Three cases of anaphylaxis following injection of a depot corticosteroid with evidence of IgE sensitization to macrogols rather than the active steroid

Macrogols or polyethylene glycols (PEG) are polymers used as excipients in many different drugs including depot corticosteroid solutions for injection. We present 3 cases of anaphylaxis due to macrogol 3350 after injection of a depot corticosteroid for arthritis or tendinitis. Evaluation, including challenges, with the pure corticosteroid and lidocaine was negative. SPT and specific IgE for latex and chlorhexidine were negative. In all cases skin prick tests (SPT) showed sensitization to macrogol of varying molecular weights, while histamine release (HR) tests to macrogols were negative. Laxatives are the only products on the Danish market declaring the concentration of macrogol 3350. All three patients underwent open titrated oral challenge with the laxative Movicol Junior^R containing macrogol 3350 as the active component. Two of the three patients reacted with anaphylaxis. The third patient was only sensitized by SPT to macrogol 6000, and a challenge with a larger dose of macrogol 3350 is planned.

During the last year three patients have been referred to our clinic on suspicion of corticosteroid allergy due to anaphylactic reactions after depot corticosteroid injections. All tolerated challenge with the pure corticosteroid, but two were found to be oral challenge positive to the excipient macrogol 3350 while the third was sensitized in SPT. However, in the third case other elicitors were excluded and despite negative challenge with Movicol Junior^R up to 6.56 g anaphylaxis to macrogol was still suspected. As the clinical effect of osmotic laxatives is primarily in the gut and <2% is absorbed [1], the challenge dose was probably too low in this patient. Due to comorbidity we have not yet performed challenge with a higher dose of macrogol to verify the allergy. Only few case reports of anaphylaxis to macrogols in corticosteroid solutions can be found in the literature [2‐5]. Macrogols are used in many drugs and other products including electrolyte lavage solutions, tablets and topical products, and anaphylaxis have been described to many different formulations via many different administration routes [6]. In patients with severe allergic reactions to chemically unrelated drugs, it is important to consider excipients such as macrogols as potential culprits. Unfortunately, this is rarely considered, and patients may have several severe reactions before macrogols (or other excipients) are suspected as in case 2. When anaphylaxis to the active drug is excluded in patients with reactions to unrelated drugs, there is a risk of labelling these cases “idiopathic anaphylaxis”, if the excipients in the drugs administered are not considered. In such cases the patient is at risk of future anaphylaxis on re-exposure to the excipients.

The sensitivity and specificity of skin tests and HR test evaluated in relation to the outcome of oral challenge to macrogol are unknown. As systemic reactions to skin testing with macrogols have been reported in several cases [6], it is important to titrate the skin test especially when including the high molecular weight macrogols, and furthermore, to extend observation time to 30 min as development of the wheal may be delayed [6]. Case 2 reacted to only high molecular weight macrogol in SPT, but was challenge positive to macrogol 3350. This finding supports the hypothesis, that clinical reactivity to macrogols is related to both amount and molecular weight, and although sensitization may occur to lower molecular weight macrogols, which more readily penetrate skin and mucosa, high molecular weight macrogols may subsequently elicit a response at lower concentrations [6]. This has implications for the skin test concentrations used, and it may be that SPT with higher molecular weight macrogols can be used to diagnose cases with reactions to lower molecular weight macrogols in the more distant past, as seemed to be the case in case 2. Another important finding from these cases is that skin reactivity may decrease or even be lost over time as has been shown regarding specific IgE for other allergens such as penicillin and chlorhexidine [7, 8]. Case 1 was skin tested 3 times during the first year, first the SPT was positive and then SPT reactivity diminished over time although challenge remained positive. Case 2 was not evaluated until 2 years after the last anaphylactic episode, and SPTs besides macrogol 20,000 were negative at this time, but challenge with macrogol 3350 (Movicol Junior^R) was positive. HR test was negative in all cases, and was not helpful to predict a reaction to macrogol in our cases. The same has been shown in other studies for both HR test and basophil activation test in relation to macrogol allergy [6].