Mustard: A Priority Food Allergen in Canada

Appendix 1: Mustard Allergy: Search Strategies (MEDLINE, EMBASE & FSTA)

Databases searched:

• Ovid Medline (R) In-Process & Other Non-Indexed Citations and Ovid Medline (R) 1950 to Present
• Ovid Medline (R) In-Process & Other Non-Indexed Citations - November 18, 2008
• Ovid Embase 1980 to 2008 Week 46
• FSTA Direct (Last updated 17 Nov 2008)

Records exported to Reference Manager (to main database: 'mustard_allergy'):

• Medline = 139 + 13 = 152
• Embase = 178
• FSTA = 28
• TOTAL = 358 references

Search Strategies

1. Mustard Plant/
2. Sinapis/
3. (mustard* or sinapis).tw.
4. (brassica adj3 (alba or juncea or nigra)).tw.
5. or/1-4
6. exp Hypersensitivity/
7. exp Urticaria/
8. (allerg* or hypersensi* or intoleran* or anaphyla* or urticaria* or hive*).tw.
9. ((sensiti* or toleran*) adj3 (mustard* or sinapis or brassica alba or brassica juncea or brassica nigra)).tw.
10. (food adj2 (challenge or rechallenge)).tw.
11. or/6-10
12. 5 and 11
13. limit 12 to humans
14. limit 13 to yr="1988-2009"

OVID MEDLINE (R) In-Process & Other Non-Indexed Citations - November 18, 2008

1. Mustard Plant/
2. Sinapis/
3. (mustard* or sinapis).tw.
4. (brassica adj3 (alba or juncea or nigra)).tw.
5. or/1-4
6. exp Hypersensitivity/
7. exp Urticaria/
8. (allerg* or hypersensi* or intoleran* or anaphyla* or urticaria* or hive*).tw.
9. ((sensiti* or toleran*) adj3 (mustard* or sinapis or brassica alba or brassica juncea or brassica nigra)).tw.
10. (food adj2 (challenge or rechallenge)).tw.
11. or/6-10
12. 5 and 11

EMBASE

1. Brassica/
2. Brassica Extract/
3. sinapis/
4. (mustard* or sinapis).tw.
5. (brassica adj3 (alba or juncea or nigra)).tw.
6. or/1-5
7. exp Hypersensitivity/
8. exp Urticaria/
9. (allerg* or hypersensi* or intoleran* or anaphyla* or urticaria* or hive*).tw.
10. ((sensiti* or toleran*) adj3 (mustard* or sinapis or brassica alba or brassica juncea or brassica nigra)).tw.
11. (food adj2 (challenge or rechallenge)).tw.
12. or/7-11
13. 6 and 12
14. limit 13 to human
15. limit 14 to yr="1988-2009"

FSTA

((KE = 'MUSTARD' OR KE = 'MUSTARD GREENS' OR KE = 'MUSTARD SEED OILS' OR KE = 'MUSTARD SEEDS') OR (CONTAINS(AF,'mustard* or sinapis or "brassica alba" or "brassica juncea" or "brassica nigra"'))) AND ((KE = 'ALLERGIES' OR KE = 'INTOLERANCE' OR KE = 'ANAPHYLAXIS' OR KE = 'URTICARIA') OR (CONTAINS(AF,'allerg* or hypersensi* or intoleran* or anaphyla* or urticaria* or hive*')) OR (CONTAINS(AF,'"food challenge*" or "food rechallenge"')))

PY: 1988-now

Appendix 2: Detailed Summaries of Pivotal Studies for the determination of the Allergenicity of Mustard (Table 1)

1. Double-Blind, Placebo-Controlled Food Challenge (DBPCFC)
   1. Randomized

      Figueroa et al. (2005) conducted a prospective, randomized, double-blind, placebo-controlled, food challenge (DBPCFC) study in 38 subjects (age: 21.9 ± 8.6 years old) who had a reported history of allergic reactions to mustard. The control group consisted of subjects paired for age and sex, who had dust-mite allergies. The study included a clinical questionnaire, skin prick tests (SPT) with panels of aero-allergens and foods, serum extraction for in vitro tests, analysis of total IgE and specific IgE to mugwort pollen, mustard, cabbage, cauliflower, broccoli, and other foods and a double-blind placebo-controlled food challenge followed by an open challenge.

