Late adverse reactions to intravascular iodine based contrast media: an update
Late adverse reactions (LAR) to contrast media (CM) are defined as reactions occurring 1 h to 1 week after exposure.
Need for review
In view of more prospective studies of LAR and new data about their pathophysiology, the Contrast Medium Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) reviewed the literature on LAR and updated their guidelines.
Clinical features and pathology
LAR after CM include symptoms such as nausea, vomiting, headache, itching, skin rash, musculoskeletal pain, and fever. Skin reactions are well-documented LAR to CM with an incidence of approximately 2%–4% after nonionic monomers. LAR are commoner by a factor of three to four after nonionic dimers. The commonest skin reactions are maculopapular rashes, erythema and skin swelling. These reactions are T cell-mediated immune reactions, and the diagnosis may be confirmed using skin tests (patch or delayed reading intradermal). The main risk factors for LAR are a previous reaction to contrast medium, a history of allergy, and interleukin-2 treatment. Most skin reactions are mild or moderate and self-limiting.
Management is symptomatic and similar to the management of other drug-induced skin reactions. To reduce the risk of repeat reactions avoidance of the relevant CM and any cross-reacting agents identified by skin testing is recommended.
KeywordsIodine based contrast media Late adverse reactions Skin rash Monomers Dimers
Most late skin reactions after intravascular iodinated contrast medium are mild or moderate and self-limiting.
Patch and delayed reading intradermal tests may help diagnosis
Drug prophylaxis is generally not recommended.
Management of late skin reactions should be symptomatic
Late adverse reactions occurring between 1 h and 1 week after intravascular iodinated contrast medium have been recognized since the mid 1980s . They were reviewed by the Contrast Medium Safety Committee (CMSC) of the European Society of Urogenital Radiology and guidelines were published in 2003 [2, 3]. Since then, there have been new insights into the pathophysiology of late skin reactions and a number of prospective studies of late adverse reactions and overviews of the subject have been published [4, 5, 6, 7, 8]. It was therefore decided to review the literature again by checking repeatedly two databases (PubMed, Web of Science) for papers published from 2003 to October 2010. Search terms included combinations of contrast media, contrast agent, induced, iodinated, late adverse reactions, skin reactions, injury, as well as the generic and brand names of the specific iodinated contrast media. Only manuscripts published in English were considered. This paper summarizes the current understanding of the frequency, pathophysiology, and clinical symptoms of delayed reactions and the factors which predispose to them. The CMSC guidelines have been updated.
The paper and guidelines were discussed among the academic members of CMSC and were also reviewed by the pharmaceutical consultants to the committee. The academic members approved the report at the CMSC Business meeting in October 2010.
Types of late reaction and their frequency after different contrast media
A variety of symptoms, which include headache, nausea, dizziness, gastro-intestinal upset, skin rashes, itching, fever and arm pain are experienced by some patients from 1 day to 1 week after intravascular iodinated contrast medium. However, the time interval of up to a week between the administration of contrast medium and the onset of symptoms often makes it difficult to obtain accurate data about the frequency of late reactions, since it often may not be clear whether the contrast medium is the cause of the symptoms. The timing and the rigour of the data collection from patients are also likely to affect the findings. Comparisons of the symptoms observed after enhanced and unenhanced CT have clarified the situation [9, 10, 11, 12, 13, 14]. These studies showed that most of the symptoms which affected the patients who had been given contrast medium for enhanced scans, but not those who had unenhanced CT, were skin rashes. It appears that skin rashes account for the majority of true late adverse reactions to iodinated contrast agents.
Frequencies of 0.52%–50.8% have been recorded for all late reactions to nonionic monomers [10, 11, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. When only skin reactions to nonionic monomers are considered, the frequencies in the week after contrast medium are lower, less than 4% [10, 14, 21, 23, 25, 26]. Although 9.7% of Schild et al.’s patients had late skin reactions after iopromide, 5.6% of their control subjects also reported late skin symptoms . Comparisons between the rates of late reactions to different nonionic monomers have shown no significant difference [20, 26, 27] The rates of late reactions to ionic monomers and nonionic monomers do not appear to be significantly different [20, 27, 28] Also, no significant difference has been shown between the rates of late reactions to nonionic monomers and the ionic dimer, ioxaglate [19, 29, 30, 31].
