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Anaphylactoid Reactions to Iodinated Contrast Media
Session 8
Anaphylactoid Reactions to Iodinated Contrast Media1 Dominique Laroche, Marie-Claude Vergnaud, Claude Lefranc¸ois, Ste´phane Hue, Henri Bricard
RATIONALE AND OBJECTIVES The mechanisms of immediate reactions to iodinated contrast media (ICM) are currently debated. Most of them and especially the minor and mild ones are being attributed to a direct, non-specific effect of the molecule (1), and a smaller number of severe cases, are suspected to be anaphylactic, IgE-depending events (2). The purpose of this study was to investigate reactions occurring immediatly after ICM injection by measuring histamine and tryptase, two specific markers of basophil and/or mast cell activation. Some patients agreed to be skin-tested in order to detect a sensitization to ICM. MATERIALS AND METHODS The inclusion criteria were the following ones: a clinical reaction appearing within 30 minutes of ICM injection, consisting of cutaneous signs and/or hypotension and/or respiratory disturbances, and blood sampling within the first hours after the reaction. Plasma histamine was measured by radioimmunoassay (Immunotech, Beckman-Coulter) total tryptase was measured by fluoroimmunoassay, -tryptase was measured by radioimmunoassay (UniCAP or RIACT, Pharmacia & Upjohn), and urinary methylhistamine was measured by radioimmunoassay (Pharmacia & Upjohn). Anti-ioxitalamate IgEs were measured as previously described (2), in patients who Acad Radiol 2002; 9(suppl 2):S431–S432 1
From the Laboratory of Medical Physics, Service de Biophysique Me´dicale, CHRU de Caen, F-14033 Caen, France (D.L.); and Service of Medicine (M.C.V.), Department of Anesthesiology (C.L., H.B.), and Department of Radiology (S.H.), University Hospital of Caen, France. Address correspondence to D.L.
©
AUR, 2002
received it. Skin tests were performed with at least 4 different ICM, including the one that elicitated the reaction. The skin tests were performed by prick-testing with the undiluted ICM solution and by intradermal testing with dilutions 1:10,000 through 1:10, as previously described (2).
RESULTS From 1997 through 2000, 21 patients (male:14; female: 7) aged 53 ⫾ 19 y (range: 14 –79 y) were included after reactions following CT scan (n ⫽ 10), intravenous urography (n ⫽ 4), intra-arterial or intracardiac injection (n ⫽ 6) (no data for 1). Five had never been administered ICM. Among the 7 who had (data not available for 9), 5 had received one or more ICM injections within the two months preceeding the reaction. None had previously reacted to ICM. Eighteen patients reacted less than 15 minutes after ICM injection and three patients reacted 20 –30 minutes after injection. The injected ICM were respectively: ioxitalamate (n ⫽ 8); iomeprol (n ⫽ 8); iobitridol (n ⫽ 3); iohexol (n ⫽ 2). Seventeen subjects had cutaneous signs (erythema: 11; urticaria: 3; skin or mucosal oedema: 7), 15 had cardiocirculatory disturbances (hypotension: 12; tachycardia: 7; cardiac arrest: 2), 10 had respiratory disturbances (coughing: 2; dyspnoea: 3; bronchoconstriction: 6), 5 had nausoea and 3 vomited. Eleven had mild or moderate reactions (grade 1: 5; grade 2: 6) and 10 had life-threatening reactions (grade 3: 8; grade 4: 2, including one death), according to the Ring and Messmer scale of severity (3). Blood samples were obtained between 5 and 60 minutes after the reaction for 14 patients, 65–200 minutes for 6, and later for 1. Urine samples were obtained for 20 patients. Six patients had normal values for all the mea-
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sured mediators. Among the 15 other patients, 4 had increases of the concentrations of one mediator, 7 of two, and 4 of the three mediators. Among the 8 patients who reacted after injection of ioxitalamate, only one had positive specific IgEs. Plasma histamine concentrations were highly increased for 3 patients and moderately increased for 6 (2 not done). Mast cell tryptase concentrations were highly increased for 5 patients, moderately increased for 5 and borderline for 3. Urinary methylhistamine concentrations were highly increased for 7 patients and borderline for 1 (1 not done). Six patients were skin-tested 8 weeks - 9 months after the reaction. All had negative prick tests. Two had also negative intradermal tests with all the tested ICM. Three had positive intradermal tests with the ICM injected before the reaction, diluted 1:10 (iomeprol: 2; ioxitalamate: 1), but negative skin tests with the other tested ICM, and one had a positive intradermal test with the responsible ICM (iomeprol) diluted 1:100 and 1:10 and with another non ionic ICM (iohexol) diluted 1:10. Among patients with grade 1 reactions, four showed no increase of mediators, although one demonstrated positive specific IgEs, the last one had an increase of urinary methylhistamine and a positive skin test. All the patients with grade 2 reactions had increases of mediators, especially tryptase. One was skin-tested and had a positive test. Among grade 3 reactions, six were accompanied by large increases of one or the other mediator. Two patients were skin-tested and they had positive tests. The 2 other patients with grade 3 reactions and the 2 patients with grade 4 reactions demonstrated no increase or too small increases of mediators to suggest an immune mechanism. One was investigated, he had negative skin tests. CONCLUSION In this series, non-ionic contrast media appeared more frequently involved in reactions than in our previous study from years 1993–1996 (2). This is probably due to the changes in the market share between ionic and nonionic ICM. Severe reactions were frequently associated with mast cell degranulation, as evidenced by the increases of tryptase concentrations, while cutaneous reac-
