent responding physicians with clinical experience of reason for deviation from the guidelines or not following 19 years or less (p =0.025 and p < 0.001, respectively) them (Tables 4 and 5). Of the 339 (30%) physicians who do not follow a guideline or follow a guideline but deviate from it, Physicians who follow a urticaria guideline more often 149 (43.9%) reported that they rely more on their perform diagnostic tests own clinical experience (Table 3). It was the most fre- Physicians who follow a urticaria guideline showed higher quent reason in all regions of the world except for rates of routinely ordering a complete blood count (CBC), Table 3 Reasons why physicians don’t follow or deviate from the guidelines Reasons Geographical regions Total n = 339 % (n) a a a a a NA n = 236 LA n =98 EU n = 167 AME n =38 AP n = 104 % (n) % (n) % (n) % (n) % (n) The guidelines do not undergo revision frequently enough 4.2 (10) 4.1 (4) 3.0 (5) 5.3 (2) 6.7 (7) 8.2 (28) I rely more on my own clinical experience 27.1 (64) 10.2 (10) 20.4 (34) 34.2 (13) 26.9 (28) 43.9 (149) I do not agree with the guidelines’ recommendations 7.2 (17) 3.1 (3) 4.2 (7) 2.6 (1) 3.8 (4) 9.4 (32) and/or conclusions Some of the recommendations are unclear to me and require 3.4 (8) 1.0 (1) 8.4 (14) 2.6 (1) 11.5 (12) 10.6 (36) further details Some of the guidelines’ recommendations cannot be 0.8 (2) 14.3 (14) 12.0 (20) 26.3 (10) 22.1 (23) 20.3 (69) implemented in my country of residence I had a negative experience with following the guidelines 1.7 (4) 0 (0) 3.6 (6) 2.6 (1) 0 (0) 3.2 (11) in my clinical practice Overly simplified approach to CSU management 22.9 (54) 7.1 (7) 15.6 (26) 10.5 (4) 9.6 (10) 29.8 (101) recommended by the guidelines that does not reflect the complexity of the disease The discrepancy and/or disagreement between the guidelines 3.0 (7) 2.0 (2) 1.8 (3) 2.6 (1) 0 (0) 3.8 (13) AME Africa/Middle-East, AP Asia-Pacific, EU Europe, LA Latin America, NA North America. the total number of respondents was 339. However, there was overlapping in the data analysis because respondents could choose more than one option Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 6 of 13 Table 4 Factors linked to adherence to the urticaria guidelines Factors % (n) of physicians, who follow the guidelines % (n) of physicians, who don’t follow the guidelines X p Age, years <40 (n = 283) 96.9 (274) 3.1 (9) 11.152 0.001 ≥40 (n = 836) 90.7 (758) 9.3 (78) Clinical experience, years ≤19 years (n = 630) 95.9 (604) 4.1 (26) 28.017 < 0.001 Over 19 years (n = 487) 87.3 (425) 12.7 (62) Department Outpatients (n = 1006) 92.0 (926) 8.0 (80/85) 0.431 0.511 Inpatients (n = 84) 94.0 (79) 6.0 (5) Age of patients Adults (n = 300) 92.3 (277) 7.7 (23) 0.029 0.865 Children (n = 193) 92.7 (179) 7.3 (14) CSU patients per week <10 (n = 870) 92.2 (802) 7.8 (68) 0.076 0.783 ≥10 (n = 247) 92.7 (229) 7.3 (18) Only in physicians who chose one of the options Values marked in bold indicate a statistically significant difference (p < 0.05) the erythrocyte sedimentation rate (ESR), C-reactive pro- regions of the world (90 vs 10%). Autoimmunity was tein (CRP), anti-thyroid antibodies, and thyroid-stimulating the most common identifiable cause of CSU (51.9%) hormone (TSH) and of performing the autologous serum andmalignancywas theleast common identifiable skin test (ASST) as compared to those who do not (Table 6). cause of CSU (4.5%). Food intolerance was a less fre- CSU due to unknown causes was reported to be much quent cause of CSU in North America (8.0%) as com- more common than CSU due to known causes, in all pared to other regions of the world (> 16.0%) (Table 7). Table 5 Factors linked to the deviation from the urticaria guidelines Factors % (n) of physicians, who %(n) of physicians, who don’t X p deviate from the guidelines deviate from the guidelines Age, years <40 (n = 140) 35.7 (50) 64.3 (90) 5.194 0.023 ≥40 (n = 428) 46.7 (200) 53.3 (228) Clinical experience, years ≤19 years (n = 323) 39.9 (129) 60.1 (194) 5.049 0.025 Over 19 years (n = 245) 49.4 (121) 50.6 (124) Patients Outpatients (n = 510) 44.5 (227) 55.5 (283) 0.029 0.865 Inpatients (n = 44) 43.2 (19) 56.8 (25) Age of patients Adults (n = 150) 55.3 (83) 44.7 (67) 7.712 0.005 Children (n = 92) 37.0 (34) 63.0 (58) CSU patients per week <10 (n = 441) 44.0 (194) 50.0 (247) 0.002 0.961 ≥10 (n = 128) 43.7 (56) 56.3 (72) Only in physicians who chose one of the options Values marked in bold indicate a statistically significant difference (p < 0.05) Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 7 of 13 Table 6 Differences in the approach to the management of CSU in respondents who do and do not follow the guidelines Test Compared groups n % (n) of physicians, who % (n) of physicians, who X p follow the guidelines don’t follow the guidelines CBC Order 854 79.2 (802) 60.5 (52) 16.011 < 0.001 No 245 20.8 (211) 39.5 (34) ESR Order 602 55.9 (566) 41.9 (36) 6.284 0.012 No 497 44.1 (447) 58.1 (50) CRP Order 527 49.0 (496) 36.0 (31) 5.299 0.021 No 572 51.0 (517) 64.0 (55) Anti-TG/TPO Order 559 51.9 (526) 38.4 (33) 5.826 0.016 No 540 48.1 (487) 61.6 (53) TSH Order 543 50.8 (515) 32.6 (28) 10.598 0.001 No 556 49.2 (498) 67.4 (58) Total IgE Order 481 56.1 (445) 58.1 (36) 0.138 0.710 No 618 43.9 (568) 41.9 (50) ECP Order 51 4.7 (48) 3.5 (3) 0.280 0.597 No 1048 95.3 (965) 96.5 (83) D-dimer Order 54 5.2 (53) 1.2 (1) 2.809 0.094 No 1045 94.8 (960) 98.8 (85) Skin prick tests Order 308 71.4 (290) 79.1 (18) 2.329 0.127 No 791 28.6 (723) 20.9 (68) Allergen-specific IgE Order 286 26.5 (268) 20.9 (18) 1.257 0.262 No 813 73.5 (745) 79.1 (68) ANA Order 407 37.7 (382) 29.1 (25) 2.538 0.111 No 692 62.3 (631) 70.9 (61) Tryptase Order 162 84.9 (153) 89.5 (9) 1.357 0.244 No 937 15.1 (860) 10.5 (77) ASST Order 186 17.7 (179) 8.1 (7) 5.121 0.024 No 913 82.3 (834) 91.9 (79) Search for chronic infections Perform 364 66.2 (342) 74.4 (22) 2.394 0.122 No 735 33.8 (671) 25.6 (64) Do not order any tests 182 15.4 (156) 30.2 (26) 12.621 < 0.001 Order at least 1 test 917 84.6 (857) 69.8 (60) CBC complete blood count, ESR erythrocyte sedimentation rate, CRP C-reactive protein, TG/TPO thyroglobulin/thyroperoxidase, TSH thyroid-stimulating hormone, ECP eosinophil cationic protein, ANA antinuclear antibodies, ASST autologous serum skin test Values marked in bold indicate a statistically significant difference (p < 0.05) Adherence to urticaria guidelines is associated with more Vice versa, more physicians from North America as frequent administration and confidence in higher efficacy compared to other countries reported that tricyclic an- of second-generation antihistamines tidepressants are highly effective (52% vs 15–33%). Phy- Updosing of second-generation H1-antihistamines sicians who follow a urticaria guideline showed higher (sgAHs, 97%) and omalizumab (96%) were reported to rates of sgAHs administration as a first-line treatment be the most effective treatment options in all regions of of CSU (p = 0.001) and more frequently observed the world. Dapsone, montelukast and H2-antihistamines higher efficacy of treatment (or had more confidence were considered effective drugs for treatment of CSU that it would work, p < 0.019) as compared to those who worldwide only by 17, 17 and 15% physicians, respect- do not follow the guidelines (Table 8). Guideline fol- ively. Less respondents from North America as com- lowers more frequently use higher than standard-dosed pared to other regions of the world reported that sgAHs and omalizumab as a second and third line sgAHs at standard dose and montelukast are highly ef- treatment, respectively, and less frequently administer first fective (48% vs 60–76 and 9% vs 13–35%, respectively). generation antihistamines, tricyclic antidepressants and Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 8 of 13 Table 7 Number of respondents from different regions of the world who find these causes of CSU as most common (n = 1098) CSU causes Geographical regions Total % (n/total) NA LA EU AME AP % (n/total) % (n/total) % (n/total) % (n/total) % (n/total) Idiopathic CSU 97.5 (315/323) 80.6 (150/186) 88 (323/367) 93.3 (56/60) 89.5 (145/162) 90.1 (989/1098) Type-I-allergy 27.5 (77/280) 27.1 (46/170) 17.9 (60/336) 19.6 (11/56) 39.6 (59/149) 25.5 (253/991) Autoimmune CSU 64.4 (201/312) 44.8 (81/181) 46.8 (166/355) 32.8 (19/58) 54.1 (80/148) 51.9 (547/1054) Systemic disorders 26.7 (79/296) 29.1 (50/172) 18.2 (62/340) 12.3 (7/57) 20.8 (31/149) 22.6 (229/1014) Malignancy 2.4 (7/288) 6.1 (10/165) 6.6 (22/334) 0 (0/56) 3.6 (5/139) 4.5 (44/982) Chronic infection 11.7 (34/290) 32.8 (58/177) 27.4 (95/347) 13.6 (8/59) 22.3 (33/148) 22.3 (228/1021) Food intolerance 8.0 (23/289) 19.7 (35/178) 16.3 (56/343) 22.4 (13/58) 26.6 (41/154) 16.4 (168/1022) AME Africa/Middle-East, AP Asia-Pacific, EU Europe, LA Latin America, NA North America. the respondents could choose more than one answer systemic corticosteroids in comparison to physicians who our knowledge, our study is the first global report of do not follow a urticaria guideline (Tables 9 and 10). how physicians approach CSU. Discussion Most physicians know and use urticaria guidelines in their Several guidelines, consensus papers, and practice pa- clinical practice rameters have been developed for the management of More than 90% of respondents stated to be aware chronic urticaria. Some studies have explored, on the na- and follow urticaria guidelines. However, there is in- tional level, if physicians know these guidelines and im- consistency between our study and other studies. For plement them in their actual clinical practice [8, 9]. To example, most respondents from Latin America in Table 8 Differences in the approach to