Contrast media and cutaneous reactions. Part 2: Delayed hypersensitivity reactions to iodinated contrast media
F. Tasker H. Fleming G. McNeill D. Creamer S. Walsh
First published: 04 June 2019 https://doi.org/10.1111/ced.13991
Conflict of interest: none declared.
Summary
Contrast media (CM) are an indispensable part of modern medical imaging. Adverse reactions to CM are uncommon, but frequently involve cutaneous symptoms. This two‐part article reviews adverse events secondary to CM that are relevant to the practising dermatologist. Part 1 covers the classification of CM, immediate hypersensitivity reactions to CM and the newly described condition, gadolinium deposition disease. Given that there has only been two case reports to our knowledge of a delayed adverse reaction to gadolinium‐based CM, this second part will focus on cutaneous delayed reactions caused by iodinated CM (ICM). Delayed hypersensitivity reactions to ICM commonly present as maculopapular exanthems, but more rarely, they can manifest as fixed drug eruptions, acute generalized exanthematous pustulosis, drug‐related eosinophilia and systemic symptoms, Stevens–Johnson syndrome/toxic epidermal necrolysis, symmetrical drug‐related intertriginous and flexural exanthema, graft‐versus‐host disease, vasculitis and iododerma. Delayed reactions to ICM may be underdiagnosed, as cutaneous symptoms may be attributed to oral medications, particularly if patients are on multiple drugs.
Introduction
Contrast media (CM) are commonly used worldwide to enhance the quality of imaging and diagnostic accuracy. Delayed hypersensitivity reactions (DHRs) are predominately caused by iodinated CM (ICM), as to our knowledge there have only been two published case reports of DHR secondary to gadolinium‐based CM.1, 2 DHRs occur within a time frame of > 1 h to 7 days after administration of CM, and are thought to be T‐cell‐mediated.2-4 DHRs occur in 0.5–23% of people receiving ICM,4, 5 and often present as a maculopapular exanthem (Fig. 1). In one study, 19% of delayed adverse reactions manifested as urticaria but the mechanism of this is unclear.6 DHR can be managed symptomatically with topical steroid and antihistamine. Rarely they present as other T‐cell‐mediated drug like skin reactions.7
Figure 1
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Exanthem secondary to iodinated contrast media.
Reactions to iodinated contrast media
Fixed drug eruption secondary to iodinated contrast media
There have been 10 reported cases of fixed drug eruption (FDE) secondary to ICM identified in the literature (Table 1).8-17 Six occurred following a computed tomography (CT) scan9, 13-17 and the culprit ICM in over half of cases was a nonionic monomeric medium.10, 12-16 Cutaneous symptoms typically presented within 24 h after CM. Location of the FDE varied and included the heel, hands, fingers and inguinal region.8, 13 Resolution was spontaneous, typically within 7 days of onset. Recurrence of FDE on subsequent exposure can occur, typically with a shorter latency due to prior sensitization.13
Table 1. Cases of fixed drug eruption following iodinated contrast media.
Study Age, years Sex Prior ICM reactiona Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Good et al., 19808 46 M Multiple episodes after intravenous pyelogram Intravenous pyelograms Not stated After several hours, developed fever that lasted 3 days. Then developed a blister on left heel Within 72 h Not stated Blister healed each time
Benson et al., 19909 51 F Not stated Chest CT Iothalamate Reactions on two different occasions, both with fixed solitary, recurrent, indurated, erythematous plaque on medial aspect of the thigh (i) Within 24 h Oral dicloxacillin (i) Resolved within days
(ii) 1 year later, within 24 h Hydrocortisone (ii) Resolved within 24 h
Borofsky et al., 199310 46 M Rash with itching several hours after ICM and aspirin Arteriogram Iohexol Erythematous patches with vesiculobullous eruptions over chest, back and upper arms. Two days later, oedematous, erythematous plaques over calves 5 h Oral Pred and antihistamine Skin lesions healed within 2 weeks
Gonzalo‐Garijo et al., 199711 72 M Not stated Cardiac catheterization Ioxoglate Pigmenting FDE. Erythematous plaques, sharply delineated without desquamation over the perineal, sacral and gluteal areas 48 h Oral Pred Resolved in 5 days
Yamauchi et al., 199712 41 F Not stated Imaging of haemodialysis shunt Iopamidol Burning sensation a few hours after iopamidol with faint erythema. Several well‐demarcated, oval‐shaped erythemas on upper and lower limbs and trunk. Some lesions developed into bullae and erosions Few hours IV Pred Not stated
Watanabe et al., 199913 67 F Not stated CT Iomeprol Reactions on two different occasions, both with pea‐sized vesicular erythematous papules on trunk and extremities; some coalesced, forming 7 large plaques on the limbs (i) 4 days (i) Oral betamethasone, glutathione, topical betamethasone. (ii) Oral bethamethasone only Lesions cleared, leaving pigmentation that faded within 6 weeks
(ii) Within few hours to 24 h
Bohm et al., 200714 61 M Same FDE 1 year before Abdominal CT Iopromide Red macule 2 cm in diameter covering a dermal infiltration in the right inguinal region. Enlarged to 15 × 8 cm accompanied by a burning sensation 4 h Not stated Disappeared after 4–5 weeks
Wright et al., 201115 57 F Prior CT scans with similar eruption Staging CT scans Iohexol Sharply demarcated erythematous patch on left breast < 15 h Not stated Resolved after 5–7 days
Frías et al., 201116 60 M Previous CT with CM and no reaction CT Ioversol Two episodes, both with pruritic erythematous and blistering eruption on backs and interdigital areas of both hands After 24 h (worse at 48–72 h) Not stated Disappeared spontaneously after 10 days
Epskamp et al., 201617 70 M CT scans at regular intervals and no reaction CT Iodixonal Bullous FDE on lateral aspect of the lower third of the middle finger; haemorrhagic bullae with erythematous background Within 24 h Not stated Resolved in 4 days
CT, computed tomography; FDE, fixed drug eruption; ICM, iodinated contrast media; IV, intravenous; Pred, prednisolone. aICM prior to the date of publication of the case.
Acute generalized exanthematous pustulosis secondary to iodinated contrast media
There have been 16 cases of acute generalized exanthematous pustulosis (AGEP) caused by ICM (Fig. 2) described. Latency of onset was between 2 h and 3 days after ICM, with almost half of the cases (7/16) being triggered by iodixanol. The authors identified a higher rate of AGEP with dimeric iso‐osmolar CM compared with monomeric low osmolality CM.18
Figure 2
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Acute generalized exanthematous pustulosis secondary to iodinated contrast media.
Drug‐related eosinophilia and systemic symptoms secondary to iodinated contrast media
Six cases19-22 of drug‐related eosinophilia and systemic symptoms (DRESS) (Fig. 3) have been reported (Table 2). The majority (5/6) of patients had multiple exposures to ICM before developing DRESS. Cutaneous symptoms arose within 1 h to 3 days, and most cases resolved within 3 weeks. One patient had received both ioversol and imipenam, leading to diagnostic doubt regarding the causative agent; however, there is some evidence in the literature that medications administered in close temporal proximity may have a synergistic effect in producing DRESS.21 In one case, a first episode of ICM‐induced DRESS was incorrectly diagnosed, and the patient was inadvertently rechallenged with ICM, leading to a second reaction.22 It is important to include ICM in causality assessment of patients with DRESS on multiple medications.
