Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement

Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

vitro [8][9][10][11] . Specifically, in a study by Rozieres et al. 11 , amoxicillin-specific T cells were still detectable both by ELISPOT and LTT assays for as long as 20 years after the occurrence of maculopapular exanthem.
Moreover, some studies demonstrated that very few patients with a T-cell-mediated hypersensitivity to penicillins lose their sensitivity and become skin-or patch-test negative within 5 years 13,14 . In another study 15 , all 49 patients with a T-cell-mediated hypersensitivity to penicillins, who were retested from 1 year to more than 10 years after the first allergy examination, continued to be positive.
For an explanation on the different types of hypersensitivity that will be explored now, please see the "general concepts" section of the main manuscript.
Type I (IgE-mediated) hypersensitivity reactions may include any combination of urticaria, angioedema, flushing, bronchospasm, hypotension, abdominal, and/or back pain 16,17 . The symptoms may start within minutes but some may be delayed for several hours. The severity may range from mild, short-lasting and self-resolved to severe anaphylaxis needing emergency room treatment. Type I hypersensitivity reactions for beta-lactam antibiotics, even severe cases, are the most likely to subside over time and most amenable to desensitization [4][5][6]18 . Skin testing, if available, will be useful in assessing the current hypersensitivity status and dictate whether challenge, avoidance, or desensitization should be pursued 18,19 . Cross-hypersensitivity among different beta-lactam antibiotic families is mainly related to similarities or identities of beta-lactam side-chain structures [20][21][22][23] . Crosshypersensitivity with cephalosporins not sharing a common side-chain is thought to be very low in penicillin-allergic patients (type I hypersensitivity) (<3%) 19,20,22 . The reverse situation, where the primary sensitivity is to a particular cephalosporin, is less clear. Cross-hypersensivitiy appears to be low to other betalactam antibiotics. However, in addition to the index cephalosporin, many tolerated challenge to other cephalosporins (20/24) but 4 reacted to other cephalosporins (2/24 with similar side chains and 2/24 with disparate side chains) 24 . The cross-hypersensitivity between the penicillin and carbapenems was demonstrated to be even lower (<1%) [25][26][27][28] . In fact, prospective studies 26,27,[29][30][31] , each performed on more than 100 subjects with a well-demonstrated IgE-mediated penicillin allergy, found a rate of cross-reactivity between penicillins and carbapenems lower than 1% by performing skin tests with different compounds (i.e., imipenem/cilastatin, meropenem, and ertapenem) and, in case of negative results, challenges with the related carbapenems.
Type II (Antibody-mediated) 16,17 . Type II hypersensitivity reactions predominantly present as druginduced hemolytic anemia (DIHA) 32 , drug-induced thrombocytopenia (DITP) 33 , and/or drug-induced neutropenia (DINP) 34 . In several series, cephalosporins (especially ceftriaxone) and penicillins (especially piperacillin) were among the most common causes of DIHA (with cephalosporin accounting for up to 50% of one DIHA series) [35][36][37][38] . The beta-lactam antibiotics: penicillins (especially piperacillin) and cephalosporins (especially ceftriaxone) were again reported in causing DITP but accounted for a much lower percentage of DITP than DIHA 33,39 . We have known of two cases of cephalosporinassociated DINP and the literature also had case reports to small series induced by penicillin and cephalosporin families [40][41][42][43] . Beta-lactam induced neutropenia needed to be distinguished from the majority of cases where the cephalosporins were used to treat neutropenic patients where neutropenia is the preexisting condition. The proposed mechanisms for the Type II reactions include antibodies directed against the drug or drug-associated immune complexes adsorbed on the cell surface (overlap Type III). How long does Type II hypersensitivity to beta-lactam antibiotics persists is unknown. In limited experience, we had encounter patients who developed the reactions years later when the drug was reintroduced when the pattern was not initially recognized. For patients who developed Type II reactions, it is generally recommended to avoid using the same or similar betalactam antibiotics. However, in the situation where the infection is severe and an appropriate nonbeta-lactam antibiotic is not available, a provider may try using another member of the same or different beta-lactam family. For DINP, Vial, et al. shown that neutropenia recurred in 2 out 21 patients but 19 tolerated the alternative betalactam antibiotics 40 . In our experience, we have only identified one patient. However, in the literature, the cases reported experiencing these reactions seem to be drug-specific, and patients seemingly tolerate alternative cephalosporin. Careful monitoring must be done under challenge or desensitization protocols.