a first line treatment of CSU in physicians who do and do not follow the guidelines Treatment Compared n %(n) of physicians, who %(n) of physicians, who X p groups follow the guidelines don’t follow the guidelines First-generation H1-antihistamines Administer 173 15.4 (160) 14.8 (13) 0.026 0.873 No 953 84.6 (878) 85.2 (75) Second-generation H1-antihistamines at standard Administer 704 64 (664) 45.5 (40) 11.868 0.001 dose No 422 36 (374) 54.5 (48) Updosed second-generation H1-antihistamines Administer 540 47.8 (496) 50.0 (44) 0.160 0.690 No 586 52.2 (542) 50.0 (44) H2-antihistamines (e.g. famotidine or ranitidine) Administer 224 19.7 (204) 22.7 (20) 0.481 0.488 No 902 80.3 (834) 77.3 (68) Ciclosporin Administer 15 1.4 (15) 0 1.289 0.256 No 1111 98.6 (1023) 100 (88) Omalizumab Administer 32 3.0 (31) 1.1 (1) 1.006 0.316 No 1094 97.0 (1007) 98.9 (87) Montelukast Administer 150 13.2 (137) 14.8 (13) 0.174 0.676 No 976 86.8 (901) 85.2 (75) Dapsone Administer 7 0.6 (6) 1.1 (1) 0.409 0.522 No 1119 99.4 (1032) 98.9 (87) Systemic corticosteroids (for less than 10 days) Administer 215 18.7 (194) 23.9 (21) 1.406 0.236 No 911 81.3 (844) 76.1 (67) Systemic corticosteroids (for more than 10 days Administer 16 1.5 (16) 0 1.376 0.241 in a row) No 1110 98.5 (1022) 100 (88) Tricyclic antidepressants (e.g. doxepin) Administer 35 3.0 (31) 4.5 (4) 0.655 0.418 No 1091 97.0 (1007) 95.5 (84) Values marked in bold indicate a statistically significant difference (p < 0.05) Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 9 of 13 Table 9 Differences in the approach to a second line treatment of CSU in physicians who do and do not follow the guidelines Treatment Compared n %(n) of physicians, who %(n) of physicians, who X p groups follow the guidelines don’t follow the guidelines First-generation H1-antihistamines Administer 156 13.1 (136) 22.7 (20) 6.297 0.012 No 970 86.9 (902) 77.3 (68) Second-generation H1-antihistamines at standard Administer 127 11.3 (117) 11.4 (10) 0.001 0.979 dose No 999 88.7 (921) 88.6 (78) Updosed second-generation H1-antihistamines Administer 651 58.8 (610) 46.6 (41) 4.931 0.026 No 475 41.2 (428) 53.4 (47) H2-antihistamines (e.g. famotidine or ranitidine) Administer 308 27.1 (281) 30.7 (27) 0.532 0.466 No 818 72.9 (757) 69.3 (61) Ciclosporin Administer 76 6.8 (71) 5.7 (5) 0.173 0.678 No 1050 93.2 (967) 94.3 (83) Omalizumab Administer 163 14.5 (150) 14.8 (13) 0.007 0.934 No 963 85.5 (888) 85.2 (75) Montelukast Administer 391 35.5 (368) 26.1 (23) 3.106 0.078 No 735 64.5 (670) 73.9 (65) Dapsone Administer 39 3.2 (33) 6.8 (6) 3.213 0.073 No 1087 96.8 (1005) 93.2 (82) Systemic corticosteroids (for less than 10 days) Administer 265 23.8 (247) 20.5 (18) 0.503 0.478 No 861 76.2 (791) 79.5 (70) Systemic corticosteroids (for more than 10 days Administer 89 7.4 (77) 13.6 (12) 4.309 0.038 in a row) No 1037 92.6 (961) 86.4 (76) Tricyclic antidepressants (e.g. doxepin) Administer 137 11.6 (120) 19.3 (17) 4.568 0.033 No 989 88.4 (918) 80.7 (71) Values marked in bold indicate a statistically significant difference (p < 0.05) our study (94%) followed any urticaria guideline with guidelines were also showed to be linked with the ad- 78% followed the EAACI/GA LEN/EDF/WAO urti- vanced age of the physicians [11–13]. For example, old caria guideline. In contrast, only 79 of 421 (19%) phy- age, male sex, and incomplete residency training were sicians from Ecuador reported to know the EAACI/ associated with disagreement with clinical practice GA LEN/EDF/WAO urticaria guideline, but more guidelines for cancer screening [13]. In contrast, com- than half of them (67%) were dermatologists and al- pared with physicians ≥50 years, younger physicians (< lergists [8]. In German-wide study, only one-third of 50 years) reported a lower level of awareness of choles- all physicians participating in the survey were familiar terol guidelines [14]. with the EAACI/GA LEN/EDF/WAO urticaria guide- We did not compare the adherence to urticaria guide- line [9]. In Italy, 56% of specialists knew the CSU lines between respondents of different specialties be- guidelines and only 27% used them regularly [10]. cause most physicians in our study were allergists and The high rates of adherence to urticaria guidelines in many of them had several specialties. However, in previ- our study can be explained by increase in guidelines ous studies the level of knowledge was highest for aller- awareness worldwide over time and the fact that most gists and/or dermatologists [8, 9], and these physicians of the participants were allergists/clinical immunolo- have significantly higher expertise in caring for patients gists (88%). with urticaria than other specialists [15]. An observa- tional study from the UK showed that allergists follow Factors associated with adherence to guidelines the urticaria guidelines more regularly and consistently Young (< 40 years) and less experienced physicians compared to dermatologists [16]. The results of this (≤19 years in practice) more often follow guidelines and study should be evaluated with caution because of the less often deviate from them than their older and more fact that Allergology is recognized as a specialty in some experienced colleagues. A similar tendency has been ob- countries (for example, in Russia) or as a subspecialty in served for other diseases, where low adherence rates to others (for example, in Germany). Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 10 of 13 Table 10 Differences in the approach to a third line treatment of CSU in physicians who do and do not follow the guidelines Treatment Compared groups n %(n) of physicians, who %(n) of physicians, who X p follow the guidelines don’t follow the guidelines First-generation H1-antihistamines Administer 93 7.7 (80) 14.8 (13) 5.345 0.021 No 1033 92.3 (958) 85.2 (75) Second-generation H1-antihistamines at standard Administer 78 6.9 (72) 6.8 (6) 0.002 0.967 dose No 1048 93.1 (966) 93.2 (82) Updosed second-generation H1-antihistamines Administer 283 25.4 (264) 21.6 (19) 0.637 0.425 No 843 74.6 (774) 78.4 (69) H2-antihistamines (e.g. famotidine or ranitidine) Administer 206 18.3 (190) 18.2 (16) 0.001 0.977 No 920 81.7 (848) 81.8 (72) Ciclosporin Administer 254 23.1 (240) 15.9 (14) 2.416 0.120 No 872 76.9 (798) 84.1 (74) Omalizumab Administer 570 51.8 (538) 36.4 (32) 7.764 0.005 No 556 48.2 (500) 63.6 (56) Montelukast Administer 319 28.9 (300) 21.6 (19) 2.135 0.144 No 807 71.1 (738) 78.4 (69) Dapsone Administer 91 7.8 (81) 11.4 (10) 1.384 0.239 No 1035 92.2 (957) 88.6 (78) Systemic corticosteroids (for less than 10 days) Administer 227 20.1 (209) 20.5 (18) 0.005 0.943 No 899 79.9 (829) 79.5 (70) Systemic corticosteroids (for more than 10 days Administer 146 12.7 (132) 15.9 (14) 0.733 0.392 in a row) No 980 87.3 (906) 84.1 (74) Tricyclic antidepressants (e.g. doxepin) Administer 134 11.7 (121) 14.8 (13) 0.751 0.386 No 992 88.3 (917) 85.2 (75) Values marked in bold indicate a statistically significant difference (p < 0.05) Impact of following the guidelines on the quality of care test (83.5%) [8]. Interestingly, 5–15% of respondents for CSU patients perform other less useful diagnostic tests, e.g. ECP According to the EAACI/GA LEN/EDF/WAO guideline, and tryptase, in patients with CSU. only differential blood count and CRP or ESR are rec- Idiopathic CSU was reported to be the most common ommended as routine diagnostic tests for CSU patients type of CSU; this is in the line with other studies [9, 17]. [1]. The US practice parameters recommend limited la- In one study, allergists and dermatologists more fre- boratory testing including a CBC with differential, ESR quently searched for CSU etiology as compared to gen- and/or CRP, liver enzymes, and TSH measurement [7]. eral practitioners [8] in contrast to the results of other Expectedly, these diagnostic tests were performed more study [9]. Although IgE-mediated allergy is a rare cause frequently by physicians who follow a urticaria guideline of CSU [1, 18], IgE-mediated allergy is considered to be in our and other studies [8, 9]. a common cause of CSU by 26% of respondents. Additional tests are indicated as an extended diag- Up to 50% of CSU patients can have circulating func- nostic program for identification of underlying causes tional IgG autoantibodies against IgE and high-affinity or eliciting factors and for ruling out possible differ- IgE receptors on mast cells and basophils [19]. Half of ential diagnoses if suggested based on history only respondents reported autoimmune CSU as the most [1]. For example, allergy is regarded as a very rare common cause of CSU and 16.9% of physicians (10.1– cause of CSU [1], and allergy testing is usually not 13.5% in other studies [8, 9]) carried out ASST as a cost-effective and does not lead to improved patient screening method for the detection of autoantibodies care outcomes [7]. However, some physicians reported [1]. ASST was applied more often by physicians who to determine total serum IgE (43.8%) and to perform were aware of and/or follow the guidelines in our and allergy skin prick testing in patients with CSU another study [9], but not in all [8]. (28.0%). In a cross-sectional study from Latin Amer- There is a universal agreement among urticaria guide- ica, total serum IgE was the most common diagnostic lines [1, 7, 20] that second generation antihistamines Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 11 of 13 (sgAHs) at a standard dose should be the first line therapy, sufficient flexibility and by educating them that guide- which is effective in improving symptoms in about 40% of lines are meant to complement, rather than substitute CSU patients [21]. Guideline followers, quite