Exploring Demodex in Chronic Urticaria: Lack of Association but Evidence for Type-2 Immune Activation in Demodex

Exploring Demodex in Chronic Urticaria: Lack of Association but Evidence for Type-2 Immune Activation in Demodex | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 21 October 2025 V1 Latest version Share on Exploring Demodex in Chronic Urticaria: Lack of Association but Evidence for Type-2 Immune Activation in Demodex Authors : Burak Celik 0009-0004-4761-965X [email protected] , Merve Kaya , and Selma Emre Authors Info & Affiliations https://doi.org/10.22541/au.176101755.52017988/v1 Published Parasite Immunology Version of record Peer review timeline 368 views 114 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Introduction: Chronic spontaneous urticaria (CSU) is a mast cell driven multifactorial disorder with complex pathogenesis. While association between CSU and internal parasites investigated, the association of ectoparasites such as Demodex mites remains elusive Aims: This study aims to compare Demodex prevalence in CSU patients with healthy controls and to evaluate selected immunologic parameters in Demodex patients Materials and Methods: A prospective case–control study was conducted including 100 patients with CSU and 50 age- and sex-matched controls. Skin surface biopsy was performed using the cyanoacrylate method, and participants were classified as Demodex -positive if more than five mites were detected within a 1 cm 2 field. Serum levels of total IgE, eosinophil counts, thyroid-stimulating hormone (TSH), free thyroxine (T4), and anti-thyroid peroxidase (anti-TPO) antibodies were measured. Results: Demodex positivity was observed in 26% of CSU patients and 26% of controls (p = 1.00). Median IgE (208.08 IU/mL, range 4.89–1207.00) and eosinophil counts (0.17 ± 0.07 × 10 9 /L) were significantly higher in Demodex-positive participants than in Demodex-negative ones (65.72 IU/mL, range 2.40–632.11, and 0.14 ± 0.09 × 10 9 /L, respectively; p < 0.05). Thyroid function parameters and antibody levels showed no significant differences between groups. Conclusions: Although Demodex prevalence did not significantly differ between CSU patients and controls, infestation was associated with elevated IgE and eosinophil levels, suggesting a type 2-skewed immune response. Demodex mites may lead to a Th2-mediated immune activation independent of CSU status. Larger studies with quantitative mite assessment and cytokine profiling are warranted to clarify this relationship. Introduction Urticaria is a mast cell-mediated condition characterized by erythematous or pale plaques, with or without angioedema, and in some cases by angioedema alone [1]. Urticaria is typically classified according to the duration of the symptoms. When the symptoms last less than six weeks, the term acute urticaria is used, whereas in chronic urticaria, symptoms last more than six weeks [2]. Depending on the population studied, lifetime prevalence of urticaria is estimated between 1-20%. Urticaria is twice as common in women, although this ratio decreases with increasing age. 20-45% of the patients with acute urticaria progress to chronic urticaria [3]. The treatment of urticaria is primarily based on elimination of triggering factors and management of the symptoms. The first line treatment of urticaria is second generation antihistamines, and if the symptoms are not controlled with standard dose of antihistamines, the dose can be increased up to fourfold of the standard dose. In refractory cases, omalizumab is generally effective in controlling disease activity [4]. Although urticaria is a relatively common disease, its pathogenesis is only partially understood. Studies on pathogenesis of urticaria are mostly focused on the cells recruited and the mediators that contribute to urticaria, understanding the mechanism of mast cell stimulation and deciphering immune processes that play a role in urticaria is partially elaborated. Infectious diseases are a well-documented trigger of urticaria for some cases, and resolution of symptoms is reported after successful elimination of the causative agent. Among various infectious diseases, parasites have been reported to be associated with some cases of urticaria, most importantly Toxocara and Anisakis simplex infections [5]. Although the relationship between urticaria and internal parasites is relatively well defined, there is paucity of data on relationship of ectoparasites and urticaria. Demodex follicularum and Demodex brevis