Late Adverse Reactions to Intravascular Iodinated Contrast Media 27 5 Late Adverse Reactions to Intravascular Iodinated Contrast Media Fulvio Stacul

CONTENTS onic monomer or dimer) (Schild 1996; Yasuda and Munechika 1998) and skin reactions appear 5.1 Introduction 27 to account for the majority of true late reactions. 5.2 Reaction Type and Severity 27 5.3 Frequency 28 The types of late skin reactions and their relative fre- 5.4 Reaction Onset and Duration 28 quencies are similar to those which occur with many 5.5 Predisposing Factors 28 other drugs (Bigby et al. 1986). Maculopapular rash 5.6 Prophylaxis 29 is observed in more than 50% of affected patients 5.7 Conclusion 29 (Hosoya et al. 2000). Other frequently occurring References 29 skin reactions are angioedema, urticaria, ery- thema, macular exanthema and scaling skin erup- tion (Bigby et al. 1986; Christiansen et al. 2000; Kanny et al. 2005; Rydberg et al. 1998; Sutton et 5.1 al. 2001, 2003; Vernassiere et al. 2004). Introduction In most cases the skin reactions are mild or moderate, i.e. they may cause discomfort and may Late adverse reactions to intravascular iodinated require specific treatment (steroids, antihistamines, contrast media are defined as reactions occurring topical emollients) (Hosoya et al. 2000; Mune- between 1 h and 1 week after contrast medium chika et al. 2003; Rydberg et al. 1998; Sutton et injection. They were first recognized in the mid- al. 2001, 2003). Depending on their site, these reac- 1980s (Panto and Davies 1986) and since then have tions cause more or less disturbance to the patient, been widely studied, particularly reactions to low the most troublesome being those affecting to the osmolality contrast media. However, many aspects palms, soles of the feet or face (Sutton et al. 2001). remain controversial and there is widespread uncer- Severe delayed reactions needing hospital treatment tainty among radiologists about the incidence, sig- and/or leading to persistent disability or death have nificance and management of late reactions. been reported, but are very rare. In the eight cases Christiansen et al. (2000) collected from the litera- ture, four had underlying serious medical conditions (Goodfellow et al. 1986; Reynolds et al. 1993; 5.2 Sadi et al. 1995; Savill et al. 1988) and there are Reaction Type and Severity only a few other case reports of serious reactions (Atasoy et al. 2003; Conroy et al. 1994; Lafitte et In reports of late reactions, the symptoms most com- al. 2004; Rosado et al. 2001; Vavrick a et al. 2002). monly described are headache, skin rash, itching, A number of pathophysiological mechanisms have nausea, dizziness, urticaria, fever, arm pain and been proposed for late skin reactions. Although the gastrointestinal disturbances. When late reactions pathogenesis is still not fully understood, it appears to enhanced and unenhanced CT were compared, that many are type IV hypersensitivity reactions, only the skin reactions occurred more frequently i.e. they are T-cell mediated (Brockow et al. 2005; in the group who received contrast medium (noni- Christiansen et al. 2000; Christiansen 2002). The skin reactions often show typical features of late hypersensitivity including exanthematous rash, positive skin tests and lymphocyte rich dermal F. Stacul, MD perivascular infiltrate sometimes accompanied by Institute of Radiology, Ospedale di Cattinara, 34149 Trieste, Italy eosinophils on skin biopsy. 28 F. Stacul

If there is doubt about whether contrast medium is studies suggest that the incidence in the 1- to 24- responsible for the skin reaction, skin testing (patch h period is 4% or less (Beyer-Enke and Zeitler and delayed intradermal tests) may be attempted 1993; Choyke et al. 1992; Pedersen et al. 1998) and (Akiyama et al. 1998; Brockow et al. 1999, 2005; in four large studies the frequency of late skin reac- Courvoisier and Bircher 1998; Gall et al. 1999; tions was 1%–3% over a period of 7 days (Hosoya Kanny et al. 2001; Schick et al. 1996; Sedano et al. et al. 2000; Munechika et al. 1999; Rydberg et al. 2001; Watanabe et al. 1999). However, the low nega- 1998; Yasuda and Munechika 1998). There do not tive predictive value of such tests should be borne appear to be significant differences in the incidence in