expectedly, for, clinical judgement. use sgAHs at a standard dose as a first line therapy more One-fifth of physicians reported that some of the guide- frequently than non-followers, while the administration of lines’ recommendations cannot be implemented in physi- other drugs was not different between the two groups. cian’s country of residency. It suggests that economic This has been proved in early national cross-sectional considerations are an important and often decisive factor studies where sgAHs taken regularly were the most com- influencing the choice of a treatment strategy. For ex- mon drugs prescribed [10, 22]. It is consistent with the ample, omalizumab is unavailable in some countries or its finding that more guidelines followers (67.4%) than cost is too high and health insurance programs do not non-followers (50%) feel that sgAHs are highly effective in cover it (for example, in Russia or Latin America [23]). CSU treatment. Systemic steroids and first generation antihistamines are As a second line therapy, the EAACI/GA LEN/EDF/ cheaper than sgAHs (for example, in Ecuador [8]) and this WAO urticaria guideline recommends the use of sgAHs can prompt a physician’s decision to prescribe them. The in higher doses up to four times the standard dose. Phy- cost-effectiveness of the treatment for CSU, especially in sicians who use urticaria guidelines more frequently se- the developing and low-income countries, should be fur- lected up-dosing for a second-line treatment in our and ther investigated in future studies. other studies [9, 10]. The EAACI/GA LEN/EDF/WAO guideline is revised For non-respondents to sgAHs up-dosing, the EAACI/ every four years by a global panel of well-known experts GA LEN/EDF/WAO guideline recommends omalizu- in the field. Interestingly, 8–10% of respondents did not mab, ciclosporin (step 4 in the US practice parameters) agree with guidelines’ recommendations and conclusions or montelukast (step 2 in the US practice parameters) as or found guideline recommendations unclear or out- a third line treatment option [1, 7]. Guideline followers dated. Again, this calls for the consideration of improve- in our and one other study [8] more frequently used ments in the development of guideline updates and omalizumab as a third line treatment in comparison to revisions. physicians who do not follow a urticaria guideline. The recommendations given by all of urticaria guidelines Our and early studies [9] showed that physicians who are similar, although some differences exist. For example, in are familiar with the guidelines are less likely to use first contrast to the EAACI/GA LEN/EDF/WAO guideline US generation antihistamines as a second and/or third line practice parameters recommend H2-antagonists and first treatment and systemic steroids (for more than 10 days in generation antihistamines for treatment of urticaria as a a row) as a second line therapy, indicating that guideline second or third line therapy, respectively [24]. Only 4% of recommendations may improve the quality of care [9]. respondents named the discrepancy and/or disagreement The treatment of CSU can depend on physician’sspe- between the guidelines as a reason not to follow them. cialty. For example, Cherrez et al. showed that allergists Taken together, reliance on own clinical experience, es- and dermatologists in Ecuador prescribed significantly pecially in older physicians, rather than economic reasons more sgAHs (regular doses) as compared to general prac- or unavailability of drugs, appears to be the most frequent titioners [8]. reason for deviation from or not following the guidelines. This observation offers the opportunity for a debate on Reasons for not following or deviation from the available medicine based on experience and evidence-based medi- urticaria guidelines cine and highlights the need for continuous medical edu- Almost one-third of physicians do not follow a guideline cation for healthcare providers. or deviate from it. The most frequent reasons given were reliance on their own clinical experience (44%) and an Limitations overly simplified approach to CSU management recom- The main limitations of our study are the bias of partici- mended by the guidelines (30%). Moreover, many physi- pant selection, the use of an online non-validated ques- cians, especially those of 40 years or older and with tionnaire and a low response rate (3.5%). The fact that clinical experience of > 19 years, follow guidelines but most participants in our study were allergists, whereas can deviate from them in some cases, e.g. in CSU is often managed by dermatologists and general difficult-to-treat CSU. This may point to a need to better practitioners, could explain some differences between our communicate to physicians, especially experienced phy- findings and those from other studies [8, 9]. There is lim- sicians, the benefits of guideline adherence and to better ited information in regards to CSU management in Af- engage them in the guideline development and review rica/Middle-East (only 64 questionnaires were filled out). process. Also, more efforts appear to be needed to im- The most recent EAACI guideline [18]appeared after we prove physician “buy-in” to guidelines by allowing for performed our study agreeing on our observations. Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 12 of 13 Conclusion used for the online survey. MSB and IA made substantial contributions to the revisions of the manuscript. All authors contributed to the interpretation of The results of our study indicate that urticaria guideline the data, critical revisions, and approved the final version of the manuscript recommendations contribute to a higher quality of pa- for submission. tient care. Most physicians worldwide follow a guideline, Ethics approval and consent to participate however, one in five deviates from them. We speculate Not applicable. there are three major reasons for deviation that should be addressed in future research. Firstly, older physicians Consent for publication Not applicable. may be prone to disproportionate reliance on their clin- ical experience and unable to fully incorporate rapidly Competing interests emerging evidence-based approaches in their routine clin- The authors declare they have no competing interests related to this work. ical practice, which highlights the need for continuous medical education for healthcare providers regardless of Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in their age group or occupying position. Secondly, the qual- published maps and institutional affiliations. ity of CSU patient care may be, to a large degree, compro- mised by the financial constraints and insufficient level of Author details Division of Immune-mediated skin diseases, I.M. Sechenov First Moscow training of the treating physicians in developing countries. State Medical University, 119991, Trubeckaya str., 8/2, Moscow, Russian It warrants more research into pharmacoeconomics and 2 Federation. Department of Infection and Immunity, Luxembourg Institute of sustainability of up-to-date CSU treatments and further Health, Esch-sur-Alzette, Luxembourg. Department of Dermatology and Venereology, Trakia University, Stara Zagora, Bulgaria. Asthma Center and propagation of new knowledge about CSU etiopathogen- Allergy Unit, Verona University Hospital, Verona, Italy. Hospital Sírio Libanês esis and treatment among practicing physicians of differ- and Post-graduation Program in Health Sciences of IAMSPE São Paulo, São ent specialties and healthcare authorities in different Paulo, Brazil. University Hospital of Montpellier, Montpellier and Sorbonne Universités, Paris, France. Faculty of Medicine, University of Medicine and countries. Finally, urticaria guidelines themselves can be a Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam. Division of cause for suboptimal patient care (for example, unclear Allergy, Pulmonary and Sleep Medicine, Department of Medicine, Mayo recommendations and discrepancies between the guide- Clinic, Jacksonville, Florida, USA. Servicio de Enfermedades del Sistema Inmune-Alergia, Hospital Universitario Príncipe de Asturias, Madrid, Spain. lines). Thus, on the one hand, urticaria guidelines should Departamento de Medicina y Especialidades Médicas, Facultad de be flexible enough to allow a physician to tailor the treat- 11 Medicina, Universidad de Alcalá, Madrid, Spain. Department of Allergy and ment to the unique profile of each patient and circum- Immunology, Cleveland Clinic Florida, Weston, Florida, USA. Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, stances specific to their country of residence; on the Germany. Allergy and Clinical Immunology Department, Centro Medico other hand, further standardization and dissemination of 14 Docente La Trinidad, Caracas, Venezuela. Department of Allergy and guidelines can increase adherence among physicians Immunology, Hospital Quirónsalud Bizkaia, Bilbao, Spain. worldwide and result in better patient care. Received: 22 February 2018 Accepted: 7 June 2018 Additional file References 1. Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, Additional file 1: The web-based questionnaire. (PDF 180 kb) et al. The EAACI/GA(2) LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy. 2014;69(7):868–87. Abbreviations 2. Gaig P, Olona M, Munoz Lejarazu D, Caballero MT, Dominguez FJ, AAAAI: American Academy of Allergy, Asthma & Immunology; Echechipia S, et al. Epidemiology of urticaria in Spain. J Investig Allergol Clin ASST: Autologous serum skin test; CBC: Complete blood count; CRP: C- Immunol. 