Dermatology: Practical and Conceptual Review | Dermatol Pract Concept 2020;10(1):e2020004 1 Dermatology Practical & Conceptual Introduction Patients with chronic urticaria (CU) often consider diet modi- fication and discuss potential trigger foods. In this review, we evaluate the evidence behind potential dietary triggers for CU including immunological triggers (eg, galactose-α-1,3-galac- tose [α-gal] in meat and Anisakis simplex in uncooked fish) and nonimmunological triggers. Nonimmunological triggers include compounds in tomatoes, food additives, herbs, wine, and other foods, as well as histamine in foods. The evidence Diet and Chronic Urticaria: Dietary Modification as a Treatment Strategy Joanna Jaros,1 Vivian Y. Shi,2 Rajani Katta3 1 University of Illinois College of Medicine, Chicago, IL, USA 2 Department of Medicine, Dermatology Division, University of Arizona at Tucson, AZ, USA 3 Dermatology, McGovern Medical School at UT Health, Bellaire, TX, USA Key words: chronic urticaria, diet, pseudoallergens, food additives, histamine Citation: Jaros J, Shi VY, Katta R. Diet and chronic urticaria: dietary modification as a treatment strategy. Dermatol Pract Concept. 2020;10(1):e2020004. DOI: https://doi.org/10.5826/dpc.1001a04 Accepted: September 25, 2019; Published: December 31, 2019 Copyright: ©2019 Jaros et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. Authorship: All authors have contributed significantly to this publication. Corresponding author: Rajani Katta, MD, McGovern Medical School at UT Health, 6800 West Loop South, Ste 180, Bellaire, TX 77401. Email: info@kattamd.com Patients with chronic urticaria (CU) often ask about dietary modification. Research has indicated that specific dietary changes may be helpful in a subset of patients. Immunological food reactions are rare, but potential triggers of CU include those seen in certain settings, as in patients with a history of tick bites, a history of raw or marinated fish ingestion, or those with celiac disease. Nonimmunological food intolerances may also contribute, although mechanism of action is not well understood. Trials of pseudoallergen-free diets and low-histamine diets have resulted in partial remission in a subset of patients, while oral provocation testing has confirmed that some patients experience worsening of symptoms after ingestion of food additives, tomatoes, herbs, seafood, alcohol, and other foods. An increased prevalence of vitamin D deficiency has also been noted in patients with CU compared with healthy controls. While oral antihistamines remain the mainstay of therapy in CU, education on poten- tial dietary factors may be offered to a selection of the group of patients. For those at risk or reporting symptoms suggestive of celiac disease, vitamin D deficiency, delayed reactions to mammalian meat, or exposure to raw fish, further workup is recommended. While education on dietary modification may be offered to other patients, this approach may benefit only a subset, and no test is available to identify these patients. A minimum of 3 weeks may be needed to determine response, and only specific diets that have been systematically studied should be considered. Any elimination diet should be used with caution because of the potential for nutritional deficiencies. ABSTRACT mailto:info@kattamd.com 2 Review | Dermatol Pract Concept 2020;10(1):e2020004 that are objectively reproducible but that do not involve an immunological mechanism. A n u m b e r o f f o o d s h a v e b e e n reported to worsen CU symptoms. These “trigger” foods include alcohol, food additives, seafood, certain vege- tables and fruits, fermented foods, and others [6]. Diagnostic and therapeutic strategies include food diaries, OPT, or elimination diets. A review of 20 studies examined a total of 1,668 patients with CU who followed a systematic elimination diet approach. These consisted of pseudo- allergen-free (PAF) diet, low-histamine (LH) diet, or fish avoidance diet used in conjunction with their antihistamine therapy [9]. Overall, these led to a com- bined complete remission in 4.9% and partial remission in 37.5% of subjects, with the highest rates reported for PAF and LH diets followed for a median duration of 3 weeks [9]. Partial remission rates in more than one-third of subjects are clearly worth further study, given the safety and low cost of these short-term dietary modifi- cations. However, any study of CU must consider the significant spontaneous remission rate. Antia et al summarized the research on the natural history of CU [3] and noted variability, with one study reporting 32% of patients symptom-free after 3 years [10] and other studies reporting about half of patients expe- riencing remission after 1 year [11,12]. Lower remission rates are seen with more severe disease, while higher rates are seen with antihistamine treatment. It is noteworthy that no control group was used in any of the aforemen- tioned dietary studies, and many patients were allowed to use antihistamines. Therefore, it is difficult to compare these