mind (Brockow et al. 2005; Vernassiere et al. of late reactions between ionic and nonionic agents 2004). Moreover, it remains to be established if skin (McCullough et al. 1989; Panto and Davies 1986; testing is also a suitable tool for selection of an alter- Pedersen et al. 1998; Yamaguchi et al. 1992), native contrast medium (Brockow et al. 2005). nor between the different nonionic monomers (Panto and Davies 1986; Pedersen et al. 1998; Yamaguchi et al. 1992). No significant differences 5.3 have been found between the nonionic monomers Frequency and the ionic dimer ioxaglate either (Bertrand et al. 1995; Mikkonen et al. 1995; Oi et al. 1997). Determining the true frequency of late adverse reac- The available evidence suggests that late skin tions to contrast media from the literature is diffi- reactions are more common with nonionic dimers. cult. First, a variety of different methodologies have In two studies conducted by the same group the been used, with different methods of data collection nonionic dimer iodixanol caused more late skin (questionnaires, patient interviews in person or by reactions than either the ionic dimer ioxaglate or phone), different start points (at a variety of times the nonionic monomers iopamidol and iomeprol from 30 min after contrast medium injection) and (Sutton et al. 2001, 2003). In another study, the different data collection periods (from 1–7 days). frequency of late skin reactions with iodixanol was A further problem is the fact that the greater the similar to that with nonionic monomer, but more time interval between the contrast medium injection of the iodixanol patients were treated with hydro- and the onset of symptoms, the more difficult it is cortisone or antihistamine (Rydberg et al. 1998). to be sure that the symptoms are contrast medium- Fransson et al. (1996), however, found no difference induced. This has been highlighted by studies of in the frequency of late skin reactions between iodix- ”background noise” by several investigators who have anol and ioxaglate. The nonionic dimer iotrolan was shown a high incidence of late symptoms after radio- withdrawn in 1995 because of the high incidence of logical investigations not using contrast medium. In late reactions, particularly skin reactions, initially one study late adverse reactions occurred in 12.4% reported from Japan but subsequently also from the of patients who had contrast medium enhanced CT, USA (Hosoya et al. 2000; Niendorf 1996). and in 10.3% who had unenhanced CT (Yasuda and Munechika 1998), and in another study approxi- mately 50% of late adverse reactions were found to 5.4 be unrelated to contrast media (Beyer-Enke and Reaction Onset and Duration Zeitler 1993). Ueda et al. (2001) reported late reac- tions in 8.4% of patients having enhanced CT, and Late skin reactions after contrast medium develop in 7.9% having plain CT. Schild (1996) reported within 1–7 days with the majority occurring within more late adverse reactions following plain CT than the first 3 days (Hosoya et al. 2000). Most reactions enhanced CT, with the exception of skin reactions are self-limiting and have resolved by 7 days, with up which were more common after enhanced CT. to three-quarters resolving within 3 days (Hosoya The frequency of late adverse reactions to noni- et al. 2000; Yoshikawa 1992). onic monomers has been reported to be between 0.52% and 23% (Bartolucci et al. 2000; Choyke et al. 1992; Cochran et al. 1993; Higashi and 5.5 Katayama 1990; Hosoya et al. 2000; Mikkonen Predisposing Factors et al. 1995; Munechika et al. 2003; Pedersen et al. 1998; Rydberg et al. 1998; Ueda et al. 2001; Yasuda A number of factors appear to predispose to the and Munechika 1998; Yoshikawa 1992). Several development of late adverse reactions. A previous Late Adverse Reactions to Intravascular Iodinated Contrast Media 29 reaction to contrast medium is an important pre- 5.6 disposing factor increasing the risk by a factor of Prophylaxis 1.7–3.3 (Hosoya et al. 2000; Mikkonen et al. 1995; Yoshikawa 1992). However, there is no evidence In view of the infrequent and self-limiting nature of that patients with a previous late reactions are at the great majority of late reactions, it does not seem increased risk for a subsequent immediate anaphy- appropriate