Figure 3
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Drug‐related eosinophilia and systemic symptoms secondary to iodinated contrast media
Table 2. Cases of drug reaction with eosinophilia and systemic symptoms following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Kanny et al., 200119
Patient 1 63 F Not stated First reaction developed after coronary arteriography, second after coronary angioplasty Ioxaglic acid meglumine both times DRESS: maculopapular eruption, fever (i) 24 h Not stated (i) Resolved in 3 weeks
(ii) 8 years later, onset 3 days (ii) Resolved in 2 weeks
Patient 2 19 M 7 scans in 3 months but no reaction – Iohexol, iobitridrol DRESS: maculopapular eruption, fever 1 h Not stated Resolved after 2 weeks
Patient 3 59 M Several scans and arteriographies but no reaction – Iohexol DRESS 12 h Not stated Resolved in 2 days
Belhadjali et al., 200820 71 F Coronary angiogram with CM 7 months previously; no reaction Transluminal angioplasty Sodium meglumine ioxitalamate DRESS based on RegiSCAR24 2 days Not stated Resolved in 17 days
Macías et al., 201321 83 F Had received ioversol and imipenum several times previously; no reaction – Ioversol DRESS based on RegiSCAR24 Several hours Systemic corticosteroids Not stated
Leguisamo et al., 22 57 F 4 abdominal CT scans with iopromide 5 months previously and had a reaction after 21 days CT Iopromide DRESS based on RegiSCAR24 (7 for previous episode, 5 for second episode) 6 h Not stated Not stated
Mini‐DRESS
George et al., 201623 76 F Prior CT 5 years previously; no reaction Abdominal CT Not stated Widespread urticated oedematous confluent exanthem on torso. Discrete urticated lesions reminiscent of targets on limbs 1–6 days Pred 30 mg, mometasone fumarate (Elocon) Improved within 5 days
CT, computed tomography; DRESS, drug reaction with eosinophilia and systemic symptoms; Pred, prednisolone; RegiSCAR, Registry of Severe Cutaneous Adverse Reactions.
Another published case described an episode of mini‐DRESS23 (that is, a systemic adverse drug reaction mimicking DRESS, but not reaching all the diagnostic criteria24) occurring 1–6 days following exposure to ICM.
Stevens–Johnson syndrome/toxic epidermal necrolysis secondary to iodinated contrast media
There have been 11 cases of Stevens–Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN) associated with ICM: 4 cases of SJS, 2 of SJS/TEN overlap and 5 of TEN (Fig. 4, Table 3).25-34 Nonionic monomeric ICM was the most frequent culprit. Of these 11 cases, 5 were female, 9 were adults (33–73 years) and 2 were paediatric cases (aged 6 and 14 years, respectively).27, 33 Onset of cutaneous symptoms occurred between 30 min and 3 days with recurrence of symptoms typically manifesting earlier. Of the 11 patients, 3 died; 2 of these had TEN.30, 34 The SCORe of Toxic Epidermal Necrosis (SCORTEN) result relating to the episodes resulting in death was not stated.
Figure 4
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Toxic epidermal necrolysis secondary to iodinated contrast media.
Table 3. Cases of Stevens–Johnson syndrome and toxic epidermal necrolysis following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
SJS
Savill et al., 198825 46 F – IV urogram Iopamidol Blistering rash involving limbs and buttocks with painful ulcers in mouth and nares. After 3 days large ulceronecrotic plaques developed, some with bullous changes on extensor limbs and trunk 8 h High‐dose Dexa and supportive therapy Multiorgan failure; died 6 weeks after admission
Hebert et al., 200426 66 F – 4 coronary catheterizations; SJS after each one First 3 time iopamidol; fourth time ioversol SJS after each procedure Dexa Premedicated with Pred 50 mg once daily for 5 days –
Laffitte et al., 200427 6 M – Cervicothoracic CT Iopentol SJS 3 days Fusidic acid (Fucidin) and mometasone fumarate (Elocon) Lesions progressively cleared
Gogna et al., 201528 73 M Multiple ioversol infusions; erythematous itchy facial rash 5–7 after CM 2 months prior Evaluation of AV fistula patency Ioversol SJS 3 days Pred 60 mg Symptom resolution
SJS/TEN overlap
Yang et al., 201529
Patient 1 61 F CT scan 2 weeks previously; uneventful CT scans Iohexol 2 weeks after second scan, generalized pruritus and widespread xerotic eczema. Over next 5 days BSA 5%, SCORTEN 1 (for age). After third CT scan, increased skin denudation (15%), conjunctival injection and haemorrhagic crusting of lips After third CT scan, within 24 h Oral Pred after second CT scan and IVIg after third scan Severe sepsis without re‐epithelialization
Patient 2 60 M CT aortograms 4 years previously; no reaction CT aortogram Iopaque (reaction on fourth scan) SJS/TEN BSA detached 11%, extended to 15%; SCORTEN 4 3 days IVIg Complete re‐epithelialization after 12 days
TEN
Kaftori et al., 198830 55 F Excretory pyelogram 60% solution of diatrizoate TEN 12 h Not stated Died 10 days after admission
Schmidt et al., 199831 36 M Multiple previous CTs; had transient skin rash once and therefore received premedication for other CTs Abdominal CT Diluted diatrizoate meglumine and diatrizoate sodium TEN with eventually 30% TBSA 30 min to several daysa Supportive management only Skin healed without scarring or alteration of pigmentation
Rosado et al., 200132 33 M 2 previous CT scans, but not reaction 4 body CTs Iohexol (i) Erythematous disseminated rash (i) 9 days after third CT Not stated –
(ii) Bullae affecting 50% of BSA (ii) 2 h after fourth CT
Lee et al., 200233 14 M Pre‐op angiocardiogram exam at 3 and 12 years of age; no adverse reaction Cardiac catheterization and angiocardiogram Ioxaglate and iohexol at 3 years of age and iopamidol at 12 years TEN 24 h IV antibiotics, corticosteroids and hydration Discharged uneventfully on 11th day
Brown et al., 201334 37 F 12 CT scans during previous years; no reaction CT Iopromide Episodes following 3 CT scans: Not stated Died of sepsis
(i) < 10% TBSA (i) < 4 days
(ii) TEN SCORTEN 3 (ii) 1 day
(iiia) TBSA 60–80% (iiia) Within minutes
(iiib) 100% TBSA (iiib) Within hours
AV, arteriovenous; BSA, body surface area; CT, computed tomography; Dexa, dexamethasone; ICM, iodinated contrast media; IV, intravenous; IVIg, intravenous immunoglobulin; Pred, prednisolone; SJS, Stevens–Johnson syndrome; SCORTEN, SCORe of Toxic Epidermal Necrosis; TBSA, total body surface area; TEN, toxic epidermal necrolysis. aWithin 30 min, itchy and patchy erythema developed; patient given diphenhydrazine and IV methylprednisolone sodium succinate (SoluMedrol) after 2 h and pethidine (Demerol) IM, and told to take Pred 60 mg that evening. Symptoms resolved. However, next day, pruritus, erythema and conjunctivitis developed, and worsened over 24–48 h.
Symmetrical drug‐related intertriginous and flexural exanthema secondary to iodinated contrast media
There are four published cases of symmetrical drug‐related intertriginous and flexural exanthema (SDRIFE) (Fig. 5) reported to be caused by ICM (Table 4). The age ranged from 57 to 80 years old; one man35 and three women.36-38 Three of the cases followed coronary angioplasty and/or an angiogram35-37 and one followed a CT scan.38 Iomeprol was used in two cases35, 37 but the CM was unknown in the other cases.36, 38 Iopromide in addition to iomeprol was also found to cause SDRIFE in one patient on two separate occasions.35 In another patient with unknown CM exposure, intravenous controlled challenge was positive to iomeprol, iopamide and ioversol, demonstrating crossreactivity amongst monomeric nonionic CM.38
Figure 5
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Symmetrical drug‐related intertriginous and flexural exanthema secondary to iodinated contrast media.
Table 4. Cases of symmetrical drug‐related intertriginous and flexural exanthema following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Arnold et al., 200635 80 M Patient not sure (i) PTCA percutaneous transluminal coronary angioplasty (i) Iomeprol SDRIFE (i) 1 day (i) Topical corticocosteroids (ii) Lasted 5 days
(ii) Coronary angiogram 5 months later (ii) Iopromide (ii) 2 days (before second CM (ii) Premedicated with oral Pred and antihistamines but limited effect (ii) Lasted > 2 weeks
Thierman et al., 2036 57 F Unknown Coronary angiogram Unknown SDRIFE 6 h Not stated Resolution with discontinuation of the offending drug
Grosber et al., 200937 78 F Coronary angiogram Iomeprol SDRIFE 15 h Pred Cleared within 15 days
Caralli et al., 201538 76 F ICM 6 years previously; no reaction CT scan Unknown SDRIFE 48 h Methylpred Improved 1 week later
CT, computed tomography; ICM, iodinated contrast media; Methylpred, methylprednisolone; Pred, prednisolone; SDRIFE, symmetrical drug‐elated intertriginous and flexural exanthema.
