Introduction to Hypersensitivity Reactions to Contrast Media 

The increased use of contrast media (CM) may give rise to an increased absolute number of total hypersensitivity reactions (HSR). The relative number of immediate HSR has decreased since the introduction of nonionic, low-osmolar ICM, while the number of non-immediate HSR is on the rise, due to an increased use of iso-osmolar ICM (Rosado Ingelmo, 2016). 

Terminology and Definitions (see also 'Definitions of Adverse Drug Reactions') 

The following definitions and terminology are based on the standard terminology recommended by the World Allergy Organisation (Cordona, 2020; Demoly, 2014; Johansson, 2004). When dealing with CM, the term allergy should be avoided as much as possible. 

Hypersensitivity: Objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus that is tolerated by normal subjects. 

Drug Hypersensitivity Reaction (DHR): adverse effects of drugs that clinically resemble allergic reactions (‘pseudo-allergic’). These include adverse reactions that are immune or nonimmune mediated. 

Drug Allergy: Hypersensitivity reactions that are associated with an immune mechanism for which evidence can be shown in the form of drug-specific antibodies or activated T lymphocytes. 

Immediate (acute, early) hypersensitivity reaction to contrast media: an adverse reaction that occurs within 1 hour of contrast agent injection. Acute reactions can either be allergy-like (IgE-mediated or not) hypersensitivity reactions or chemotoxic responses. 

Non-immediate (delayed, late) hypersensitivity reaction to contrast media: an adverse reaction that occurs between 1 hour and 1 week after contrast agent injection. 

Figure 1 Schematic of adverse drug reaction types 

Adverse drug reaction (ADR): a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man (WHO definition) (See Figure 1 Schematic of adverse drug reaction types).

ADR can be classified in multiple types, and for contrast media types A, B and D are most relevant. Type A (augmented) reactions result from an exaggeration of a drug’s normal pharmacological actions when given at the usual therapeutic dose and are normally dose dependent. These include all physiologic reactions. Type B (bizarre) reactions are novel responses that are not expected from the known pharmacological actions of the drug. These are less common, and so may only be discovered for the first time after a drug has already been made available for general use. These include allergic or non-allergic hypersensitivity reactions. Type D, or ‘delayed’ reactions, become apparent sometime after the use of a medicine. The timing of these may make them more difficult to detect. These include Nephrogenic Systemic Fibrosis (NSF) or iodine-induced hyperthyroidism (Edwards, 2000). 

Anaphylaxis: Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction characterized by being rapid in onset with potentially life-threatening airway, breathing, or circulatory problems and is usually, although not always, associated with skin and mucosal changes (Cordona, 2020; WHO ICD-11 definition). 

Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled (Cordona, 2020): 

1. Acute onset of an illness (minutes to several hours) with simultaneous involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 

And at least one of the following: 

1. Respiratory compromise (e.g., dyspnoea, wheezing/bronchospasm, stridor, reduced PEF, hypoxemia) 
2. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 
3. Severe gastrointestinal symptoms (e.g., severe crampy abdominal pain, repetitive vomiting), especially after exposure to non-food allergens

2. Acute onset of hypotensiona or bronchospasmb or laryngeal involvementc after exposure to a known or highly probable allergend for that patient (minutes to several hours), even in the absence of typical skin involvement. 

^{Note: a hypotension defined as a decrease in systolic BP greater than 30% from that person's baseline, or a systolic BP less than <90 mmHg. b. Excluding lower respiratory symptoms triggered by common inhalant allergens or food allergens perceived to cause “inhalational” reactions in the absence of ingestion. c. Laryngeal symptoms include stridor, vocal changes, odynophagia. d. An allergen is a substance (usually a protein) capable of triggering an immune response that can result in an allergic reaction. Most allergens act through an IgE-mediated pathway, but some non-allergen triggers can act independent of IgE (for example, via direct activation of mast cells).} 

Immediate hypersensitivity reactions to contrast media 

Pathophysiology

Hypersensitivity reactions to CM are poorly understood. Recent research suggests that hypersensitivity reactions to nonionic CM are a heterogeneous disease. It can develop from multiple mechanisms such as IgE-dependent, complement dependent, direct membrane effects of CM, and possibly other mechanisms that have not been identified yet (Zhai, 2017). When an allergic drug reaction is suspected, DHR is the preferred term, because true drug allergy and nonallergic DHR may be difficult to differentiate based on the clinical presentation alone, especially in cases of acute severe DHR (Demoly, 2014). 