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Academic Radiology, Vol 9, Suppl 2, 2002
tions were not. This finding is in agreement with our previous study (2) and with the study of Mita and coleagues (4). Anti-ioxitalamate IgEs were demonstrated in only one patient out of 8 (12.5%), which is consistent with the 9.8% positivity found by Mita and coleagues for reactors to ioxaglate (4). Skin tests appeared positive for 4 patients, who had reacted to a non-ionic ICM (n ⫽ 3) or to an ionic, high osmolality ICM (n ⫽ 1). For three of them, only the higher tested concentration (1:10 dilution) elicitated a skin response, which some authors consider as a non-specific mechanism. However their skin did not react, or reacted less, to other ICM not involved in the reaction, suggesting specificity. In a small series of reactors, Dewachter and coleagues reported positive intradermal tests with ICM diluted 1:100 or 1:10, together with increased concentrations of tryptase (5). A large prospective study of systematic skin testing prior to administration of ICM has shown that only 2.4% of subjects had positive intradermal tests when using a 1:10 dilution of ICM (6), showing that the specificity of the test is as high as 97.6%. These data provide a new insight into the mechanisms of severe immediate reactions to ICM. As reactions are rare, protocols should aim at studying them thoroughly, during the reaction by measurements of mediators and by skin testing afterwards. Large accumulations of results are necessary to understand the mechanisms for a better safety for patients. REFERENCES 1. Lieberman P. Anaphylactoid reactions to radiocontrast material. Clin Rev Allergy 1991; 9:319 –38. 2. Laroche D, Aimone-Gastin I, Dubois F, Huet H, Ge´rard P, Vergnaud MC, Mouton-Faivre, Gue´ant JL, Laxenaire MC, Bricard H. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998; 209:183–90. 3. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977; i:466 –9. 4. Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998; 53:1133– 40. 5. Dewachter P, Mouton-Faivre C, Felden F. Allergy and contrast media. Allergy 2001; 56:250 –1. 6. Guillen Toledo J, Guido Bayardo R. Anamnesis and skin test to prevent fatal reactions to iodinated contrast media. Rev Alerg Mex 2000; 47: 22–5. [Spanish]
Anaphylactoid Reactions to Iodinated Contrast Media1 Dominique Laroche, Marie-Claude Vergnaud, Claude Lefranc¸ois, Ste´phane Hue, Henri Bricard
RATIONALE AND OBJECTIVES The mechanisms of immediate reactions to iodinated contrast media (ICM) are currently debated. Most of them and especially the minor and mild ones are being attributed to a direct, non-specific effect of the molecule (1), and a smaller number of severe cases, are suspected to be anaphylactic, IgE-depending events (2). The purpose of this study was to investigate reactions occurring immediatly after ICM injection by measuring histamine and tryptase, two specific markers of basophil and/or mast cell activation. Some patients agreed to be skin-tested in order to detect a sensitization to ICM. MATERIALS AND METHODS The inclusion criteria were the following ones: a clinical reaction appearing within 30 minutes of ICM injection, consisting of cutaneous signs and/or hypotension and/or respiratory disturbances, and blood sampling within the first hours after the reaction. Plasma histamine was measured by radioimmunoassay (Immunotech, Beckman-Coulter) total tryptase was measured by fluoroimmunoassay, -tryptase was measured by radioimmunoassay (UniCAP or RIACT, Pharmacia & Upjohn), and urinary methylhistamine was measured by radioimmunoassay (Pharmacia & Upjohn). Anti-ioxitalamate IgEs were measured as previously described (2), in patients who Acad Radiol 2002; 9(suppl 2):S431–S432 1
From the Laboratory of Medical Physics, Service de Biophysique Me´dicale, CHRU de Caen, F-14033 Caen, France (D.L.); and Service of Medicine (M.C.V.), Department of Anesthesiology (C.L., H.B.), and Department of Radiology (S.H.), University Hospital of Caen, France. Address correspondence to D.L.
©
AUR, 2002
received it. Skin tests were performed with at least 4 different ICM, including the one that elicitated the reaction. The skin tests were performed by prick-testing with the undiluted ICM solution and by intradermal testing with dilutions 1:10,000 through 1:10, as previously described (2).
