Concomitant Celiac Disease and Wheat Allergy

454 Practitioner's Corner

reason, the protein bands detected in IgE immunoblotting (11- 14 kDa) could be indicative of sensitization to S wallisii, since Concomitant Celiac Disease and Wheat Allergy: we cannot ensure that profilin or a profilin with a low cross- 2 Case Reports reactivity pattern is the protein responsible for hypersensitivity in this case, as suggested elsewhere. Lombardi C1, Savi E2, Passalacqua G3 It is important to consider ornamental houseplants that do 1Departmental Unit of Allergology, Clinical Immunology & not produce pollen as possible sources of indoor allergens, Pneumology, Fondazione Poliambulanza, Brescia, Italy since other parts of these plants may cause immediate 2Departimental Unit of Allergology, G.Da Saliceto Hospital, hypersensitivity and may be more likely to do so than common Piacenza, Italy molds, house dust mites, and pet hair or dander. 3Allergy and Respiratory Diseases, Policlinico San Martino- University of Genoa, Genoa, Italy Funding The authors declare that no funding was received for the J Investig Allergol Clin Immunol 2019; Vol. 29(6): 454-456 doi: 10.18176/jiaci.0421 present study.

Conflicts of Interest Key words: Celiac disease. Wheat flour allergy. Diagnosis. Molecular diagnosis. Autoimmune disease. The authors declare that they have no conflicts of interest. Palabras clave: Enfermedad celíaca. Alergia a la harina de trigo. Diagnóstico. Diagnóstico molecular. Enfermedad autoimmune. References

1. Kanerva L, Estlander T, Aalto-Korte K. Occupational protein contact dermatitis and rhinoconjunctivitis caused by Wheat flour (Triticum aestivum) is a major food source spathe (Spathiphyllum) flowers. Contact Dermatitis. 2000 throughout the world. It is used in the manufacture of bread, Jun;42(6):369-70. pasta, and cereals. Wheat can cause various diseases, including 2. Cahen YD, Lundberg M, Wüthrich B. Indoor allergy to IgE-mediated food allergy, wheat-dependent exercise-induced spathe flower (Spathiphyllum floribundum). Allergy. 1997 anaphylaxis, respiratory allergy (baker’s asthma), celiac Jan;52(1):114-5. disease, and nonceliac gluten sensitivity. Wheat allergy is 3. Mitchell J, et al. Plants and plant products injurious to the skin. an IgE-mediated response to any of the proteins present in Vancouver, British Columbia, Canada: Greengrass Ltd, 1979 wheat, including gluten. Its prevalence varies depending 4. Kanerva L, Mäkinen-Kiljunen S, Kiistala R, Granlund H. on age and region from 0.4% to 4% [1]. Around 65% of Occupational allergy caused by spathe flower (Spathiphyllum children outgrow this allergy by the age of 12 months. Celiac wallisii). Allergy. 1995 Feb;50(2):174-8. disease is an autoimmune disorder with an aberrant response 5. Kanerva L, Estlander T, Petman L, Mäkinen-Kiljunen S. to gluten proteins (present in wheat, barley, and rye) with Occupational allergic contact urticaria to yucca (Yucca subsequent atrophy of intestinal villi, impaired intestinal aloifolia), weeping fig (Ficus benjamina), and spathe flower absorption, and malnutrition. The symptoms of wheat allergy (Spathiphyllum wallisii). Allergy. 2001 Oct;56(10):1008-11. can range from mild to life-threatening and include skin 6. Bradford MM. A rapid and sensitive method for the quantitation rash, nausea, abdominal pain, vomiting/diarrhea, respiratory of microgram quantities of protein utilizing the principle of symptoms, and even anaphylaxis. Onset is usually within protein-dye binding. Anal Biochem. 1976 May 7;72:248-54. minutes, more rarely within 1-2 hours. A tentative diagnosis 7. Purillä P, Keskinen H, Leino T, Tupasela O, Tuppurainen M. can be made using skin prick testing or a specific serum IgE Occupational asthma caused by decorative flowers: review and assay. Nonetheless, the assessment of IgE with the whole case reports. Int Arch Occup Environ Health. 1994;66(2):131-6. wheat extract is poorly sensitive and specific owing to cross- 8. Jordan-Wagner DL, Whisman BA, Goetz DW. Cross- reactivity with other allergenic molecules. Wheat proteins are allergenicity among celery, cucumber, carrot, and watermelon. classified into albumins, salt-soluble globulins, and insoluble Ann Allergy. 1993 Jul;71(1):70-9. prolamins (gliadins and glutenins). Molecular tests can identify 9. Mäkinen-Kiljunen S, Turjanmaa K, Palosuo T, Reunala T. the presence of specific IgE against individual components: Characterization of latex antigens and allergens in surgical glutenins, gliadin, ω-5 gliadin, α-amylase inhibitors, lipid gloves and natural rubber by immunoelectrophoretic methods. transfer proteins, and Tri a 14 [2,3]. We report what could be J Allergy Clin Immunol. 1992 Aug;90(2):230-5. the first 2 cases of concomitant celiac disease and IgE-mediated allergy to wheat proteins. Manuscript received November 13, 2018; accepted for The first patient was a 15-year-old girl who was diagnosed publication May 20, 2019. with celiac disease at the age of 6 years based on symptoms, positive antitransglutaminase IgA level (240 IU/mL, [normal Valeria Herrera-Lasso Regás value <7 IU/mL], Thermo Fisher Scientific), antiendomysial Allergy Department IgA (1:256), and duodenal biopsy findings. She remained University Hospital Joan XXIII on a gluten-free diet, with clinical benefits and normal Tarragona, Spain E-mail: [email protected] immunological test results. She came to our emergency