      A commercial yellow mustard sauce was masked in a natural yoghurt-based vehicle, containing a mixture of vanilla, lemon juices, sugar and yellow colouring. The mustard sauce was composed of water, S. alba seeds (14% w/v), vinegar, salt, turmeric, paprika and cloves, and the sauce was free of sulphites. Apart from mustard, all patients tolerated all of the ingredients in both the mustard sauce and the vehicle. Subjects were randomly assigned to either the mustard or placebo (vehicle) group.

      Subjects were challenged with increasing doses, 80, 240, 800, 2400 and 6480 mg of mustard sauce, during 15-min intervals until symptoms appeared or a cumulative dose of 10 g of mustard sauce was administered. Subjects who had negative results during the blind challenge were free to participate in an open feeding study of up to 25 g of mustard sauce. There was a 2-hour interval between the first (blind) and second (open) part of the oral challenges. A mustard allergy was considered positive if the subject had symptoms after a challenge with mustard and not after a challenge with the placebo.

      Of the 38 patients included in the study, 11% had a previous history of systemic anaphylaxis. Food challenges were not performed when a subject had a history of severe anaphylaxis to mustard (adverse reaction involving at least three target organs or with demonstrated vascular collapse). Fourteen patients did not undergo DBPCFC because of either severe symptoms (n = 4) or because of denial of consent (n = 10). Therefore, the DBPCFC was performed in 24 of the 38 patients. Of the 24 subjects who underwent the DBPCFC, 14 subjects (58%) were considered to have responded positive for a mustard allergy.

      Oral allergy syndrome (OAS) was the most frequent symptom observed (71%) among subjects, characterized by pruritus and mild angioedema of the lips, tongue, palate and throat, followed by a rapid resolution of symptoms. One patient showed angioedema and bronchial asthma after mustard ingestion and another subject reacted with systemic anaphylaxis. All patients completely recovered within 90 minutes after symptomatic treatment.

      The mean cumulative reactive dose of mustard sauce (±SD) was 891.4 ± 855.2 mg, equivalent to 124.8 ± 119.7 mg of mustard. Patients with positive outcomes showed significantly greater mustard SPT results than those with negative outcomes (8.2 ± 3.7 vs 5.3 ± 2.4 mm, P < 0.05). The receiver-operating characteristic (ROC) curve analysis yielded a cut-off value for commercial mustard SPT of 8 mm, with a specificity of 90% (95% CI, 55.5- 98.3) and a sensitivity of 50% (95% CI, 23.1-76.9).

      A significant association between mustard hypersensitivity and mugwort pollen sensitization was found (97% of patients) with a partial cross-reactivity demonstrated by in vitro inhibition assays. All patients showed sensitization to other members of Brassicaceae family and cross-reactivity among them was also confirmed. Moreover, significant associations with nut (97%), leguminous (95%), corn (79%), and Rosaceae fruit (90%) sensitizations were also observed. Approximately 40% of these food sensitizations were symptomatic, including food-dependent exercise-induced anaphylaxis in six patients (2%).

      Conclusions by the authors indicated that "mustard allergy is a not-uncommon disorder that can induce severe reactions" and that the significant associations with mugwort pollinosis and several plant derived food allergies suggests that a "new mustard-mugwort allergy syndrome" may exist. They also point out a relationship between this syndrome and food-dependent exercise-induced anaphylaxis.

   2. Non-Randomized

      Morisset et al. (2003) conducted the first DBPCFC prospective study to assess the allergenicity of mustard. Thirty subjects (28 children and two adults) were included in this study, subjects ages ranged from 3-20 years and 11 females and 19 males participated. Twenty-seven (27/30) subjects were screened for mustard-specific immunoglobulin E (IgE) using radioallergosorbent test (RAST). Twenty-four subjects participated in a DBPCFC and 6 subjects participated in a single-blind, placebo-controlled, food challenge (SBPCFC). A history of food allergies were suspected among the subjects based on a history of urticaria and angioedema, atopic dermatitis, asthma, abdominal pain, and episodes of diarrhea. For inclusion to the study, subjects were selected on the basis of a positive prick test (SPT) to ground mustard seeds (Brassica nigra), mustard flour (B. juncea), metabisulfite-free strong mustard seasoning (B. juncea) and a commercialized extract (B. nigra).