Allergy-like hypersensitivity reactions may or may not be truly IgE-mediated. In general, allergy can be either antibody- or cell-mediated. Cell-mediated reactions usually occur after one or several days, while antibody-mediated reactions tend to be more immediate. A well-known reason for immediate reactions is the presence of antigen specific IgE antibodies attached to the surface of mast cells and basophil granulocytes. After cross-linking of IgE antibodies on the surface of these cells, a degranulation process follows, resulting in production of histamine and many other mediator substances. Other stimuli can also cause degranulation such as the degree of ionization, osmolality, and temperature of the injected solution. Some drugs such as fluoroquinolones are known to cause histamine release without the presence of specific IgE, via non-IgE-dependent activation routes of the mast cell (McNeil, 2015). 

Compared to reactions to iodine-based CM, reactions to gadolinium-based CA are more frequently IgE-mediated, and thus true allergic reactions (Clement, 2018). 

Remember: Not all symptoms experienced by patients in the hour after contrast agent injections are adverse reactions to the contrast agent. Patient anxiety may cause symptoms after contrast agent administration, known as the Lalli effect (Lalli, 1974). 

Clinical features and risk factors 

The same acute adverse reactions are seen after intravascular administration of iodine-based contrast media and after gadolinium-based contrast agents or ultrasound contrast agents. 

The term adverse drug reaction (ADR) is wider than hypersensitivity reactions, and includes several chemotoxic effects of CM injection (ADR type A), such as a feeling of warmth, dry mouth, or mild pain during injection, etc. Therefore, incidence figures between studies on hypersensitivity reactions and studies on ADR (for example post-marketing surveillance studies) can vary. 

In Radiology, hypersensitivity reactions are usually discriminated into mild, moderate, or severe reactions as outlined below. It must be realized that in Allergology other classifications are used, discriminating reactions as allergic, non-allergic, or type A adverse reactions (see Figure 1 Schematic of adverse drug reaction types and Torres, 2021). 

The chance that a reaction can be classified as allergic is lower when the reaction is mild or moderate. It is important to note that re-exposure to CM after an initial mild reaction never causes a moderate or severe reaction (Lee, 2017; Davenport, 2009). 

Mild reactions include allergy-like hypersensitivity reactions such as scattered urticaria/pruritus, limited cutaneous oedema, itchy/scratchy throat, nasal congestion, and sneezing/conjunctivitis/ rhinorrhoea. This category also includes physiologic reactions such as limited nausea/vomiting, transient flushing/warmth/chills, headache/dizziness/anxiety, altered taste, mild hypertension or spontaneously resolving vasovagal reactions (ACR, 2022; ESUR, 2018; Wang, 2008). 

Moderate reactions include allergy-like reactions such as diffuse urticaria/pruritus, diffuse erythema with stable vital signs, facial oedema without dyspnoea, throat tightness/hoarseness without dyspnoea, and mild wheezing/bronchospasm. Physiologic reactions include protracted nausea/vomitus, hypertensive urgency, isolated chest pain, and vasovagal reactions responsive to treatment (ACR, 2022; ESUR, 2018; Wang, 2008). 

Severe reactions include allergy-like reactions such as diffuse erythema with hypotension, diffuse/facial oedema with dyspnoea, laryngeal oedema with stridor, and severe wheezing/ bronchospasm with hypoxia, and generalized anaphylactic reaction/shock. Severe physiologic reactions include treatment-resistant vasovagal reactions, arrhythmia, hypertensive emergencies, and convulsions/seizures. Also, to this category belong pulmonary oedema and cardiopulmonary arrest (ACR, 2022; ESUR, 2018; Wang, 2008). 

Risk factors 

Risk factor analysis is often done by retrospective observational studies without control groups (see also chapter chapter 3.5.3 Risk Factors for Hypersensitivity Reactions to Contrast Media). Risk factors for hypersensitivity are not fully established. Additional risk factors for immediate HSR that are common to allergic drug reactions include poorly controlled bronchial asthma, concomitant medications (e.g., ACE inhibitors, ß-blockers, and proton pump inhibitors), rapid administration of the drug, mastocytosis, autoimmune diseases, and viral infections (Rosado Ingelmo, 2016). 

In Radiology literature, the most consistently reported risk factors for hypersensitivity reactions to CM are (ACR, 2022): 

1. A prior hypersensitivity reaction to contrast media. 

2. A history of allergy, particularly multiple severe allergies (atopy). 

3. A history of asthma requiring treatment. 

Female gender could not be substantiated as an independent risk factor for hypersensitivity reactions, but age may be relevant (Endrikat, 2022). 