improvements with that expected via spontaneous remission. Despite these caveats, results were promising. The median duration of dietary change was only 3 weeks, and approximately one- third of patients reported improvement. Furthermore, several studies have doc- cells [7]. This results in vasodilation, sensory nerve activation, and plasma extravasation, ultimately resulting in dermal edema and wheals [2]. Treat- ment with antihistamines significantly reduces these clinical findings [5]. A number of factors can cause mast cell activation, both immunological and nonimmunological. Immunoglobulin E (IgE)-mediated reactions are the pri- mary immunological trigger [6]. Non- immunological mechanisms are less well understood, but include medications, infections, food, and alcohol, among others [2]. Food allergies, which are due to defined immunological mechanisms, have been shown to be rare causes of CU. Sánchez et al administered food challenge tests (utilizing 410 common foods) to 164 patients with CU and 38 controls. Positive challenge tests occurred in only 1.2% of CU and 0.7% of control subjects [8]. Food IgE sensitization was similar in both groups (17.5% vs 16.5%, respectively) [8]. Therefore, despite the high frequency of self-reported food sensitivities, single foods are unlikely CU triggers. However, a number of other studies have presented intriguing results demonstrating that groups of foods may worsen CU. Specif- ically, elimination diets have improved symptoms in a subset of patients with CU, while oral provocation testing (OPT) has resulted in flares. Chronic Urticaria and Diet Research has demonstrated that food allergies are extremely rare causes of CU. Food allergies that may result in symptoms of CU include α-gal allergy (meat) and A simplex allergy (fish nem- atode). Immunological reactions may occur due to gluten ingestion in celiac disease. F o o d i n t o l e r a n c e s i n C U a r e described more often than food allergies and are distinct from allergy [2]. These are defined as food-related symptoms and potential mechanisms behind these trigger foods is presented. Finally, we explore the increased prevalence of vita- min D deficiency in CU. Background Urticaria is a relapsing-remitting condi- tion with significant impact on quality of life (QOL). Clinically, half of patients present with only cutaneous wheals, 10% with angioedema, and 40% with both [1] and individual lesions classi- cally last ≤24 hours. Current guidelines classify urticaria as acute vs chronic, based on duration less than or greater than 6 weeks. CU is further subclassi- fied as spontaneous (no specific elic- iting factor involved) vs inducible [2]. The lifetime prevalence in the general population is estimated at 9% and has significant impact on patients’ QOL [3]. CU is particularly challenging for patients, as it is frequently treatment-re- sistant, long-standing, and idiopathic. This review focuses on dietary modi- fications for CU, with an emphasis on chronic spontaneous urticaria. Pathogenesis The etiology of CU is not well under- stood, and the majority of cases are con- sidered idiopathic or due to autoreactiv- ity [4]. At this time, neither European nor US guidelines recommend exten- sive laboratory testing or skin biopsy [2]. Therapy is focused on symptom management, with H1 antihistamines as the mainstay [5]. On a cellular level, the primary inflammatory cells are mast cells and basophils [3]. Activation of mast cells results in degranulation and release of preformed mediators, including vaso- active substances such as histamine and proinflammatory mediators such as tumor necrosis factor. Mast cells also release newly synthesized leukotrienes, prostaglandins, cytokines, and platelet activating factor [6]. These mediators in turn activate and recruit other immune https://www-sciencedirect-com.ezproxy.galter.northwestern.edu/topics/medicine-and-dentistry/urticaria https://www-sciencedirect-com.ezproxy.galter.northwestern.edu/topics/medicine-and-dentistry/angioedema https://www-sciencedirect-com.ezproxy.galter.northwestern.edu/topics/medicine-and-dentistry/laboratory-testing Review | Dermatol Pract Concept 2020;10(1):e2020004 3 well understood, as they do not act via IgE and are negative on skin testing. A wide number of compounds and foods may act as pseudoallergens [2]. These include natural compounds (including certain fruits, spices, vegetables), arti- ficial additives (dyes, preservatives, fla- vorings), and vasoactive compounds (acetyl salicylic acid, histamine, and nitric oxide) [10]. Testing is typically with trial of elimination diet (ie, exclud- ing compounds and foods reported as pseudoallergens) followed by OPT [31]. Despite the inherent difficulty, pseudoallergens have been studied in numerous trials. A systematic review summarized multiple PAF diet trials, encompassing 1,555 patients [9]. Over- all, nearly 5% of patients showed com- plete remission, while 37% showed par- tial remission after median duration of 3 weeks. Although none had a control group, several trials reported