Three MPS cases were studied. Here, they are presented in chronological order of observation. A 38-year-old patient (patient 1) was diagnosed with Hunter syndrome, at age 6. Only at age 30, the patient could be treated with ERT (idursulfase), 24 mg, given weekly intravenously in 1–3 h. This therapeutic approach was initially well tolerated. However, after one year of treatment, he developed urticaria localized particularly at the upper limbs, approx. 90’ after beginning ERT infusion. The treatment was then discontinued, until June 2019, when the patient, then 38, restarted the weekly infusions of idursulfase (24 mg), at the Rare Disease Unit of Bari University Hospital. The first 6 administrations were tolerated without side effects. However, during the seventh infusion, he developed generalized urticaria again. The infusion was halted and hydrocortisone (500 mg) and chlorpheniramine (10 mg) were administered, with resolution of symptoms. No epinephrine was required. The patient was then referred to the Allergic Disease Unit at the same Hospital.

In consideration of the anamnesis (repeated urticarial events, immediate nature of the reactions, prompt response to anti-allergic treatment), a case of immediate allergy to idursulfase was suspected and a thorough allergy workup was performed, with the purpose of desensitizing the patient, in order to avoid further discontinuation of ERT. Thus, we performed SPT and IDT. SPT, were performed by full-strength idursulfase solution (2 mg/ml) and proved negative. For IDT, we used increasing idursulfase concentrations: 0.002 mg/ml, 0.02 mg/ml, 0.2 mg/ml, respectively. The tests proved positive. While 0.002 mg/ml concentration produced no reaction, the 0.02 mg/ml idursulfase concentration yielded a wheal of 10 mm (average diameter), deemed as positive. According to the protocol adopted [25], IDT with 0.2 mg/ml concentration was not performed (due to the 10 mm diameter wheal obtained with the 0.02 mg/ml concentration).

LPT could not be performed, in this case. Since the skin test results were suggestive of immediate-type hypersensitivity, considering the absolute necessity of maintaining ERT, we devised and implemented a 3-bag, 12-step rapid desensitization protocol, according to Castells [13]. Thus, we used 3 idursulfase dilutions at increasing concentrations: 0.00048 mg/ml, 0.0048 mg/ml, 0.048 mg/ml. The weekly target dose was 24 mg, given intravenously (calculated on the patient body weight). The rapid desensitization protocol is reported in Table 1. The procedure was implemented for 8 consecutive times, with no adverse events, with the exception of the first infusion, when at step 12 (infusion rate 150 ml/h) mild itchy urticarial lesions were observed at the level of the axillary spaces, the chest and abdomen, treated with chlorphenamine 10 mg and hydrocortisone 500 mg, intravenously. The infusion rate was reduced to 40 ml/h for approx. 60’ and then gradually brought back at 150 ml/h. The procedure was finalized, without further adverse reactions.

Having resumed ERT, we sought to restore immune tolerance by an 11-step AIT-like desensitization protocol. While continuing the weekly intravenous administrations of idursulfase, according to the rapid desensitization protocol described, idursulfase was also administered subcutaneously every second day, with increasing concentrations of the offending drug, for 11 consecutive times, starting from 0.008 mg at step 1- day 1 up to 4 mg at step 7- day 14, with a 500-fold increase (Table 3). Notably, 4 mg represented 17% of the whole weekly dose and was readily tolerated. Step 7 was then repeated 4 more times, up to step 11- day 26. Dosages at each step of the AIT-like protocol were given fractionated by three subcutaneous injections, from step 1 to step 4, and by 4 injections, from step 5 to step 11. Single injections were given 20’ apart from each other and were performed at the level of the external side of the arm, like in the classic subcutaneous AIT. Sessions lasted from 90’ to 120’, including 30’ of final observation for possible side effects. At steps 1 and 2, idursulfase was diluted 1:100 (0.02 mg/ml). At steps 3 and 4, the drug was diluted 1:10 (0.2 mg/ml). From step 5 to 11, the drug was used undiluted (Table 3). The total dose administered at the end of the procedure (day-26) was 23.58 mg (almost equivalent to the weekly intravenous target dose of 24 mg). Overall, the desensitization procedure was well tolerated. No side effects, either immediate or delayed, local or general, were recorded. No premedication was required, throughout the protocol. Upon completion of the AIT-like desensitization procedure, idursulfase was delivered on a weekly basis for 22 months, according to a simplified schedule: i.e., full-strength concentration (0.048 mg/ml; 24 mg in 500 ml saline), at a rate of 150 ml/h for approx. 3 h. After completion of the AIT-like course, anti-allergic premedication was reduced to fexofenadine 180 mg given orally the night before ERT. For the first two infusions, fexofenadine 180 mg was given orally also 1 h prior of ERT. No adverse events were recorded, with this simplified schedule. In this case, due to circumstantial reasons, no AIT-like maintenance injections were given (see below).

