Adverse Reaction in Patients with Drug Allergy History After Simultaneous Intravenous Fundus Fluorescein Angiography and Indocyanine Green Angiography

Introduction

Traditional intravenous fundus fluorescein angiography (IVFA) is the most useful tool for the evaluation of retinal disorders. However, sodium fluorescein can be easily camouflaged in the presence of intra-retinal or preretinal blood and is incapable of remaining within the choroidal vasculature due to its relatively small molecular structure. Thus, it is limited in the diagnosis of hemorrhagic retinal or subretinal diseases. In order to capture better pictures of the retinal and choroidal structure, the indocyanine green angiography (ICGA) is introduced, which provides an alternative option and becomes an important adjunct procedure to IVFA for better visualization of choroidal pathology. ¹ In addition, with simultaneous IVFA and ICGA being recently available, anatomic localization of lesions, retinal versus choroidal, can be simultaneously matched by both location and time without having to correlate ophthalmoscopic findings with 2 separate angiograms. ²

IVFA is generally a safe and documented adverse reaction that occurs in 4.8%–8.3% of cases.^3–5 ICGA has been reported to be better tolerated than IVFA.^1,6 The adverse reaction of IVFA ranges from transient nausea and vomiting, discoloration of the skin, mucous membranes and urine, flushing of the skin, pruritis, and urticaria, to allergic shock and death. Fatal anaphylaxis has been reported, with a mortality rate in the range of 1 in 220,000 examinations. ⁷ An allergy history of drug and/or food has been identified as one of the major risk factors for an adverse reaction during angiography.^8–10 It is known that patients who have experienced an allergic reaction tend to get cross-sensitivity and have an increased risk for hypersensitivity. ¹¹ Therefore, an increased incidence of an adverse reaction might be observed in these patients with drug allergy history. However, little information regarding clinical safety of simultaneous IVFA and ICGA, particularly in patients with drug allergy history, was published. In order to examine a possible correlation, we compare the incidence and constitution of adverse reactions in patients with or without drug allergy history after simultaneous IVFA and ICGA.

Methods

Records for 390 consecutive outpatients with drug allergy history who received simultaneous intravenous IVFA and ICGA at the Eye Center, Second Affiliated Hospital, College of Medicine, Zhejiang University, from February 2007 to March 2011 were retrospectively reviewed according to the guidelines indicated by the Zhejiang University Medical School Institutional Review Board. During this period, 3426 outpatients without drug allergy history had undergone simultaneous intravenous IVFA and ICGA. Drug allergy history, concomitant medications, comorbid conditions, indication for angiography, and adverse reactions of the patients were recorded.

Contraindications included close angle glaucoma, allergic asthma, severe hypertension, hepatic and renal function failure, pregnancy, and known hypersensitivity to sodium fluorescein and iodine. A subcutaneous injection of sodium fluorescein (10% fluorescite; Alcon Laboratories, Inc.) and indocyanine green (Jishi Co. Ltd.) of 0.1 mL each, respectively, was administered for the skin test. An intravenous injection of 10% sodium fluorescein with a 10 mg/kg concentration and 25 mg of indocyanine green were infused into the antecubital vein of the elbow or radial vein of the wrist after passing the skin test. The simultaneous intravenous IVFA and ICGA were examined by the Heidelberg Retina Angiograph (HRA; Heidelberg Engineering). The symptoms and time of the adverse reaction were recorded during angiography.

The adverse reaction to IVFA and ICGA was categorized into 3 arbitrary levels as previously published: mild, moderate, and severe, which were dependent on the duration, the need for medical intervention, and the final outcomes after the allergy reaction had occurred.^7,12 Mild reactions are self-limiting, including transient nausea and vomiting, sneezing, pruritis, and could be recovered without treatment. Moderate reactions include urticaria, syncope, thrombophlebitis, fever, and tissue necrosis, which could be gradually relieved after medical treatment. Side effects such as myocardial infarction, cardiac arrest, seizures, and death are classified as severe reactions.

Comparisons were performed using the Student's t-test for numerical variables and the chi-square test, relative risk (RR), and confidence interval (CI) of 95% for categorical variables. Differences were considered statistically significant when the P value was <0.05. All the tests were 2-sided with a confidence level set at 95%. Data analysis was performed using SPSS for Windows software (version 12.0, SPSS, Inc.).

Results

Of the 390 patients with drug allergy history, the average age was 43.9±14.8 years (range, 16–75 years). Two hundred and twenty-eight patients (58.5%) were men, and 162 patients (41.5%) were women. The average age of the patients without drug allergy history was 44.8±15.9 years (range, 11–80 years). In this population of 3426 patients, 1880 (54.9%) were men, and 1546 (45.1%) were women. Demographic information is listed in Table 1. In 390 outpatients with drug allergy history, 177 patients had penicillin allergy, 82 patients had sulfonamide allergy, 56 patients had cephalosporin allergy, 34 patients had aminoglycoside allergy, and 41 patients had 2 or more drug allergies. The ocular diseases consist of 83 cases of macular degeneration, 74 cases of central serous chorioretinopathy, 37 cases of optic neuritis or ischemic optic neuropathy, 47 cases of diabetic retinopathy, 64 cases of central or branch retinal vein occlusion, 46 cases of central exudative chorioretinopathy, and 39 cases of other ocular diseases.