are two different species of ectoparasites under genus of Demodex that inhabitant human skin. Demodex species nurture on keratin and sebum, and they do not trigger any pathological process unless their numbers increase excessively. They can trigger local inflammation and have role in various dermatologic and ophthalmologic conditions namely blepharitis, rosacea, pityriasis folliculorum, and periorbital dermatitis-like reactions [6]. Given the limited evidence on the relationship between external parasites and chronic urticaria, we aimed to investigate the potential association between Demodex mites, the most common ectoparasites of human skin, and chronic urticaria. Materials and Method This prospective case–control study was approved by the local ethics committee of Bilkent City Hospital (decision date: October 4, 2023; approval number: 4109) and conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrollment in the study. A total of 100 patients with chronic spontaneous urticaria (CSU), and 50 age and sex-matched individuals who presented to the dermatology clinic for benign nevi screening were included in the study. Individuals with active infection, known chronic heart, liver, or kidney disease, participants with a history of omalizumab use within 3 months, diagnosis of inducible urticaria, pregnancy and known malignancy were excluded from the study. For all the participants age, gender, and past medical history were recorded. Laboratory values of ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGT (gamma‑glutamyl transferase), LDH (lactate dehydrogenase), T4 (thyroxine), TSH (thyroid stimulating hormone), anti‑TPO (anti‑thyroid peroxidase antibody), total IgE (total immunoglobulin E), and CRP (C‑reactive protein) were measured from peripheral blood drawn from the antecubital vein after at least 8 hours of fasting. In CSU group, the disease activity was assessed with a validated scale, urticaria activity score (UAS) [1]. Skin surface biopsy (SSB) was performed from all the participants with cyanoacrylate glue as described by Marks and Dawber in 1971 [7]. To obtain SSB, one drop of cyanoacrylate was applied to a glass slide which was then pressed onto the forehead, cheek, and chin of each participant. After one minute, the slide was gently removed, and the specimen was examined under 40× magnification using immersion oil for 1 cm 2 of field which was previously marked on the glass slide. Participants were classified as Demodex -positive if more than five mites were observed in any examined field. Statistical Analysis Statistical analyses were performed using R software, version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) The normality of continuous numeric variables was assessed with examination of histograms and numeric tests, namely Shapiro-Wilk and Kolmogorov-Smirnov tests. For normally distributed parameters, Student’s t-test was used for comparison. The Mann-Whitney U test was implemented when the numeric values were not distributed normally. A p < 0.05 was considered statistically significant. Results The age and sex distribution of all participants are presented in Table 1. In the CSU group, 79 patients had severe disease, 15 had moderate disease, 5 had mild disease, and 1 patient had well-controlled disease. Among CSU patients, 40 were managed with bilastine, 22 cetirizine, 8 levocetirizine, 5 desloratadine, 3 fexofenadine, 3 ebastine, 1 ketotifen, and 23 were prescribed more than one antihistamine. The most common combination among patients using multiple antihistamines was bilastine with desloratadine, used by 17 patients. There was no significant difference in UAS among the antihistamine regimens ( p = 0.42). 45 of 100 CSU patients had both wheals and angioedema, 55 of 100 patients had only wheals, and there were no CSU patients who presented only with angioedema. The most common comorbidity in the patient and control groups was Hashimoto thyroiditis, with prevalence of 13% and 4%, respectively; however, the difference was not statistically significant ( p = 0.14). The mean TSH values in patient and control group were 1.80 ± 1.58 and 1.49 ± 0.80 µIU/mL respectively with no significant difference between the two groups ( p = 0.11). In the CSU group, the mean TPO level was 230.63 ± 63.47 IU/mL whereas in the control group it was 76.64 ± 21.8 IU/mL, indicating a statistically significant difference ( p =0.013). The mean free T4 level in the CSU group was 1.27 ± 0.52 ng/dL, and in the control group it was 1.22 ± 0.68 ng/dL. The