Patient 2. A 35-year-old farmer was diagnosed with Scheie syndrome at age 13. The patient was treated with weekly administrations of laronidase since diagnosis, at the Metabolic Diseases Unit of Giovanni XXIII Bari University Hospital. Thus, 39.44 mg (6,800 U) of laronidase, diluted in 250 ml saline, were given by slow intravenous infusion in about 6 h (the infusion rate was increased from 5 ml/h up to 50 ml/h every 15’ and then kept at 50 ml/h till the end). This therapeutic approach was well tolerated until July 2021, when the patient developed diffuse urticaria and lip angioedema, 10’ after starting the infusion. The treatment was suspended and corticosteroids and antihistamines were administered, with resolution of symptoms. The patient was then referred to the Allergy Unit of the same hospital. A thorough allergy workup was performed with the purpose of desensitizing the patient, in consideration of the need discontinuation of laronidase therapy. Thus, we performed SPT and IDT with laronidase. For the SPT, we used full-strength solution of laronidase (100 U/ml; 0.58 mg/ml). For the IDT, we used increasing concentrations of laronidase: 0.0058 mg/ml (dilution 1:100) and 0.058 mg/ml (dilution 1:10). While SPT were negative, IDT were positive at both 1:100 dilution and 1:10 dilution, with average wheal diameter of 7 and 8.5 mm, respectively. Furthermore, LPT with BrdU assay was performed, with a negative result, adding to the possible immediate-type nature of the allergic reactions suffered. Given the need of continuing the ERT, in consideration of the clinical history and the results of the skin tests (suggestive of immediate hypersensitivity) we devised and implemented a 3-bag, 12-step protocol of rapid desensitization. The target dose was 39.44 mg – 6,800 U, intravenously (calculated on patient body weight). Thus, we used 3 laronidase dilutions at increasing concentrations: 0.00079 mg/ml – 0.136 U/ml (in 100 ml saline), 0.0079 mg/ml – 1.36 U/ml (in 100 ml saline), 0.079 mg/ml – 13.6 U/ml (in 500 ml saline). The procedure lasted 5 h and 47’and was performed 4 consecutive times. The rapid desensitization protocol is reported in Table 2.

At step 11 of the first infusion, the patient developed severe generalized urticaria and angioedema of the lips. We administered hydrocortisone (100 mg) and chlorpheniramine (10 mg) intravenously and, in the absence of a prompt resolution, adrenaline, 0.5 mg intramuscularly, leading to immediate remission. The infusion was stopped. However, the desensitization procedure was repeated the next day. This time, without any side effects, upon premedication with betamethasone 2 mg and fexofenadine 180 mg, per os, the night before, at 08:00 p.m., and chlorphenamine 10 mg and dexamethasone 4 mg, intravenously, just before starting the procedure.

During the following three desensitization procedures, ensuring the weekly ERT administration, no adverse effects occurred. Premedication with dexamethasone and chlorphenamine, at the same dosage as above, was given at the beginning of the rapid desensitization procedure.

Moreover, in order to induce long-lasting immune tolerance, also in consideration of the fact that the weekly ERT had to be given for life, an 11-step AIT-like desensitization protocol was devised and implemented (Table 4), rather similar to that previously adopted for idursulfase. The protocol foresaw 4 daily subcutaneous injections, given 20’ apart from each other, at any of the 11 steps, every second day. Increasing concentrations of laronidase were used: 0.058 mg/ml (10 U/ml) at steps 1 and 2; 0.58 mg/ml (100 U/ml) at steps 3 to 6; 2.9 mg/ml (500 U/ml) at steps 6 to 11 (Table 4). Thus, at step 1- day 1, 9 U of laronidase were injected. While 2,000 U were given at step 8 - day 16 (222-fold increase). Notably, 2,000 U corresponded to 34% of the weekly dose. The 2,000 U dose was then repeated three more times up to step 11- day 23. Altogether, 10,400 U were administered at the end of the procedure. No adverse reactions occurred. No premedication was required. After completion of the AIT-like desensitization procedure (Table 4), we resumed giving laronidase by intravenous administration, on a weekly basis, reducing both infusion time and premedication. Thus, the patient tolerated the weekly laronidase ERT according to the standard protocol adopted before the emergence of the first HSR: full-strength concentration (0.157 mg/ml − 27.2 U/ml; 39.44 mg − 6,800 U, in 250 ml saline), with 5 steps at increasing rate of administration (10 ml/h, 20 ml/h, 40 ml/h, 80 ml/h, 100 ml/h, respectively). The first 4 steps lasted 15’ each, while the fifth one lasted 127’. The procedure was completed in 3 h and 7’. Premedication consisted of antihistamines only, particularly oxatomide 30 mg per os, the night before and 30’ before the infusion, and chlorphenamine 10 mg intravenously between step 4 and step 5 of the infusion. Moreover, in order to maintain the immuno-tolerance state, we administered 2,000 U of 5-fold concentered laronidase subcutaneously (4 subcutaneous injections of 1 ml), once a month, as for the classic AIT.

