Iodine Allergy for Ophthalmologists
True iodine allergy is rare and although contrast reactions do occur with CT scans with contrast, the mechanism for these reactions is likely not directly iodine related. Povidone iodine (PI) sometimes causes irritation, which is frequently mistaken for an allergy. In patients that report an iodine “allergy”, it is important for clinicians to counsel and educate patients that the benefits of the antiseptic PI far outweigh the risk of substantial ocular morbidity. Allergy testing can be pursued by patient request for PI, but true PI allergy is exceedingly rare. In those patients with a proven PI allergy, dilute chlorhexidine (0.02%) can be applied instead to the cornea and conjunctiva. In summary, PI is very well tolerated and an important antiseptic in ophthalmology.
Ophthalmologists regularly encounter patients who decline imaging and pre-operative sterilization protocols that include iodine (including povidone-iodine (PI)) due to presumed “allergy to iodine”. Because iodine plays a vital role in numerous physiological functions in the human body and is found in thyroid hormone and amino acids, it is biologically implausible to have a true elemental iodine allergy. Biological plausibility is a critical component in evaluating the strength of evidence for causality as part of the Bradford Hill criteria. In fact, iodine deficiency causes serious developmental problems, such as intellectual disability. Rectifying this issue is important because PI is the preferential choice of antiseptics for ophthalmic procedures.
The confusion regarding iodine allergy is based on reactions to iodine-based contrast or shellfish allergy and may have gained greater momentum in the 1970s. It is not clear how seafood allergies and iodine allergies became linked. It is possible that physicians created this inaccurate link through radiocontrast material. Radiopaque contrasts dyes depend on iodine to generate images. This is because the innermost electron binding of iodine mirrors that of incident X-rays. The photoelectric absorption of iodine occurs efficiently and forms a shadow on photosensitive film to produce the image.
Witten et al reported that acute reactions to radiocontrast were associated with a history of seafood allergy in 6% of patients. However, 6% of patients with a history of asthma, 7% of those with a history of hives of unknown cause, and 6% of those with a history of “miscellaneous food allergies” also had reactions to radiocontrast dye. A frequently cited survey connecting seafood allergies to radiocontrast dye stated that patient with any allergy had 2.2 times greater likelihood of having a reaction to radiocontrast, with seafood allergies having statistically similar rates to other allergies.
The impression that “seafood allergy” increased the risk of contrast allergy has led some patients and physicians to believe that these patients were allergic to iodine. Although shellfish often has a high concentration of iodine, the presumed mechanism of shellfish allergy is due to the protein, tropomyosin (the protein involved in muscle contraction) and not iodine. The mechanism of radiocontrast dye reactions however is multifactorial and less clearly defined.
One proposed mechanism may be related to hypertonicity. A study showed a fourfold decrease and fivefold decrease in all reactions and serious reactions with use of a low-osmotic contrast. Another proposed mechanism is nonallergic, with the release of basophil and mast cell mediators from direct cell membrane effects or indirect activation of complement. Allergic/ immunologic mechanism of radiocontrast likely plays a role, but Prieto-Garcia et. al. found that patients who had an immediate hypersensitivity reaction to iodinated contrast material did not have a reaction when administered another agent. As iodine is universally found in all contrast, this study further supports that iodine allergy is unlikely.
Iodine is also not entirely benign and cases of direct iodine toxicity causing thyrotoxicosis have been reported after exogenous iodine administration (Jod Basedow phenomenon). This iodine-induced hyperthyroidism is a rare cause of thyrotoxicosis but characteristically follows the administration of exogenous iodine in iodinated contrast media (ICM) used for computed tomography (CT) scans, angiography, and other imaging studies.
Iodine in Ophthalmology
Povidone-iodine (PI) is a chemical complex of triiodide (I3) and the polymer povidone (polyvinylpyrrolidone), with the latter acting as a transporter for the iodine. It comprises of 9-12% of slowly released available iodine. PI began commercial use in 1955.1 It oxidizes water, which harms the microbial membrane proteins. This mechanism gives it coverage against viruses, fungi (except spores), mycobacteria, protozoa, and even multidrug-resistant gram-positive-negative bacteria. To date there have been no reports of bacterial resistance to PI and PI exhibits a wide spectrum of coverage against microbial organisms. In addition, there has been no evidence for resistance to antibiotics. Thus, PI has established its place as a common and widely accepted antisepsis for a wide range of procedures and surgeries in ophthalmology.
As an intermediate level disinfectant, PI is suitable for sterilization of skin and mucous membranes in individuals. Application of PI prior to surgery has been found to significantly reduce the risk of endophthalmitis in intraocular surgery. The European Society of Cataract and Refractive Surgery recommends 5-20% PI application to the cornea, conjunctival sac, and periocular skin for at least three minutes before surgery. In fact, for patients that did not receive PI due to self-reported iodine allergy before anti-vascular endothelial growth factor (VEGF) injections, the endophthalmitis rate was high (9.4%, 5 of 53 patients). Of note, none of these patients who subsequently received PI after acquiring endophthalmitis developed an allergic reaction. A systematic review assessed preoperative PI before cataract surgery and found it to receive the highest clinical recommendation (B, moderately important) compared to all other reported prophylactic interventions.