RESULTS From 1997 through 2000, 21 patients (male:14; female: 7) aged 53 ⫾ 19 y (range: 14 –79 y) were included after reactions following CT scan (n ⫽ 10), intravenous urography (n ⫽ 4), intra-arterial or intracardiac injection (n ⫽ 6) (no data for 1). Five had never been administered ICM. Among the 7 who had (data not available for 9), 5 had received one or more ICM injections within the two months preceeding the reaction. None had previously reacted to ICM. Eighteen patients reacted less than 15 minutes after ICM injection and three patients reacted 20 –30 minutes after injection. The injected ICM were respectively: ioxitalamate (n ⫽ 8); iomeprol (n ⫽ 8); iobitridol (n ⫽ 3); iohexol (n ⫽ 2). Seventeen subjects had cutaneous signs (erythema: 11; urticaria: 3; skin or mucosal oedema: 7), 15 had cardiocirculatory disturbances (hypotension: 12; tachycardia: 7; cardiac arrest: 2), 10 had respiratory disturbances (coughing: 2; dyspnoea: 3; bronchoconstriction: 6), 5 had nausoea and 3 vomited. Eleven had mild or moderate reactions (grade 1: 5; grade 2: 6) and 10 had life-threatening reactions (grade 3: 8; grade 4: 2, including one death), according to the Ring and Messmer scale of severity (3). Blood samples were obtained between 5 and 60 minutes after the reaction for 14 patients, 65–200 minutes for 6, and later for 1. Urine samples were obtained for 20 patients. Six patients had normal values for all the mea-
S431
LAROCHE ET AL
sured mediators. Among the 15 other patients, 4 had increases of the concentrations of one mediator, 7 of two, and 4 of the three mediators. Among the 8 patients who reacted after injection of ioxitalamate, only one had positive specific IgEs. Plasma histamine concentrations were highly increased for 3 patients and moderately increased for 6 (2 not done). Mast cell tryptase concentrations were highly increased for 5 patients, moderately increased for 5 and borderline for 3. Urinary methylhistamine concentrations were highly increased for 7 patients and borderline for 1 (1 not done). Six patients were skin-tested 8 weeks - 9 months after the reaction. All had negative prick tests. Two had also negative intradermal tests with all the tested ICM. Three had positive intradermal tests with the ICM injected before the reaction, diluted 1:10 (iomeprol: 2; ioxitalamate: 1), but negative skin tests with the other tested ICM, and one had a positive intradermal test with the responsible ICM (iomeprol) diluted 1:100 and 1:10 and with another non ionic ICM (iohexol) diluted 1:10. Among patients with grade 1 reactions, four showed no increase of mediators, although one demonstrated positive specific IgEs, the last one had an increase of urinary methylhistamine and a positive skin test. All the patients with grade 2 reactions had increases of mediators, especially tryptase. One was skin-tested and had a positive test. Among grade 3 reactions, six were accompanied by large increases of one or the other mediator. Two patients were skin-tested and they had positive tests. The 2 other patients with grade 3 reactions and the 2 patients with grade 4 reactions demonstrated no increase or too small increases of mediators to suggest an immune mechanism. One was investigated, he had negative skin tests. CONCLUSION In this series, non-ionic contrast media appeared more frequently involved in reactions than in our previous study from years 1993–1996 (2). This is probably due to the changes in the market share between ionic and nonionic ICM. Severe reactions were frequently associated with mast cell degranulation, as evidenced by the increases of tryptase concentrations, while cutaneous reac-
S432
Academic Radiology, Vol 9, Suppl 2, 2002
tions were not. This finding is in agreement with our previous study (2) and with the study of Mita and coleagues (4). Anti-ioxitalamate IgEs were demonstrated in only one patient out of 8 (12.5%), which is consistent with the 9.8% positivity found by Mita and coleagues for reactors to ioxaglate (4). Skin tests appeared positive for 4 patients, who had reacted to a non-ionic ICM (n ⫽ 3) or to an ionic, high osmolality ICM (n ⫽ 1). For three of them, only the higher tested concentration (1:10 dilution) elicitated a skin response, which some authors consider as a non-specific mechanism. However their skin did not react, or reacted less, to other ICM not involved in the reaction, suggesting specificity. In a small series of reactors, Dewachter and coleagues reported positive intradermal tests with ICM diluted 1:100 or 1:10, together with increased concentrations of tryptase (5). A large prospective study of systematic skin testing prior to administration of ICM has shown that only 2.4% of subjects had positive intradermal tests when using a 1:10 dilution of ICM (6), showing that the specificity of the test is as high as 97.6%. These data provide a new insight into the mechanisms of severe immediate reactions to ICM. As reactions are rare, protocols should aim at studying them thoroughly, during the reaction by measurements of mediators and by skin testing afterwards. Large accumulations of results are necessary to understand the mechanisms for a better safety for patients. REFERENCES 1. Lieberman P. Anaphylactoid reactions to radiocontrast material. Clin Rev Allergy 1991; 9:319 –38. 2. Laroche D, Aimone-Gastin I, Dubois F, Huet H, Ge´rard P, Vergnaud MC, Mouton-Faivre, Gue´ant JL, Laxenaire MC, Bricard H. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998; 209:183–90. 3. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977; i:466 –9. 4. Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998; 53:1133– 40. 5. Dewachter P, Mouton-Faivre C, Felden F. Allergy and contrast media. Allergy 2001; 56:250 –1. 6. Guillen Toledo J, Guido Bayardo R. Anamnesis and skin test to prevent fatal reactions to iodinated contrast media. Rev Alerg Mex 2000; 47: 22–5. [Spanish]