department with generalized urticaria, lip swelling, abdominal although the diagnosis was not based on molecular data [5]. pain, diarrhea, vomiting, and respiratory distress (PaO2, The relationship between allergy and autoimmune disorders 89 mmHg). She promptly recovered after intravenous is complex and poorly understood, especially in wheat allergy methylprednisolone and intramuscular epinephrine. Symptoms and celiac disease, although some hypotheses can be put had occurred thirty minutes after eating flat bread during a party. forward [6]. No consumption of alcohol or medications could be documented. Kreiner et al [7] identified shared susceptibility loci and Tryptase serum levels were increased (14 µg/mL) during the similarities in pathways between allergy and autoimmune acute phase, although they returned to normal (7.4 µg/mL) diseases, suggesting partially shared mechanisms. IgE after 48 hours, thus supporting the diagnosis of anaphylaxis. autoantibodies have been known to be present in patients IgE to wheat was 1.5 kU/L, with gluten-specific IgE at with autoimmune disease for more than 40 years, although 2.4 kU/L. The molecular diagnosis revealed sensitization to autoantibodies are not associated with a higher rate of atopy. gliadin (4.9 kU/L) and rTri a 19.0101 (ω-5 gliadin) (5.6 kU/L). Nevertheless, IgE was recently suggested to be an active Findings for Tri a 14 were negative. The skin prick test, which trigger of autoimmunity through mechanisms involving the was performed 2 weeks after the episode, was positive for secretion of type-I interferons by plasmacytoid dendritic cells, gliadin (8 mm) (ALK-Abelló) but negative for the whole recruitment of basophils to lymph nodes, and activation of wheat extract. We deduced that the anaphylactic reaction was adaptive immune responses through B and T cells. There is elicited by ω-5 gliadin. The detailed clinical history revealed also evidence supporting the role of IgE receptors in dendritic that, after years following a strict diet the patient started to eat cell function. The activation of these cells by the immune wheat occasionally. The occasional consumption of wheat- complexes of DNA-specific IgE antibodies can also induce containing food after a long period with a gluten-free diet B-cell differentiation and plasma cell formation [8]. The may have induced sensitization to ω-5 gliadin. The patient involvement of B cells has also been hypothesized. CD5+ was again instructed to avoid the culprit allergens and received B cells can have a negative regulatory function, and their the epinephrine auto-injector. Nevertheless, she continued to deficiency can worsen both allergic and autoimmune diseases experience wheat-induced anaphylaxis. No exercise-induced (such as experimental autoimmune encephalomyelitis, chronic condition was documented. colitis, and lupus-like models of autoimmunity) [9]. The second patient was a 54-year-old woman who was first In conclusion, the 2 cases we describe support the possible diagnosed with celiac disease at the age of 26. She followed a coexistence of autoimmune and IgE-mediated diseases. The gluten-free diet, although her clinical history revealed episodes of presence of IgE specific for Tri a 14, gluten, gliadin, and ω-5 anaphylaxis after the ingestion of wheat-containing foods, with gliadin should be considered a diagnostic marker in patients raised serum tryptase (15.8 ng/mL [baseline, 4.3 ng/mL]). She with confirmed celiac disease who experience anaphylaxis [10] was referred to our emergency department with hypotension, after ingestion of food containing wheat. It is reasonable to generalized urticaria, lip swelling, abdominal pain, diarrhea/ hypothesize that the occasional consumption of wheat flour– vomiting, and dyspnea. The episode was rapidly controlled containing proteins could trigger IgE-mediated sensitization with intramuscular epinephrine, intravenous corticosteroids, overlapping with a pre-existing autoimmune disease. and antihistamines combined with rehydration. The patient was taking nebivolol, which was temporarily withdrawn. She had Funding previously experienced oral allergy syndrome with peach, but The authors declare that no funding was received for the no systemic signs. The skin prick test performed 3 weeks after present study. the reaction was positive for whole wheat extract (diameter, 7 mm), but negative for gliadin and lipid transfer protein. Serum IgE was positive for wheat flour, hazelnut, carrot, Conflicts of Interest peach, and apple. The molecular diagnosis showed positive The authors declare that they have no conflicts of interest. results for Tri a 14 (3.5 kU/L), nTri a aA_TI (α-amylase) (3.0 kU/L), Mal d 1 (0.5 kU/L), Pru p 1 (0.3 kU/L), Api g 1 (0.2 kU/L), Cor a 1 (0.5 kU/L), and Ara h 8 (0.5 KU/L). The References results for Cor a 8, Ara h 9, and Pru p 3 were negative. No specific IgE against Tri a 19 (ω-5 gliadin) was detected. The 1. Longo G, Berti I, Burks AW, Krauss B, Barbi E. IgE-mediated patient was provided with detailed information, including food allergy in children. Lancet. 2013;382:1656-64. a strict avoidance diet, in order to prevent further episodes. 2. Nilsson N, Sjölander S, Baar A, Berthold M, Pahr S, Vrtala S, et Celiac disease is a gluten-induced immune-mediated al. Wheat allergy in children evaluated with challenge and IgE condition characterized by a specific genotype (HLA-DQ2 and antibodies to wheat components. Pediatr Allergy Immunol. HLA-DQ8) and production of tissue-specific autoantibodies 2015;26:119-25. (transglutaminase and endomysium). The inflammatory 3. Sander I, Rihs H-P, Doekes G, Quirce S, Krop E, Rozynek P et process targets the intestinal mucosa, although various al. Component-resolved diagnosis of baker’s allergy based on nonspecific symptoms may also be present, suggesting specific IgE to recombinant wheat flour proteins. J Allergy Clin the systemic nature of the disease [4]. We report 2 cases Immunol. 2015;135:1529-37. of an exceptional association between celiac disease and a 4. Leonard MM, Sapone A, Catassi C, Fasano A. Celiac documented IgE-mediated allergic disease that resulted in Disease and Nonceliac Gluten Sensitivity: A Review. JAMA. anaphylaxis. A similar case has been reported in the literature, 2017;318:647-56.

