A. Case study
A 40-year-old woman presented with a recent history of adverse reactions to various types of shellfish. She had had a mild reaction (general flushing and erythema) to the ingestion of a meal consisting of a large quantity of fish and shellfish (a seafood platter). In the following 6 months, she had had 2 anaphylactic experiences: 1 almost immediately after eating 3 oysters, and another to a pasta dish that she had not known contained mussels. Because she had developed erythema upon the administration of iodinated X-ray contrast media 16 years before, the diagnosis of "iodine allergy" was made. No tests were done to confirm this. The patient was referred to a dietitian for an iodine-free diet.

THOUGHT PROCESS:
In many cases, the diagnosis of a referral should be reassessed to make sure that it is correct. According to the history given, could one be absolutely sure that the diagnosis of "iodine allergy" was correct? Questions that could be asked include:
a. Does the patient tolerate other iodine-containing foods such as fish and iodated salt?
b. What fish did she have as part of the seafood platter? Could she be sensitive to that species alone and not other species of fish?
c. Did the patient always react to shellfish after she ate it?
d. Could one develop an allergy for the first time at the age of 40?

DISCUSSION:
a. She had always eaten fish and iodated salt without any adverse reaction.
b. She had eaten canned tuna as part of the seafood platter; she had also eaten it after the incident without experiencing adverse reactions.
c. The patient had never reacted to any food prior to eating the seafood platter. Thereafter, she had had only the 2 encounters with shellfish, to which she had severe reactions.
d. Yes.

It was therefore clear that the patient was reacting to shellfish but not fish, but both contain iodine: so it was unlikely that the patient was reacting to iodine.

THOUGHT PROCESS:
a. What about the reaction to the iodinated contrast media? Was that not due to an "iodine allergy"?
b. What else could have caused the reaction she experienced to the shellfish? Do the symptoms seem like those of an allergy or an intolerance?

DISCUSSION:
a. Research can thus far not prove that adverse reactions to contrast media are due to its iodine content. It has been suggested that adverse reactions result from the contrast molecule as a whole rather than the elemental iodine. So it was probable that the patient's reaction to the contrast media was not due to iodine.
b. The symptoms the patient experienced seemed more like those of an allergy. To confirm that it was an allergy, a total IgE and a serum-specific IgE to shellfish were done. Both the results were high: total IgE 88 (class 5) and IgE to shellfish 78 (class 5).

Using the results of the blood tests and the history, the diagnosis of an allergy to shellfish was made. In such a case, the diagnosis can be confirmed with an oral challenge, unless, of course, the patient has had an anaphylactic reaction, as here.

TIP for Allergy Advisor users: When "fish" is entered into the main search function, "Items, Substances & Allergens", this will bring up "iodine" under the list of "Possible additional constituents", with a risk of 2. This indicates that an adverse reaction to iodine is not very likely. When one clicks on "iodine", a window will open up to show more information on iodine: the foods that contain iodine, and other background information on iodine, as well as the adverse reactions to iodine that have been recorded in the literature. Under "Substances", one can find a list of foods with the levels of iodine they contain.

B. More information:
Iodine is an essential trace element required for a number of metabolic functions, in particular the synthesis of thyroid hormones, which are crucial for normal growth and development.^1,2 Dietary sources of iodine include seaweed and fish, iodised salt, various medicines, and iodates added to bread as a preservative.^1,3 Oriental foods are particularly rich in iodine: for example, 100g of dry kelp (konbu) contains as much as 170mg of iodine, while 100g of wakame seaweed contains 10mg of iodine.¹ Milk products (including butter and cheese) and eggs are also rich in iodine. The iodine content can vary in the same food for various reasons, such as seasonal changes. One study showed that milk samples taken during summer contained 70 micrograms/kg, and milk during winter 370 micrograms/kg on average.⁴

The colorant erythrosine (Food Red 14/FD&C Red no. 3), which is widely used in foods, cosmetics, and pharmaceutical products, contains 4 molecules of iodine and could therefore be seen as a source of iodine exposure.5,6

Adverse reactions to iodine:
It is well known that a deficiency of or a toxicity to iodine can result in adverse reactions such as goiter.⁷ This newsletter will focus on other types of adverse reactions that have been related to iodine-containing substances.