      For the oral challenges mustard seasoning was used which contained 33% mustard seeds and was free of metabisulfite or other spices and flavoring. The taste of mustard was masked in very cold soft drinks and the soft drinks were used as the placebo. The amount of mustard seasoning tested was selected on the basis of routine consumption. Increasing doses of 10, 30, 100, 300, and 900 mg of mustard seasoning were administered every 20 minutes until a cumulative dose of 1340 mg of mustard seasoning was obtained. There was a 24-h interval between the administration of the mustard seasoning and the placebo.

      Seven of the 30 subjects (23%) who participated in food challenges were considered positive. The mean skin prick test results in the positive and negative subjects were as follows: 5.5 mm vs 5.9 mm for the commercialized extract; 10.9 mm vs 5.8 mm for B. nigra ground seeds (P < 0.01), 9.9 mm vs 7.1 mm for B. juncea flour (n.s. P > 0.25) and 11.5 mm vs 9.1 mm for the metabisulfite-free mustard seasoning (n.s. P > 0.1). The mean specific IgE values determined by RAST were higher but not significantly different. The SPT conducted with different mustards showed increasing reactivity in the following order: 5.8 mm (1.5-15) for the commercialized extract, 6.9 mm (0.5-18) for B. nigra ground seeds, 7.9 mm (1-20) for B. juncea flour, and 9.7 mm (3-20) for the metabisulfite free strong mustard seasoning. The difference in mean diameters of wheals induced by SPT with the commercialized extract and the strong mustard seasoning were statistically significant (P < 0.005). The mean of mustard specific-IgE values was 8.7 KU/l (0.35-72.4).

      The authors concluded that positive skin prick tests and the presence of specific IgE were not predictive of the mustard allergy and suggested that positive results from a SBPCFC or a DBPCFC should be required before recommending avoidance diets. They also noted that the seriousness of certain reactions argues for an informative labeling because mustard is often a masked in many manufactured sauces.

2. Single-Blind, Placebo-Controlled Food Challenge (SBPCFC)
   1. Non-Randomized

      Rance et al. (2000 & 2001) investigated 36 children, 22 males and 14 females, aged 10 months to 15 years (average age 5.5 years) with a positive mustard SPT using an open or single-blind, placebo controlled food challenge (SBPCFC). The initial presenting clinical features among subjects were atopic dermatitis (52%), and urticaria and/or angioedema (37%), and asthma (9%). In one subject laryngeal edema with oral allergy syndrome and rhinoconjunctivitis (2%) was observed. No anaphylaxis was reported among subjects. First-degree family atopy was reported for 29 of the 36children (81%). Subjects were compared to 22 control subjects who did not have a history of food allergies.

      Children were tested with increasing doses of 1, 5, 10, 20, 50, 100, 250, and 500 mg of mustard. The administration of the mustard and the placebo were separated by a 4-hour interval. The type, source or protein concentration of mustard used in the challenge was not specified. Symptoms that developed within a few minutes to 2 h after the last dose of the food challenge were considered for the diagnosis.

      Fifteen children of 36 entered in the study (42%) were confirmed to be allergic to mustard (positive SBPCFC) and 21 children were non-allergic (negative SBPCFC). The cumulative reactive dose by open challenge or SBPCFC varied from 1 to 936 mg. No reactions to placebo were observed. The mean cumulative reactive dose was 153 mg. The reactions observed during the SBPCFC were urticaria (14 cases), rhinoconjunctivitis (three cases), angioedema (one case), oral allergy syndrome (one case), and eczema (one case). There was no significant difference in the food allergies and associated inhalant allergen sensitizations between the two groups. In the allergic group, the mean wheal diameter for mustard SPT was 8.8 mm and the median concentration of mustard serum (s) IgE 14.8 kU/l.

      The authors noted that 8 of the 15 positive reactions to mustard (53%) reported a history of symptoms after mustard ingestion starting under 3 years of age. Authors suggest that sensitization to mustard may occur in utero or during lactation.

Appendix 3: Glossary of Medical Terms

The medical terms used throughout the document and tables are listed below alphabetically. The source of the definition is captured in the endnotes.