Graft‐versus‐host disease secondary to iodinated contrast media
Three patients with successful allogenic bone marrow transplantation developed cutaneous graft‐versus‐host disease (GvHD) to nonionic dimer CM (Table 5).39 All patients had prior GvHD, and the authors suggested that immune complexes could have triggered or precipitated already present or latent cutaneous GvHD.39 Skin GvHD manifesting as generalized erythroderma occurred 6 h after the administration of CM in two patients, while in the third patient, cutaneous GvHD occurred days after initial exposure to iodixanolum and 2 h after repeated exposure several months later, presenting as a generalized maculopapular violaceous rash. All patients required oral immunosuppression for treatment of their skin, and there was resolution within a few weeks for one patient and 10 weeks for the second; the final patient was still requiring treatment at the time the paper was published.39
Table 5. Cases of graft‐versus‐host disease following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Vavricka et al., 200239
Patient 1 49 M Y CT Iodixanolum Generalized erythroderma with a pruritic and painful skin rash. Initially involving facial skin, palms and soles. Dry mouth and conjunctivae 6 h Pred and cetirizine Resolved within a few weeks
Patient 2 30 F Y CT Iodixanolum (i) Acute GvHD (i) 2 days (i) Methylpred initially; refractory. Daclizumab and ciclosporin switched to tacrolimus (i) Stabilized
(ii) Almost 4 months later, generalized maculopapular violaceous rash: grade 2 GvHD (ii) 2 h (ii) Already on tacrolimus, Methylpred and clemastin; refractory. Therefore Pred 100 mg/day, daclizumab and MMF started (ii) Resolved over 10 weeks
Vavricka et al., 200239 Case 3 38 M Y CT chest Iopromidium Generalized erythroderma. In the later phase, generalized poikiloderma with thinning of the epidermis and dermis, telangiectasia, reticulated pigmentation over the whole body 6 h Immunosuppression Still requiring immunosuppressive therapy at time of writing the paper in 2002
CT, computed tomography; GvHD, graft‐versus‐host disease; ICM, iodinated contrast media; Methylpred, methylprednisolone; MMF, mycopheolate mofetil; Pred, prednisolone.
Vasculitis secondary to iodinated contrast media
Five cases of vasculitis secondary to ICM have been reported in the literature (Table 6).40-43 Cutaneous signs generally occurred 8–48 h after exposure and generally affected the extremities. A palpable purpuric rash was the presenting feature in all patients. Two cases developed bullous and haemorrhagic areas, which progressed to ulceration.41, 43 The two cases that followed exposure to high osmolality CM (HOCM) resulted in necrotizing vasculitis associated with fever, indicating a potentially higher risk of vasculitis with HOCM.
Table 6. Cases of vasculitis following iodinated contrast media.
Study Age, years Sex Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Kerdel et al., 198440 Case 1 72 M (i) IV urogram (i) Not stated (i) Asymptomatic papular eruption on both lower extremities. Violaceous purpuric eruption on lower extremities (i) 10 days – Spontaneous resolution of the rash in 10–14 days
(ii) Cardiac catheterization (ii) Diatrizoate meglumine and diatrizoate sodium (ii) Fever 39.7 °C and palpable papular purpuric rash on lower extremities (ii) 12–16 h
Kerdel et al., 198440 Case 2 61 M Superior mesenteric angiogram Diatrizoate meglumine and diatrizoate sodium Generalized palpable purpuric papular rash 22 h – Skin rash and renal function spontaneously resolved in 10 days
Reynolds et al., 199341 60 F IV urogram Iopamidol Maculopapular rash on the arms, but rapidly spread; developed bullous lesions and haemorrhagic areas, which progressed to ulceration. Lesions around the eyes and periorbital oedema. Deep mouth ulcers and enlargement of parotid glands 24 h Pred –
Viegas et al., 201142 77 M Abdominal CT Iodixanol Vasculitic cutaneous reaction affecting both feet – later progressed to both hands 8 h Methlypred followed by Pred –
Goodfellow et al., 198643 69 F IV urogram Iohexol Marked periorbital oedema and a maculopapular rash over the shins, thighs, shoulders and forearms. Over 24 h the rash became bullous and haemorrhagic and rapidly progressed to the formation of large, necrotic ulcers. Conjunctivitis. Necrosis of upper eyelids 48 h High‐dose steroids and peritoneal dialysis Died 13 days after ICM, as a result of multiorgan involvement in the vasculitic process
CT, computed tomography; ICM, iodinated contrast media; IV intravenous; Methylpred, methylprednisolone; Pred, prednisolone.
Iododerma
Iododerma, a type of halogenoderma, is a rare neutrophilic dermatosis occurring after exposure to iodine including ICM, irrigation of wounds with povidine iodine, ingestion of iodide supplements and the use of amiodorone. In total, 17 cases of iododerma caused by ICM have been identified (Table 7).44-60 These comprised 10 women and 7 men, with an average age of 59 years (range 49–81 years). Lesions most commonly appeared on the face and upper body with satellite lesions on the extremities, characterized by an acneiform, pustular and haemorrhagic bullous or nodular vegetative eruption. The majority of cases (13/17) had renal insufficiency, which likely caused impaired iodine clearance.47 The average time to onset was 2–3 days, faster than the onset of other halogenodermas, which usually develop after continuous exposure over months. Time to resolution was 2–6 weeks. Extracutaneous manifestations included four cases of conjunctivitis47, 49, 51, 55 and three cases of salivary gland swelling.51, 52, 55 There were also three cases of respiratory insufficiency, and two of these patients died.53, 60
Table 7. Cases of iododerma secondary to iodinated contrast media.
