A. Case study
A 19-year-old girl had a severe asthma attack after eating a meal consisting of rump steak, mashed potatoes, and boiled peas and carrots. She was a known asthmatic, but had had severe asthma attacks only during or after exercise. (The attacks were in fact exercise-induced.)

She had eaten these foods before without experiencing any respiratory distress. The only apparent difference was that this was the first time that she had eaten instant mashed potatoes. When the ingredients of the mashed potatoes were studied, the only "unusual" ingredient appeared to be sulfur dioxide. She was questioned about her intake of other sources of sulfites. It was determined that she had experienced a severe attack before, after eating dried fruit. Also, whenever she drank certain fruit juices, she would either start coughing or develop a tight chest. These foods all contain significant amounts of sulfites.

How does one confirm that it is sulfites causing an asthma attack?
In this case, it was quite clear what was causing the attacks, so the patient was instructed to avoid all sulfite-containing foods and beverages. But one can confirm a diagnosis by doing a double-blind placebo-controlled challenge. The patient could be given home-made mashed potato with added sulfites, and regular home-made mashed potato could be the placebo.

TIP for Allergy Advisor users: When entering "Potato (instant, mashed)", "Fruit (dried)" and "Fruit juice" into the "Pattern search" function on the main menu of Allergy Advisor, the program searches for constituents that are common to 2 or 3 of the items entered. "Sulfites/sulphites" were the only constituent that was common to all 3 food items. A diet sheet for the avoidance of sulfites in the diet can be printed for a patient from the "Management" menu of the program.

B. More information:
Sulfites are the most versatile and widely used of all food additives. They are most often preservatives, but also offer other useful properties (discussed below). They are often used for two or more actions.

Sulfites or sulfiting agents include sulfur dioxide (SO2; E220), sulfurous acid (H2SO3) and the inorganic sulfite salts that may produce SO2 under certain circumstances.¹ These salts include sodium sulfite (E221), sodium bisulfite/sodium hydrogen sulfite (E222), sodium metabisulfite (E223), potassium metabisulfite (E224), calcium sulfite (E226), calcium hydrogen sulfite/calcium bisulfite (E227) and potassiumbisulfite (E228). All of these are chemically equivalent. The term "sulfites" is often used to refer collectively to substances with E-numbers 220-228.^2,3 After the addition of sulfites to a food, they are eventually broken down to SO2, which is the active component that preserves food products.

Sulfites are permitted additives in food products, although they are subject to certain governmental regulations regarding their amounts, labelling and marketing. Sulfites also occur naturally in certain foods (e.g., mushrooms and Parmesan cheese), especially in fermented foods such as wines.^1,4,5

Sulfites in the food industry

Medication
Sulfites are used in many drugs, including injectables, inhalants and oral liquid and oral solid preparations. They can also be found in topical, ophthalmic, rectal and vaginal preparations.^10,11

They are used as preservatives,⁴ as antioxidants, and in the preparation of water-soluble derivatives of normally insoluble drugs.² Small amounts of sulfites may be used in the original processing of dextrose, gelatine and starch, which are afterwards frequently incorporated into pharmaceuticals as inert ingredients.^2,3

Recorded adverse reactions to sulfites
Adverse reactions have been reported to ingested, inhaled, and parenterally administered sulfites.⁶ The reactions may be immediate or delayed,² and the reported symptoms include dermatologic, respiratory, or gastrointestinal signs and symptoms.^4,5

Sulfite sensitivity occurs most often in asthmatics. These reactions can be severe and potentially life-threatening. Adverse reactions to sulfites in nonasthmatics are uncommon. Steroid-dependent asthmatics or those with a higher degree of airway hyperreactivity are at greater risk of experiencing a reaction to sulfite-containing foods.^1,3,4,5,8

Sulfite-induced asthma is typically triggered by oral ingestion of a sulfite-containing food, beverage or drug, but can also be triggered by the inhalation of SO2. A far lower dose of inhaled sulfites is required to induce a reaction, compared to ingested sulfites.¹

Although there is some disagreement on prevalence, a number of studies have indicated that 3-10% of all chronic asthmatics are sulfite-sensitive, with a higher prevalence in those who are steroid-dependent.^{1,2,3,6,8,9,12}

Studies regard a drop of more than 20% in FEV1 induced by exposure to a sulfite-containing food or drink as significant, but even a 10% drop should be regarded as clinically significant, as patients experience definite symptoms at this level.¹³

For normal individuals, exposure to sulfites at levels set by legislation appears to pose little risk. Toxicity studies in volunteers showed that ingesting 400mg sulfites daily for 25 days produces no adverse effects.^1,4