Anaphylaxis

A systemic allergic reaction that can be fatal within minutes, either through swelling that shuts off airways or through a dramatic drop in blood pressure. Contact with or ingestion of an allergen may set off a chain reaction in a person's immune system that may lead to swelling of the airways, loss of blood pressure, and loss of consciousness, resulting in anaphylactic shock. Some anaphylactic reactions involve only one organ system, such as the respiratory tract or skin. However, in anaphylaxis, several systems are usually affected simultaneously, including the upper and lower respiratory tracts, cardiovascular system, and gastrointestinal tract.

Asthma

A common disorder in which chronic inflammation of the bronchial tubes (bronchi) makes them swell, narrowing the airways. Asthma involves only the bronchial tubes and does not affect the air sacs (alveoli) or the lung tissue (the parenchyma of the lung) itself ⁱ

Atopic dermatitis

Dermatitis is an umbrella term for local inflammation of the skin; Atopic Dermatitis refers to the underlying inflammation being dominated by an IgE-antibody associated reaction ⁱⁱ

Atopy

A personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and develop typical symptoms such as asthma, rhinoconjunctivitis or eczema/dermatitis

Angioedema

Characterized by locally diffuse and painful soft-tissue swelling that may be asymmetric, especially on the eyelids, lips, face, and tongue but also on the back of hands or feet and on the genitals. Edema of the upper airways may cause respiratory distress. Complete airway obstruction may occur

Bronchial Asthma

Refer to the definition of asthma.

Bronchospasm

Spasmodic contraction of the muscular walls of the bronchial air passages to the lungs, as in asthma, which makes breathing difficult

Conjunctivitis

Inflammation of the mucous membrane lining the inner surface of the eyelids and covering the front part of the eyeball ^iv

Cardiovascular

The heart and the blood vessels as a unified body system ^iv

Diaphoresis

Perspiration, especially when profuse ^iv

Dyspnea

Shortness of breath ^iv

Eczema

A non-contiguous skin disorder, characterized by inflammation, itching, and the formation of scales ^iv

Erythema

An abnormal redness of the skin caused by various agents, as sunlight, drugs, etc., that irritate and congest the capillaries ^iv

Exercise induced Anaphylaxis

Exercise can induce an allergic reaction to food. The usual scenario is that of a person eating a specific food and then exercising. As the individual exercises and their body temperature increases, they begin to itch, gets lightheaded, and soon develops the characteristic allergic reactions of hives, asthma, abdominal symptoms, and even anaphylaxis. Refer to the definition of anaphylaxis or systemic reaction. ⁱ

Glottis

The opening between the vocal cords in the larynx ^iv

Gastrointestinal

The stomach and the intestines ^iv

Hypotension

Abnormally low blood pressure ^iv

Hypoxia

An abnormal condition resulting from a decrease in the oxygen supplied to or utilized by body tissue ^iv

Incontinence

Inability to restrain a natural discharge of urine from the body ^iv

Oral Allergy Syndrome

Oral allergy syndrome is a type of cross-reactivity. This syndrome occurs in people who are highly sensitive, for example, to ragweed or birch pollen. During the seasons that these allergens pollinate, the affected individual may find that when he or she tries to eat fruits, chiefly melons and apples, a rapid onset of itching is experienced in the mouth and throat, and the fruit cannot be eaten. The symptoms of this allergy, which is caused simply by the direct contact of the food with the lining of the mouth and throat, resolve rapidly. ⁱ

Rhinitis

Hypersensitivity symptoms from the nose, eg, itching, sneezing, increased secretion, and blockage ⁱ

Rhinoconjunctivitis

Allergic conjunctivitis, is also called "rhinoconjunctivitis," it is the most common allergic eye disorder. The condition is usually seasonal and is associated with hay fever. The main cause is pollens, although indoor allergens such as dust mites, molds, and dander from household pets such as cats and dogs may affect the eyes year-round. Typical complaints include itching, redness, tearing, burning, watery discharge, and eyelid swelling. To a large degree, the acute (initial) symptoms appear related to histamine release ⁱ

Stridor

A harsh, high-pitched whistling sound, produced in breathing by an obstruction in the bronchi, trachea, or larynx ^iv

Syncope

The temporary loss of consciousness followed by the return to full wakefulness; fainting ⁱ

Systemic reactions

Several systems within the body are affected simultaneously, including the upper and lower respiratory tracts, cardiovascular system, and gastrointestinal tract.^iv Refer to Anaphylaxis.

Urticaria

An allergic skin condition characterized by itching, burning, stinging, and the formation of smooth patches, or wheals, usually red; hives ^iv