5. Borghini R, Donato G, Marino M, Casale R, Tola MD, Picarelli A. In extremis diagnosis of celiac disease and concomitant Survey of Opinion of Spanish Physicians on the Role wheat allergy. Turk J Gastroenterol. 2018;29:515-7. of Eosinophils in Asthma and Other Diseases 6. Torres JA, Sastre J, de las Heras M, Cuesta J, Lombardero M, Ledesma A IgE-mediated cereal allergy and latent celiac Plaza V1, Blanco M2, Delgado J3, Martínez I4, Zubeldía JM5, disease. J Invest Allergol Clin Immunol. 2008;18:407-14 Molina J6 7. Kreiner E, Waage J, Standl M, Brix S, Pers TH, Alves AC, et 1Director del Comité Ejecutivo de la Guía Española para el al. Shared genetic variants suggest common pathways in Manejo del Asma (GEMA), Servei de Pneumologia i Allèrgia, allergy and autoimmune diseases. J Allergy Clin Immunol. Hospital de la Santa Creu i Sant Pau, Institut d’Investigació 2017;140:771-81. Biomèdica Sant Pau (IIB Sant Pau), Universitat Autònoma de 8. Ettinger R, Karnell JL, Henault J, Panda SK, Riggs JM, Kolbeck R, Barcelona, Barcelona, Spain et al. Pathogenic mechanisms of IgE-mediated inflammation 2Servicio de Neumología, Complejo Hospitalario Universitario in self-destructive autoimmune responses. Autoimmunity. de A Coruña, A Coruña, Spain 2017;50:25-36. 3Hospital Universitario Virgen Macarena, Sevilla, Spain 9. Noh G, Lee JH. Regulatory B cells and allergic diseases. Allergy 4Hospital Universitario Son Espases, Palma, Spain Asthma Immunol Res. 2011;3:168-77. 5Hospital Universitario Gregorio Marañón, Madrid, Spain 10. Kennard B. Thomas L, Rutkowski I, Azzu K, Yong PFK, 6Centro de Salud Francia, Fuenlabrada, Spain Kastemow B, et al. A multicenter evaluation of diagnosis and management of omega 5-gliadin allergy (also known J Investig Allergol Clin Immunol 2019; Vol. 29(6): 456-458 as wheat-dependent exercise induced anaphylaxis) in 132 doi: 10.18176/jiaci.0423 adults. J Allergy Clin Immunolol Pract. 2018;6:1892-7. Key words: Eosinophils. Biomarker. Severity. Biologic drug. Quality of life. Palabras clave: Eosinófilos. Biomarcador. Gravedad. Fármaco biológico. Calidad de vida.