2004;14(3):214–20. reactive protein; CSU: Chronic spontaneous urticaria; ESR: Erythrocyte 3. Lapi F, Cassano N, Pegoraro V, Cataldo N, Heiman F, Cricelli I, et al. sedimentation rate; JMG: Junior Member Group; sgAHs: Second generation Epidemiology of chronic spontaneous urticaria: results from a nationwide, antihistamines; TSH: Thyroid-stimulating hormone; WAO: World Allergy population-based study in Italy. Br J Dermatol. 2016;174(5):996–1004. Organization 4. O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997;136(2):197–201. Acknowledgements 5. Maurer M, Weller K, Bindslev-Jensen C, Gimenez-Arnau A, Bousquet PJ, The authors thank the World Allergy Organization for the resources to carry Bousquet J, et al. Unmet clinical needs in chronic spontaneous urticaria. A out and publish this paper. GA(2)LEN task force report. Allergy. 2011;66(3):317–30. 6. Fine LM, Bernstein JA. Urticaria guidelines: consensus and controversies in the Funding European and American guidelines. Curr Allergy Asthma Rep. 2015;15(6):30. The study was supported by WAO (the dissemination of the questionnaire 7. Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The via WAO online resources, the hosting of the questionnaire and data and diagnosis and management of acute and chronic urticaria: 2014 update. funding the authors’ APC fees to the publisher of the WAO Journal). J Allergy Clin Immunol. 2014;133(5):1270–7. 8. Cherrez A, Maurer M, Weller K, Calderon JC, Simancas-Racines D, Cherrez Ojeda I. Authors’ contributions Knowledge and management of chronic spontaneous urticaria in Latin America: PK drafted the article and contributed to the conception and design of the a cross-sectional study in Ecuador. World Allergy Organ J. 2017;10(1):21. study, analysis and interpretation of data. MM made substantial contributions 9. Weller K, Viehmann K, Brautigam M, Krause K, Siebenhaar F, Zuberbier T, to the conception and design of the study and revised the article critically et al. Management of chronic spontaneous urticaria in real life–in for important intellectual content. PK, DP, RD, MC, LKT, DLP, AGE, DAA, VD accordance with the guidelines? A cross-sectional physician-based survey and KW contributed substantially to the development of the questionnaire study. J Eur Acad Dermatol Venereol. 2013;27(1):43–50. Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 13 of 13 10. Rimoldi M, Rossi O, Rota N. State of the art of chronic spontaneous urticaria in Italy: a multicentre survey to evaluate physicians’ and patients’ perspectives. BMJ Open. 2016;6(10):e012378. 11. Adedeji AR, Tumbo J, Govender I. Adherence of doctors to a clinical guideline for hypertension in Bojanala district, north-West Province, South Africa. Afr J Prim Health Care Fam Med. 2015;7(1). Art. #776, 6 pages. 12. Kenefick H, Lee J, Fleishman V. In: Everett W, editor. Improving Physician Adherence to Clinical Practice Guidelines: Barriers and Strategies for Change. USA: New England Healthcare Institute; 2008. p. 55. 13. Tudiver F, Herbert C, Goel V. Why don't family physicians follow clinical practice guidelines for cancer screening? CMAJ. 1998;159(7):797–8. 14. Christian AH, Mills T, Simpson SL, Mosca L. Quality of cardiovascular disease preventive care and physician/practice characteristics. J Gen Intern Med. 2006;21(3):231–7. 15. Henderson RL Jr, Fleischer AB Jr, Feldman SR. Allergists and dermatologists have far more expertise in caring for patients with urticaria than other specialists. J Am Acad Dermatol. 2000;43(6):1084–91. 16. Wu CH, Ardern-Jones MR, Eren E, Venter C. An observational study of the diagnosis and Management of Chronic Urticaria in the UK. Int Arch Allergy Immunol. 2015;167(1):1–8. 17. Maurice-Tison S, Pouyanne J, Doutre MS. General practitioners, dermatologists, allergists, and the management of chronic urticaria. Results of a practice survey. Ann Dermatol Venereol. 2003;130(1):1S160–73. 18. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al., The EAACI/GA(2)LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update. Allergy. 2018. https://doi.org/10.1111/all.13397. [Epub ahead of print]. 19. Kolkhir P, Church MK, Weller K, Metz M, Schmetzer O, Maurer M. Autoimmune chronic spontaneous urticaria: what we know and what we do not know. J Allergy Clin Immunol. 2017;139(6):1772–81. e1 20. Ortonne JP. Chronic urticaria: a comparison of management guidelines. Expert Opin Pharmacother. 2011;12(17):2683–93. 21. Guillen-Aguinaga S, Jauregui Presa I, Aguinaga-Ontoso E, Guillen-Grima F, Ferrer M. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. Br J Dermatol. 2016;175(6):1153–65. 22. Ferrer M, Jauregui I, Bartra J, Davila I, del Cuvillo A, Montoro J, et al. Chronic urticaria: do urticaria nonexperts implement treatment guidelines? A survey of adherence to published guidelines by nonexperts. Br J Dermatol. 2009; 160(4):823–7. 23. Wilches P, Calderon JC, Cherrez A, Cherrez Ojeda I. Omalizumab for chronic urticaria in Latin America. World Allergy Organ J. 2016;9(1):36. 24. Beck LA, Bernstein JA, Maurer M. A review of international recommendations for the diagnosis and management of chronic Urticaria. Acta Derm Venereol. 2017;97(2):149–58. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Allergy Organization Journal Springer Journals

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Abstract

Background: The approaches to the diagnosis and treatment of chronic spontaneous urticaria (CSU) differ in various parts of the world. We sought to determine the adherence to international and national urticaria guidelines as well as the motives to deviate from the guidelines among physicians worldwide. Methods: A web-based questionnaire was created and launched via e-mail by the World Allergy Organization (WAO) to representatives of all WAO Member Societies, the members of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the members of the WAO Junior Members Group (JMG), regardless of the specialty, affiliation, or nationality in March 2017. Results: We received 1140 completed surveys from participating physicians from 99 countries. Virtually all participants (96%) were aware of at least one urticaria guideline and reported that they follow a guideline. However, one in five physicians who follow a guideline (22%) reported to deviate from it. Reliance on own clinical experience is the most frequent reason for deviation from guidelines or not following them (44%). Young (< 40 years) and less experienced physicians more often follow a guideline and less often deviate than older and experienced ones. Physicians who follow a urticaria guideline showed higher rates of routinely ordering a complete blood count, the erythrocyte sedimentation rate, C-reactive protein, anti-thyroid antibodies, and thyroid-stimulating hormone and of performing the autologous serum skin test as compared to those who do not. Physicians who follow a urticaria guideline showed higher rates of using second generation antihistamines as their first-line treatment of CSU (p = 0.001) and more frequently observed higher efficacy of these drugs (or had more confidence that it would work, p < 0.019)ascomparedtothose whodonot follow the guidelines. Conclusions: Physicians’ characteristics (e.g. age, clinical experience, and specialty) and country specifics and regional features (e.g. availability of drugs for CSU treatment) importantly influence adherence to urticaria guidelines and CSU patient care and should be addressed in more detail in future research. Keywords: Chronic spontaneous urticaria, Guidelines, Worldwide, Guideline adherence, Urticaria treatment, Urticaria management, Global survey * Correspondence: pavel.kolkhir@yandex.ru Division of Immune-mediated skin diseases, I.M. Sechenov First Moscow State Medical University, 119991, Trubeckaya str., 8/2, Moscow, Russian Federation Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This 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. Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 2 of 13 Background disease, and treatment options used). There were 11 Chronic spontaneous urticaria (CSU) is a mast single-choice and 13 multiple-choice questions. cell-driven disease that is defined as the occurrence of wheals, angioedema, or both for more than 6 weeks due Recruitment and dissemination to known or unknown causes [1]. CSU affects up to 1% The survey was beta tested and approved by the WAO of the general population [2, 3]. It exerts a devastating JMG Steering Committee and WAO leadership before impact on patients’ quality of life [4, 5]. dissemination among participants. It was disseminated via The approaches to the diagnostic workup and treatment email by the WAO office to representatives of WAO of CSU patients differ in various parts of the world, and Member Societies as well as members of AAAAI and the there are discrepancies between national consensus papers WAO JMG in March 2017, with no restrictions applied to and guidelines and the international EAACI/GA LEN/ the specialty, affiliation, or nationality of the participants. EDF/WAO guideline [1, 6, 7]. The impact of guidelines on The email contained a link (Internet address) to the online the diagnostic workup and treatment strategy selection in questionnaire that was unique to each participating every day clinical practice needs further research. How member. A reminder to participate was sent in April 2017. many physicians know urticaria guidelines? How many Participants were given 30 days to reply and were guaran- physicians use them to guide their clinical practice? What teed complete anonymity. are the reasons for not following the available guidelines? What is the impact of following the guidelines on the Statistical analysis quality of care for urticaria patients? These questions