However, comparisons between nonionic monomers and dimers have shown that late skin reactions are commoner with the nonionic dimers [13, 26, 31, 32]. In Sutton et al.’s two studies, late skin reactions occurred three to four times more commonly with the nonionic dimer iodixanol than with the nonionic monomers iopamidol and iomeprol and the ionic dimer ioxaglate [26, 31]. While Rydberg et al. found no significant difference in the frequency of late skin reactions between iodixanol and iohexol they did note that more of the iodixanol patients needed treatment with antihistamine or hydrocortisone . However, Fransson found no significant difference in late reactions between iodixanol and ioxaglate .
In 1995 the dimer iotrolan was withdrawn from intravascular use because of the high incidence of late skin reactions, particularly in Japan but also in the US [23, 34]. Schild et al. undertook a prospective study comparing iotrolan and iopromide from 1996 to 2002 . They found significantly higher rates of late skin reactions with the dimer iotrolan than with the monomer iopromide .
The types of skin reaction which occur as late adverse reactions to iodinated contrast media are very similar to late onset skin reactions to other drugs . It is now recognized that the majority of late skin reactions to drugs are mediated by T-cells [36, 37, 38]. Over recent years, increasing evidence has accumulated that late adverse skin reactions to iodinated contrast media are also likely to be T-cell mediated [37, 39, 40].
Skin biopsies of the affected areas show the typical findings of late hypersensitivity with a lymphocyte rich perivascular infiltrate, sometimes associated with eosinophilia . Immunohistological examination has shown that the lymphocytes are predominantly cells of the CD45Ro and CD8 subsets, supporting a T-cell mediated immune reaction .
Important clinical evidence has come from skin tests undertaken on reactors. Three types of tests are used, skin prick, intradermal and patch tests. The skin prick and intradermal tests can identify both IgE-mediated and T-cell mediated reactions depending on the time of reading: 15 min for Ig-E mediated and 24–48 h for T-cell mediated. The patch test, which, like the intradermal test, is read late, identifies T-cell mediated reactions only. Generally, intradermal tests are performed with iodinated contrast medium diluted 1–10 in normal saline and patch tests are performed with undiluted contrast medium.
Several investigators have shown positive patch and/or delayed-reading intradermal tests to the culprit iodine based contrast medium in subjects with late skin reactions [7, 37, 40, 41]. About 50% of patients also reacted to structurally similar contrast media [23, 42, 43]. Akiyama’s series  included 58 patients with erythema multiforme-like skin reactions after nonionic contrast medium. All patients had positive intradermal tests at 24 h after the causative contrast agent, and 79% had positive patch tests after 48 h, read at 0.5 and 24 h after patch removal. Of the 58 patients, 54% showed cross-sensitivity with other nonionic contrast agents, but there was no cross-sensitivity to ionic contrast media or inorganic iodine. These observations support the potential immunogenic role of iodine based contrast media molecules and indicate that sensitivity to iodine is not the cause [6, 45, 46]. In Brockow’s series , which included 220 patients with either immediate or late reactions, up to 47% of 98 late reactors were skin test positive. Kanny et al.  also obtained evidence of a T-cell mediated mechanism in their study of 13 adverse contrast media reactions in 12 patients, with positive skin prick tests in two patients, positive patch tests in ten patients, and positive intradermal tests in nine patients at 24 and 48 h. Cross reactivity was seen in nine out of Kanny’s 12 patients  and other drug sensitivities were noted in 6. However, in Vernassiere’s series of 15 patients patch and intradermal tests were positive in fewer late reactors , suggesting that larger studies are needed to establish the negative predictive values of these tests. In addition, if a patient with a confirmed late reaction to a contrast medium needs further contrast medium administration, skin testing may be a suitable tool for choosing an alternative contrast agent .
The observation that contrast agents can cause activation of peripheral blood lymphocytes from reactors in vitro  also supports the likely immunogenic role of iodine based contrast medium. This is further substantiated by the recent demonstration of the involvement of dendritic cells in the recognition and presentation to the cells of contrast medium in patients with delayed reactions to contrast media .
Clinical features of late skin reactions
The majority of late skin reactions occur within 3 days of contrast medium administration [13, 23, 24]. Maculopapular rashes are frequent, occurring in over 50% of patients with late reactions . There is often associated erythema, swelling and pruritus . Other reactions include urticaria, angioedema (late occurring immediate reactions) and scaling eruptions [21, 26, 31, 36, 47]. Most late skin reactions are mild [13, 21, 23, 24, 26, 31]. They are usually self-limiting and resolve within 7 days. Up to 75% resolve within 3 days [17, 23].