Type III (antigen-antibody immune complex/complement-mediated) 16,17 . Serum sickness (SS) and serum sickness-like reactions (SSLR) are the prototypical Type III hypersensitivity reaction where the antigen-antibody immune complex of the right size deposit into various tissues, often fixing complements and leads to urticaria/non-urticarial rashes, arthralgia, adenopathy, fever, and other symptoms. All beta-lactam groups have been reported to cause SS or SSLR [44][45][46][47][48] . For chemotherapeutic agents that have caused SS or SSLR, we had used an IV desensitization protocol with steroid/antihistamine pretreatment which generally allowed the patients to continue the chemotherapy for a small number of courses with modulation of the symptoms. This is generally not worth doing in cases of antibiotics. Drug-induced hypersensitivity vasculitis may present as palpable purpura, petechia, fever, arthralgia, and/or GI symptoms. It differs from SS in that the small blood vessels showed vasculitis features. It can be seen in a small percentage of patients who received betalactam antibiotics 49,50 . There has been no reported attempt at desensitization for drug-induced vasculitis, however, administration of other members of the same family may work. Arthus type hypersensitivity has not been reported for beta-lactam antibiotics.
Type IV (T cells, non-T immune cells, cytokine-mediated) subtypes 17 . Beta-lactam antibiotics have been associated with all four subtypes, including overlaps. The most common and least damaging Type IV subtype is the late-onset exanthematous maculopapular/morbilliform rash and the least damaging. It may be accompanied by superficial desquamation, fever, +/-eosinophilia, and +/-mild end-organ damage. The mechanism may represent an overlap of Type IVb and IVc). Typically the rash starts centrally and spread peripherally, at times clearing centrally even as the peripheral involvement increases (personal observations). The reactions generally resolve over several days to weeks without permanent damage. This maculopapular/morbilliform sensitivity to penicillin and cephalosporin tends to wane and is often lost for patients over time (however, as explained before, some authors argue that well-characterized Type IV hypersensitivity seems to be a long-lasting condition). Skin test generally is negative (5-10% may have concurrent Type I hypersensitivity and be skin test positive) and most patients tolerate a challenge years later. A small percentage remains sensitive.
Cross-hypersensitivity among different beta-lactam antibiotic families for the maculopapular/morbilliform rash is unclear. In our experience, it appears to be higher than for Type I reactions and in the range from 5-15%. However, some data in the literature indicate that even in this type of hypersensitivity the cross-reactivity among beta-lactams is mainly related to side chain similarity or identity 20,23 . In a study of 214 consecutive adults with a well-demonstrated T-cell- How long does the hypersensitivity of DRESS, SJS, and TEN persist is also uncertain as the general approach has been the avoidance of the drugs. AGEP is a rare member of the type IV subgroup characterized by neutrophilic pustules that are attributed to T cell inducing neutrophils and eosinophils. In fixed drug eruption (FDE), the rahs reoccurs in the same location and is often associated with post-inflammatory hyperpigmentation. FDE is generally attributed to CD8+ T cells. Amoxicillin and Ceftriaxone have been reported to cause FDE in case reports [55][56][57][58][59] .
Other mechanisms and/or combinations. Not all cases of beta-lactam antibiotic sensitivity can be nicely divided into one of the above categories. During intravenous desensitizations to cephalosporins, we have encountered occasional cases where there appeared to be a threshold drug infusion rate.
Above this infusion rate the patient repeatedly develop reaction but would subside once we lower the infusion rate below the threshold. This suggests that under certain circumstances, cephalosporin may have direct mast cell degranulation (DMCD) property similar to vancomycin antibiotic. Drug fever may accompany types II, III, and IV. In some cases, patients may develop hypersensitivity that involves several different pathways (Type I and Type IV, Type I and Type III, etc).