to warn patients with no special risk lactic reaction (Hosoya et al. 2000; Yamagughi et factors about the possibility of a late reaction. How- al. 1992; Yoshikawa 1992). A history of allergy is a ever, it is recommended that patients who have had further risk factor (Higashi and Katayama 1990; a previous late skin reaction after contrast medium Hosoya et al. 2000; Munechika et al. 1999, 2003; Oi administration who suffer from major drug or con- et al. 1997; Yoshikawa 1992), increasing the likeli- tact allergy or who have received interleukin-2 are hood of a reaction approximately twice. A history warned about the possibility of a late skin reaction of drug and contact allergy especially seems to pre- and told to contact a doctor if they have a problem. dispose to late skin reactions after contrast medium If patients who have previously had a late skin reac- exposure (Aoki and Takemura 2002; Kanny et al. tion to iodinated contrast medium require further 2005; Vernassiere et al. 2004). A seasonal varia- contrast medium, it is recommended that an alterna- tion in the incidence of late skin reactions has been tive contrast medium is chosen and steroid prophy- described with 45% of reactions occurring in the laxis is given (Watanabe et al. 1999). However, period April to June in Finland (Mikkonen et al. because of frequent cross-reactivity among different 2000). A relation to the pollen season and/or to the contrast media, change of contrast agent is no guaran- possible photosensitizing effect of contrast media tee against a repeat reaction (Brockow et al. 2005). have been postulated. A significantly higher inci- dence of late adverse reactions during the pollen season was confirmed by Munechika et al. (2003). 5.7 Females are more likely to develop late adverse reac- Conclusion tions than males (Bartolucci et al. 2000; Higashi and Katayama 1990; Hosoya et al. 2000; Mikkonen Late adverse reactions to iodinated contrast media et al. 1995; Oi et al. 1997). Coexisting diseases also have been recognized for 20 years. They are mainly appear to predispose to late reactions, especially mild or moderate skin reactions which develop from renal disease, but also cardiac and liver disease and 1 hour to 7 days after contrast medium administra- diabetes mellitus (Bartolucci et al. 2000; Hosoya tion and usually resolve within 3–7 days. The major- et al. 2000; Mikkonen et al. 1995). Some of the most ity of these cutaneous reactions are T-cell mediated severe skin reactions reported occurred in patients allergic reactions. A simple guideline can be found with systemic lupus erythematosus or patients who in the Appendix. were taking hydralazine which induces a lupus-like syndrome in some patients (Goodfellow et al. 1986; Reynolds et al. 1993; Savill et al. 1988). Bone marrow transplantation patients were reported to References be another risk group for severe contrast medium induced skin eruptions (Vavrick a et al. 2002). Akiyama M, Nakada T, Sueki H et al (1998) Drug eruption The increased incidence of late reactions to con- caused by nonionic iodinated X-ray contrast media. Acad Radiol 5 [Suppl 1]:S159–S161 trast media in patients who have received inter- Aoki Y, Takemura T (2002) Allergies correlated to adverse reac- leukin-2 (IL-2) immunotherapy is well documented, tions induced by non-ionic monomeric and ionic dimeric with an increased frequency of two to four times contrast media for contrast enhanced CT examination. (Choyke et al. 1992; Fishman et al. 1991; Oldham Radiol Technol 58:1245–1251 et al. 1990; Shulman et al. 1993; Zukiwski et al. Atasoy M, Erdem T, Sari RF (2003) A case of acute general- ized exanthematous pustulosis (AGEP) possibly induced 1990). Skin rash, pruritus and flu-like syndrome by iohexol. J Dermatol 30:723–726 were all more frequent in patients who had received Bartolucci F, Cecarini M, Gabrielli G et al (2000) Reazioni tar- IL-2 (Choyke et al. 1992). dive a un mezzo di contrasto radiologico (iopamidolo - Bracco). Radiol Med 100:273–278 Bertrand P, Delhommais A, Alison D, Rouleau P (1995) Imme- diate and delayed tolerance of iohexol and ioxaglate in lower limb phlebography: a double-blind comparative study in humans. Acad Radiol 2:683–686 30 F. Stacul

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