While cervical cancer is the cause of highest cancer mortality in developing countries, cytology-based screening programs are sporadic due to technical and financial constraints. Visual methods of inspection of cervix with application of acetic acid (VIA) or Lugol’s iodine (Schiller’s test or VILI) are potential alternatives for mass screening [1]. This report describes a life threatening hypersensitivity reaction to Lugol’s iodine, drawing attention of program managers and researchers to the possible risk, need for training and resources to manage such an event at cervical cancer screening program. Fatality in screening clinics, especially at community level could impede implementation of an effective program.

A 22-year-old Indian female presented with recurrent vaginal discharge to an outpatient clinic of the National AIDS Research Institute (NARI), Pune, India. She was not a known case of diabetes or hypertension. Azole-resistant vaginal candidiasis was diagnosed by culture at NARI and was treated successfully with local gentian violet application for seven days. A thorough work up could not be performed as she became pregnant subsequently. She revisited the clinic 15 weeks postpartum in March 2013, with recurrence of vaginal discharge.

Per speculum examination revealed curdy discharge and inflammation of cervix and vagina. Samples for wet mount, gram stain examination and Pap smear were collected. VIA, VILI and colposcopic examination revealed no significant abnormalities. Gentian violet was applied after cleaning vagina and cervix with normal saline as the wet mount preparation revealed budding yeast. Shortly after the procedure, she developed cough, hive-like swelling on trunk and limbs, swelling of lips and tongue, conjunctival hyperaemia, vomiting and urge to pass stools. She did not give history of drug or food allergy, asthma, atopy or previous exposure to iodine. She was not on any concurrent medication. Her pulse was not palpable and systolic blood pressure was 70 mm of Hg. Intramuscular antihistamine was injected immediately. Intravenous glucocorticoids, and antiemetic were administered through an IV line obtained with difficulty due to peripheral vascular collapse and a maintenance IV infusion was continued in head low position. As her condition improved and stabilized with this treatment, she was admitted for observation in a tertiary care hospital. Documentation and explanation about avoiding exposure to iodine were given to her.

Further investigations could not be performed in this case to confirm causality to Lugol’s Iodine, as she did not report back to the clinic. Hence causality is determined by exclusion. Her last food consumption was 60 minutes prior to the event and consisted of routinely consumed food. She was exposed to acetic acid, Lugols’ Iodine, normal saline and gentian violet on the day of her clinic visit. Local acetic acid application is not known to cause hypersensitivity reaction. Gentian violet is less likely to be the causative agent as previous multiple exposures were uneventful. As she developed initial symptoms within few minutes after colposcopic examination, it is presumed that Lugol’s iodine was the causative agent. Augmented absorption of high concentration iodine in Lugol’s Iodine due to vaginal inflammation could have accelerated complement-related activation of mastocytes responsible for the reaction.

Abnormal vaginal discharge could be of malignant, infective or non specific aetiology. Cervical malignancy is a preventable cancer through routine screening. Visual methods of inspection of cervix with application of acetic acid or Lugol’s iodine, to rule out premalignant cervical condition are inexpensive, simple to perform, lesions could be identified and and treated during the same visit. Estimated reduction of lifetime risk of cervical cancer by 25% through a single screening with visual methods at 35 years makes it a promising strategy in low resource but high prevalence countries [2]. Moreover it is recommended that this examination could also be performed by nurses and midwives in primary care settings [3]. Though guidelines for National Cervical Screening Program in India recommends VIA as the method of visual inspection, studies confirm that the sensitivity and specificity of VIA can be improved by VILI when used in combination [4].

Mild to severe life threatening reactions to Radio Contrast Material (RCM) containing Iodine [5] are reported in literature. Anaphylactoid reactions occur in approximately 1% to 3% of patients who receive ionic radiocontrast media (RCM) and less than 0.5% of patients who receive nonionic agents [6]. Anaphylaxis after wound and vaginal cleansing with Povidone Iodine has also been described [7, 8], but the allergenic determinant was probably povidone. Lugol’s Iodine, a strong iodine solution, used for staining the cervical epithelium to identify premalignant lesions, contains 5 gms of Iodine and 10 gms of Potassium Iodide in 100 ml of distilled water. To date, just one case of severe hypersensitivity reaction has been reported following cervical application of Lugol’s Iodine before colposcopic examination [9].

Drug allergy is defined as an immunologically mediated response to a pharmaceutical and/or formulation agent in a sensitized person. Anaphylaxis caused by rapid IgE-mediated immune release of vasoactive mediators from tissue mast cells and peripheral basophils requires reexposure to an allergen. Whereas pseudoallergic (anaphylactoid) reactions are immediate systemic reactions that mimic anaphylaxis but are caused by non–IgE-mediated release of mediators from mast cells and basophils. IgE is not considered to play a role in the majority of these reactions [6].

Available information on iodine hypersensitivity is based on literature of iodine containing radio contract material. Simple atoms or molecules such as iodine or contrast material do not have the complexity required for antigenicity, although theoretically they might act as haptens. Haptens are agents that are too small to act as antigens by themselves but that, by binding to larger carrier molecules, provoke an antibody response to the hapten-carrier complex. Iodine acting as a hapten, could provoke a specific immune response leading to sensitization. An antigen-antibody reaction then occurs when the patient is subsequently re-exposed to the compound containing iodine [10]. Investigations including the basophil activation test confirmed that IgE-mediated anaphylaxis to iodine is rare but may be one of the possible mechanisms [11]. But most common mechanism of idiosyncratic contrast reactions is due to activation of complement or other mediators of the nonspecific immune system.

Similar mechanism of non immunological mediated hypersensitivity reaction to lugol’s iodine could have led to this patient developing life threatening symptoms. Inorganic iodide contained in the Lugol’s iodine by itself does not bind to protein. But it gets converted to free iodine through oxidative action of reactive oxygen produced by activated phagocytes. This free iodine having undergone protein iodinization could have activated the complement system leading to subsequent symptoms [9, 12]. It is also likely that some patients are more susceptible to protein iodinization due to vaginal inflammation. In this particular case it is assumed that augmented absorption and protein iodinization of high concentration iodine and potassium iodide in Lugol’s Iodine due to vaginal inflammation could have accelerated complement-related activation of mastocytes and basophils responsible for the reaction. The fact that Lugol’s Iodine could provoke life threatening hypersensitive reaction very rapidly, calls for awareness and preparedness to manage the reaction promptly.

Visual method of cervical cancer screening being a feasible strategy in low resource settings [1], medical and paramedical staff using Lugol’s Iodine for Schiller’s test/VILI should also be trained to identify and manage hypersensitivity reactions. It is also essential that all emergency medications are available at sites where VILI is performed.

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

The authors declare that they have no competing interests.

MA identified the reaction, managed the case, conceived and drafted the manuscript. SK helped in managing the case, did the literature search and compiled it and helped in manuscript writing. ARR reviewed the article critically and gave final approval of the article for submission. RRG contributed intellectually and copyedited the manuscript. All authors read and approved the final manuscript.

The authors would like to acknowledge the role of the medical staff of NARI Aadhar Arogya Clinic in prompt life saving management of this case. All authors have read and approved the final manuscript. All authors are staff of National AIDS Research Institute and they do not have any other source of funding.

Dr. Sanjay Mehendale, MD, MPH, Director, and Scientist G, National Institute of Epidemiology [Indian Council of Medical Research], Chennai, India recommends publication of this article.