The antimicrobial properties of PI do not seem to be associated with the concentration of the drop, but instead to the extent of free iodine: 5 ppm in a 10% solution; 13 ppm in a 1% solution; 24 ppm in a 0.1% solution; and 13 ppm in a 0.01% solution. Therefore, lower concentrations of PI (down to 0.1%) have the highest bactericidal activity. Solutions with higher concentrations of PI require more time to kill bacteria, but their effect is longer. Corneal epithelial toxicity resulting from conjunctival lavage with PI has been shown. It is dose dependent but uncommon with concentrations less than 1%. PI is safe for use in the majority of patients. However, it should be avoided in pregnant women with gestations less than 32 weeks, patients receiving lithium, or patients with hyperthyroidism or dermatitis herpetiformis.
True iodine allergy is rare and although contrast reactions do occur with CT scans with contrast, the mechanism for these reactions is likely not directly iodine related. PI sometimes causes irritation, which is frequently mistaken for an allergy. In patients that report an iodine “allergy”, it is important for clinicians to counsel and educate patients that the benefits of the antiseptic PI far outweigh the risk of substantial ocular morbidity. Allergy testing can be pursued by patient request for PI, but true PI allergy is exceedingly rare. In those patients with a proven PI allergy, dilute chlorhexidine (0.02%) can be applied instead to the cornea and conjunctiva. In summary, PI is very well tolerated and an important antiseptic in ophthalmology.
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1. Stewart MW. Doctor I Have an Iodine Allergy. Ophthalmol Ther. 2022;11(3):931-938.
- ↑ 2. Dailey J, Rosman L, Silbergeld EK. Evaluating biological plausibility in supporting evidence for action through systematic reviews in public health. Public Health. 2018;165:48-57.
- ↑ 3. Beaty AD, Lieberman PL, Slavin RG. Seafood allergy and radiocontrast media: are physicians propagating a myth?. Am J Med. 2008;121(2):158.e1-158.e1584.
- ↑ 4. Witten DM, Hirsch FD, Hartman GW. Acute reactions to urographic contrast medium: incidence, clinical characteristics and relationship to history of hypersensitivity states. Am J Roentgenol Radium Ther Nucl Med. 1973;119(4):832-840.
- ↑ 5.0 5.1 5.2 5.3 5. Schabelman E, Witting M. The relationship of radiocontrast, iodine, and seafood allergies: a medical myth exposed. J Emerg Med. 2010;39(5):701-707.
- ↑ 6. Shehadi WH. Adverse reactions to intravascularly administered contrast media. A comprehensive study based on a prospective survey. Am J Roentgenol Radium Ther Nucl Med. 1975;124(1):145-152.
- ↑ 7.0 7.1 7.2 7. Modjtahedi BS, van Zyl T, Pandya HK, Leonard RE 2nd, Eliott D. Endophthalmitis After Intravitreal Injections in Patients With Self-reported Iodine Allergy. Am J Ophthalmol. 2016;170:68-74.
- ↑ 8. Prieto-García A, Tomás M, Pineda R, et al. Skin test-positive immediate hypersensitivity reaction to iodinated contrast media: the role of controlled challenge testing. J Investig Allergol Clin Immunol. 2013;23(3):183-189.
- ↑ 9.0 9.1 9.2 9. Rose HR, Zulfiqar H. Jod Basedow Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; January 7, 2022.
- ↑ 10. Grzybowski A, Kanclerz P, Myers WG. The use of povidone-iodine in ophthalmology. Curr Opin Ophthalmol. 2018;29(1):19-32.
- ↑ 11. Alves PJ, Gryson L, Hajjar J, et al. Role of antiseptics in the prevention and treatment of infections in nursing homes [published online ahead of print, 2022 Oct 7]. J Hosp Infect. 2022;S0195-6701(22)00317-6.
- ↑ 12. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology. 1991;98(12):1769-1775.
- ↑ 13. Shimada H, Nakashizuka H, Grzybowski A. Prevention and Treatment of Postoperative Endophthalmitis Using Povidone-Iodine. Curr Pharm Des. 2017;23(4):574-585.
- ↑ 14. Barry P, Cordoves L, Susanne G. ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery: Data Dilemmas and Conclusions 2013 [Internet] 2022; Available from: www.escrs.org/ endophthalmitis/guidelines/ENGLISH.pdf.
- ↑ 15. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery: an evidence-based update. Ophthalmology. 2002;109(1):13-24.
- ↑ 16. Berkelman RL, Holland BW, Anderson RL. Increased bactericidal activity of dilute preparations of povidone-iodine solutions. J Clin Microbiol. 1982;15(4):635-639.
- ↑ 17. Jiang J, Wu M, Shen T. The toxic effect of different concentrations of povidone iodine on the rabbit's cornea. Cutan Ocul Toxicol. 2009;28(3):119-124.
- ↑ 18. RxList. Iodine. https://www.rxlist.com/iodine/ supplements.htm. Accessed 18 Oct 2022.
- ↑ 19. Lachapelle JM. A comparison of the irritant and allergenic properties of antiseptics. Eur J Dermatol. 2014;24(1):3-9.