a. Adverse reactions due to dietary sources of iodine

There is very little evidence that dietary sources of iodine can result in an allergic reaction. One article by Kubota et al., however, discusses adverse reactions due to the iodine content of foods. The researchers stated that several patients had developed pustular and/or maculopapular eruptions after ingesting iodine-containing vitamin supplements and konbu in salad. Exacerbations of acne may also be related to iodine ingestion.1

There has been a report of a 60-year-old Japanese woman who experienced generalized pruritus for 30 years due to the ingestion of iodine-containing food. At age 50, she developed erythroderma from iodine-containing X-ray contrast material. When she stopped eating iodine-containing foods, she experienced no further eruptions or pruritus. However, after mistakenly drinking konbu tea, she developed a burning sensation in her mouth within 30 minutes. She also experienced edematous erythema on her face, neck and upper back, as well as bilateral conjunctival congestion 12 hours later.¹

There has also been a report of a 4-year-old boy with an iodine sensitivity who was put on a restricted diet and thereafter demonstrated both short stature and hypothyroidism.1 To date no relationship has, however, been established between a sensitivity to iodine and seafood or fish allergy.

b. Iodinated contrast media
Adverse reactions to iodinated X-ray contrast media (ICM) have been reported to occur in 0.5-2% of recipients^8,9, and the substance can be responsible for acute or delayed reactions.^10,11 It has been proposed that the reaction to ICM is in fact due to the contrast molecule as a whole rather than to the iodine component.³

Some adverse reactions to ICM are considered allergy-like, with cutaneous, cardiovascular, respiratory, and digestive symptoms. Reactions are more frequent with ionic than with non-ionic material^8,9,12, but the frequency of deaths (which are quite rare4) is almost identical.¹²

Acute reactions to ICM can vary from mild (flushing, nausea, arm pain, pruritis, vomiting, headache and mild urticaria) to severe and life-threatening (severe manifestations of those reactions mentioned, convulsions, unconsciousness, laryngeal oedema, severe bronchospasm, pulmonary oedema, severe cardiac dysrhythmias and arrest, and cardiovascular and pulmonary collapse).¹¹

Delayed reactions occur within 1 hour to 1 week after contrast medium injection. The symptoms are usually mild and include fever, rash, flushing, dizziness, pruritis, arthralgia, diarrhoea, nausea, vomiting, headache and occasionally hypotension. A few cases of serious delayed reactions such as shock, hypotension, angiodema and dyspnoea have also been reported.^9,11

A seasonal variation in the incidence of late adverse skin reactions has been reported. A study from Finland found that most skin reactions occurred in sun-exposed areas of the body and peaked during the months of May and June. The authors postulated a photosensitizing effect of ICM.¹¹

There are several predisposing factors to contrast reactions, including previous adverse reactions, a history of asthma or bronchospasm, a history of allergy or atopy, cardiac disease, dehydration, haematological or metabolic conditions, renal disease, infancy, old age, anxiety, and certain medications. These factors increase the risk of a person having severe adverse reactions.^8,11,13,14

The exact pathogenesis of adverse reactions to ICM is unclear. There is, however, increasing evidence that a significant proportion of the reactions are not due to an allergy but are T-cell-mediated.3,8,9,13 IgE-mediated anaphylaxis is rare, but it may be one of the severe adverse reactions to ICM.12

c. Povidone-iodine
Povidone-iodine (polyvinylpyrrolidone-iodine, or PVP-I) solution is an effective and generally safe disinfectant agent or antiseptic. It is used throughout the world not only in the surgical field but also in dermatology.^15,16

Adverse reactions to PVP-I are uncommon and may be due to a contact allergy or irritation of the skin. Most skin reactions to PVP-I are in fact due to skin irritation rather than allergy, especially after prolonged exposure to the solution. When PVP-I is used for patch testing in the aqueous state, a false-positive result is likely to arise due to the irritation caused. It has also been suggested that the iodine component of the solution is not likely to be the cause.^3,15,16,17

Transcutaneous absorption of iodide in neonates and in burn patients can result in iodism (a mild toxic syndrome characterized by hyper-salivation, coryza, sneezing, conjunctivitis, headache, laryngitis, bronchitis, stomatitis, parotitis, enlargement of the submaxillary glands, skin rashes and gastric upsets). One case of a systemic anaphylactoid reaction due to vaginal use of povidone-iodine has been reported.3