OPT. Over- all, observational studies of PAF diets have reported substantial reduction in medication usage [32], improved QOL scores [32], and significant decrease in leukotriene E4 levels [33]. Certain foods have been shown to trigger urticaria in diet-responsive patients during OPT, including tomatoes, food additives, wine, and herbs. In one study, 73% of patients reported improve- ment after only 3 weeks of PAF diet [34]. All responders later experienced symp- toms after consuming a challenge meal rich in pseudoallergens [34]. OPT with distillation extract from whole tomatoes resulted in positive urticarial reactions in more than 50% [34]. The culprit com- ponent remains unknown, as reactions were also common (32%) in those given a tomato fraction lacking salicylic acid or p-hydroxybenzoate [34]. Of note, 46% of patients continuing dietary modifi- cation had full remission at 6 months [34]. In a similar study, 202 patients with CU underwent the same dietary modi- fication for 3 months. Among 62% of patients (126/202) who improved and later underwent OPT with placebo con- trols, 37% reacted to food additives [35]. published reports from Spain and Italy. The antigen may be present in raw, mar- inated, or smoked fish [19], and larvae may be implicated [20]. A randomized controlled trial of 213 Italian subjects with CU found that nearly 50% were sensitized to A simplex on skin prick testing [21]. A 6-month diet excluding marinated and raw fish led to resolution of CU in 77%, compared with 2% in controls [22]. Other studies have not been as promising. A smaller trial found no improvement in either sensitized or nonsensitized patients after 3 months of avoidance [22,23]. Additional studies have reported no change with fish-free diets, despite association between CU and A simplex positivity on skin prick testing [24]. It is theorized that mast cell activation in patients with CU and parasitic infec- tions, such as A simplex, may involve the action of specific IgE, Th2 cytokine skewing, eosinophil recruitment to skin, and activation of the coagulation and complement systems [25]. With addi- tional studies reporting benefit from fish- free diets [26], it is reasonable to either test at-risk patients or recommend trial avoidance. Research has also demon- strated that those allergic to A simplex can consume frozen fish (−20°C for 48 hours) without risk of severe reaction [27]. Smoked fish is not recommended owing to potential reactivity to heat-sta- ble A simplex antigens [19]. Gluten Autoimmune diseases, including celiac disease, have been linked to CU [28]. Case reports describe patients with celiac disease who develop CU follow- ing gluten ingestion [29,30]. Therefore, for patients reporting symptoms sugges- tive of celiac disease, further workup is recommended. Pseudoallergens Pseudoallergic reactions are not con- sidered true allergy. Rather, they are a type of nonallergic hypersensitivity reaction. The mechanism of action is not umented positive blinded OPT in a sig- nificant percentage of diet-responsive patients. Therefore, despite the lack of controlled trials, it appears that some patients have dietary triggers that may be contributing to CU. Galactose-α-1,3-Galactose Allergy Galactose-α-1,3-galactose (α-gal) is an oligosaccharide expressed on glyco- proteins and glycolipids of nonprimate mammals [13,14]. It can be transmitted to humans by ticks, including the lone star tick Amblyomma americanum in the United States and other tick species in Europe and Australia [15]. Injection of α-gal during a tick bite results in development of IgE-mediated allergy to the α-gal antigen [16]. This antigen is then encountered when consuming mammalian meat (eg, beef, pork), as well as during infusions of the monoclo- nal antibody cetuximab [16]. In a study of 245 patients, symptoms included urti- caria (93%), gastrointestinal distress (64%), and anaphylaxis (60%) [17]. Symptom onset associated with α-gal hypersensitivity is typically delayed, occurring 2-6 hours after meat consumption [17]. Given the atypical timing, patients are frequently misdiag- nosed with idiopathic CU [14]. In one study, 20 of 29 patients with a diagnosis of CU had detectable serum α-gal anti- bodies, and of these, 95% reported tick bites [18]. Avoidance of mammalian meat led to full remission in 9, and par- tial remission in 5 patients [18]. At this time, it is not known whether hypersen- sitivity will eventually improve. In summary, a food diary may iden- tify delayed responses to meat, with confirmation via blood test for α-gal IgE antibodies. In those with antibod- ies, recommended treatment is allergen avoidance. Anisakis Simplex Hypersensitivity to A simplex, a sea fish nematode, may result in CU in coastal regions where uncooked fish is fre- quently consumed, with many of the 4 Review | Dermatol Pract Concept 2020;10(1):e2020004 lowing ingestion of foods containing lesser levels of histamine. This is thought to arise from a mismatch between accu- mulated histamine (from single foods and combinations of foods) and an