difference between the two groups was not significant ( p = 0.64). In the CSU group, 26 participants (26%) had a positive Demodex status, and in the control group, 13 participants (26%) were Demodex‑positive. The difference between the two groups was not statistically significant ( p =1.00). Among different CSU severity groups there was no significant difference in positive demodex status ( p = 0.110). In all the participants with positive demodex status median IgE level was 208.08 (4.89–1207.00) IU/mL, whereas in the participants with negative demodex status median IgE level was 65.72 (2.40–632.11) IU/mL (Fig.1), there was a statistically significant difference in IgE levels between Demodex positive and Demodex negative participants ( p =0.046). In all the participants with positive Demodex, the mean eosinophil count was 0.17 ± 0.06 ×10⁹/L, whereas in participants without Demodex, it was 0.14 ± 0.09 ×10⁹/L (Fig.2). There was a significant difference in eosinophil counts between the two Demodex status groups ( p =0.033). The mean TSH, T4 and TPO levels in Demodex positive individuals was 1.57 ± 0.76 µIU/mL, 1.14 ± 0.30 ng/dL and 200.57 ± 721.20 IU/mL respectively. Whereas the mean TSH, T4 and TPO levels in Demodex negative individuals was 1.74 ± 1.57 µIU/mL, 1.62 ± 3.72 ng/dL and 171.83 ± 549.42 IU/mL respectively. Between Demodex positive and Demodex negative individuals there was no significant difference in TSH, T4 and TPO statistically ( p = 0.50, p = 0.18, p = 0.82, respectively). Discussion Our data indicates that there was no difference in Demodex prevalence in CSU and control group. Interestingly, participants with positive Demodex status had an increased level of IgE levels and eosinophil count in their peripheral blood regardless of their CSU status. This may indicate a predominant type-2 skewed immune response to Demodex mites. The association between CSU and internal parasites has been recognized for decades. Among the internal parasites comorbidity of CSU and internal parasites reported to be range between 0% to 74% in different studies, depending on the population studied. Among internal parasites, Blastocystis hominis , Anisakis simplex , and Toxocara species have been most frequently reported in association with chronic spontaneous urticaria [7]. Despite extensive research on internal parasites in CSU, there is limited number of studies focused on CSU and ectoparasites. A case report describes a patient diagnosed with scabies who presented with chronic urticaria as the initial manifestation [8]. Aeroallergens derived from house dust mites also have been suggested as potential triggers for chronic urticaria; however, the strength and consistency of this association remains uncertain [9]. The relationship between Demodicosis and systemic conditions is also partially explored. Previously Topcu et al. demonstrated an association between Hashimoto thyroiditis and Demodex infestation and they postulated that xerosis due to hypothyroidism may lead to increased Demodex number [10]. In a similar study Yucel et. al showed a correlation between demodex count and TPO levels [11]. However, in our study no significant difference was found between demodex positive and negative participants in terms of TSH, T4 and TPO. There are also two studies reported increased number of Demodex in rheumatoid arthritis and sickle cell anemia [12,13]. However, the pathophysiologic link is still not clear, and these findings should be verified in larger groups. Our data also indicate that the patients with increased Demodex density had increased levels of IgE and eosinophil, indep e ndent from their CSU status. This finding might be contributary in explaining immunity against demodex mites. The immune response to Demodex is complex and remains incompletely understood. Both innate and adaptive immune response including cellular and humoral immunity may be important in the control of Demodex colonization. HLA A3‐Cw4, A3‐Cw2, A3‐B17, A3‐B35 and B35‐Cw4 haplotypes are reported to be positively associated with Demodex predisposition, whereas HLA‐A2 phenotype may be protective [14]. In one of the earliest studies focusing on immune response to demodex, Rufli and Buchner demonstrated that T-helper cells constitute the predominant immune cell population involved in the immune response in patients with rosacea-associated demodicosis [15]. Further supporting crucial role of T-helper cells, in ocular demodicosis, it was shown that the patients with ocular demodicosis had