Approach to patients with a history of hypersensitivity to beta-lactam antibiotics o If the initial reaction was delayed onset exanthematous maculopapular/ morbilliform rash +/-superficial desquamation, fever, +/-eosinophilia, and +/-mild end-organ damage, skin test with penicillin and the desired beta-lactam antibiotics, if available, to rule out concurrent IgE-mediated sensitivity. Skin test generally is negative (5-7% may have concurrent Type I and be skin test positive). If the skin test is negative or if skin testing is not available, may proceed with the challenge protocol if there has been at least 1-2 years elapsed since the initial reaction. In our experience, patients who tolerated a challenge with 250-500mg of the beta-lactam antibiotic generally will tolerate subsequent courses of a beta-lactam antibiotic in the same family. A small percentage, however, may develop the same or similar reaction upon taking a full course even when they tolerated the initial challenge. Cross-hypersensitivity among different beta-lactam antibiotic families for the maculopapular/morbilliform rash is unclear. In our experience, it appeared to be higher than for Type I reactions and in the range from 5-15%, although some data in the literature indicate that even in this type of hypersensitivity the cross-reactivity among beta-lactams is mainly related to side chain similarity or identity.
o If it's highly likely that the patient has tolerated the same or a different member of the same family of beta-lactam antibiotics, one may proceed with the challenge or test dose protocol of the tolerated beta-lactam antibiotic. o If the initial reaction was vague or not available, and if there is no interval tolerance of beta-lactam antibiotics, the recommended protocol is the following: ▪ Penicillin skin tests should be performed if available.
• If the skin test is negative, may proceed with the challenge or test dose protocols.
• If the skin test is positive, then should consider alternative antibiotics, including challenge or test dose of a different beta-lactam antibiotic family. If an alternative antibiotic is not suitable or available, then one may proceed with the desired member of the same beta-lactam antibiotic family under the IV or oral desensitization protocol depending on the desired formulation of the antibiotic to be used.

▪ If penicillin skin tests are not available
• History remote (>5 years). May proceed with a challenge or test dose protocol with a different beta-lactam antibiotic family and one that does not share a common side chain.
• If the reaction is recent (<2 years). If a suitable non-beta-lactam antibiotic is not available, and no evidence of scarring from severe SJD, TEN, or end-organ damage from DRESS, may proceed with desensitization protocol, preferable with a different beta-lactam antibiotic family and one that does not share a common side chain.
Penicillin and other beta-lactam antibiotics skin testing o Continue to observe for at least 60 min after the 2 nd dose at the office and monitor for next several days at home. Patient instructed to take pictures and call for any significant delayed reaction.
o If the history stated that the initial reaction was delayed for many doses and days, consider continuing a 3-day challenge of 250-500mg once to twice a day for 3 days and monitor for the whole week.
o If the patient needs the antibiotic to treat an infection, then extend the course to complete the treatment.
Beta-lactam antibiotics inpatient challenge/test dose protocol: Typical starting concentration for patients with severe systemic reactions to previous beta-lactam antibiotic infusions. 3 Typical starting concentration for patients with moderate systemic reactions to previous beta-lactam antibiotic infusions. This will save 2 steps and 30min. 4 Optional step for highly sensitive patients. 5 Continue at this infusion rate for the remainder of the dosage. 6 Minimize concurrent narcotic and other direct mast degranulators if possible 7 May need to stay just below a threshold beta-lactam antibiotic infusion rate the first day and advance as tolerated (infrequently seen for cephalosporin). Unpublished protocol • Open capsule or crush beta-lactam antibiotic tablet 250mg and suspend in 25ml of water to make 10.0mg/ml solution (suspension).
• 10ml of beta-lactam antibiotic 10mg/ml solution add to 90ml of water to made the 1.0mg/ml solution • 10ml of beta-lactam antibiotic 1.0mg/ml solution add to 90ml of water to made the 0.1mg/ml solution • Obtain informed consent.
• Examine vital signs, oral mucosa, skin, and chest before the start.
• Shake up each solution well before taking out the appropriate amount with the appropriate size syringe for taking • Monitor blood pressure, skin, GI side effect, or other adverse symptoms.
• If adverse reaction develops, then repeat that dose or cut down to the previous dose. Lengthen protocol accordingly.
• Stay with the patient until 60 min after the first 250mg tablet or capsule is given.