need SPSS v.22 (Armonk, NY: IBM Corp, USA) was used for all to be addressed on a global level. The answers to these analyses. Analyses of the difference in frequencies across questions can be of significant value in updating and revis- groups were performed with the Pearson Chi-squared test ing the current guidelines and improving patient care. and a p value ≤0.05 was considered significant. The World Allergy Organization (WAO) Junior Mem- bers Group (JMG) Steering Committee developed a ques- Results tionnaire to survey the opinions on a whole variety of Demographics of study participants questions regarding CSU management and the use of A total of 32,356 individuals from 149 countries were guidelines. The questionnaire targeted the WAO members, invited to take part in the survey. We received 1140 including, but not limited to the representatives of the con- (3.5%) completed surveys from participating physicians stituent national societies of WAO, having the authority to from 99 countries, with most residing in Europe (33.2%) vote on their behalf, the WAO JMG and the American and North America (28.9%) (Table 1). Most of the Academy of Allergy, Asthma & Immunology (AAAAI) respondents were allergists/clinical immunologists members. We sought to determine, in physicians from (88.7%), followed by pediatricians (16.5%), dermatolo- around the world, the knowledge of and adherence to inter- gists (4.5%) and general practitioners (2.2%) (Table 2). national and national urticaria guidelines as well as the mo- One hundred and fifty-seven participants had more than tives to deviate from them. one specialty. The majority of participants were ≥ 40 years old (74.8%) and almost half of respondents had clinical experience of > 19 years (43.9%). Two thirds and Methods half of the participants worked in academic institutions Study survey and/or had a private practice. Most participants (88.9%) A web-based questionnaire (Additional file 1:FigureS1) reported to see primarily outpatients, both adults and was created and circulated among the members of the children with CSU (53.7%). Only 22% of physicians WAO JMG Steering Committee for revisions (July–Sep- reported to see ≥10 CSU patients per week. tember 2016). The protocol was approved by the WAO Executive Committee and Board of Directors (25 October More than 90% of physicians follow the urticaria 2016). The questionnaire was created de novo and has not guidelines, but almost one-fourth of them deviate been previously validated. The final version consisted of 24 Virtually all participants (1086 of 1126, 96%) were aware questions including survey participant demographic infor- of one or more urticaria guidelines, and almost all of them mation (country of residence, gender, age, specialty, clinical reported to follow a guideline (n = 1038 of 1086, 96%) experience and type of practice) and those concerning CSU (Fig. 1). The most widely used guideline was the inter- management (patients’ age, number of CSU patients seen national EAACI/GA LEN/EDF/WAO urticaria guideline per week, number of CSU patients with angioedema, [1] (58.9%), followed by the American AAAAI/ACAAI awareness, adherence and/or deviation of current guide- Joint Task Force practice parameters for the diagnosis and lines, examination of a CSU patient, including general management of acute and chronic urticaria [7](38.1%) laboratory work-up and targeted search for the cause of the and national guidelines (22.7%). Expectedly, the US Joint Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 3 of 13 Table 1 A geographical distribution of the respondents participating in the survey (n = 1140) North America Latin America Europe Africa/Middle-East Asia-Pacific (n = 330, 28.9%) (n = 193, 16.9%) (n = 379, 33.2%) (n = 64, 5.6%) (n = 174, 15.3%) Canada Argentina Albania Algeria Australia United States Bolivia Armenia Cyprus Bangladesh US Virgin Islands Brazil Austria Egypt Cambodia Chile Azerbaijan Ethiopia Hong Kong Colombia Belarus Iran India Costa Rica Belgium Israel Indonesia Cuba Bulgaria Kenya Japan Dominican Republic Croatia Lebanon Jordan Ecuador Czech Republic Oman Korea El Salvador Denmark Qatar Kuwait Guatemala Estonia South Africa Malaysia Honduras Finland Tunisia Mongolia Mexico France Nepal Panama Georgia New Zealand Paraguay Germany Pakistan Peru Greece Peoples Republic of China Uruguay Guernsey Philippines Venezuela Hungary Saudi Arabia Iceland Singapore Ireland Sri Lanka Italy Taiwan Kosovo Thailand Latvia United Arab Emirates Lithuania Uzbekistan Macedonia Viet Nam Moldova Montenegro Netherlands Poland Portugal Romania Russia Serbia Slovakia Slovenia Spain Sweden Switzerland Turkey Ukraine United Kingdom Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 4 of 13 Table 2 Characteristics of survey respondents (n = 1140) Characteristics of respondents Geographical regions Total % (n) NA LA EU AME AP % (n/total) % (n/total) % (n/total) % (n/total) % (n/total) Specialty (n = 1138) Allergists/ Clinical Immunologists 98.2 (324/330) 97.4 (187/192) 83.1 (315/379) 79.7 (51/64) 76.9 (133/173) 88.7 (1010) Dermatologists 0.3 (1/330) 0.5 (1/192) 9.8 (37/379) 0 6.9 (12/173) 4.5 (51) Pediatricians 4.2 (14/330) 25.5 (49/192) 17.4 (66/379) 23.4 (15/64) 25.4 (44/173) 16.5 (188) General Practitioners 0.6 (2/330) 3.1 (6/192) 1.6 (6/379) 6.2 (4/64) 4 (7/173) 2.2 (25) Gender (n = 1117) Male 58.5 (189/323) 55.1 (102/185) 43.7 (163/373) 57.1 (36/63) 58.4 (101/173) 53.0 (591) Female 41.5 (134/323) 44.9 (83/185) 56.3 (210/373) 42.9 (27/63) 41.6 (72/173) 47.0 (526) Age, years (n = 1132) < 40 22.9 (75/327) 27.6 (53/192) 28.2 (106/376) 17.2 (11/64) 23.1 (133/173) 25.2 (285) ≥40 77.1 (252/327) 72.4 (139/192) 71.8 (270/376) 82.8 (53/64) 76.9 (133/173) 74.8 (847) Clinical experience, years (n = 1130) ≤19 50.3 (164/326) 53.9 (104/193) 58.2 (217/373) 60.9 (39/64) 63.2 (110/174) 56.1 (634) Over 19 49.7 (162/326) 46.1 (89/193) 41.8 (156/373) 39.1 (25/64) 36.8 (64/174) 43.9 (496) Place of work (n = 1140) Private practice 63.9 (211/330) 82.4 (159/193) 34.6 (131/379) 54.7 (35/64) 46.0 (80/174) 54.0 (616) University clinic 70.3 (232/330) 68.4 (132/193) 57.5 (218/379) 59.4 (38/64) 71.8 (125/174) 65.3 (745) Hospital 11.8 (39/330) 39.4 (76/193) 43.3 (164/379) 42.2 (27/64) 58.6 (102/174) 35.8 (408) Specialized urticaria centre 0.9 (3/330) 4.7 (9/193) 2.9 (11/379) 3.1 (2/64) 0.3 (3/174) 2.4 (28) Department (n = 1140) Outpatients 97.3 (321/330) 89.6 (173/193) 82.3 (312/379) 81.3 (52/64) 89.1 (155/174) 88.9 (1013) Inpatients 0.9 (3/330) 8.8 (17/193) 12.4 (47/379) 10.9 (7/64) 6.9 (12/174) 7.5 (86) Outpatients and inpatients 1.8 (6/330) 1.6 (3/193) 5.3 (20/379) 7.8 (5/64) 4.0 (7/174) 3.6 (41) Age of patients (n = 1131) Adults 16.5 (54/327) 17.2 (33/192) 42.0 (158/376) 10.9 (7/64) 30.8 (53/172) 27.0 (305) Children 9.5 (31/327) 16.7 (32/192) 19.4 (73/376) 18.8 (12/64) 27.9 (71/172) 19.3 (219) Adults and children 74.0 (242/327) 66.1 (127/192) 38.6 (145/376) 70.3 (45/64) 41.3 (48/172) 53.7 (607) Number of CSU patients per week (n = 1127) < 10 75.5 (247/327) 78.8 (152/193) 80.7 (302/374) 71.0 (44/62) 78.4 (134/171) 78.0 (879) ≥10 24.5 (80/327) 21.2 (41/193) 19.3 (72/374) 29.0 (18/62) 21.6 (37/171) 22.0 (248) Patients with angioedema, % from the total number of CSU patients (n = 1131) ≤20 37.7 (123/326) 58.5 (113/193) 51.7 (195/377) 55.6 (35/63) 66.3 (114/172) 51.3 (580) > 20 62.3 (203/326) 41.5 (80/193) 48.3 (182/377) 44.4 (28/63) 33.7 (58/172) 48.7 (551) Adherence to the urticaria guidelines (n = 1126) Follow the guidelines Any of three below 88.0 (286/325) 93.8 (180/192) 97.3 (365/375) 85.7 (54/63) 89.5 (153/171) 92.2 (1038) EAACI/WAO/GA LEN/EDF 16.3 (53/325) 78.1 (150/192) 82.4 (309/375) 68.3 (43/63) 63.2 (108/171) 58.9 (663) US practice parameters 81.2 (264/325) 32.3 (62/192) 9.1 (34/375) 28.6 (18/63) 29.8 (51/171) 38.1 (429) National 7.1 (23/325) 26.0 (50/192) 32.5 (122/375) 14.3 (9/63) 30.4 (52/171) 22.7 (256) Follow any but deviate 40.0 (80/200) 28.1 (25/89) 49.4 (79/160) 58.1 (18/31) 53.8 (49/91) 22.3 (251) Do not follow 12.0 (39/325) 6.3 (12/192) 2.7 (10/375) 14.3 (9/63) 10.5 (18/171) 7.8 (88) AME Africa/Middle-East, AP Asia-Pacific, EU Europe, LA Latin America, NA North America. respondents could choose more than one option Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 5 of 13 Latin America, where the most common reason, pro- vided by 14.3% of respondents, was that some of the guidelines’ recommendations cannot be implemented in their country of residence. The second most preva- lent reason for deviating from guideline recommenda- tions (29.8%) was that the approach to CSU management recommended by the guidelines was seen as overly simplified and not reflecting the com- plexity of the disease. The least frequent reasons were the discrepancy and/or disagreement between the guidelines (3.8%) and a negative experience with following the guidelines in clinical practice (3.2%). Nine percent of participants did not agree with the Fig. 1 Adherence to the urticaria guidelines. Physicians were asked if guidelines’ recommendations and/or conclusions. they know and follow the current guidelines for management of urticaria. Results are expressed as percentage of participants who Young and less experienced physicians more often follow chose the corresponding guidelines (one respondent could choose several answers) a guideline and less often deviate than older and experienced ones Physicians who are less than 40 years of age more Task Force practice parameters are used more often often reported that they adhere to urticaria guidelines and in North America and the EAACI/GA LEN/EDF/ less often deviate as compared to responding physicians of WAO urticaria guidelines are more known