Study Age years Sex RI? Scan ICM Skin lesions Time to develop skin lesions Management of cutaneous lesions Outcome
Duperrat and Saurat, 198544 70 F Yes IV pyelogram Not stated Necrotic, bullous and pustular eruption. Face (nose), trunk, upper limbs 1 day Local Recovery
Heydenreich et al., 197745 52 M Yes Urogram Metrizoate, then diatrizoate 12 days later Red papules on forehead, then on face and arms during the following days. 4 days later, scattered papules and pustules with heavy inflammation of the surrounding skin. Larger ulcerated lesion on nose. Scattered blisters on erythematous base with serous or slightly haemorrhagic contents 4 days after high dose/second scan Topical zinc liniment Skin eruption disappeared within 3 weeks
Perroud and Delacretaz, 197746 59 M Yes Lymphogram Lipidol Vegetating nodules on face and all 4 limbs 2 days Systemic corticosteroids Healed, leaving perforated nasal septum
Sparrow et al., 197947 62 F Transient nephritis (i) IV pyelogram (i) Diatrizoate Raised red plaques studded with vegetating masses of pus‐filled bullae and impetiginous crusts. On face (infraorbital regions, nose, chin, cheeks and scalp; symmetrical) and on one wrist (i) 4 days Antibiotics and ACTH Eruption subsided in 4 weeks leaving hypertrophic scarring
(ii) Lymphangiogram (ii) Lipiodol (ii) 8 days
Roujeau et al., 198548 64 M Yes Bronchial artery angiogram Not stated Purpuric and vesicobullous eruption resembling EM on legs, fingers, back and scalp 3 days Local and systemic corticosteroids, haemodialysis (no relief) Recovery after 1 month
Lauret et al., 198549 68 F Yes IV pyelogram Diatrizoate Aseptic pustules which quickly evolved into vegetating masses on the face (cheeks and orbits) and 4 limbs 3 days Haemodialysis and local care Good healing within 1.5 months
Boudoulas et al.50 45 M No Oral cholecystogram Iopanoic acid Multiple 0.05–2 cm vesiculopustular, vegetating, nodular lesions, with ulceration predominantly on the face, neck and trunk. Few scattered lesions on the extremities 2 days after 2 exposures to iopanoic acid 40 mg of pred daily 50% clearing of the skin lesions in 1 week. During his 3‐week hospitalization, skin lesions completely resolved
Vailliant et al., 199051 72 F Yes (i) Radiogram of Thomas shunt Ioxaglate (i) Face, scalp, elbows and papular purpura on legs (i) 2 days Not stated Skin signs resolved within 2 weeks first time
(ii) 2 months later, ICM injected (ii) Vegetative ulcerative masses on face, elbows and scalp; papular purpura on legs (ii) 36 h later Skin signs and dyspnoea resolved within 3 weeks
Chang et al., 199752 69 F Yes Abdominal CT scan Diatrizoate Asymptomatic papular eruption on the elbows and extensor forearms. Over 2 days fungating to vegetative plaques with purulent bullae developed on the scalp, face, neck and upper chest. Slightly tender oral mucosal erosions 4 days Triamcinolone acetonide ointment 0.1% and wet dressings Significant improvement 2 weeks after CT. 4 weeks after onset of the eruption, there was > 95% resolution
Miranda‐Romero et al., 199953 65 F Yes Cardiac catheterization Not stated Two vegetating 3 cm wide masses on both cheeks. Pustular vesicular lesions on the extremities (elbows and lower limb) 5 days 1 : 1000 copper sulphate solution Patient died 2 weeks later; likely secondary to cardiorespiratory condition
Wang et al., 200454 49 F Yes Radiographic evaluation of a thrombosed dialysis graft in arm Not stated Pustular (0.5–2 cm) and pseudobullous plaques with erythematous and indurated bases on face (cheek, nose, orbits and forehead). Oedema on face and eyelids 3 days Not stated Not stated
Rothman et al., 201355 81 M No Serial CT scans Iodixanol Irregular, blanching, erythematous papules and plaques on the forehead, upper extremities and proximal lower extremities, and a single crusted acneiform lesion on the chin. Oedema on upper lip; vegetating ulcers on lip and tongue 1 day Topical steroids All lesions resolved within 2 weeks; parotid and mandibular gland enlargement and tenderness improved as well
Stavert et al., 201356 Not stated M Yes Abdominal CT Diatrizoate 5 cm reddish‐brown plaque composed of numerous coalescing vesicles and haemorrhagic pustules, with intermixed serous and haemorrhagic crust. Similar vesicles and pustules on nasal bridge and tip, bilateral conchal bowls and scalp. 2 days later, 0.5–1 cm purpuric macules and haemorrhagic vesicles on bilateral hands and nails 3 days Not stated 7 days after CM exposure, patient reported improvement in tenderness without new lesions. Several weeks later the lesions had completely resolved
Young et al., 201457 60 F Yes Two abdominal CT scans (i) Ioversol Asymptomatic bullous eruption on the patient's face, chest and upper extremities 2–3 days Pred 1 mg/kg tapered over 1 month Complete resolution of the eruption and renal failure after 1 month
(ii) Iohexol
Chalela et al., 201658 57 M No Urogram Iodinated CM stated only Pustular eruptions with multiple coalescing vesicles and pus‐filled bullae on face and ears, trunk, arms and legs Several hours Thalidomide Completely resolved within 4 weeks
Hesseler et al., 201859 47 F Yes Abdominal aortogram Iopamidol Haemorrhagic vesicopustular eruption on face, circumferential on neck, chest, and dorsal hands 2 days Diuresis and intravenous Methylpred. Transitioned to Pred taper over 6 weeks Progressive improvement of the skin lesions. At 6 months there was complete resolution of the skin lesions without post‐inflammatory hyperpigmentation
Yeh et al., 201860 27 F Yes Two CT scans on separate occasions Not stated Large, vegetative, beefy‐red and crateriform nodules and ulcers on face and oral mucosa. Haemorrhagic bullae on bilateral hands and feet. Significant facial oedema 2–3 days Not stated Patient died from acute respiratory failure within 48 h of hospital transfer
ACTH, adrenocorticotropic hormone; CT, computed tomography; EM, erythema multiforme; ICM, iodinated contrast media; Methylpred, methylprednisolone; Pred, prednisolone; RI, renal insufficiency.
Testing for delayed hypersensitivity reactions to iodinated contrast media
Skin tests can be used to identify the suspected culprit agent that has caused a DHR to ICM. The European Society of Contact Dermatitis recommend that patch testing is valuable for maculopapular rashes, SDRIFE, AGEP, FDE61 and DRESS.62 In FDE, patch testing is typically positive on lesional skin but not intact skin.61 Patch testing is however of less value in urticaria, SJS, TEN and vasculitis.61
Intradermal tests (IDTs) with delayed positive results can be seen in maculopapular rashes and FDE. However, IDTs are contraindicated in erythema multiforme, SJS, TEN and leucocytoclastic vasculitis.61
IDTs with delayed readings combined with patch testing are needed for optimal sensitivity to increase the chances of detecting DHR.6 However, only up to 47% of delayed reactions had positive skin tests; therefore, if skin tests are negative, a drug provocation test may confirm the diagnosis and identify an alternative CM in patients with prior DHR to ICM.63
Discussion
We have presented an overview of delayed reactions including both mild and severe cutaneous adverse reactions (SCARs) to ICM reported in the literature. SCARs secondary to ICM may be underdiagnosed and thus under‐reported in the literature, particularly in patients who are medically complex and taking numerous medications. Failure to recognize a severe reaction to ICM may result in inadvertent re‐exposure, and more precipitous and severe reaction. Consideration of ICM as a possible culprit agent is essential in the evaluation of any patient with a SCAR.
Learning points
DHRs to iodinated reactions are thought to be T‐cell mediated, and typically present as mild to moderate maculopapular exanthems, which are often self‐limiting.
DHRs rarely present as FDE, AGEP, DRESS and SJS/TEN, SDRIFE, GvHD, vasculitis or iododerma.
DHR to ICM are probably under diagnosed, as the cutaneous reaction may be mistaken for other more likely culprits, particularly if patients are on multiple drugs.
DHRs tend to manifest more quickly in people who have had a prior reaction to ICM.
Iododerma is a rare neutrophilic dermatosis that can occur after exposure to ICM often in patients with renal insufficiency.
Iododerma is associated with extracutaneous manifestations such as conjunctival injection, swelling of the glands (parotid/submandibular/submaxillary) and respiratory insufficiency.
References
CPD questions
Learning objective
To demonstrate knowledge of delayed hypersensitivity reactions to contrast media.
Question 1
Delayed hypersensitivity reactions to iodinated contrast media will most likely present as which of the following?
Stevens–Johnson syndrome/toxic epidermal necrolysis.
Maculopapular exanthem.
Fixed drug eruption.
Acute generalized exanthematous pustulosis.
Drug‐related eosinophilia and systemic symptoms.
Question 2
Which of the following statements is correct concerning the recurrence of delayed hypersensitivity reactions, such as fixed drug eruption and Stevens–Johnson syndrome/toxic epidermal necrolysis, following subsequent exposure to iodinated contrast media?
There is a shorter latency period before recurrence.
There is a longer latency period before recurrence.
Recurrence usually appears on the trunk.
Recurrence usually appears on the abdomen.
Recurrence usually appears on the scalp.
Question 3
Of the six cases reported in the literature on drug‐related eosinophilia and systemic symptoms (DRESS) caused by iodinated contrast media how many of them were exposed to contrast media multiple times before manifesting symptoms and signs of DRESS?
0.
2.
4.
5.
6.
Question 4
Which of the following conditions can rarely occur as a delayed hypersensitivity reaction to iodinated contrast media?
Behçet disease.
Graft‐versus‐host disease.
Acanthosis nigrans.
Folliculitis.
Keratoacanthoma.
Question 5
Iododerma is associated with which of the following extracutaneous manifestations?
Conjunctivitis.
Swelling of the glands.
Swelling of the extremities.
Cardiovascular compromise.
Abdominal pain.