Should a person who is sensitive to one form of iodine avoid all other sources of iodine?
Patients are frequently asked about iodine or seafood allergy before ICM is administered, because of a commonly held belief among health professionals that there is cross-reactivity between an allergy to ICM and an allergy to iodine-rich foods. However, little evidence exists that elemental iodine or iodide is responsible for the reactions to ICM or povidone-iodine, and no evidence exists that it is involved in seafood allergy.³ But individuals with allergies or hypersensitivity are more likely to experience contrast material-related anaphylactoid reactions, compared with patients without allergies. Therefore, before deciding between prescribing ionic versus non-ionic contrast material, any potential risk factors, including the severity of previous reactions to food, drugs or contrast material, should be carefully assessed.¹⁸

It has been proposed that the only adverse effect of contrast material that can convincingly be ascribed to free iodide is iodide mumps (swelling of the submandibular, sublingual and parotid salivary glands) and other manifestations of iodism.³

The proposed mechanisms of a reaction to ICM, seafood allergy and povidone-iodine are distinctly different. It is suggested that reactions to ICM are due to the activation of non-specific immune mediators by the contrast molecule. The seafood allergy is due to an IgE-mediated hypersensitivity to seafood protein (see the Educational Newsletter of June 2003 on adverse reactions to fish). The skin reactions to providone-iodine are due to an irritation. Studies could not prove that the condition "iodine allergy" exists or that there is any cross-reactivity between these 3 sources of iodine.³ There are also, however, no reports in the literature that prove that adverse reactions to elemental iodine (in whatever form) do not occur. This indicates that iodine allergy is either very rare or does not exist, or that the methodology used in studies examining iodine allergy was flawed.

compiled by Karen du Plessis B.Sc. Diet. karen@allergyadvisor.com Food & Allergy Consulting & Testing Services (FACTS) PO Box 565 Milnerton 7435 South Africa

C. Comments by our editors

Prof Janice M. Joneja Ph. D., RDN This single case study elegantly incorporates examples of a number of factors that are often ignored or misunderstood in the diagnosis and management of adverse reactions to foods: Assumptions about the culprit food are made without sufficient information, for example, in this case, that iodine "allergy" was the cause of the patient's reaction, based solely on the fact that in the past she had experienced an adverse reaction to an iodinated radiocontrast dye, but had eaten fish without any adverse consequences Misconceptions about the nature of allergic and intolerance reactions; in this case the probably erroneous idea that iodine in food can trigger an anaphylactic reaction. Anaphylactic reactions to foods are almost invariably caused by antigenic proteins that induce allergen-specific IgE. Non-protein agents can induce IgE, but only when they act as haptens, coupled to a protein. There is currently no evidence that iodine is able to provoke an haptenic IgE response via the oral route An increasing number of examples of food allergy following initial sensitization to the allergen via the cutaneous route are appearing in the literature. It is very likely that this method of sensitization has been greatly underestimated. Allergists should be alert to the possibility that patients who have not previously demonstrated an allergic response to foods may suddenly develop an anaphylactic reaction to a food after exposure to the allergen after sensitization through injection (for example, accidental puncture); contact via abraded, inflamed skin, such as occurs in eczema, erythema, or trauma; or even as a result of skin tests, particularly intradermal tests. In these situations the allergen reaches immune cells directly and by-passes the normal antigen processing barrier of the gut-associated lymphoid tissue that occurs via the oral route.