Under these conditions, when this report was written, the standard weekly infusion protocol had been performed at home for 8 months, without any adverse events.

Patient 3. A 9-year-old boy was diagnosed with Hunter syndrome in 2017 at the Metabolic Disease Unit of Giovanni XXIII Pediatric Hospital of Bari. Thus, he started the weekly ERT with idursulfase. Twenty-four mg of idursulfase, in 250 ml saline, were given at home by slow intravenous infusion for about 4 h (the infusion rate was approx. 60 ml/h). ERT was well tolerated till July 2021, when the boy developed diffuse urticaria during the last minutes of infusion (no premedication had been administered). The same reaction occurred at the successive infusion. On both occasions antiallergic therapy was given with resolution of symptoms. However, home ERT was discontinued and the subsequent administrations of idursulfase were performed at the Metabolic Disease Unit. During the first two ERT infusions the patient developed urticaria and dysphonia. Corticosteroids and antihistamines were administrated with symptom resolution. But the full dosage ERT administration was interrupted. The idursulfase dosage was then lowered to only 4 mg, tolerated for 5 months, up to December 2021, when, due to deterioration of the clinical conditions, the boy was referred to our Allergy Clinic. An allergy workup was carried out with the purpose of restoring the weekly full 24 mg idursulfase dosage by implementing a rapid desensitization protocol.

A blood sample of the patient was sent to Geneva-Meyrin, Switzerland, for anti-idursulfase IgE assessment. The assay proved negative.

Thus, we performed SPT and IDT with idursulfase. While SPT yielded a negative result, IDT were positive at both 1:100 and 1:10 dilution, with an average wheal diameter of 7 and 9 mm, respectively. LPT with BrdU assay was also performed, with a negative result.

In consideration of the clinical history and the results of the skin tests, suggestive of immediate hypersensitivity, and the need to contnue the weekly ERT, we implemented a 3-bag, 12-step protocol of rapid desensitization, according to Castells. The target dose was also in this case 24 mg, intravenously (calculated on patient body weight). Thus, we adopted the same rapid desensitization protocol as for patient 1 (Table 1).

At the first infusion, premedication given to the patient was: cetirizine 7.5 mg, orally, the night before the infusion, and chlorphenamine 5 mg intravenously, 30’ before the infusion. Moreover, 5 mg of chlorphenamine were given between step 8 and step 9. However, during step 12, the little patient developed severe generalized urticaria. The infusion rate was lowered and hydrocortisone, 200 mg intravenously, and cetirizine, 5 mg orally, were given with resolution of symptoms. The 150 ml/h infusion rate was then resumed and the ERT was completed.

Because of this reaction, a week later, the second rapid desensitization procedure was carried out according to a modified 4-bag, 20-step protocol and, on the same day, AIT-like desensitization was started (day1- step1), performed according to the protocol implemented for patient 1 (Table 3). The whole AIT-like desensitization cycle was completed about one month later, (step 11; Table 3). Meanwhile, the first 20-step rapid desensitization procedure again was accompanied by generalized urticaria, requiring chlorphenamine and flow rate reduction (in spite of that, the procedure was anyway completed). However, the successive two intravenous infusions (modified 20-step procedure), overlapping the subcutaneous AIT-like injections of idursulfase, were successfully completed without HSR and required neither supplementary medication nor flow rate lowering. Thus, with the next 5 weekly intravenous infusions, we rapidly decreased the number of bags and step, and consequently the time required for administering ERT, down to only one solution strength (24 mg/250 ml saline; 0.096 mg/ml), given in 6 steps, in approx. 2 h (10, 20, 40, 80, 150, 180 ml/h, with increase every 15’, apart from the last step which lasted approx. 1 h).

At the time when this manuscript was written, the weekly simplified ERT protocol had been administered 12 times without any HSR and with only a light premedication (cetirizine 7.5 mg, orally, the night before and 30’ before the infusion). The AIT-like desensitization was maintained with a monthly 4 mg dose of idursulfase, given subcutaneously (to date, for 5 months).