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F. Tasker H. Fleming G. McNeill D. Creamer S. Walsh
First published: 04 June 2019 https://doi.org/10.1111/ced.13991
Conflict of interest: none declared.
Summary
Contrast media (CM) are an indispensable part of modern medical imaging. Adverse reactions to CM are uncommon, but frequently involve cutaneous symptoms. This two‐part article reviews adverse events secondary to CM that are relevant to the practising dermatologist. Part 1 covers the classification of CM, immediate hypersensitivity reactions to CM and the newly described condition, gadolinium deposition disease. Given that there has only been two case reports to our knowledge of a delayed adverse reaction to gadolinium‐based CM, this second part will focus on cutaneous delayed reactions caused by iodinated CM (ICM). Delayed hypersensitivity reactions to ICM commonly present as maculopapular exanthems, but more rarely, they can manifest as fixed drug eruptions, acute generalized exanthematous pustulosis, drug‐related eosinophilia and systemic symptoms, Stevens–Johnson syndrome/toxic epidermal necrolysis, symmetrical drug‐related intertriginous and flexural exanthema, graft‐versus‐host disease, vasculitis and iododerma. Delayed reactions to ICM may be underdiagnosed, as cutaneous symptoms may be attributed to oral medications, particularly if patients are on multiple drugs.
Introduction
Contrast media (CM) are commonly used worldwide to enhance the quality of imaging and diagnostic accuracy. Delayed hypersensitivity reactions (DHRs) are predominately caused by iodinated CM (ICM), as to our knowledge there have only been two published case reports of DHR secondary to gadolinium‐based CM.1, 2 DHRs occur within a time frame of > 1 h to 7 days after administration of CM, and are thought to be T‐cell‐mediated.2-4 DHRs occur in 0.5–23% of people receiving ICM,4, 5 and often present as a maculopapular exanthem (Fig. 1). In one study, 19% of delayed adverse reactions manifested as urticaria but the mechanism of this is unclear.6 DHR can be managed symptomatically with topical steroid and antihistamine. Rarely they present as other T‐cell‐mediated drug like skin reactions.7
Figure 1
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Exanthem secondary to iodinated contrast media.
Reactions to iodinated contrast media
Fixed drug eruption secondary to iodinated contrast media
There have been 10 reported cases of fixed drug eruption (FDE) secondary to ICM identified in the literature (Table 1).8-17 Six occurred following a computed tomography (CT) scan9, 13-17 and the culprit ICM in over half of cases was a nonionic monomeric medium.10, 12-16 Cutaneous symptoms typically presented within 24 h after CM. Location of the FDE varied and included the heel, hands, fingers and inguinal region.8, 13 Resolution was spontaneous, typically within 7 days of onset. Recurrence of FDE on subsequent exposure can occur, typically with a shorter latency due to prior sensitization.13
Table 1. Cases of fixed drug eruption following iodinated contrast media.
Study Age, years Sex Prior ICM reactiona Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Good et al., 19808 46 M Multiple episodes after intravenous pyelogram Intravenous pyelograms Not stated After several hours, developed fever that lasted 3 days. Then developed a blister on left heel Within 72 h Not stated Blister healed each time
Benson et al., 19909 51 F Not stated Chest CT Iothalamate Reactions on two different occasions, both with fixed solitary, recurrent, indurated, erythematous plaque on medial aspect of the thigh (i) Within 24 h Oral dicloxacillin (i) Resolved within days
(ii) 1 year later, within 24 h Hydrocortisone (ii) Resolved within 24 h
Borofsky et al., 199310 46 M Rash with itching several hours after ICM and aspirin Arteriogram Iohexol Erythematous patches with vesiculobullous eruptions over chest, back and upper arms. Two days later, oedematous, erythematous plaques over calves 5 h Oral Pred and antihistamine Skin lesions healed within 2 weeks
Gonzalo‐Garijo et al., 199711 72 M Not stated Cardiac catheterization Ioxoglate Pigmenting FDE. Erythematous plaques, sharply delineated without desquamation over the perineal, sacral and gluteal areas 48 h Oral Pred Resolved in 5 days
Yamauchi et al., 199712 41 F Not stated Imaging of haemodialysis shunt Iopamidol Burning sensation a few hours after iopamidol with faint erythema. Several well‐demarcated, oval‐shaped erythemas on upper and lower limbs and trunk. Some lesions developed into bullae and erosions Few hours IV Pred Not stated
Watanabe et al., 199913 67 F Not stated CT Iomeprol Reactions on two different occasions, both with pea‐sized vesicular erythematous papules on trunk and extremities; some coalesced, forming 7 large plaques on the limbs (i) 4 days (i) Oral betamethasone, glutathione, topical betamethasone. (ii) Oral bethamethasone only Lesions cleared, leaving pigmentation that faded within 6 weeks
(ii) Within few hours to 24 h
Bohm et al., 200714 61 M Same FDE 1 year before Abdominal CT Iopromide Red macule 2 cm in diameter covering a dermal infiltration in the right inguinal region. Enlarged to 15 × 8 cm accompanied by a burning sensation 4 h Not stated Disappeared after 4–5 weeks
Wright et al., 201115 57 F Prior CT scans with similar eruption Staging CT scans Iohexol Sharply demarcated erythematous patch on left breast < 15 h Not stated Resolved after 5–7 days
Frías et al., 201116 60 M Previous CT with CM and no reaction CT Ioversol Two episodes, both with pruritic erythematous and blistering eruption on backs and interdigital areas of both hands After 24 h (worse at 48–72 h) Not stated Disappeared spontaneously after 10 days
Epskamp et al., 201617 70 M CT scans at regular intervals and no reaction CT Iodixonal Bullous FDE on lateral aspect of the lower third of the middle finger; haemorrhagic bullae with erythematous background Within 24 h Not stated Resolved in 4 days
CT, computed tomography; FDE, fixed drug eruption; ICM, iodinated contrast media; IV, intravenous; Pred, prednisolone. aICM prior to the date of publication of the case.
Acute generalized exanthematous pustulosis secondary to iodinated contrast media
There have been 16 cases of acute generalized exanthematous pustulosis (AGEP) caused by ICM (Fig. 2) described. Latency of onset was between 2 h and 3 days after ICM, with almost half of the cases (7/16) being triggered by iodixanol. The authors identified a higher rate of AGEP with dimeric iso‐osmolar CM compared with monomeric low osmolality CM.18
Figure 2
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Acute generalized exanthematous pustulosis secondary to iodinated contrast media.
Drug‐related eosinophilia and systemic symptoms secondary to iodinated contrast media
Six cases19-22 of drug‐related eosinophilia and systemic symptoms (DRESS) (Fig. 3) have been reported (Table 2). The majority (5/6) of patients had multiple exposures to ICM before developing DRESS. Cutaneous symptoms arose within 1 h to 3 days, and most cases resolved within 3 weeks. One patient had received both ioversol and imipenam, leading to diagnostic doubt regarding the causative agent; however, there is some evidence in the literature that medications administered in close temporal proximity may have a synergistic effect in producing DRESS.21 In one case, a first episode of ICM‐induced DRESS was incorrectly diagnosed, and the patient was inadvertently rechallenged with ICM, leading to a second reaction.22 It is important to include ICM in causality assessment of patients with DRESS on multiple medications.