in other ≥40 years of age (p = 0.001 and p = 0.023, respectively). countries of the world. One in five physicians who Responding physicians with clinical experience of > 19 follow a guideline (22%) reported to deviate from it. years statistically more often deviate from the guide- lines and less frequently follow them as compared to Reliance on own clinical experience is the most frequent responding physicians with clinical experience of reason for deviation from the guidelines or not following 19 years or less (p =0.025 and p < 0.001, respectively) them (Tables 4 and 5). Of the 339 (30%) physicians who do not follow a guideline or follow a guideline but deviate from it, Physicians who follow a urticaria guideline more often 149 (43.9%) reported that they rely more on their perform diagnostic tests own clinical experience (Table 3). It was the most fre- Physicians who follow a urticaria guideline showed higher quent reason in all regions of the world except for rates of routinely ordering a complete blood count (CBC), Table 3 Reasons why physicians don’t follow or deviate from the guidelines Reasons Geographical regions Total n = 339 % (n) a a a a a NA n = 236 LA n =98 EU n = 167 AME n =38 AP n = 104 % (n) % (n) % (n) % (n) % (n) The guidelines do not undergo revision frequently enough 4.2 (10) 4.1 (4) 3.0 (5) 5.3 (2) 6.7 (7) 8.2 (28) I rely more on my own clinical experience 27.1 (64) 10.2 (10) 20.4 (34) 34.2 (13) 26.9 (28) 43.9 (149) I do not agree with the guidelines’ recommendations 7.2 (17) 3.1 (3) 4.2 (7) 2.6 (1) 3.8 (4) 9.4 (32) and/or conclusions Some of the recommendations are unclear to me and require 3.4 (8) 1.0 (1) 8.4 (14) 2.6 (1) 11.5 (12) 10.6 (36) further details Some of the guidelines’ recommendations cannot be 0.8 (2) 14.3 (14) 12.0 (20) 26.3 (10) 22.1 (23) 20.3 (69) implemented in my country of residence I had a negative experience with following the guidelines 1.7 (4) 0 (0) 3.6 (6) 2.6 (1) 0 (0) 3.2 (11) in my clinical practice Overly simplified approach to CSU management 22.9 (54) 7.1 (7) 15.6 (26) 10.5 (4) 9.6 (10) 29.8 (101) recommended by the guidelines that does not reflect the complexity of the disease The discrepancy and/or disagreement between the guidelines 3.0 (7) 2.0 (2) 1.8 (3) 2.6 (1) 0 (0) 3.8 (13) AME Africa/Middle-East, AP Asia-Pacific, EU Europe, LA Latin America, NA North America. the total number of respondents was 339. However, there was overlapping in the data analysis because respondents could choose more than one option Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 6 of 13 Table 4 Factors linked to adherence to the urticaria guidelines Factors % (n) of physicians, who follow the guidelines % (n) of physicians, who don’t follow the guidelines X p Age, years <40 (n = 283) 96.9 (274) 3.1 (9) 11.152 0.001 ≥40 (n = 836) 90.7 (758) 9.3 (78) Clinical experience, years ≤19 years (n = 630) 95.9 (604) 4.1 (26) 28.017 < 0.001 Over 19 years (n = 487) 87.3 (425) 12.7 (62) Department Outpatients (n = 1006) 92.0 (926) 8.0 (80/85) 0.431 0.511 Inpatients (n = 84) 94.0 (79) 6.0 (5) Age of patients Adults (n = 300) 92.3 (277) 7.7 (23) 0.029 0.865 Children (n = 193) 92.7 (179) 7.3 (14) CSU patients per week <10 (n = 870) 92.2 (802) 7.8 (68) 0.076 0.783 ≥10 (n = 247) 92.7 (229) 7.3 (18) Only in physicians who chose one of the options Values marked in bold indicate a statistically significant difference (p < 0.05) the erythrocyte sedimentation rate (ESR), C-reactive pro- regions of the world (90 vs 10%). Autoimmunity was tein (CRP), anti-thyroid antibodies, and thyroid-stimulating the most common identifiable cause of CSU (51.9%) hormone (TSH) and of performing the autologous serum andmalignancywas theleast common identifiable skin test (ASST) as compared to those who do not (Table 6). cause of CSU (4.5%). Food intolerance was a less fre- CSU due to unknown causes was reported to be much quent cause of CSU in North America (8.0%) as com- more common than CSU due to known causes, in all pared to other regions of the world (> 16.0%) (Table 7). Table 5 Factors linked to the deviation from the urticaria guidelines Factors % (n) of physicians, who %(n) of physicians, who don’t X p deviate from the guidelines deviate from the guidelines Age, years <40 (n = 140) 35.7 (50) 64.3 (90) 5.194 0.023 ≥40 (n = 428) 46.7 (200) 53.3 (228) Clinical experience, years ≤19 years (n = 323) 39.9 (129) 60.1 (194) 5.049 0.025 Over 19 years (n = 245) 49.4 (121) 50.6 (124) Patients Outpatients (n = 510) 44.5 (227) 55.5 (283) 0.029 0.865 Inpatients (n = 44) 43.2 (19) 56.8 (25) Age of patients Adults (n = 150) 55.3 (83) 44.7 (67) 7.712 0.005 Children (n = 92) 37.0 (34) 63.0 (58) CSU patients per week <10 (n = 441) 44.0 (194) 50.0 (247) 0.002 0.961 ≥10 (n = 128) 43.7 (56) 56.3 (72) Only in physicians who chose one of the options Values marked in bold indicate a statistically significant difference (p < 0.05) Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 7 of 13 Table 6 Differences in the approach to the management of CSU in respondents who do and do not follow the guidelines Test Compared groups n % (n) of physicians, who % (n) of physicians, who X p follow the guidelines don’t follow the guidelines CBC Order 854 79.2 (802) 60.5 (52) 16.011 < 0.001 No 245 20.8 (211) 39.5 (34) ESR Order 602 55.9 (566) 41.9 (36) 6.284 0.012 No 497 44.1 (447) 58.1 (50) CRP Order 527 49.0 (496) 36.0 (31) 5.299 0.021 No 572 51.0 (517) 64.0 (55) Anti-TG/TPO Order 559 51.9 (526) 38.4 (33) 5.826 0.016 No 540 48.1 (487) 61.6 (53) TSH Order 543 50.8 (515) 32.6 (28) 10.598 0.001 No 556 49.2 (498) 67.4 (58) Total IgE Order 481 56.1 (445) 58.1 (36) 0.138 0.710 No 618 43.9 (568) 41.9 (50) ECP Order 51 4.7 (48) 3.5 (3) 0.280 0.597 No 1048 95.3 (965) 96.5 (83) D-dimer Order 54 5.2 (53) 1.2 (1) 2.809 0.094 No 1045 94.8 (960) 98.8 (85) Skin prick tests Order 308 71.4 (290) 79.1 (18) 2.329 0.127 No 791 28.6 (723) 20.9 (68) Allergen-specific IgE Order 286 26.5 (268) 20.9 (18) 1.257 0.262 No 813 73.5 (745) 79.1 (68) ANA Order 407 37.7 (382) 29.1 (25) 2.538 0.111 No 692 62.3 (631) 70.9 (61) Tryptase Order 162 84.9 (153) 89.5 (9) 1.357 0.244 No 937 15.1 (860) 10.5 (77) ASST Order 186 17.7 (179) 8.1 (7) 5.121 0.024 No 913 82.3 (834) 91.9 (79) Search for chronic infections Perform 364 66.2 (342) 74.4 (22) 2.394 0.122 No 735 33.8 (671) 25.6 (64) Do not order any tests 182 15.4 (156) 30.2 (26) 12.621 < 0.001 Order at least 1 test 917 84.6 (857) 69.8 (60) CBC complete blood count, ESR erythrocyte sedimentation rate, CRP C-reactive protein, TG/TPO thyroglobulin/thyroperoxidase, TSH thyroid-stimulating hormone, ECP eosinophil cationic protein, ANA antinuclear antibodies, ASST autologous serum skin test Values marked in bold indicate a statistically significant difference (p < 0.05) Adherence to urticaria guidelines is associated with more Vice versa, more physicians from North America as frequent administration and confidence in higher efficacy compared to other countries reported that tricyclic an- of second-generation antihistamines tidepressants are highly effective (52% vs 15–33%). Phy- Updosing of second-generation H1-antihistamines sicians who follow a urticaria guideline showed higher (sgAHs, 97%) and omalizumab (96%) were reported to rates of sgAHs administration as a first-line treatment be the most effective treatment options in all regions of of CSU (p = 0.001) and more frequently observed the world. Dapsone, montelukast and H2-antihistamines higher efficacy of treatment (or had more confidence were considered effective drugs for treatment of CSU that it would work, p < 0.019) as compared to those who worldwide only by 17, 17 and 15% physicians, respect- do not follow the guidelines (Table 8). Guideline fol- ively. Less respondents from North America as com- lowers more frequently use higher than standard-dosed pared to other regions of the world reported that sgAHs and omalizumab as a second and third line sgAHs at standard dose and montelukast are highly ef- treatment, respectively, and less frequently administer first fective (48% vs 60–76 and 9% vs 13–35%, respectively). generation antihistamines, tricyclic antidepressants and Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 8 of 13 Table 7 Number of respondents from different regions of the world who find these causes of CSU as most common (n = 1098) CSU causes Geographical regions Total % (n/total) NA LA EU AME AP % (n/total) % (n/total) % (n/total) % (n/total) % (n/total) Idiopathic CSU 97.5 (315/323) 80.6 (150/186) 88 (323/367) 93.3 (56/60) 89.5 (145/162) 90.1 (989/1098) Type-I-allergy 27.5 (77/280) 27.1 (46/170) 17.9 (60/336) 19.6 (11/56) 39.6 (59/149) 25.5 (253/991) Autoimmune CSU 64.4 (201/312) 44.8 (81/181) 46.8 (166/355) 32.8 (19/58) 54.1 (80/148) 51.9 (547/1054) Systemic disorders 26.7 (79/296) 29.1 (50/172) 18.2 (62/340) 12.3 (7/57) 20.8 (31/149) 22.6 (229/1014) Malignancy 2.4 (7/288) 6.1 (10/165) 6.6 (22/334) 0 (0/56) 3.6 (5/139) 4.5 (44/982) Chronic infection 11.7 (34/290) 32.8 (58/177) 27.4 (95/347) 13.6 (8/59) 22.3 (33/148) 22.3 (228/1021) Food intolerance 8.0 (23/289) 19.7 (35/178) 16.3 (56/343) 22.4 (13/58) 26.6 (41/154) 16.4 (168/1022) AME Africa/Middle-East, AP Asia-Pacific, EU Europe, LA Latin America, NA North America. the respondents could choose more than one answer systemic corticosteroids in comparison to physicians who our knowledge, our study is the first global report of do not follow a urticaria guideline (Tables 9 and 10). how physicians approach CSU. Discussion Most physicians know and use urticaria guidelines in their Several guidelines, consensus papers, and practice pa- clinical practice rameters have been developed for the management of More than 90% of respondents