indi- vidual’s capacity for histamine metabo- lism and clearance [42]. Some individu- als may be more susceptible to ingested histamine, such as those with impaired diamine oxidase activity [43]. Intestinal diamine oxidase prevents dietary hista- mine uptake into the blood, and genetic factors, medical conditions, and alcohol may all reduce enzyme activity [44]. Certain foods contain higher lev- els of histamine, especially those with higher microbial activity or deteriora- tion [44]. Seafood may contain higher levels depending on storage conditions and microbial exposure, as microbes convert amino acids such as histidine to biogenic amines [45]. Fermented foods are therefore also likely to have higher levels, including aged cheeses, dry sausage, and fermented soy [46]. Some plant foods have demonstrated higher levels as well, including tomatoes, egg- plant, spinach, and avocado, although plant foods have demonstrated great variability in content [47]. Some CU patients report improve- ment on LH diets. In one study of 56 patients with both CU and gastrointes- tinal symptoms, 61% noted improve- ment after 3 weeks, with the greatest reduction in the strongly affected sub- group [48]. Another study also reported posi- tive results, but indicated that response was unlikely due to decreased histamine ingestion [42]. In this study, 157 patients consumed a histamine-free, low pseu- doallergen diet, with 46% reporting reduced CU activity [42]. All patients were then tested with oral histamine in a double-blind, placebo-controlled trial. While 17% reacted, no relationship was seen between response to diet and response to histamine. The researchers concluded that diets low in pseudoaller- gens may improve symptoms, but this response is not likely due to dietary his- cially to identify potential responders and elucidate mechanism of action, it may be offered as adjunct therapy. Patients should be counseled that mul- tiple foods should be excluded for up to 3 weeks before response may be seen. For responders, staged reintroduction of foods should then resume. Food Additives Food additives, including dyes, preser- vatives, and artificial sweeteners [38], have been studied as components of PAF diets, as well as independently. In one double-blind, placebo-controlled study of 838 patients, 31% experienced symptom improvement on a diet free of food additives [39]. One confounding factor is that such a diet may also be low in other pseudoallergens. Food additives seem unlikely to be isolated triggers, given results of a challenge trial. In this study, 100 patients with CU were chal- lenged with 11 food additives, includ- ing dyes, preservatives, and artificial sweeteners [40]. Only 2 patients had an urticarial reaction on initial single-blind challenge, and neither reacted on second challenge. In conclusion, food additives alone do not appear to be a CU trig- ger, but a diet free of food additives (and presumably free of other potential triggers) may be helpful in a subset of patients. Histamine The vasoactive amine histamine is released from mast cells and is an important CU mediator, and antihista- mines are considered as mainstay ther- apy [3]. Thus, researchers have evalu- ated LH diets as adjunct therapy for CU. Ingestion of excess histamine may result in significant cutaneous as well as systemic symptoms, as in cases of hista- mine “poisoning” following ingestion of foods (such as certain fish) contain- ing high levels of histamine. Affected individuals have experienced pruri- tus, angioedema, wheals, and systemic symptoms [41]. Histamine intolerance may occur as well, with symptoms fol- In another study evaluating 33 CU patients with known history of pseu- doallergic reactions, 76% reacted to whole tomatoes, 50% to a panel of common food additives, 47% to herbal extracts in oil, and 44% to white wine [31]. Researchers then tested steam distillates and residues of these foods. Overall, patients reacted more strongly to tomato steam distillates (45%) than residue (15%) [31]. The tested residue was rich in histamine, salicylates, and proteins, and as only 15% of patients reacted to this residue, these are con- sidered less likely triggers. When the tomato distillate was further analyzed by mass spectrometry, major ingredi- ents included aldehydes, ketones, and alcohol, making these good targets for further study [31]. The exact mechanism of pseudo- allergen activity is unknown, but one hypothesis centers on non-IgE depen- dent histamine release from mast cells. In vitro analysis of skin biopsy specimens found that tomato extract enhances his- tamine release from mast cells through co-stimulation of substance P or C5a, but not IgE [31]. Food components may also act via mast cell-independent effects. For example, it has been pro- posed that foods rich in cinnamaldehyde (eg, tomatoes and spices such as cinna- mon and cloves) may worsen rosacea by activating transient receptor potential channels to promote neurogenic vaso- dilation [36,37]. Overall, PAF diets have improved symptoms in a subset of