Incidence of acute hypersensitivity reactions 

Incidence after iodine-based contrast media 

The incidence is highest after iodine-based contrast media and lowest after ultrasound contrast agents. The incidence of acute adverse reactions has declined considerably after the introduction of low-osmolar and iso-osmolar iodine-based contrast media (ACR, 2022; ESUR, 2018). 

In the early days of low-osmolar media, the classic Japanese study (Katayama, 1990) reported relatively high adverse drug reaction rates after nonionic CM of up to 3,1%, with severe and very severe reactions occurring in 0,44%. In contrast, more recent studies with large patient cohorts focusing more specifically on hypersensitivity (allergic-like) reactions have shown considerably lower incidence rates of 0,15 to 0,69% with severe reactions occurring in 0,005 to 0,013% (Hunt, 2009; Mortele, 2005; Wang, 2008). 

Hypersensitivity reactions after non-vascular CM administration (either oral, rectal, intraductal, intravesical or intra-articular) are rare (see also the overview in Safe Use of Contrast Media, part 2). Such reactions occur slower, and the incidence is much lower than after intravascular administration and will be influenced by the integrity and condition of the wall of the cavity into which the contrast agent is administered (for example inflamed mucosa may lead to leakage into the intravascular compartment). Nevertheless, severe reactions can occur, even with non-vascular CM administration (Davis, 2015). 

Incidence using specific iodinated contrast media

Large post-marketing surveillance studies of iobitridol and iodixanol have shown acute adverse events of 0,58-0,59% with severe events in 0,004 to 0,010% (Maurer, 2011; Zhang, 2014). A third study using iopromide is more difficult to compare due to different definitions, and had higher rates of 2,49% and 0,034%, respectively (Palkowitsch, 2014). It must be noted that physiologic reactions (feeling of warmth, metallic taste) make up a considerable part of these events. 

More recently, the hypersensitivity reaction rate after iopromide was 0,74% in adults and 0,38% in elderly (Endrikat, 2022). In the same study population, the hypersensitivity reaction rate was 0.7% after intravenous administration vs. 0.2% after intra-arterial administration (Endrikat, 2020). 

In addition, several retrospective observational studies have looked at differences in acute hypersensitivity rates among iodine-based CM. Although imperfect, these studies indicate a somewhat higher rate for iopromide and iomeprol compared to other CM (An, 2019; Gomi, 2010; Kim, 2017; Seong, 2014). It remains controversial whether iobitridol has a lower percentage, as indicated in one study (Kim, 2017). 

Incidence after gadolinium-based contrast agents 

Recent studies in large adult patient cohorts focusing on hypersensitivity (allergic-like) reactions have shown low incidence rates of 0,06-0,17% with severe reactions occurring in 0,003-0,006% (Aran, 2015; Behzadi, 2018; Dillman, 2007; Prince, 2011). More recent studies showed overall rates of 0,15-0,40%. For severe reactions rates were 0,002-0,004% in general populations and 0,033% in a population undergoing cardiac MRI (Ahn, 2022; McDonald, 2019; Uhlig, 2019). 

In a large meta-analysis, the overall rate was 92 per 100,000 gadolinium-based contrast agent (GBCA) injections (0,09%) with severe reactions occurring in 5,2 per 100,000 injections (0,005%). It was shown that the type of GBCA is of influence on the number of reactions. Linear nonionic GBCA had an incidence of 15 per 100,000 and linear ionic GBCA of 52 per 100,000. However, these GBCA are no longer available in Europe. The macrocyclic GBCA had slightly higher rates, macrocyclic ionic GBCA 90 per 100,000 and macrocyclic nonionic GBCA 160 per 100,000. The highest rate was for linear ionic GBCA with protein-binding, 170 per 100,000 injections (Behzadi, 2018). 

Comparing specific GBCA, in one study more hypersensitivity reactions occurred after gadobenate and gadobutrol compared with gadodiamide or gadoterate injection (McDonald, 2019), while in another study most acute reactions occurred with gadoteridol and most delayed reactions with gadoterate (Ahn, 2022). 

Breakthrough, protracted and biphasic hypersensitivity reactions 

So-called “breakthrough” hypersensitivity reactions are recurring reactions despite premedication with corticosteroids and H1-antihistamines. The occurrence in published series is variable, 2 to 17%. These reactions are most often of similar severity as the original (culprit) reaction for which premedication was prescribed. Breakthrough reactions can be severe in incidental cases. Unfortunately, no data on the number of IgE-mediated reactions are available (Davenport, 2009; Mervak, 2015). 