Figure 3
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Drug‐related eosinophilia and systemic symptoms secondary to iodinated contrast media
Table 2. Cases of drug reaction with eosinophilia and systemic symptoms following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Kanny et al., 200119
Patient 1 63 F Not stated First reaction developed after coronary arteriography, second after coronary angioplasty Ioxaglic acid meglumine both times DRESS: maculopapular eruption, fever (i) 24 h Not stated (i) Resolved in 3 weeks
(ii) 8 years later, onset 3 days (ii) Resolved in 2 weeks
Patient 2 19 M 7 scans in 3 months but no reaction – Iohexol, iobitridrol DRESS: maculopapular eruption, fever 1 h Not stated Resolved after 2 weeks
Patient 3 59 M Several scans and arteriographies but no reaction – Iohexol DRESS 12 h Not stated Resolved in 2 days
Belhadjali et al., 200820 71 F Coronary angiogram with CM 7 months previously; no reaction Transluminal angioplasty Sodium meglumine ioxitalamate DRESS based on RegiSCAR24 2 days Not stated Resolved in 17 days
Macías et al., 201321 83 F Had received ioversol and imipenum several times previously; no reaction – Ioversol DRESS based on RegiSCAR24 Several hours Systemic corticosteroids Not stated
Leguisamo et al., 22 57 F 4 abdominal CT scans with iopromide 5 months previously and had a reaction after 21 days CT Iopromide DRESS based on RegiSCAR24 (7 for previous episode, 5 for second episode) 6 h Not stated Not stated
Mini‐DRESS
George et al., 201623 76 F Prior CT 5 years previously; no reaction Abdominal CT Not stated Widespread urticated oedematous confluent exanthem on torso. Discrete urticated lesions reminiscent of targets on limbs 1–6 days Pred 30 mg, mometasone fumarate (Elocon) Improved within 5 days
CT, computed tomography; DRESS, drug reaction with eosinophilia and systemic symptoms; Pred, prednisolone; RegiSCAR, Registry of Severe Cutaneous Adverse Reactions.
Another published case described an episode of mini‐DRESS23 (that is, a systemic adverse drug reaction mimicking DRESS, but not reaching all the diagnostic criteria24) occurring 1–6 days following exposure to ICM.
Stevens–Johnson syndrome/toxic epidermal necrolysis secondary to iodinated contrast media
There have been 11 cases of Stevens–Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN) associated with ICM: 4 cases of SJS, 2 of SJS/TEN overlap and 5 of TEN (Fig. 4, Table 3).25-34 Nonionic monomeric ICM was the most frequent culprit. Of these 11 cases, 5 were female, 9 were adults (33–73 years) and 2 were paediatric cases (aged 6 and 14 years, respectively).27, 33 Onset of cutaneous symptoms occurred between 30 min and 3 days with recurrence of symptoms typically manifesting earlier. Of the 11 patients, 3 died; 2 of these had TEN.30, 34 The SCORe of Toxic Epidermal Necrosis (SCORTEN) result relating to the episodes resulting in death was not stated.
Figure 4
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Toxic epidermal necrolysis secondary to iodinated contrast media.
Table 3. Cases of Stevens–Johnson syndrome and toxic epidermal necrolysis following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
SJS
Savill et al., 198825 46 F – IV urogram Iopamidol Blistering rash involving limbs and buttocks with painful ulcers in mouth and nares. After 3 days large ulceronecrotic plaques developed, some with bullous changes on extensor limbs and trunk 8 h High‐dose Dexa and supportive therapy Multiorgan failure; died 6 weeks after admission
Hebert et al., 200426 66 F – 4 coronary catheterizations; SJS after each one First 3 time iopamidol; fourth time ioversol SJS after each procedure Dexa Premedicated with Pred 50 mg once daily for 5 days –
Laffitte et al., 200427 6 M – Cervicothoracic CT Iopentol SJS 3 days Fusidic acid (Fucidin) and mometasone fumarate (Elocon) Lesions progressively cleared
Gogna et al., 201528 73 M Multiple ioversol infusions; erythematous itchy facial rash 5–7 after CM 2 months prior Evaluation of AV fistula patency Ioversol SJS 3 days Pred 60 mg Symptom resolution
SJS/TEN overlap
Yang et al., 201529
Patient 1 61 F CT scan 2 weeks previously; uneventful CT scans Iohexol 2 weeks after second scan, generalized pruritus and widespread xerotic eczema. Over next 5 days BSA 5%, SCORTEN 1 (for age). After third CT scan, increased skin denudation (15%), conjunctival injection and haemorrhagic crusting of lips After third CT scan, within 24 h Oral Pred after second CT scan and IVIg after third scan Severe sepsis without re‐epithelialization
Patient 2 60 M CT aortograms 4 years previously; no reaction CT aortogram Iopaque (reaction on fourth scan) SJS/TEN BSA detached 11%, extended to 15%; SCORTEN 4 3 days IVIg Complete re‐epithelialization after 12 days
TEN
Kaftori et al., 198830 55 F Excretory pyelogram 60% solution of diatrizoate TEN 12 h Not stated Died 10 days after admission
Schmidt et al., 199831 36 M Multiple previous CTs; had transient skin rash once and therefore received premedication for other CTs Abdominal CT Diluted diatrizoate meglumine and diatrizoate sodium TEN with eventually 30% TBSA 30 min to several daysa Supportive management only Skin healed without scarring or alteration of pigmentation
Rosado et al., 200132 33 M 2 previous CT scans, but not reaction 4 body CTs Iohexol (i) Erythematous disseminated rash (i) 9 days after third CT Not stated –
(ii) Bullae affecting 50% of BSA (ii) 2 h after fourth CT
Lee et al., 200233 14 M Pre‐op angiocardiogram exam at 3 and 12 years of age; no adverse reaction Cardiac catheterization and angiocardiogram Ioxaglate and iohexol at 3 years of age and iopamidol at 12 years TEN 24 h IV antibiotics, corticosteroids and hydration Discharged uneventfully on 11th day
Brown et al., 201334 37 F 12 CT scans during previous years; no reaction CT Iopromide Episodes following 3 CT scans: Not stated Died of sepsis
(i) < 10% TBSA (i) < 4 days
(ii) TEN SCORTEN 3 (ii) 1 day
(iiia) TBSA 60–80% (iiia) Within minutes
(iiib) 100% TBSA (iiib) Within hours
AV, arteriovenous; BSA, body surface area; CT, computed tomography; Dexa, dexamethasone; ICM, iodinated contrast media; IV, intravenous; IVIg, intravenous immunoglobulin; Pred, prednisolone; SJS, Stevens–Johnson syndrome; SCORTEN, SCORe of Toxic Epidermal Necrosis; TBSA, total body surface area; TEN, toxic epidermal necrolysis. aWithin 30 min, itchy and patchy erythema developed; patient given diphenhydrazine and IV methylprednisolone sodium succinate (SoluMedrol) after 2 h and pethidine (Demerol) IM, and told to take Pred 60 mg that evening. Symptoms resolved. However, next day, pruritus, erythema and conjunctivitis developed, and worsened over 24–48 h.
Symmetrical drug‐related intertriginous and flexural exanthema secondary to iodinated contrast media
There are four published cases of symmetrical drug‐related intertriginous and flexural exanthema (SDRIFE) (Fig. 5) reported to be caused by ICM (Table 4). The age ranged from 57 to 80 years old; one man35 and three women.36-38 Three of the cases followed coronary angioplasty and/or an angiogram35-37 and one followed a CT scan.38 Iomeprol was used in two cases35, 37 but the CM was unknown in the other cases.36, 38 Iopromide in addition to iomeprol was also found to cause SDRIFE in one patient on two separate occasions.35 In another patient with unknown CM exposure, intravenous controlled challenge was positive to iomeprol, iopamide and ioversol, demonstrating crossreactivity amongst monomeric nonionic CM.38
Figure 5
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Symmetrical drug‐related intertriginous and flexural exanthema secondary to iodinated contrast media.
Table 4. Cases of symmetrical drug‐related intertriginous and flexural exanthema following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Arnold et al., 200635 80 M Patient not sure (i) PTCA percutaneous transluminal coronary angioplasty (i) Iomeprol SDRIFE (i) 1 day (i) Topical corticocosteroids (ii) Lasted 5 days
(ii) Coronary angiogram 5 months later (ii) Iopromide (ii) 2 days (before second CM (ii) Premedicated with oral Pred and antihistamines but limited effect (ii) Lasted > 2 weeks
Thierman et al., 2036 57 F Unknown Coronary angiogram Unknown SDRIFE 6 h Not stated Resolution with discontinuation of the offending drug
Grosber et al., 200937 78 F Coronary angiogram Iomeprol SDRIFE 15 h Pred Cleared within 15 days
Caralli et al., 201538 76 F ICM 6 years previously; no reaction CT scan Unknown SDRIFE 48 h Methylpred Improved 1 week later
CT, computed tomography; ICM, iodinated contrast media; Methylpred, methylprednisolone; Pred, prednisolone; SDRIFE, symmetrical drug‐elated intertriginous and flexural exanthema.