The single most commonly reported reaction is bronchospasm; and the most serious reactions are anaphylactic shock, loss of consciousness and death.^2,3,4,5,9,14

Other reported symptoms include tachypnea, dyspnea, wheezing, chest tightness, hypotension, tachycardia, headache, dizziness, weakness, severe flushing, generalized urticaria, angioedema, tingling, pruritus, rhinitis, conjunctivitis, dysphagia, abdominal pain and cramping, diarrhoea, nausea and vomiting. For most of these symptoms, diagnostic challenges were not undertaken to confirm the reported adverse reaction.^1,2,3,4,9

Sulfite-containing drugs may produce adverse reactions in susceptible individuals. Sources implicated include intravenous injections containing as little as 2mg of sodium metabisulfite, eyedrops, inhaled products, and local dental anesthetic injections containing as little as 0.9mg of sodium bisulfite.2,3,10,12,15 It should be noted that a far lower dose of sulfite-containing inhalant or injectable drug is needed to induce a reaction than would be the case with oral ingestion of sulfite-containing products. No adverse reactions to sulfites in orally administered pharmaceutical solutions have been reported. Direct topical contact with sulfites, especially in the presence of moisture, has caused skin reactions in food service personnel who handle sulfites.2

What is the mechanism of action of sulfites?
This has not been fully elucidated in the literature.^2,3,5,9,16 There have been reported cases in which sulfite-sensitive patients had positive skin prick tests to sulfites, which would indicate an IgE-mediated reaction, but the overwhelming majority of reactions are likely to be non-IgE-mediated.^1,2,4,5 Suggested mechanisms are:

Onset of adverse reactions to sulfites
After exposure to sulfites through inhalation, intravenous injection or ingestion of solutions, the onset of an adverse reaction is usually rapid, occurring immediately or within 1-5 minutes. There have been several reports of sulfite-sensitivity reactions induced by drinking acidic sulfite-containing solutions, e.g., fruit juices. Most of these reactions also occurred immediately after ingestion or within 1-2 minutes. In acidic sulfite solutions, the predominant sulfiting agent is sulfur dioxide. Such rapid-onset reactions seem to rule out the possibility of intestinal absorption occurring before the adverse reaction is elicited. Some researchers have speculated that in these cases the absorption occurs by the inhalation of sulfur dioxide that is vaporized from the solution, or from absorption through the oral mucosa. It has also been suggested that sulfite-sensitive receptors in the oral cavity trigger an orobronchial reflex.^2,4,9

When sulfites are taken in capsule form or mixed with food, the onset generally takes longer (an average of 15-30 minutes), although some reactions to solid food particles have occurred immediately. Delayed reactions may be attributable to intestinal absorption.^2,9 Sulfite sensitivity reactions are evidently dose-related, resulting in considerable variability among individuals. As in the case of lactose intolerance, an individual may be able to tolerate a dose until his or her stores of enzymes are depleted. The reaction may occur only once the threshold has been reached.

Diagnosis of a sulfite-sensitivity
In general, the double-blind placebo-controlled challenge is regarded as the gold standard. Patients may be challenged with capsules, neutral solutions, or acidic solutions of metabisulfite. There is no standardized procedure for challenging with sulfites. Challenges should be tailored to a patient's history of reaction. The inhalation option is the most likely to provoke asthma; a challenge with sulfites in solution is optimal for patients who have reacted to beverages; and in patients with a history of response to particular foods, food challenges are preferable.¹

Because the mechanism of action is not clear, double-blind placebo-controlled challenges may not be useful in all cases of sulfite-sensitivity-for example, where the mechanism of action is a deficiency in sulfite-oxidase. Enzyme levels may be variable, and results of the double-blind placebo-controlled challenge may therefore vary every time it is done.

The CAST blood test has some value in assisting in diagnosis in some individuals.

In most cases, it may not even be necessary to do a challenge to confirm the diagnosis. The patient can merely avoid sulfite-containing products.

In cases where a definite diagnosis is essential, e.g., where other causes need to be excluded, the necessary precautions should be taken to assure the safety of the patient, since life-threatening reactions can occur.^8,17,18

Management of a sulfite-sensitivity
The only course of action is to avoid sulfite-treated foods and drugs. There is no evidence that sulfite-sensitive individuals need to avoid foods containing less than 10ppm residual SO2 equivalents.^1,2,4,17 But this level, in the atmosphere, may be high enough to trigger a reaction upon inhalation in asthmatics. If a reaction occurs, the necessary medical treatment should of course be given.