increased levels of IL-17 and IL-1β, in their tear fluid and after successful treatment of demodicosis the levels of cytokines decreased to their normal level [16]. In 5 patients described in Israeli patients with (STAT)1 heterozygous gain-of-function mutation, which is characterized by reduced IL-17 levels and chronic mucocutaneus candidiasis, also had demodicosis [17]. Akilov et al. observed that the patient with excessive Demodex outgrown associated with increased levels of CD95+ cells in the peripheral blood whereas there was no difference between CD3+, CD4+, CD5+ and CD16+ cells between normal controls and Demodex patients [18]. The contribution of humoral immune mechanisms to the defense against Demodex infestation is less elucidated compared to cellular immunity. Compared to healthy controls patients with increased demodex density was shown to have increased levels of IgM levels in their peripheral blood while there was no difference in levels of IgA, IgG, circulatory immune complexes, serum complement activity, and phagocytosis activity index [19]. Parasitic infections have been long associated with induction of type 2 immunity that leading to peripheral eosinophilia and increased Ige levels in peripheral blood. Among the parasitosis, helminthic infections such as Strongyloides stercoralis, Schistosoma, Wuchereria bancrofti, Loa loa, Onchocerca volvulus, and Ascaris lumbricoides most associated with eosinophilia and increased IgE levels [20]. According to our result, Demodex species can also induce eosinophilia and IgE in the peripheral blood. In consistent with our findings, Roberto et al. previously showed that ILC-2 and IL-13 is crucial for controlling Demodex mite colonization, and murine models lacking components of type-2 immunity may present with inflammatory demodicosis [21]. Furthermore, Park et al. described two patients who developed demodicosis after 1.5-year 2-year use of omalizumab a medication suppressing IgE, further supports the notion that IgE and type 2 immunity is crucial for control of Demodex mites [22]. In our study increased number of Demodex might have triggered type-2 skewed immune response and increased IgE and eosinophilia in peripheral blood. To conclude, our findings imply a possible role of Demodex mites skewing T cell mediated cellular response toward Th2 pathway. The lack of association between Demodex numbers and CSU supports the current paradigm of perceiving CSU as an autoimmune disorder, yet the possibility that in a subset of CSU the pathogenesis is mainly driven by type2 immunity cannot be excluded. Further studies with larger number of patients with more specific approaches with better diagnosis methods and examining peripheral blood IL-4, IL-5 and IL-13 may further elucidate immune response to demodex. Furthermore, we reported demodex status in a binary fashion using the threshold of five mites. A more sensitive approach would be comparing the demodex numbers in the future studies such that a significant difference might be observed. References 1. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, Bernstein JA, Bindslev-Jensen C, Brzoza Z, Buense Bedrikow R, Canonica GW, Church MK, Craig T, Danilycheva IV, Dressler C, Ensina LF, Giménez-Arnau A, Godse K, Gonçalo M, Grattan C, Hebert J, Hide M, Kaplan A, Kapp A, Katelaris CH, Kocatürk E, Kulthanan K, Larenas-Linnemann D, Leslie TA, Magerl M, Mathelier-Fusade P, Meshkova RY, Metz M, Nast A, Nettis E, Oude-Elberink H, Rosumeck S, Saini SS, Sánchez-Borges M, Schmid-Grendelmeier P, Staubach P, Sussman G, Toubi E, Vena GA, Vestergaard C, Wedi B, Werner RN, Zhao Z, Maurer M; Endorsed by the following societies: AAAAI, AAD, AAIITO, ACAAI, AEDV, APAAACI, ASBAI, ASCIA, BAD, BSACI, CDA, CMICA, CSACI, DDG, DDS, DGAKI, DSA, DST, EAACI, EIAS, EDF, EMBRN, ESCD, GA²LEN, IAACI, IADVL, JDA, NVvA, MSAI, ÖGDV, PSA, RAACI, SBD, SFD, SGAI, SGDV, SIAAIC, SIDeMaST, SPDV, TSD, UNBB, UNEV and WAO. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018 Jul;73(7):1393-1414. 2. Kolkhir P, Giménez-Arnau AM, Kulthanan K, Peter J, Metz M, Maurer M. Urticaria. Nat Rev Dis Primers. 2022 Sep 15;8(1):61. 3. Fricke J, Ávila G, Keller T, Weller K, Lau S, Maurer M, Zuberbier T, Keil T. Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis. Allergy. 2020 Feb;75(2):423-432. 4. Hon KL, Li JTS, Leung AKC, Lee VWY. Current and emerging pharmacotherapy for chronic spontaneous Urticaria: a focus on non-biological therapeutics. Expert Opin Pharmacother. 2021 Mar;22(4):497-509. 