Graft‐versus‐host disease secondary to iodinated contrast media
Three patients with successful allogenic bone marrow transplantation developed cutaneous graft‐versus‐host disease (GvHD) to nonionic dimer CM (Table 5).39 All patients had prior GvHD, and the authors suggested that immune complexes could have triggered or precipitated already present or latent cutaneous GvHD.39 Skin GvHD manifesting as generalized erythroderma occurred 6 h after the administration of CM in two patients, while in the third patient, cutaneous GvHD occurred days after initial exposure to iodixanolum and 2 h after repeated exposure several months later, presenting as a generalized maculopapular violaceous rash. All patients required oral immunosuppression for treatment of their skin, and there was resolution within a few weeks for one patient and 10 weeks for the second; the final patient was still requiring treatment at the time the paper was published.39
Table 5. Cases of graft‐versus‐host disease following iodinated contrast media.
Study Age, years Sex Prior ICM reaction Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Vavricka et al., 200239
Patient 1 49 M Y CT Iodixanolum Generalized erythroderma with a pruritic and painful skin rash. Initially involving facial skin, palms and soles. Dry mouth and conjunctivae 6 h Pred and cetirizine Resolved within a few weeks
Patient 2 30 F Y CT Iodixanolum (i) Acute GvHD (i) 2 days (i) Methylpred initially; refractory. Daclizumab and ciclosporin switched to tacrolimus (i) Stabilized
(ii) Almost 4 months later, generalized maculopapular violaceous rash: grade 2 GvHD (ii) 2 h (ii) Already on tacrolimus, Methylpred and clemastin; refractory. Therefore Pred 100 mg/day, daclizumab and MMF started (ii) Resolved over 10 weeks
Vavricka et al., 200239 Case 3 38 M Y CT chest Iopromidium Generalized erythroderma. In the later phase, generalized poikiloderma with thinning of the epidermis and dermis, telangiectasia, reticulated pigmentation over the whole body 6 h Immunosuppression Still requiring immunosuppressive therapy at time of writing the paper in 2002
CT, computed tomography; GvHD, graft‐versus‐host disease; ICM, iodinated contrast media; Methylpred, methylprednisolone; MMF, mycopheolate mofetil; Pred, prednisolone.
Vasculitis secondary to iodinated contrast media
Five cases of vasculitis secondary to ICM have been reported in the literature (Table 6).40-43 Cutaneous signs generally occurred 8–48 h after exposure and generally affected the extremities. A palpable purpuric rash was the presenting feature in all patients. Two cases developed bullous and haemorrhagic areas, which progressed to ulceration.41, 43 The two cases that followed exposure to high osmolality CM (HOCM) resulted in necrotizing vasculitis associated with fever, indicating a potentially higher risk of vasculitis with HOCM.
Table 6. Cases of vasculitis following iodinated contrast media.
Study Age, years Sex Scan ICM Skin lesions Time to develop skin lesions after ICM Management of cutaneous lesions Outcome
Kerdel et al., 198440 Case 1 72 M (i) IV urogram (i) Not stated (i) Asymptomatic papular eruption on both lower extremities. Violaceous purpuric eruption on lower extremities (i) 10 days – Spontaneous resolution of the rash in 10–14 days
(ii) Cardiac catheterization (ii) Diatrizoate meglumine and diatrizoate sodium (ii) Fever 39.7 °C and palpable papular purpuric rash on lower extremities (ii) 12–16 h
Kerdel et al., 198440 Case 2 61 M Superior mesenteric angiogram Diatrizoate meglumine and diatrizoate sodium Generalized palpable purpuric papular rash 22 h – Skin rash and renal function spontaneously resolved in 10 days
Reynolds et al., 199341 60 F IV urogram Iopamidol Maculopapular rash on the arms, but rapidly spread; developed bullous lesions and haemorrhagic areas, which progressed to ulceration. Lesions around the eyes and periorbital oedema. Deep mouth ulcers and enlargement of parotid glands 24 h Pred –
Viegas et al., 201142 77 M Abdominal CT Iodixanol Vasculitic cutaneous reaction affecting both feet – later progressed to both hands 8 h Methlypred followed by Pred –
Goodfellow et al., 198643 69 F IV urogram Iohexol Marked periorbital oedema and a maculopapular rash over the shins, thighs, shoulders and forearms. Over 24 h the rash became bullous and haemorrhagic and rapidly progressed to the formation of large, necrotic ulcers. Conjunctivitis. Necrosis of upper eyelids 48 h High‐dose steroids and peritoneal dialysis Died 13 days after ICM, as a result of multiorgan involvement in the vasculitic process
CT, computed tomography; ICM, iodinated contrast media; IV intravenous; Methylpred, methylprednisolone; Pred, prednisolone.
Iododerma
Iododerma, a type of halogenoderma, is a rare neutrophilic dermatosis occurring after exposure to iodine including ICM, irrigation of wounds with povidine iodine, ingestion of iodide supplements and the use of amiodorone. In total, 17 cases of iododerma caused by ICM have been identified (Table 7).44-60 These comprised 10 women and 7 men, with an average age of 59 years (range 49–81 years). Lesions most commonly appeared on the face and upper body with satellite lesions on the extremities, characterized by an acneiform, pustular and haemorrhagic bullous or nodular vegetative eruption. The majority of cases (13/17) had renal insufficiency, which likely caused impaired iodine clearance.47 The average time to onset was 2–3 days, faster than the onset of other halogenodermas, which usually develop after continuous exposure over months. Time to resolution was 2–6 weeks. Extracutaneous manifestations included four cases of conjunctivitis47, 49, 51, 55 and three cases of salivary gland swelling.51, 52, 55 There were also three cases of respiratory insufficiency, and two of these patients died.53, 60
Table 7. Cases of iododerma secondary to iodinated contrast media.