While most hypersensitivity reactions to CM are uniphasic, other patterns may also occur. A protracted reaction is defined as a reaction lasting > 5h in which symptoms incompletely resolve. This pattern is rare following CM, occurring in only 4% of anaphylactic (severe) reactions and may be predicted by a low responsiveness to initial adrenaline therapy (Kim, 2018). 

A biphasic reaction is defined as a reaction recurring 0 to 72h after an initial hypersensitivity reaction. The median time for start of the second reaction is 8 to 12h after the first reaction. This pattern is also rare, occurring in 10% of anaphylactic (severe) reactions (Rohacek, 2014). Usually, the second reaction is of similar severity or milder than the initial reaction. Predictors for biphasic anaphylaxis are severe initial symptoms requiring adrenaline redosing or a long (> 40 min) duration of the initial reaction. An observation time of 6-12h after the initial anaphylactic reaction has resolved is practical (Lee, 2016; Kim, 2018 and 2019). The use of corticosteroids in this setting is controversial and is not recommended (Gabrielli 2019; Lee, 2016; Simons, 2015). 

For ultrasound contrast agents the risk is low, but no large series have been published to date. Most adverse reactions are cardiovascular, and the incidence of hypersensitivity reactions is 0,009% with severe reactions occurring in 0,004% (Khawaja, 2010). 

Classification 

Historically, hypersensitivity reactions to CM have been graded as mild, moderate, or severe. This radiological classification shows overlap with other used classifications, such as the World Allergy Organisation (WAO) classification (Johansson, 2004) and modifications of the Ring - Messmer classification of allergic reactions (Ring, 1977; Table 1 Severity grading of anaphylactic reactions (modified Ring and Messmer)). 

Table 1 Severity grading of anaphylactic reactions (modified Ring and Messmer) 

Classification according to the most severe symptom, no symptom is mandatory 

A practical summary classification of acute hypersensitivity reactions to contrast media for radiological practices may be (free after ACR, 2022; ESUR, 2018): 

Mild: Itching, sneezing, flushing, conjunctivitis, rhinorrhoea, epiphora, nausea, short-duration, or incidental vomiting, altered taste, limited (localized) scattered urticaria. 

Moderate: Generalized or extensive urticaria, diffuse erythema without hypotension, facial or angioedema without dyspnoea, mild wheezing/bronchospasm, protracted vomiting, mild isolated hypotension. 

Severe: Severe wheezing/bronchospasm, profound hypotension, pulmonary oedema, generalized anaphylactic reaction, seizures/convulsions, respiratory arrest, and cardiac arrest. 

It is important to note that re-exposure to CM after an initial mild reaction never causes a moderate or severe reaction (Lee, 2017; Davenport, 2009). In addition to this, the risk of an IgE-mediated allergic reaction (and thus the risk of severe reactions in case of re-exposure) is low in moderate reactions without cutaneous symptoms. Therefore, in the classification most used in allergology only reactions with cutaneous symptoms (urticaria or angioedema) are classified as allergic-like (Torres, 2021). 

Nonimmediate (late, delayed) hypersensitivity reactions to Contrast Media 

Clinical features 

A nonimmediate hypersensitivity reaction (NIHR) is a delayed hypersensitivity reaction > 1h after contrast administration (usually > 24h). NIHR usually presents as a maculopapular exanthema (MPE): skin rash consisting of patches (maculae) and nodules (papulae) spread over body and extremities. It normally heals within days to weeks, and if treatment is required, topical or oral steroids can be applied. 

Many patients show a variety of nonspecific symptoms, which include headache, nausea, dizziness, gastro-intestinal upset, mild fever, and arm pain (Bellin, 2011; Christiansen, 2000). When compared to control populations (Loh, 2010), skin rashes with erythema and swelling are the most frequent true nonimmediate hypersensitivity reactions. Most patients present with cutaneous symptoms like other drug-induced skin eruptions, usually in the form of a macular or maculopapular exanthema. The exanthema usually occurs 2 to 10 days after first exposure to ICM and 1 to 2 days after re-exposure to the same ICM. Most reactions are mild to moderate in severity, are usually self-limiting and resolve within 1 week (Bellin, 2011). 

Discrimination should be made between mild-to-moderate NIHR and rare severe NIHR with danger signs, the so-called severe cutaneous adverse drug reactions (SCAR), such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis (TEN), acute generalized exanthemic pustulosis (AGEP), and Stevens-Johnson syndrome (SJS) (Brockow, 2019; Soria, 2021). 