5. Kolkhir P, Balakirski G, Merk HF, Olisova O, Maurer M. Chronic spontaneous urticaria and internal parasites–a systematic review. Allergy. 2016 Mar;71(3):308-22. 6. Chioveanu FG, Niculet E, Torlac C, Busila C, Tatu AL. Beyond the Surface: Understanding Demodex and Its Link to Blepharitis and Facial Dermatoses. Clin Ophthalmol . 2024;18:1801-1810. 7. Marks R, Dawber RP. Skin surface biopsy: an improved technique for the examination of the horny layer. Br J Dermatol . 1971;84(2):117-123. 8. Muller I, Brinker A. A Case of Scabies Presenting as Chronic Urticaria. Mil Med . 2020;185(9-10):e1854-e1856. 9. Chen Q, Wang W, Yang X, et al. Characteristics and Clinical Significance of Atopy in Chronic Spontaneous Urticaria: A Cross-Sectional Observational Study. Int Arch Allergy Immunol . 2024;185(12):1248-1253. 10. Topçu Dursun A, Bayramgürler D, Odyakmaz Demirsoy E, Şikar Aktürk A, Kıran R, Sayman N. Could there be an association between Hashimoto’s thyroiditis and demodex infestation?. J Cosmet Dermatol . 2022;21(10):5141-5147. 11. Yücel MB, Ünal E, Ertaş R. Demodicosis and Thyroid Autoimmunity: Unravelling the Connection. Parasite Immunol . 2025;47(7):e70016. 12. Yazisiz H, Çekİn Y, Sezer İ, Bostan F, KoÇlar FG. Demodex Species Frequency and Risk Factors in Patients With Rheumatoid Arthritis. Arch Rheumatol . 2020;35(3):376-384. Published 2020 Feb 7. 13. Kaya OA, Akkucuk S, Ilhan G, Guneri CO, Mumcuoglu K. The Importance of Demodex Mites (Acari: Demodicidae) in Patients With Sickle Cell Anemia. J Med Entomol . 2019;56(3):599-602. 14. Akilov OE, Mumcuoglu KY. Association between human demodicosis and HLA class I. Clin Exp Dermatol . 2003;28(1):70-73. 15. Rufli T, Büchner SA. T-cell subsets in acne rosacea lesions and the possible role of Demodex folliculorum. Dermatologica . 1984;169(1):1-5. 16. Kim JH, Chun YS, Kim JC. Clinical and immunological responses in ocular demodecosis. J Korean Med Sci . 2011;26(9):1231-1237. 17. Shamriz O, Lev A, Simon AJ, et al. Chronic demodicosis in patients with immune dysregulation: An unexpected infectious manifestation of Signal transducer and activator of transcription (STAT)1 gain-of-function. Clin Exp Immunol . 2021;206(1):56-67. 18. Akilov OE, Mumcuoglu KY. Immune response in demodicosis. J Eur Acad Dermatol Venereol . 2004;18(4):440-444. 19. El-Bassiouni SO, Ahmed JA, Younis AI, Ismail MA, Saadawi AN, Bassiouni SO. A study on Demodex folliculorum mite density and immune response in patients with facial dermatoses. J Egypt Soc Parasitol . 2005;35(3):899-910. 20. Webster J, Stauffer W, Mitchell T, et al. Cross-Sectional Assessment of the Association of Eosinophilia with Intestinal Parasitic Infection in U.S.-Bound Refugees in Thailand: Prevalent, Age Dependent, but of Limited Clinical Utility. Am J Trop Med Hyg . Published online March 7, 2022. 21. Ricardo-Gonzalez RR, Kotas ME, O’Leary CE, et al. Innate type 2 immunity controls hair follicle commensalism by Demodex mites. Immunity . 2022;55(10):1891-1908.e12. 22. Park S, Oh Y, Chu H, Park CO. Development of Demodicosis after Omalizumab Injection. Ann Dermatol . 2023;35(Suppl 1):S182-S183. Table 1. Distribution of age and sex in patient and control groups Patient Group Control Group p Age Mean ± SD (min-max) 41.88 ± 15.43 (18-77 ) 42.74± 15.67 (18-70) 0.81 Sex Female (%) 60 (%60) 32 (%64) 0.22 Male (%) 40 (%40) 18 (36) Total (n) 100 (%100) 50 (%100) Figure 1. Distribution of IgE by Demodex Status Figure 2. Eosinophil counts by Demodex Status Information & Authors Information Version history V1 Version 1 21 October 2025 Peer review timeline Published Parasite Immunology Version of Record 17 Mar 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords cell demodex folliculorum eosinophil humoral immunity immunological terms parasite Authors Affiliations Burak Celik 0009-0004-4761-965X [email protected] Ankara Sehir Hastanesi Gogus Hastaliklari Klinigi View all articles by this author Merve Kaya Ankara Sehir Hastanesi Gogus Hastaliklari Klinigi View all articles by this author Selma Emre Ufuk Universitesi Tip Fakultesi View all articles by this author Metrics & Citations Metrics Article Usage 368 views 114 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Burak Celik, Merve Kaya, Selma Emre. Exploring Demodex in Chronic Urticaria: Lack of Association but Evidence for Type-2 Immune Activation in Demodex. Authorea . 21 October 2025. DOI: https://doi.org/10.22541/au.176101755.52017988/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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