Study Age years Sex RI? Scan ICM Skin lesions Time to develop skin lesions Management of cutaneous lesions Outcome
Duperrat and Saurat, 198544 70 F Yes IV pyelogram Not stated Necrotic, bullous and pustular eruption. Face (nose), trunk, upper limbs 1 day Local Recovery
Heydenreich et al., 197745 52 M Yes Urogram Metrizoate, then diatrizoate 12 days later Red papules on forehead, then on face and arms during the following days. 4 days later, scattered papules and pustules with heavy inflammation of the surrounding skin. Larger ulcerated lesion on nose. Scattered blisters on erythematous base with serous or slightly haemorrhagic contents 4 days after high dose/second scan Topical zinc liniment Skin eruption disappeared within 3 weeks
Perroud and Delacretaz, 197746 59 M Yes Lymphogram Lipidol Vegetating nodules on face and all 4 limbs 2 days Systemic corticosteroids Healed, leaving perforated nasal septum
Sparrow et al., 197947 62 F Transient nephritis (i) IV pyelogram (i) Diatrizoate Raised red plaques studded with vegetating masses of pus‐filled bullae and impetiginous crusts. On face (infraorbital regions, nose, chin, cheeks and scalp; symmetrical) and on one wrist (i) 4 days Antibiotics and ACTH Eruption subsided in 4 weeks leaving hypertrophic scarring
(ii) Lymphangiogram (ii) Lipiodol (ii) 8 days
Roujeau et al., 198548 64 M Yes Bronchial artery angiogram Not stated Purpuric and vesicobullous eruption resembling EM on legs, fingers, back and scalp 3 days Local and systemic corticosteroids, haemodialysis (no relief) Recovery after 1 month
Lauret et al., 198549 68 F Yes IV pyelogram Diatrizoate Aseptic pustules which quickly evolved into vegetating masses on the face (cheeks and orbits) and 4 limbs 3 days Haemodialysis and local care Good healing within 1.5 months
Boudoulas et al.50 45 M No Oral cholecystogram Iopanoic acid Multiple 0.05–2 cm vesiculopustular, vegetating, nodular lesions, with ulceration predominantly on the face, neck and trunk. Few scattered lesions on the extremities 2 days after 2 exposures to iopanoic acid 40 mg of pred daily 50% clearing of the skin lesions in 1 week. During his 3‐week hospitalization, skin lesions completely resolved
Vailliant et al., 199051 72 F Yes (i) Radiogram of Thomas shunt Ioxaglate (i) Face, scalp, elbows and papular purpura on legs (i) 2 days Not stated Skin signs resolved within 2 weeks first time
(ii) 2 months later, ICM injected (ii) Vegetative ulcerative masses on face, elbows and scalp; papular purpura on legs (ii) 36 h later Skin signs and dyspnoea resolved within 3 weeks
Chang et al., 199752 69 F Yes Abdominal CT scan Diatrizoate Asymptomatic papular eruption on the elbows and extensor forearms. Over 2 days fungating to vegetative plaques with purulent bullae developed on the scalp, face, neck and upper chest. Slightly tender oral mucosal erosions 4 days Triamcinolone acetonide ointment 0.1% and wet dressings Significant improvement 2 weeks after CT. 4 weeks after onset of the eruption, there was > 95% resolution
Miranda‐Romero et al., 199953 65 F Yes Cardiac catheterization Not stated Two vegetating 3 cm wide masses on both cheeks. Pustular vesicular lesions on the extremities (elbows and lower limb) 5 days 1 : 1000 copper sulphate solution Patient died 2 weeks later; likely secondary to cardiorespiratory condition
Wang et al., 200454 49 F Yes Radiographic evaluation of a thrombosed dialysis graft in arm Not stated Pustular (0.5–2 cm) and pseudobullous plaques with erythematous and indurated bases on face (cheek, nose, orbits and forehead). Oedema on face and eyelids 3 days Not stated Not stated
Rothman et al., 201355 81 M No Serial CT scans Iodixanol Irregular, blanching, erythematous papules and plaques on the forehead, upper extremities and proximal lower extremities, and a single crusted acneiform lesion on the chin. Oedema on upper lip; vegetating ulcers on lip and tongue 1 day Topical steroids All lesions resolved within 2 weeks; parotid and mandibular gland enlargement and tenderness improved as well
Stavert et al., 201356 Not stated M Yes Abdominal CT Diatrizoate 5 cm reddish‐brown plaque composed of numerous coalescing vesicles and haemorrhagic pustules, with intermixed serous and haemorrhagic crust. Similar vesicles and pustules on nasal bridge and tip, bilateral conchal bowls and scalp. 2 days later, 0.5–1 cm purpuric macules and haemorrhagic vesicles on bilateral hands and nails 3 days Not stated 7 days after CM exposure, patient reported improvement in tenderness without new lesions. Several weeks later the lesions had completely resolved
Young et al., 201457 60 F Yes Two abdominal CT scans (i) Ioversol Asymptomatic bullous eruption on the patient's face, chest and upper extremities 2–3 days Pred 1 mg/kg tapered over 1 month Complete resolution of the eruption and renal failure after 1 month
(ii) Iohexol
Chalela et al., 201658 57 M No Urogram Iodinated CM stated only Pustular eruptions with multiple coalescing vesicles and pus‐filled bullae on face and ears, trunk, arms and legs Several hours Thalidomide Completely resolved within 4 weeks
Hesseler et al., 201859 47 F Yes Abdominal aortogram Iopamidol Haemorrhagic vesicopustular eruption on face, circumferential on neck, chest, and dorsal hands 2 days Diuresis and intravenous Methylpred. Transitioned to Pred taper over 6 weeks Progressive improvement of the skin lesions. At 6 months there was complete resolution of the skin lesions without post‐inflammatory hyperpigmentation
Yeh et al., 201860 27 F Yes Two CT scans on separate occasions Not stated Large, vegetative, beefy‐red and crateriform nodules and ulcers on face and oral mucosa. Haemorrhagic bullae on bilateral hands and feet. Significant facial oedema 2–3 days Not stated Patient died from acute respiratory failure within 48 h of hospital transfer
ACTH, adrenocorticotropic hormone; CT, computed tomography; EM, erythema multiforme; ICM, iodinated contrast media; Methylpred, methylprednisolone; Pred, prednisolone; RI, renal insufficiency.
Testing for delayed hypersensitivity reactions to iodinated contrast media
Skin tests can be used to identify the suspected culprit agent that has caused a DHR to ICM. The European Society of Contact Dermatitis recommend that patch testing is valuable for maculopapular rashes, SDRIFE, AGEP, FDE61 and DRESS.62 In FDE, patch testing is typically positive on lesional skin but not intact skin.61 Patch testing is however of less value in urticaria, SJS, TEN and vasculitis.61
Intradermal tests (IDTs) with delayed positive results can be seen in maculopapular rashes and FDE. However, IDTs are contraindicated in erythema multiforme, SJS, TEN and leucocytoclastic vasculitis.61
IDTs with delayed readings combined with patch testing are needed for optimal sensitivity to increase the chances of detecting DHR.6 However, only up to 47% of delayed reactions had positive skin tests; therefore, if skin tests are negative, a drug provocation test may confirm the diagnosis and identify an alternative CM in patients with prior DHR to ICM.63
Discussion
We have presented an overview of delayed reactions including both mild and severe cutaneous adverse reactions (SCARs) to ICM reported in the literature. SCARs secondary to ICM may be underdiagnosed and thus under‐reported in the literature, particularly in patients who are medically complex and taking numerous medications. Failure to recognize a severe reaction to ICM may result in inadvertent re‐exposure, and more precipitous and severe reaction. Consideration of ICM as a possible culprit agent is essential in the evaluation of any patient with a SCAR.
Learning points
DHRs to iodinated reactions are thought to be T‐cell mediated, and typically present as mild to moderate maculopapular exanthems, which are often self‐limiting.
DHRs rarely present as FDE, AGEP, DRESS and SJS/TEN, SDRIFE, GvHD, vasculitis or iododerma.
DHR to ICM are probably under diagnosed, as the cutaneous reaction may be mistaken for other more likely culprits, particularly if patients are on multiple drugs.
DHRs tend to manifest more quickly in people who have had a prior reaction to ICM.
Iododerma is a rare neutrophilic dermatosis that can occur after exposure to ICM often in patients with renal insufficiency.
Iododerma is associated with extracutaneous manifestations such as conjunctival injection, swelling of the glands (parotid/submandibular/submaxillary) and respiratory insufficiency.
References
CPD questions
Learning objective
To demonstrate knowledge of delayed hypersensitivity reactions to contrast media.
Question 1
Delayed hypersensitivity reactions to iodinated contrast media will most likely present as which of the following?
Stevens–Johnson syndrome/toxic epidermal necrolysis.
Maculopapular exanthem.
Fixed drug eruption.
Acute generalized exanthematous pustulosis.
Drug‐related eosinophilia and systemic symptoms.
Question 2
Which of the following statements is correct concerning the recurrence of delayed hypersensitivity reactions, such as fixed drug eruption and Stevens–Johnson syndrome/toxic epidermal necrolysis, following subsequent exposure to iodinated contrast media?
There is a shorter latency period before recurrence.
There is a longer latency period before recurrence.
Recurrence usually appears on the trunk.
Recurrence usually appears on the abdomen.
Recurrence usually appears on the scalp.
Question 3
Of the six cases reported in the literature on drug‐related eosinophilia and systemic symptoms (DRESS) caused by iodinated contrast media how many of them were exposed to contrast media multiple times before manifesting symptoms and signs of DRESS?
0.
2.
4.
5.
6.
Question 4
Which of the following conditions can rarely occur as a delayed hypersensitivity reaction to iodinated contrast media?
Behçet disease.
Graft‐versus‐host disease.
Acanthosis nigrans.
Folliculitis.
Keratoacanthoma.
Question 5
Iododerma is associated with which of the following extracutaneous manifestations?
Conjunctivitis.
Swelling of the glands.
Swelling of the extremities.
Cardiovascular compromise.
Abdominal pain.
Instructions for answering questions
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This activity will be available for CPD credit for 2 years following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional period.
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