Manuscript received March 11, 2019; accepted for publication May 31, 2019.

Giovanni Passalacqua Eosinophilic asthma is the most common inflammatory Associate Professor phenotype, accounting for over 25% of all patients with severe Allergy and Respiratory Diseases asthma. It is characterized by abnormal production of cytokines Policlinico San Martino - University of Genoa from type 2 helper T lymphocytes and type 2 innate lymphoid Pad. Maragliano – L.go R Benzi 10 cells (ILC-2s), such as IL-4, IL-5, and IL-13, as well as a 16133 Genoa, Italy persistent increase and activation of eosinophils in blood and E-mail: [email protected] airways despite treatment with high-dose corticosteroids [1,2]. Blood and sputum eosinophilia are associated with more severe disease, poorer control, and worse prognosis [3]. The most direct way to diagnose severe eosinophilic asthma is through diagnosis of severe asthma, which is characterized by ≥2 exacerbations per year, dependence on oral corticosteroids to achieve asthma control, and a persistent increase in the eosinophil count in blood and the airways [2]. Eosinophils represent approximately 1% of peripheral blood leukocytes, and their differentiation, survival, and activation are regulated mainly by IL-5 [4]. Irrespective of the presence of allergy, severe, uncontrolled eosinophilic asthma is treated with biological drugs that target either eosinophils or the IL-5 pathway. On the one hand, biologic therapies targeting eosinophils include drugs blocking eosinophil recruitment, such as bertilimumab, which prevents accumulation of these cells in tissues [5]. On the other hand, drugs targeting the IL-5 pathway may be used, either directly against IL-5 (mepolizumab and reslizumab) or the IL-5 receptor (IL-5Ra) (benralizumab) [6-9]. By blocking the interaction between IL-5 and its receptor, the eosinophil count in blood and the airway decreases, as does survival of these cells, thus decreasing the symptoms of the disease. Another treatment approach includes inhibition of IL-4Ra by blocking the action of IL-4 and IL-13. This strategy prevents the stimulation of type 2 inflammation,