stated to be aware chronic urticaria. Some studies have explored, on the na- and follow urticaria guidelines. However, there is in- tional level, if physicians know these guidelines and im- consistency between our study and other studies. For plement them in their actual clinical practice [8, 9]. To example, most respondents from Latin America in Table 8 Differences in the approach to a first line treatment of CSU in physicians who do and do not follow the guidelines Treatment Compared n %(n) of physicians, who %(n) of physicians, who X p groups follow the guidelines don’t follow the guidelines First-generation H1-antihistamines Administer 173 15.4 (160) 14.8 (13) 0.026 0.873 No 953 84.6 (878) 85.2 (75) Second-generation H1-antihistamines at standard Administer 704 64 (664) 45.5 (40) 11.868 0.001 dose No 422 36 (374) 54.5 (48) Updosed second-generation H1-antihistamines Administer 540 47.8 (496) 50.0 (44) 0.160 0.690 No 586 52.2 (542) 50.0 (44) H2-antihistamines (e.g. famotidine or ranitidine) Administer 224 19.7 (204) 22.7 (20) 0.481 0.488 No 902 80.3 (834) 77.3 (68) Ciclosporin Administer 15 1.4 (15) 0 1.289 0.256 No 1111 98.6 (1023) 100 (88) Omalizumab Administer 32 3.0 (31) 1.1 (1) 1.006 0.316 No 1094 97.0 (1007) 98.9 (87) Montelukast Administer 150 13.2 (137) 14.8 (13) 0.174 0.676 No 976 86.8 (901) 85.2 (75) Dapsone Administer 7 0.6 (6) 1.1 (1) 0.409 0.522 No 1119 99.4 (1032) 98.9 (87) Systemic corticosteroids (for less than 10 days) Administer 215 18.7 (194) 23.9 (21) 1.406 0.236 No 911 81.3 (844) 76.1 (67) Systemic corticosteroids (for more than 10 days Administer 16 1.5 (16) 0 1.376 0.241 in a row) No 1110 98.5 (1022) 100 (88) Tricyclic antidepressants (e.g. doxepin) Administer 35 3.0 (31) 4.5 (4) 0.655 0.418 No 1091 97.0 (1007) 95.5 (84) Values marked in bold indicate a statistically significant difference (p < 0.05) Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 9 of 13 Table 9 Differences in the approach to a second line treatment of CSU in physicians who do and do not follow the guidelines Treatment Compared n %(n) of physicians, who %(n) of physicians, who X p groups follow the guidelines don’t follow the guidelines First-generation H1-antihistamines Administer 156 13.1 (136) 22.7 (20) 6.297 0.012 No 970 86.9 (902) 77.3 (68) Second-generation H1-antihistamines at standard Administer 127 11.3 (117) 11.4 (10) 0.001 0.979 dose No 999 88.7 (921) 88.6 (78) Updosed second-generation H1-antihistamines Administer 651 58.8 (610) 46.6 (41) 4.931 0.026 No 475 41.2 (428) 53.4 (47) H2-antihistamines (e.g. famotidine or ranitidine) Administer 308 27.1 (281) 30.7 (27) 0.532 0.466 No 818 72.9 (757) 69.3 (61) Ciclosporin Administer 76 6.8 (71) 5.7 (5) 0.173 0.678 No 1050 93.2 (967) 94.3 (83) Omalizumab Administer 163 14.5 (150) 14.8 (13) 0.007 0.934 No 963 85.5 (888) 85.2 (75) Montelukast Administer 391 35.5 (368) 26.1 (23) 3.106 0.078 No 735 64.5 (670) 73.9 (65) Dapsone Administer 39 3.2 (33) 6.8 (6) 3.213 0.073 No 1087 96.8 (1005) 93.2 (82) Systemic corticosteroids (for less than 10 days) Administer 265 23.8 (247) 20.5 (18) 0.503 0.478 No 861 76.2 (791) 79.5 (70) Systemic corticosteroids (for more than 10 days Administer 89 7.4 (77) 13.6 (12) 4.309 0.038 in a row) No 1037 92.6 (961) 86.4 (76) Tricyclic antidepressants (e.g. doxepin) Administer 137 11.6 (120) 19.3 (17) 4.568 0.033 No 989 88.4 (918) 80.7 (71) Values marked in bold indicate a statistically significant difference (p < 0.05) our study (94%) followed any urticaria guideline with guidelines were also showed to be linked with the ad- 78% followed the EAACI/GA LEN/EDF/WAO urti- vanced age of the physicians [11–13]. For example, old caria guideline. In contrast, only 79 of 421 (19%) phy- age, male sex, and incomplete residency training were sicians from Ecuador reported to know the EAACI/ associated with disagreement with clinical practice GA LEN/EDF/WAO urticaria guideline, but more guidelines for cancer screening [13]. In contrast, com- than half of them (67%) were dermatologists and al- pared with physicians ≥50 years, younger physicians (< lergists [8]. In German-wide study, only one-third of 50 years) reported a lower level of awareness of choles- all physicians participating in the survey were familiar terol guidelines [14]. with the EAACI/GA LEN/EDF/WAO urticaria guide- We did not compare the adherence to urticaria guide- line [9]. In Italy, 56% of specialists knew the CSU lines between respondents of different specialties be- guidelines and only 27% used them regularly [10]. cause most physicians in our study were allergists and The high rates of adherence to urticaria guidelines in many of them had several specialties. However, in previ- our study can be explained by increase in guidelines ous studies the level of knowledge was highest for aller- awareness worldwide over time and the fact that most gists and/or dermatologists [8, 9], and these physicians of the participants were allergists/clinical immunolo- have significantly higher expertise in caring for patients gists (88%). with urticaria than other specialists [15]. An observa- tional study from the UK showed that allergists follow Factors associated with adherence to guidelines the urticaria guidelines more regularly and consistently Young (< 40 years) and less experienced physicians compared to dermatologists [16]. The results of this (≤19 years in practice) more often follow guidelines and study should be evaluated with caution because of the less often deviate from them than their older and more fact that Allergology is recognized as a specialty in some experienced colleagues. A similar tendency has been ob- countries (for example, in Russia) or as a subspecialty in served for other diseases, where low adherence rates to others (for example, in Germany). Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 10 of 13 Table 10 Differences in the approach to a third line treatment of CSU in physicians who do and do not follow the guidelines Treatment Compared groups n %(n) of physicians, who %(n) of physicians, who X p follow the guidelines don’t follow the guidelines First-generation H1-antihistamines Administer 93 7.7 (80) 14.8 (13) 5.345 0.021 No 1033 92.3 (958) 85.2 (75) Second-generation H1-antihistamines at standard Administer 78 6.9 (72) 6.8 (6) 0.002 0.967 dose No 1048 93.1 (966) 93.2 (82) Updosed second-generation H1-antihistamines Administer 283 25.4 (264) 21.6 (19) 0.637 0.425 No 843 74.6 (774) 78.4 (69) H2-antihistamines (e.g. famotidine or ranitidine) Administer 206 18.3 (190) 18.2 (16) 0.001 0.977 No 920 81.7 (848) 81.8 (72) Ciclosporin Administer 254 23.1 (240) 15.9 (14) 2.416 0.120 No 872 76.9 (798) 84.1 (74) Omalizumab Administer 570 51.8 (538) 36.4 (32) 7.764 0.005 No 556 48.2 (500) 63.6 (56) Montelukast Administer 319 28.9 (300) 21.6 (19) 2.135 0.144 No 807 71.1 (738) 78.4 (69) Dapsone Administer 91 7.8 (81) 11.4 (10) 1.384 0.239 No 1035 92.2 (957) 88.6 (78) Systemic corticosteroids (for less than 10 days) Administer 227 20.1 (209) 20.5 (18) 0.005 0.943 No 899 79.9 (829) 79.5 (70) Systemic corticosteroids (for more than 10 days Administer 146 12.7 (132) 15.9 (14) 0.733 0.392 in a row) No 980 87.3 (906) 84.1 (74) Tricyclic antidepressants (e.g. doxepin) Administer 134 11.7 (121) 14.8 (13) 0.751 0.386 No 992 88.3 (917) 85.2 (75) Values marked in bold indicate a statistically significant difference (p < 0.05) Impact of following the guidelines on the quality of care test (83.5%) [8]. Interestingly, 5–15% of respondents for CSU patients perform other less useful diagnostic tests, e.g. ECP According to the EAACI/GA LEN/EDF/WAO guideline, and tryptase, in patients with CSU. only differential blood count and CRP or ESR are rec- Idiopathic CSU was reported to be the most common ommended as routine diagnostic tests for CSU patients type of CSU; this is in the line with other studies [9, 17]. [1]. The US practice parameters recommend limited la- In one study, allergists and dermatologists more fre- boratory testing including a CBC with differential, ESR quently searched for CSU etiology as compared to gen- and/or CRP, liver enzymes, and TSH measurement [7]. eral practitioners [8] in contrast to the results of other Expectedly, these diagnostic tests were performed more study [9]. Although IgE-mediated allergy is a rare cause frequently by physicians who follow a urticaria guideline of CSU [1, 18], IgE-mediated allergy is considered to be in our and other studies [8, 9]. a common cause of CSU by 26% of respondents. Additional tests are indicated as an extended diag- Up to 50% of CSU patients can have circulating func- nostic program for identification of underlying causes tional IgG autoantibodies against IgE and high-affinity or eliciting factors and for ruling out possible differ- IgE receptors on mast cells and basophils [19]. Half of ential diagnoses if suggested based on history only respondents reported autoimmune CSU as the most [1]. For example, allergy is regarded as a very rare common cause of CSU and 16.9% of physicians (10.1– cause of CSU [1], and allergy testing is usually not 13.5% in other studies [8, 9]) carried out ASST as a cost-effective and does not lead to improved patient screening method for the detection of autoantibodies care outcomes [7]. However, some physicians reported [1]. ASST was applied more often by physicians who to determine total serum IgE (43.8%) and to perform were aware of and/or follow the guidelines in our and allergy skin prick testing in patients with CSU another study [9], but not in all [8]. (28.0%). In a cross-sectional study from Latin Amer- There is a universal agreement among urticaria guide- ica, total serum IgE was the most common diagnostic