PEG hypersensitivity usually triggered by molecular weights of 3350, higher

Key takeaways:

• 57.1% of patients with PEG allergy had experienced grade III anaphylaxis.
• Skin prick testing with PEG 3350 had 51% sensitivity.
• Four index drugs triggered two-thirds of cases.

Hypersensitivity to polyethylene glycols is not a common cause of anaphylaxis induced by drugs, according to a study published in Annals of Allergy, Asthma & Immunology.

When PEG hypersensitivity does happen, it generally is provoked by molecular weights of 3350 and higher, Oyindamola Stephanie Kayode, MD, consultant allergist, department of adult allergy, Guy’s and St. Thomas’ NHS Foundation Trust, and colleagues wrote.

Although they are rare, the researchers said, hypersensitivity reactions to PEG have been increasing in frequency. Also, the researchers continued, patients endure re-exposure and multiple reactions before they are diagnosed.

Patients and reactions

The retrospective study reviewed the records of 44 adults (mean age, 38.25 years; age range, 18-72 years; 32 women) who presented with suspected immediate PEG hypersensitivity at four tertiary allergy centers in the United Kingdom between October 2013 and December 2020.

The 30 patients with known medical comorbidities included 16 with a history of atopy such as asthma, allergic rhinitis, eczema or food allergy.

With a median of 6 months, times between reaction and review by an allergy service ranged from 0.75 to 72 months. Also, patients experienced a range of one to four immediate hypersensitivity reactions before review.

The cohort experienced 70 different PEG-related drug reactions, including two patients who experienced reactions to four medications, four patients who experienced reactions to three medications, 12 patients who experienced reactions to two medications, and 26 with reactions to a single medication.

Forty (57%) of these drugs were oral, and 22 (31%) were intramuscular or intravenous. The most common index drugs among the 70 reported were macrogol laxatives (n = 16; 23%), depo-medroxyprogesterone (Pfizer; n = 13; 19%), oral penicillin V (Sandoz; n = 7; 10%) and depo-methylprednisolone (Pfizer; n = 7; 10%).

The most common macrogol laxatives included Moviprep (Norgine Ltd; n = 7), with 100,000 mg of PEG 3350 per sachet, and Movicol (Norgine Ltd; n = 6), with 13,125 mg of PEG 3350 per sachet.

Affecting one patient each, other implicated macrogol laxatives included Klean-prep (Norgine Ltd), with 59,000 mg of PEG 3350 per sachet; Laxido (Galen Ltd), with 13,125 mg of PEG 3350 per sachet; and Peglax (Casen Recordati), with 10,000 mg of PEG 4000 per sachet.

With 60 reactions total, the 42 patients with PEG allergy included 24 (57.1%) who experienced Brown’s grade III anaphylaxis, 17 (40.5%) who experienced grade II and one (2.4%) who experienced grade I as their most severe reaction. The different routes of administration were not associated with any significant difference in reaction grade.

The 19 reactions among 19 patients where acute and baseline serum mast cell tryptase (MCT) levels were measured had a median increase of 53 µg/L (range, 13-114) in acute MCT. The researchers called this increase significant and equal to a median 9.1-fold increase (range, 2.1-26.5).

Also, the median baseline MCT was 6.1 µg/L (range, 3-10), and the median acute MCT was 53 µg/L (range, 13-114). The research noted that the normal range is 2 µg/L to 11.4 µg/L.

Testing results

Providers confirmed PEG hypersensitivity in 42 (95%) of the patients, including 24 positive skin prick tests, 15 positive intradermal tests (IDT) and three positive drug provocation tests (DPTs).

The full cohort had SPTs for PEG, including 42 who were tested for PEG 3350 and one who was tested for PEG 8000. PEG concentrations ranged from 1 mg/L (0.1%) to 100 mg/mL (10%), and 41 of these patients were tested with the 10% concentration.