patients. How- ever, efficacy across studies has been highly variable and no trial has been placebo-controlled. Regardless, many responders have demonstrated positive OPT. In addition, Zuberbier et al empha- size that pseudoallergic reactions are “known to be dose-dependent and fre- quently not restricted to just one agent” [31]. Therefore, single food challenge tests may not be as useful as elimination of multiple potential trigger foods. In summary, while the value of PAF diet requires further investigation, espe- Review | Dermatol Pract Concept 2020;10(1):e2020004 5 tion on potential dietary factors may be offered to a selected group of patients. A food diary is recommended, and those with suspected delayed meat or A sim- plex allergy should be offered testing. In those at risk or reporting symptoms suggestive of celiac disease or vitamin D deficiency, further workup is recom- mended (Table 1). For other patients, a 3-week elim- ination diet trial may be considered, excluding foods known to be pseudo- allergens or those high in histamine (Table 2). ingestion. Nonimmunological reactions to foods are reported more frequently. Trials of specific elimination diets have reported high rates of response after an average duration of only 3 weeks. In addition, OPT has confirmed that some patients experience worsening of symp- toms after ingestion of foods including food additives as well as natural foods such as tomatoes, herbs, seafood, alco- hol, and others. The specific mechanism of action is not known. In conclusion, while oral antihis- tamines are first-line therapy, educa- tamine [42]. Further clouding the issue is that oral histamine challenge tests may provoke responses even in those with no history of food intolerance; in one study, close to 50% of volunteers reacted [49]. In conclusion, LH diets may be help- ful in a subset of patients with CU, but the reason remains unclear. LH diets tend to be low in pseudoallergens [48], which is one possible explanation [42]. At this time, no accurate testing is avail- able to determine potential responders. The Role of Vitamin D The potential immunomodulatory role of vitamin D in urticaria has received increasing attention [50]. A recent meta-analysis of 14 studies and 1,655 patients found that prevalence of vita- min D deficiency is significantly higher in patients with CU than in healthy controls [51]. Another meta-analysis confirmed these findings and proposed that CU is associated specifically with vitamin D deficiency, not insufficiency [52]. Vitamin D deficiency is defined by serum 25-hydroxyvitamin D <20 ng/dL and insufficiency between 20 and 29 ng/dL [53]. Early interventional studies reported t h a t v i t a m i n D s u p p l e m e n t a t i o n improved CU symptom severity, particu- larly in treatment-resistant patients with low baseline levels [54]. A later system- atic review reported results of 7 studies describing CU improvement after high- dose vitamin D supplementation, but doses and duration of use varied widely, indicating need for further study [55]. In summary, testing for vitamin D deficiency in those at risk, along with supplementation as appropriate, may be useful adjunctive therapy for patients with CU. Conclusions I m m u n o l o g i c a l f o o d a l l e r g i e s are extremely rare but might be poten- tial causes of CU in certain settings, as in patients with a history of tick bites or a history of raw, marinated, or smoked fish Table 1. Selected Tests for Suspected Dietary Factors in Chronic Urticaria Patients reporting flares 2-6 hours following ingestion of lamb, pork, or beef, especially in those with history of tick bites I g E s e r u m a n t i b o d y t e s t for α-gal History of raw, marinated, or smoked fish inges- tion, particularly in coastal European regions IgE serum antibody test for Anisakis simplex Symptoms suggestive of celiac disease Serum antibody testing for celiac disease and referral to gastroenterologist Risk factors for vitamin D deficiency Serum vitamin D levels α-gal = galactose-α-1,3-galactose; IgE = immunoglobulin E. Table 2. Foods Reported as Nonimmunological Chronic Urticaria Triggers Food Group Reported Triggers (Suggest Avoidance) Seafood • Avoid all except freshly caught and frozen fish, which is then cooked Meat • Aged sausages/smoked meats/processed meats Dairy • Fermented dairy (aged cheeses, yogurt, sour cream) Vegetables • Tomatoes • Spinach, eggplant, avocado • Fermented vegetables such as sauerkraut and kimchi • Overripe vegetables Fruits • All fruits • All fruit juices Beverages • Alcohol • Herbal tea Other • Any fermented foods • Food additives (dyes, preservatives, artificial sweeteners) • Spices and herbs • Chocolate • Chewing gum/candy *Consider trial of 3-week avoidance as adjunct to antihistamine therapy in treat- ment-resistant patients. *Includes foods listed on the pseudoallergen-free diet and the low-histamine diet. 6 Review | Dermatol Pract Concept 2020;10(1):e2020004 16. Qian J, Liu T, Yang L, Daus A, Crowley R, Zhou Q. 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