Occasionally, severe reactions occur and may cause significant morbidity, hospital admission and even death. Half of the eight severe cases reviewed by Christiansen et al.  had an underlying severe medical condition [49, 50, 51, 52]. There have been a few other case reports of serious reactions, including cases of severe angioneurotic edema and rash , moderate laryngeal edema and conjunctivitis, severe pruritus, and generalized urticaria [14, 36, 53, 54, 55].
When there has been a possible late skin reaction to an iodinated contrast agent, skin testing with either a patch test or a delayed reading intradermal test should be considered to try to obtain confirmation [8, 37, 40, 42, 43, 44, 45, 46, 56, 57, 58].
Management of late skin reactions
A variety of factors predisposing to late adverse reactions have been described. A history of allergy increases the likelihood of a late reaction by a factor of two [13, 15, 17, 23, 24, 25, 30]. Drug or contact sensitivity appears to be particularly important [37, 47, 59]. A previous contrast medium reaction increases the risk of late reaction by a factor of 1.7–3.3 [17, 19, 23]. However, patients who had immediate reactions to CM did not have a higher rate of late reactions to the same CM injection [17, 23, 27].
Women appear more susceptible to late reactions than men [13, 15, 17, 19, 22, 44]. In Finland, seasonal variation in the incidence of late reactions has been noted. 45% of late reactions occurred between April and June, and it has been suggested that contrast media may cause photosensitisation or that the pollen season may increase the predisposition to late reactions . Patients of Japanese descent may be more susceptible to late reactions .
Munechika et al.  reported a higher incidence of late reactions following CT (3.3%) than intravenous urography (1.1%). However their study involved over 100 hospitals and the doses of contrast medium given are not stated.
A variety of underlying diseases appear to predispose to late reactions, especially renal impairment, but also cardiac and liver disease and diabetes mellitus [19, 22, 23], although this remains controversial. Very severe late reactions have occurred in patients with systemic lupus erythematosus (SLE) and in patients being treated with hydralazine, which may produce a syndrome resembling SLE [49, 50, 51]. Severe skin reactions have also been described after bone marrow transplantation .
In patients receiving immunotherapy with interleukin-2 (IL-2), late reactions occur two to four times more often [16, 62, 63, 64, 65]. Choyke et al. noted that skin rash, pruritus and flu-like syndrome were commoner after contrast medium in patients who had received IL-2 . Interestingly, both IL-2 and pre-existing stimulation of the immune system in SLE reduce the threshold for T-cell activation by enhanced cytokine secretion or monocyte activation [41, 66].
Since late reactions occur infrequently and are usually self-limiting, it does not seem appropriate to warn patients without special risk factors about the possibility of a late reaction. Patients at increased risk of a late reaction, such as patients having IL-2 treatment, patients who have had a previous contrast medium reaction or who have a strong allergic history, especially of drug or contact sensitivity, should be warned about the possibility of a late reaction and advised to contact a doctor if they have a problem.
In patients who have previously had a skin reaction after iodinated contrast medium, patch and delayed reading intradermal tests may be helpful to confirm that the contrast medium was responsible. Skin tests can also be used to evaluate whether there is cross-reactivity with other agents. If these patients require further investigations with iodinated contrast medium, the agent responsible for their previous late reaction and any cross-reacting agents should be avoided if possible.
ESUR 2011 guidelines for late adverse reactions to intravascular iodine based contrast media
A late adverse reaction to intravascular iodine based contrast medium is defined as a reaction which occurs 1 h to 1 week after contrast medium injection.
Skin reactions similar in type to other drug induced eruptions. Maculopapular rashes, erythema, swelling and pruritus are most common. Most skin reactions are mild to moderate and self-limiting.
A variety of late symptoms (e.g., nausea, vomiting, headache, musculoskeletal pains, fever) have been described following contrast medium, but many are not related to contrast medium.
Risk factors for skin reactions:
Previous late contrast medium reaction.
Use of nonionic dimers.
Symptomatic and similar to the management of other drug-induced skin reactions e.g. antihistamines, topical steroids and emollients.
Patients who have had a previous contrast medium reaction, or who are on interleukin-2 treatment should be advised that a late skin reaction is possible and that they should contact a doctor if they have a problem.
Patch and delayed reading intradermal tests may be useful to confirm a late skin reaction to contrast medium and to study cross-reactivity patterns with other agents.
To reduce the risk of repeat reaction, use another contrast agent than the agent precipitating the first reaction. Avoid agents which have shown cross-reactivity on skin testing.
Drug prophylaxis is generally not recommended.
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