lines [1, 7, 20] that second generation antihistamines Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 11 of 13 (sgAHs) at a standard dose should be the first line therapy, sufficient flexibility and by educating them that guide- which is effective in improving symptoms in about 40% of lines are meant to complement, rather than substitute CSU patients [21]. Guideline followers, quite expectedly, for, clinical judgement. use sgAHs at a standard dose as a first line therapy more One-fifth of physicians reported that some of the guide- frequently than non-followers, while the administration of lines’ recommendations cannot be implemented in physi- other drugs was not different between the two groups. cian’s country of residency. It suggests that economic This has been proved in early national cross-sectional considerations are an important and often decisive factor studies where sgAHs taken regularly were the most com- influencing the choice of a treatment strategy. For ex- mon drugs prescribed [10, 22]. It is consistent with the ample, omalizumab is unavailable in some countries or its finding that more guidelines followers (67.4%) than cost is too high and health insurance programs do not non-followers (50%) feel that sgAHs are highly effective in cover it (for example, in Russia or Latin America [23]). CSU treatment. Systemic steroids and first generation antihistamines are As a second line therapy, the EAACI/GA LEN/EDF/ cheaper than sgAHs (for example, in Ecuador [8]) and this WAO urticaria guideline recommends the use of sgAHs can prompt a physician’s decision to prescribe them. The in higher doses up to four times the standard dose. Phy- cost-effectiveness of the treatment for CSU, especially in sicians who use urticaria guidelines more frequently se- the developing and low-income countries, should be fur- lected up-dosing for a second-line treatment in our and ther investigated in future studies. other studies [9, 10]. The EAACI/GA LEN/EDF/WAO guideline is revised For non-respondents to sgAHs up-dosing, the EAACI/ every four years by a global panel of well-known experts GA LEN/EDF/WAO guideline recommends omalizu- in the field. Interestingly, 8–10% of respondents did not mab, ciclosporin (step 4 in the US practice parameters) agree with guidelines’ recommendations and conclusions or montelukast (step 2 in the US practice parameters) as or found guideline recommendations unclear or out- a third line treatment option [1, 7]. Guideline followers dated. Again, this calls for the consideration of improve- in our and one other study [8] more frequently used ments in the development of guideline updates and omalizumab as a third line treatment in comparison to revisions. physicians who do not follow a urticaria guideline. The recommendations given by all of urticaria guidelines Our and early studies [9] showed that physicians who are similar, although some differences exist. For example, in are familiar with the guidelines are less likely to use first contrast to the EAACI/GA LEN/EDF/WAO guideline US generation antihistamines as a second and/or third line practice parameters recommend H2-antagonists and first treatment and systemic steroids (for more than 10 days in generation antihistamines for treatment of urticaria as a a row) as a second line therapy, indicating that guideline second or third line therapy, respectively [24]. Only 4% of recommendations may improve the quality of care [9]. respondents named the discrepancy and/or disagreement The treatment of CSU can depend on physician’sspe- between the guidelines as a reason not to follow them. cialty. For example, Cherrez et al. showed that allergists Taken together, reliance on own clinical experience, es- and dermatologists in Ecuador prescribed significantly pecially in older physicians, rather than economic reasons more sgAHs (regular doses) as compared to general prac- or unavailability of drugs, appears to be the most frequent titioners [8]. reason for deviation from or not following the guidelines. This observation offers the opportunity for a debate on Reasons for not following or deviation from the available medicine based on experience and evidence-based medi- urticaria guidelines cine and highlights the need for continuous medical edu- Almost one-third of physicians do not follow a guideline cation for healthcare providers. or deviate from it. The most frequent reasons given were reliance on their own clinical experience (44%) and an Limitations overly simplified approach to CSU management recom- The main limitations of our study are the bias of partici- mended by the guidelines (30%). Moreover, many physi- pant selection, the use of an online non-validated ques- cians, especially those of 40 years or older and with tionnaire and a low response rate (3.5%). The fact that clinical experience of > 19 years, follow guidelines but most participants in our study were allergists, whereas can deviate from them in some cases, e.g. in CSU is often managed by dermatologists and general difficult-to-treat CSU. This may point to a need to better practitioners, could explain some differences between our communicate to physicians, especially experienced phy- findings and those from other studies [8, 9]. There is lim- sicians, the benefits of guideline adherence and to better ited information in regards to CSU management in Af- engage them in the guideline development and review rica/Middle-East (only 64 questionnaires were filled out). process. Also, more efforts appear to be needed to im- The most recent EAACI guideline [18]appeared after we prove physician “buy-in” to guidelines by allowing for performed our study agreeing on our observations. Kolkhir et al. World Allergy Organization Journal (2018) 11:14 Page 12 of 13 Conclusion used for the online survey. MSB and IA made substantial contributions to the revisions of the manuscript. All authors contributed to the interpretation of The results of our study indicate that urticaria guideline the data, critical revisions, and approved the final version of the manuscript recommendations contribute to a higher quality of pa- for submission. tient care. Most physicians worldwide follow a guideline, Ethics approval and consent to participate however, one in five deviates from them. We speculate Not applicable. there are three major reasons for deviation that should be addressed in future research. Firstly, older physicians Consent for publication Not applicable. may be prone to disproportionate reliance on their clin- ical experience and unable to fully incorporate rapidly Competing interests emerging evidence-based approaches in their routine clin- The authors declare they have no competing interests related to this work. ical practice, which highlights the need for continuous medical education for healthcare providers regardless of Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in their age group or occupying position. Secondly, the qual- published maps and institutional affiliations. ity of CSU patient care may be, to a large degree, compro- mised by the financial constraints and insufficient level of Author details Division of Immune-mediated skin diseases, I.M. Sechenov First Moscow training of the treating physicians in developing countries. State Medical University, 119991, Trubeckaya str., 8/2, Moscow, Russian It warrants more research into pharmacoeconomics and 2 Federation. Department of Infection and Immunity, Luxembourg Institute of sustainability of up-to-date CSU treatments and further Health, Esch-sur-Alzette, Luxembourg. Department of Dermatology and Venereology, Trakia University, Stara Zagora, Bulgaria. Asthma Center and propagation of new knowledge about CSU etiopathogen- Allergy Unit, Verona University Hospital, Verona, Italy. Hospital Sírio Libanês esis and treatment among practicing physicians of differ- and Post-graduation Program in Health Sciences of IAMSPE São Paulo, São ent specialties and healthcare authorities in different Paulo, Brazil. University Hospital of Montpellier, Montpellier and Sorbonne Universités, Paris, France. Faculty of Medicine, University of Medicine and countries. Finally, urticaria guidelines themselves can be a Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam. Division of cause for suboptimal patient care (for example, unclear Allergy, Pulmonary and Sleep Medicine, Department of Medicine, Mayo recommendations and discrepancies between the guide- Clinic, Jacksonville, Florida, USA. Servicio de Enfermedades del Sistema Inmune-Alergia, Hospital Universitario Príncipe de Asturias, Madrid, Spain. lines). Thus, on the one hand, urticaria guidelines should Departamento de Medicina y Especialidades Médicas, Facultad de be flexible enough to allow a physician to tailor the treat- 11 Medicina, Universidad de Alcalá, Madrid, Spain. Department of Allergy and ment to the unique profile of each patient and circum- Immunology, Cleveland Clinic Florida, Weston, Florida, USA. Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Berlin, stances specific to their country of residence; on the Germany. Allergy and Clinical Immunology Department, Centro Medico other hand, further standardization and dissemination of 14 Docente La Trinidad, Caracas, Venezuela. Department of Allergy and guidelines can increase adherence among physicians Immunology, Hospital Quirónsalud Bizkaia, Bilbao, Spain. worldwide and result in better patient care. Received: 22 February 2018 Accepted: 7 June 2018 Additional file References 1. 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World Allergy Organization JournalSpringer Journals

Published: Jul 4, 2018

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