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D. References
1. Kubota Y, Koga T, Nakayama J. Iodine allergy induced by consumption of iodine-containing food. Contact Dermatitis. 2000 May;42(5):286-7.
2. Beers MH, Berkow R. The Merck Manual of Diagnosis and Therapy. Seventeenth Edition. Merck Research Laboratories, NJ, 1999.
3. Coakley FV, Panicek DM. Iodine allergy: an oyster without a pearl? AJR Am J Roentgenol. 1997 Oct;169(4):951-2.
4. Wenlock RW, Buss DH, Moxon RE, Bunton NG. Trace nutrients. 4. Iodine in British food. Br J Nutr 1982;47(3):381-390.
5. Poulsen E. Case study: erythrosine. Food Addit Contam. 1993 May-Jun;10(3):315-23.
6. Gardner DF, Utiger RD, Schwartz SL, Witorsch P, Meyers B, Braverman LE, Witorsch RJ. Effects of oral erythrosine (2',4',5',7'-tetraiodofluorescein) on thyroid function in normal men. Toxicol Appl Pharmacol. 1987 Dec;91(3):299-304.
7. Mahan LK, Escott-Stump S. Krause's Food, Nutrition & Diet Therapy. Tenth Edition. WB Saunders Company, Pennsylvania, 2000.
8. Christiansen C, Pichler WJ, Skotland T. Delayed allergy-like reactions to X-ray contrast media: mechanistic considerations. Eur Radiol. 2000;10(12):1965-75.
9. Webb JA, Stacul F, Thomsen HS, Morcos SK; Members Of The Contrast Media Safety Committee Of The European Society Of Urogenital Radiology. Late adverse reactions to intravascular iodinated contrast media. Eur Radiol. 2003 Jan;13(1):181-4. Epub 2002 Sep 10.
10. Nicolie B. [Allergy to iodinated contrast media] Allerg Immunol (Paris). 2002 Oct;34(8):302-4.
11. Morcos SK, Thomsen HS. Adverse reactions to iodinated contrast media. Eur Radiol. 2001;11(7):1267-75.
12. Laroche D, Namour F, Lefrancois C, Aimone-Gastin I, Romano A, Sainte-Laudy J, Laxenaire MC, Gueant JL. Anaphylactoid and anaphylactic reactions to iodinated contrast material. Allergy. 1999;54 Suppl 58:13-6.
13. Moneret-Vautrin DA, Kanny G, Morisset M, Beaudouin E, Renaudin JM. [Anaphylactoid reactions and late skin reactions to iodinated contrast media: present state of the question--idea development] Rev Med Interne. 2001 Oct;22(10):969-77.
14. Hosoya T, Yamaguchi K, Akutsu T, Mitsuhashi Y, Kondo S, Sugai Y, Adachi M. Delayed adverse reactions to iodinated contrast media and their risk factors. Radiat Med. 2000 Jan-Feb;18(1):39-45.
15. Niedner R. Cytotoxicity and sensitization of povidone-iodine and other frequently used anti-infective agents. Dermatology. 1997;195 Suppl 2:89-92.
16. Kozuka T. Patch testing to exclude allergic contact dermatitis caused by povidone-iodine. Dermatology. 2002;204 Suppl 1:96-8.
17. Nishioka K, Seguchi T, Yasuno H, Yamamoto T, Tominaga K. The results of ingredient patch testing in contact dermatitis elicited by povidone-iodine preparations. Contact Dermatitis. 2000 Feb;42(2):90-4.
18. Leder, R. How well does a history of seafood allergy predict the likelihood of an adverse reaction to i.v. contrast material? AJR Am J Roentgenol 1997; 169(3): 906-7.

2. True or false: There is convincing evidence that dietary sources of iodine can result in an allergic reaction.
(a.) True
(b.) False

3. True or false: There is convincing evidence that adverse reactions to iodinated contrast material are due to the iodine component.
(a.) True
(b.) False

4. Which of the following is true regarding the onset of adverse reactions to iodinated X-ray contrast material?
(a.) It is acute.
(b.) It is delayed.
(c.) It can be acute or delayed.

5. Which of the following is not true regarding adverse reactions to providone iodine?
(a.) They are uncommon.
(b.) Most skin reactions are due to skin irritation rather than allergy, especially after prolonged exposure to the solution.
(c.) The cause is probably due to the iodine component of the solution.

6. True or false: No evidence exists that elemental iodine or iodide is involved in seafood allergy.
(a.) True
(b.) False

7. What is the proposed mechanism of a reaction to iodinated contrast material?
(a.) activation of non-specific immune mediators
(b.) IgE-mediated hypersensitivity
(c.) irritation

8. What is the proposed mechanism for providone-iodine skin reactions?
(a.) activation of non-specific immune mediators
(b.) IgE-mediated hypersensitivity
(c.) irritation