Pathophysiology 

There is evidence that drug-specific T-cells play an important role in nonimmediate hypersensitivity reactions. In skin reactions an infiltrate in the dermis consisting of activated CD4+ or CD8+ T-cells and eosinophils is usually found (Christiansen, 2000 and 2003; Schönmann, 2020). 

In vitro studies have shown two different pathways of CM recognition which both require major histocompatibility complex (MHC) molecules for stimulation: a) direct binding of CM to the T-cell receptor or MHC molecule (p-i concept), and b) after uptake and processing by antigen-presenting cells and presented to T-cells via MHC-II molecules ((pro)hapten concept) (Keller, 2009). 

The hapten-independent pathway could explain results of cross-reactivity analyses that revealed that CM-specific activated T-cell clones reacted to CM with shared structural elements. 

It has been postulated that CM do not induce a primary immune response, but instead interact with receptors on activated memory T-cells raised against other foreign substances (non-allergic NIHR). Patients with nonimmediate hypersensitivity should not be at risk for an immediate hypersensitivity reaction (mediated by IgE or other mechanisms) upon re-exposure to CM. 

Risk factors 

Established risk factors for nonimmediate hypersensitivity reactions to iodine-based CM include a previous hypersensitivity reaction and IL-2 immunotherapy. Most CM-associated nonallergic NIHR are associated with iso-osmolar CM (ACR, 2022; Bellin, 2011; ESUR, 2018). 

Patients with a history of nonimmediate hypersensitivity reactions to ICM are not at increased risk for immediate HSR to ICM as these reactions are mechanistically unrelated (Christiansen, 2003; Mazori, 2018). 

Incidence of nonimmediate hypersensitivity reactions 

The frequency of nonimmediate hypersensitivity reactions to CM varies greatly between studies and is believed to be between 1-3% of patients after iodine-based CM administration and only very rarely after gadolinium-based CA administration (Bellin, 2011; Christiansen, 2000). 

Incidence using specific iodine-based CM 

Nonimmediate skin reactions tend to be more common after iodixanol (Benin, 2011; Sutton, 2003). The incidence of nonimmediate hypersensitivity reactions is not significantly different for the other iodine-based low-osmolar CM (Bellin, 2011). 

Cross-reactivity between contrast media 

Cross-reactivity between iodine-based CM 

Most of the current cross-reactivity data come from skin testing. Cross-reactivity in late hypersensitivity reactions is probably caused by the presence of CM-specific T-cells, some of which may show a broad cross-reactivity pattern. There may be a link between the chemical structure of iodine-based CM and the pattern of cross-reactivity, but results are inconsistent. 

Several studies have shown considerable cross-reactivity between different iodine-based CM, but specific data on immediate versus nonimmediate hypersensitivity reactions are lacking until now. In the larger studies, most cross-reactivity has been seen between the nonionic dimer iodixanol and its monomer iohexol, with relatively fewer positive skin reactions with iobitridol (Clement, 2018; Hasdenteufel, 2011; Lerondeau, 2016; Yoon, 2015). 

Based on cross-reactivity patterns iodine-based CM may be divided in three groups, with relatively high intra-group cross-reactivity but less intergroup cross-reactivity (Lerondeau, 2016). Based on additional data, it seems reasonable to add iopromide to group A as well and possibly remove ioxithalamate and iopamidol (Schrijvers, 2018). 

Table 2 Cross-reactivity grouping of iodine-based CM (Lerondeau, 2016) may be helpful for selecting an alternative agent for imaging studies. 

Table 2 Cross-reactivity grouping of iodine-based CM (Lerondeau, 2016) 

Note: Iopamidol and Ioxaglate are no longer available on the market in The Netherlands 

Cross-reactivity between gadolinium-based CM 

Information on cross-reactivity between GBCA is limited to case reports. Skin testing and provocation tests in such cases have shown that cross-reactivity among macrocyclic GBCA may be more extensive than among linear GBCA (Gallardo Higueras, 2021; Grüber, 2021). 

Cross-reactivity between iodine-based and gadolinium-based CM 

A recent study examined the risk of reactions to both iodine-based CM and gadolinium-based CA in the same patient in a large patient cohort. The incidence of primary hypersensitivity reactions was 0,047% and the incidence of secondary reactions 0,024%. Nearly all reactions were mild, requiring no treatment. Therefore, cross-reactivity between iodine-based and gadolinium-based CM is an extremely rare event (Sodagari, 2018). 

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