There were 26 positive SPTs, and 21 patients (51%) were deemed sensitive to PEG 3350 overall. This sensitivity increased to 71.4% (n = 10 of 14) when macrogol laxatives were implicated as index drugs and to 66.7% (n = 4 of 6) when depo-methylprednisolone was implicated as the index drug.

With concentrations ranging from 0.0203% to 1%, IDTs with PEG 3350 were positive in 14 of 17 (82%) patients tested, increasing total SPT and IDT sensitivity to 85% (n = 35 of 41) of patients tested.

Nine patients with negative SPT and IDT results with PEG 3350 had tests with higher molecular weights, with positive results for eight patients with PEG 8000 and/or PEG 20,000 at 0.1% to 10% concentrations.

Eighteen patients had SPTs and IDTs to PEG-free formulations of their index drugs when they were available, and all the tests were negative.

Five patients had SPTs for PS80, but only one patient had a positive result, and that was an IDT with a hundred-fold dilution of triamcinolone acetonide (Kenalog, Bristol Myers Squibb) that included 0.004 mg/L of PS80. This patient also had a negative IDT for a preservative-free and excipient-free triamcinolone acetonide.

Five of the seven patients who had DPT had positive results. Symptoms included hypotension, tachycardia, urticaria, flushing, nausea, sneezing and cough or wheeze.

However, the authors only considered a possible PEG allergy for two of these patients after they had a positive DPT to their index drug, which was depo-methylprednisolone. These two patients had positive SPT tests for PEG as well.

The other three patients with positive DPT results had negative SPT results for 10% PEG 3350. One had a positive macrogol DPT without any previous IDT. The other two had negative IDTs for their index drug.

Additionally, one patient had a reaction to their index drug, which was depo-medroxyprogesterone with 20.3 mg of PEG 3350 per 1 mL, but later tolerated an oral DPT of 1 cumulative macrogol powder sachet with 13,125 mg of PEG 3350.

Two patients in the full cohort (4.5%) had confirmed PEG tolerance following negative DPT results for macrogol or depo-methylprednisolone and negative SPT and IDT results for PEG 3350 and/or the index drug.

One patient in the full cohort (2%) developed urticaria and angioedema after simultaneous 10% SPTs for PEGs with molecular weights ranging from 200 to 20,000. Intravenous hydrocortisone and oral H1 antihistamine were used to treat the patient.

During IDTs with 0.1% to 1% macrogol laxatives and/or 0.203% to 0.0203% depo-medroxyprogesterone, five patients developed systemic reactions including chest tightness (n = 3), generalized itch (n = 2), urticaria (n = 1) erythema (n = 1) and rhinitis (n = 1).

Nine of the 42 patients with PEG allergy tolerated five different drugs with brands that all included PEG. Seven of these patients tolerated H1 antihistamines that included PEG.

COVID-19 vaccines

Sixteen of 21 patients with confirmed vaccination status had been vaccinated for COVID-19 with a median three doses (range, two to four). Seven had received three doses and four had received two doses of the Oxford/AstraZeneca vaccine.

Three received and tolerated two doses of the Oxford/AstraZeneca vaccine as well as a Pfizer/BioNTech (0.05 mg of PEG 2000 per 0.3 mL dose) or Moderna (PEG 2000) booster.

One patient tolerated two doses of the Pfizer/BioNTech vaccine, and another tolerated four doses of it.

The five patients who had tolerated one or more doses of the Pfizer/BioNTech or Moderna vaccines included four who had a grade II reaction and one who had a grade III reaction as their most severe index PEG drug reaction before vaccination.

Four of these patients had index PEG molecular weights of 3350, and the index PEG molecular weight for the fifth ranged from 3350 to 20,000.

Conclusions, next steps

Although these findings indicate that PEG hypersensitivity generally happens when the molecular weight of the PEG in the drug is at 3350 or higher, the researchers said, further evaluation with a larger data set are needed.

Also, the researchers said that providers should source manufacturer and brand details when they are taking drug histories from patients with suspected PEG allergy since two-thirds of these cases were triggered by four index drugs.