Twenty-eight of the 390 patients (7.2%) with drug allergy history had an adverse reaction, while 145 of the 3426 patients (4.2%) without drug allergy history had an adverse reaction (Table 2). A higher incidence of an adverse reaction was observed in patients with drug allergy history (P=0.008, RR=1.75, CI=1.51–2.66), implying that drug allergy history might increase the incidence of the adverse reaction. The constitution of various adverse reactions according to our classification was also listed in Table 2. In the patients with drug allergy history, 18 patients (4.6%) had mild adverse reactions such as nausea and vomiting, and 10 patients (2.6%) had a moderate reaction, including 5 patients (1.3%) who experienced shortness of breath, 4 patients (1.0%) who experienced local redness and swelling, and 1 patient (0.3%) who experienced urticaria. No life-threatening complications such as cardiac arrest and anaphylactic shock were reported. However, in patients without drug allergy history, a mild reaction occurred in 121 patients (3.5%), and a moderate reaction occurred in 24 patients (0.7%). A statistically significant difference in the severity grading of an adverse reaction between patients with drug allergy historuy and those without drug allergy history was observed (P=0.001).

In 28 patients with an adverse reaction who had previous drug allergy, 22 of the 28 (78.5%) patients had an immediate reaction during the period of angiography, and 6 patients (21.5%) had a delayed reaction at half to 2 h after angiography. Eighteen patients who had had a mild reaction were gradually relieved without treatment; 10 patients of a moderate degree were recovered after oxygen inhalation and antianaphylactic treatment.

In 390 patients with drug allergy history, 11 of 177 patients (6.2%) with penicillin allergy, 6 of 82 patients (7.3%) with sulfonamide allergy, 5 of 56 patients (8.9%) with cephalosporin allergy, 2 of 34 patients (5.8%) with aminoglycoside allergy, and 4 of 41 patients (9.8%) with 2 or more than 2 drug allergies suffered from an adverse reaction (Table 3). No statistical significance was found in the incidence of an adverse reaction among the patients with a history of different drug allergies (P>0.05).

Discussion

IVFA and ICGA are commonly performed and are valuable diagnostic methods for retinal and choroid diseases. In general, these 2 angiographies are safe, although the frequency of the adverse reaction is variable in different reports.^3,5 The incidence was reported as ranging from 4.8% to 8.3% of IVFA, and a more adverse reaction occurred following IVFA than ICGA.

In this study, we investigated the incidence of an allergy reaction after simultaneously dosing fluorescein and indocyanine green dye during angiography in the patients with or without drug allergy. The patients with drug allergy history comprised a high-risk group with a much higher incidence (7.2%) of an adverse response to IVFA and ICGA, implying that drug allergy history might increase the incidence of an adverse reaction. In fact, 28 of 390 patients (7.2%) with drug allergy history had an adverse reaction, while 145 of 3425 patients (4.2%) with no drug allergy history had an adverse reaction. Moreover, patients with drug allergy history tended to suffer a higher incidence (2.6%) of a moderate adverse reaction compared with those who had no drug allergy history (0.7%). However, the possible mechanism for this difference was not well understood. One possible explanation is that a higher cross-reactivity may exist in patients with drug allergy history, in the presence of a common antigenic determinant in the cross-reacting drugs. ¹³ For example, in a sulfamethoxazole hypersensitivity model, the complete sulfanilamide core structure would be present to elicit the cross-reactivity to other sulfonamides. ¹⁴ Another explanation is that it may derive from a nonspecific binding of drugs to IgE. A high level of hydrophobic IgE in the serum of a patient who is allergic to a hydrophobic drug seems to be a risk factor for IgE cross-reactivity to another drug. ¹⁵ For example, penicillin in hydrophobic compounds containing a C₆H₅ phenyl ring (cyclohexenyl derivatives), and these compounds can strongly bind to the external hydrophobic areas of globular proteins and, therefore, nonspecifically bind IgE. ¹⁵

Skin prick tests and intradermal tests have been attempted since many years in the diagnosis of an immediate hypersensitivity reaction to contrast media, but a negative test result does not exclude contrast media as a responsible agent. In this study, the skin tests for all patients were negative. It is unclear why the skin test is negative in these cases. One possible explanation could be that individuals with a negative skin test did not react to the contrast media.^16–18 At present, no commercial indocyanine green or fluorescein sodium-specific serum IgE assay is available, and the value of cellular tests, such as basophil activation tests, still has to be evaluated. Laroche et al. have considered the determination of plasma histamine and tryptase immediately after a reaction to contrast media, which may confirm basophil or mast cell mediator release. ¹⁹ However, recent studies indicate that these tests may be of limited value.

It is really difficult to predict and prevent the adverse reaction during the examination process. Once it happens, the physician records the time and symptoms of the adverse reaction, and takes emergent actions to handle it. In this study, most of the patients had a mild adverse reaction and were gradually relieved without treatment; those patients with a moderate degree of the reaction were recovered after oxygen inhalation and antianaphylactic treatment. This demonstrates that drug allergy history is not an absolute contraindication to simultaneous IFVA and ICGA, though these patients tend to have higher incidence and more severity of an adverse reaction.

In conclusion, simultaneous IFVA and ICGA are generally safe procedures with an acceptable incidence of an adverse reaction. However, patients with drug allergy history seem to have a higher incidence and greater severity of an adverse reaction.