D. References
1. Metcalfe DD, Sampson HS, Simon RA. Food allergy: adverse reactions to foods and food additives 3rd edition. Blackwell Publishing, 2003.
2. Dalton-Bunnow MF. Review of sulfite sensitivity. Am J Hosp Pharm. 1985 Oct;42(10):2220-6.
3. Challen RG. Sulphite content of Australian pharmaceutical products. Med J Aust. 1990 Feb 19;152(4):196-8.
4. Joneja JV. Dealing with Food Allergies. A practical guide to detecting culprit foods and eating a healthy, enjoyable diet. Bull Publishing Company, USA, 2003.
5. Lester MR. Sulfite sensitivity: significance in human health. J Am Coll Nutr. 1995 Jun;14(3):229-32.
6. Gunnison AF, Jacobsen DW. Sulfite hypersensitivity. A critical review. CRC Crit Rev Toxicol. 1987;17(3):185-214.
7. Montano Garcia ML. [Adverse reactions induced by food additives: sulfites] Rev Alerg Mex. 1989 May-Jun;36(3):107-9.
8. Giffon E, Vervloet D, Charpin J. [Suspicion on sulfites] Rev Mal Respir. 1989;6(4):303-10.
9. Settipane GA. Adverse reactions to sulfites in drugs and foods. J Am Acad Dermatol. 1984 Jun;10(6):1077-80.
10. Smolinske SC. Review of parenteral sulfite reactions. J Toxicol Clin Toxicol. 1992;30(4):597-606.
11. Dalton-Bunnow MF. Sulfite content of drug products. Am J Hosp Pharm. 1985 Oct;42(10):2196-2201.
12. Perusse R, Goulet JP, Turcotte JY. Sulfite, asthma and vasoconstrictors. J Can Dent Assoc. 1989 Jan;55(1):55-6.
13. Steinman HA, le Roux M, Potter PC. Sulphur dioxide sensitivity in South African asthmatic children. S Afr Med J 1993;83:387-390.
14. Perusse R, Goulet JP, Turcotte JY. Contraindications to vasoconstrictors in dentistry: Part II. Hyperthyroidism, diabetes, sulfite sensitivity, cortico-dependent asthma, and pheochromocytoma. Oral Surg Oral Med Oral Pathol. 1992 Nov;74(5):687-91.
15. Fisher AA. Reactions to injectable local anesthetics. Part IV: Reactions to sulfites in local anesthetics. Cutis. 1989 Oct;44(4):283-4.
16. Jamieson DM, Guill MF, Wray BB, May JR. Metabisulfite sensitivity: case report and literature review. Ann Allergy. 1985 Feb;54(2):115-21.
17. Miltgen J, Marotel C, Natali F, Vaylet F, L'Her P. [Clinical aspects and diagnosis of sulfite intolerance. Apropos of 9 patients] Rev Pneumol Clin. 1996;52(6):363-71.
18. Bush RK, Zoratti E, Taylor SL. Diagnosis of sulfite and aspirin sensitivity. Clin Rev Allergy. 1990 Summer-Fall;8(2-3):159-78.

2. Which of the following is not a well-known function of sulfites in the food industry?
(a.) Preservative
(b.) Antioxidant
(c.) Colourant
(d.) Bleaching

3. Which of the following is not true regarding sulfite-sensitive asthmatics?
(a.) Reactions can be severe and potentially life threatening.
(b.) Steroid-dependent asthmatics are at greater risk of experiencing a reaction to sulfite-containing foods.
(c.) A far lower dose of inhaled sulfites is required to induce a reaction, compared to ingested sulfites.
(d.) Sulfite-containing drugs do not affect asthmatics.

4. Which of the following is seen as a possible mechanism of action of sulfite-sensitive reactions?
(a.) IgE-mediated reaction
(b.) Sulfite-oxidase deficiency
(c.) Cholinergic-reflex mechanism
(d.) All of the above

5. True or false: The onset of an adverse reaction after exposure to sulfites through inhalation, intravenous injection or ingestion of solutions is usually rapid, occurring immediately or within 1-5 minutes.
(a.) True
(b.) False

6. True or false: When sulfites are taken in capsule form or mixed with food, the onset is generally longer (averaging 15-30 minutes).
(a.) True
(b.) False

7. Which of the following is suggested as the preferred diagnostic tool for sulfite sensitivity?
(a.) Blood test
(b.) Skin prick test
(c.) Open challenge
(d.) Double-blind placebo-controlled challenge

8. True or false: Sulfite-sensitive individuals should avoid all foods that contain even a small amount of sulfite.
(a.) True
(b.) False