Medical algorithm: Diagnosis and treatment of drug hypersensitivity reactions to biologicals, 2024 update
Authors: Barbara Carolyn Yang, Mariana Castells
Journal: Allergy (2024)

Since the last publication of this medical algorithm in 2020,1 our definition of biologicals has expanded from meaning only monoclonal antibodies (mAbs) to mean drugs made from organic molecules that are produced exclusively by living organisms and specifically target a gene or protein for therapy.2 Within this broader definition are included exogenous hormones (e.g., insulin and levothyroxine), modern vaccines (e.g., the mRNA SARS-CoV-2 vaccines), and nanobodies (e.g., calplacizumab, an FDA-approved therapy for acquired thrombotic thrombocytopenic purpura).3 Alongside these novel vaccines,4, 5 nanobodies,6 and hormones,7 mAbs continue to carry the risk of both local and systemic hypersensitivity reactions (HSRs) due to their biological origins.8 The reported incidence of biologic HSRs ranges from 5% to 10%.9, 10 The categorization of HSRs to biologicals goes beyond the Gell and Coombs classifications (types I through IV) to include infusion reactions, cytokine release reactions (CRRs), and mixed reactions (having features of both Type I and CRRs).11, 12 Classification is best defined by a reaction's phenotype (clinical presentation) and endotype (underlying mechanism and related biomarkers). Figure 1 enumerates the reaction types by phenotype. Identification of the reaction type determines management—Type II and Type III reactions are ineligible for rapid drug desensitization (RDD), and an alternative therapy should be sought as re-exposure in these cases can be fatal. It is useful to measure serum tryptase and IL-6 levels in the short time right after a reaction (i.e., tryptase levels peak 1–2 h after a reaction and can be detected for up to 24 h in more severe reactions). Tryptase elevation is defined as 1.2 × baseline +2 ng/mL and is most closely associated with Type I reactions. IL-6 elevation is most closely associated with CRRs. Infusion reactions and CRRs have some overlap of symptoms but unlike CRRs, infusion reactions are self-limited with subsequent exposures, and patients respond very well to slowing down the infusion rate of the original medication. Symptoms may also be controlled with or without premedication, such as steroids.11 The first step to determine eligibility for RDD is risk stratification (Figure 2A). The severity of the initial HSR is classified using a modified Brown classification (grade 1: mild, grade 2: moderate, and grade 3: severe).13 If the initial reaction was a severe cutaneous adverse reaction (SCAR) (e.g., SJS, DRESS, AGEP, TEN, or serum sickness-like reactions), the patient is ineligible for desensitization and the medication should be altogether avoided. There are multiple case reports of the successful use of benralizumab for severe cases of DRESS refractory to steroids that then allowed continued treatment with the culprit drug with regular infusion.14-17 Basophil activation testing (BAT) shows promise as an in vitro test.18 The test remains a research tool due to lack of sensitivity and specificity (depending on the drug in question), the difficulty of isolating basophils for testing because of variability in patient population, and their sensitivity to steroid premedication, but should be further developed and standardized to avoid delays in treatment as the administration of first-line therapy is most often time-sensitive.19 Skin testing (ST) is performed 2–3 weeks after a reaction to minimize false-negative results. A positive ST is highly suggestive of a Type I reaction and predicts a high chance of success with RDD. One of the difficulties with performing ST using biologicals is their high cost. In many national healthcare models, not everyone has health insurance and would have to pay out of pocket for each dose of medication necessary for ST or drug provocation testing (DPT).20 One possible workaround recommended in a recent WAO committee statement is to work with pharmacy to use remnants from vials to make ST dilutions or by arranging to have DPT or even RDD on the same day as ST so that a small amount of drug from a regular dose can be used for ST21. It would be of utmost advantage for pharmaceutical companies to make available small quantities of a biological at a fraction of the cost, specifically for allergy testing to avoid wasting an entire dose. In addition, the concentration of biologicals to be used for ST and the threshold for positivity is also not standardized. Because of these limitations, ST for biologicals may not be performed in every scenario. When possible, we perform ST with an undiluted original drug. We have yet to find prospective studies in the literature that have published positive and negative predictive values of ST to specific biologics, so this is as-of-yet unknown. Another change to this algorithm is the emphasis on delabeling patients who can be determined to not have a drug allergy, to diagnose drug allergy accurately, and to save resources for RDD for those who truly need it through DPT, also known as a graded/diagnostic challenge.22 Those with negative ST and a moderate initial reaction would benefit the most from DPT. In one patient population, it has been shown that 49% of all patients with documented HSR to a biological drug had a negative DPT and was thus able to avoid RDD and move directly to standard infusion.23 DPT performed on the same day as the initial reaction, named in some centers as a "restart protocol," can lead to successful administration of drug because of mast cell anergy (depletion of mast cell granules) from the initial reaction but would be a false-negative result because of inability to predict how the patient will respond at the next dose.24 Up to 15% of patients who have a positive DPT can have severe reactions with 4% having hemodynamic changes.25 Rapid drug desensitization itself is not a "cookbook" but rather a regimen of personalized medicine tailored to each patient's needs. Management of drug HSR requires a multidisciplinary approach involving allergy & immunology, pharmacy, laboratory staff, nursing, the patient's primary team, consulting subspecialists, and easy access to critical care (to help manage the highest-risk patients in an ICU setting, if needed).21 An allergist/immunologist is ideally suited to lead such a team, as they can offer expertise in allergy-specific methods, ensuring delabeling and RDD to the greatest variety of drugs while minimizing risks and preserving patient safety. Premedication is crucial and selection is based on the phenotype and endotype of the initial reaction (Figure 2B).12 Breakthrough reaction symptoms most often mirror the symptoms found in the original reaction, which is why we attempt to mitigate those symptoms with specific premedication. For example, patients with an initial reaction matching a cytokine release phenotype may benefit from premedication for fevers/rigors, nausea, pain, and headache including fluids, possibly steroids, and COX-inhibitors, whereas those matching more of an immediate HSR may instead benefit from premedication for flushing, pruritus, rash, and bronchospasm. The next step after premedication is the desensitization itself (Figure 3). Those with the greatest risk still benefit from the original 3-bag, 12-step RDD protocol, but current protocols allow those with low and moderate risk to receive a 1-bag protocol as this has been shown with multiple biologicals to be safe and effective.26-28 Certain drugs lend themselves to primarily be administered via a 1-bag protocol, such as cetuximab, which comes from the manufacturer in a proprietary buffer solution without supplying the buffer separately for custom dilution.23 Patients with an even higher risk can begin RDD with even longer 4-bag protocols with even more steps. Breakthrough reactions are treated symptomatically (Figure 2C). From our institutional experience, reactions are most likely to occur during the next-to-last or the last step of a desensitization. We also find that after a successful RDD, desensitization is maintained if the patient continues to be exposed to the medication on a regular basis (such as with subsequent cycles of chemotherapy). When sufficient time has passed without exposure, the patient will have become resensitized and will likely require RDD again for re-exposure if therapy necessitates it. In children, most HSRs are induced by biologicals, and of these, the most common implicated drugs are mAbs.29 There are a couple caveats for performing RDD in the pediatric population. First, RDD protocols for dosing and dose escalation per step should be weight-based.30 Second, systemic steroid premedication may not be ideal as higher doses of steroids have potentially more harmful effects in children and such risks should be examined on a case-by-case basis. An international consensus on standardization of RDD protocols for children is still very much needed. Phenotype switching is a phenomenon where the phenotype of a breakthrough reaction changes from one type to another type (e.g., from type I or mixed reaction to CRR or vice versa). This necessitates early recognition and adaptation of the protocol to appropriately deal with the breakthrough reactions and allow RDD to continue.31 For example, if a reaction switches to more of a Type I or mixed type, the patient may benefit from omalizumab premedication as there are numerous case series demonstrating benefit in the use of omalizumab as premedication in RDD.32-35 If a reaction switches to a CRR type, there may theoretically be a role for tocilizumab and steroid premedication and dose reduction with simultaneous increase in rate of intravenous fluids. As breakthrough reactions become more mild or less frequent, fewer steps may be used for RDD, and as breakthrough reactions become more severe, additional steps may be added. It should be emphasized that a significant portion of breakthrough reactions to biologicals appear to be CRRs. There are two major recommendations from the most recent AAAAI drug allergy practice parameter update regarding management of HSR to biologicals.36 First, if the history of a patient's reaction is not entirely consistent with a legitimate HSR, it may be safe to re-expose the patient with a slowed rate of infusion, with or without premedications. Second, for patients with overt immediate HSR or a severe reaction such as anaphylaxis, empiric RDD is preferred. There are unique considerations for RDD to specific mAbs. Rituximab (anti-CD20 chimeric mAb) can rapidly affect tumor burden leading to tumor lysis syndrome, the release of cytokines with simultaneous activation of mast cells, leading to mixed reactions (HSR having features of both Type I and CRRs). Such reactions are generally very amenable to RDD with much experience at our institution.37 A significant portion of omalizumab (anti-IgE mAb) HSRs are delayed (>7% occur >12 h later).38, 39 With infliximab (anti-TNF-⍺ mAb), it is important to note that premedication with corticosteroids has not been shown to be effective in reducing the rate of HSR.40 HSR to cetuximab (anti-EGFR chimeric mAb) can occur on even the very first administration due to preformed IgE against galactose-alpha-1,3-galactose (alpha-gal) from sensitization by the Lone Star tick (causing red meat allergy syndrome).41, 42 Testing for alpha-gal IgE is necessary prior to any cetuximab exposure to prevent HSR.43, 44 Positive patients still have a high success rate receiving cetuximab through RDD, especially via a 1-bag protocol.27, 45 A snapshot of 81 oncology studies using biologics showed an incidence of 63% for the formation of specific anti-drug antibodies (ADAs).46 Exploration into diagnostic evaluation of ADAs is ongoing with some ELISA assays now commercially available that can be used to identify type I hypersensitivity that is drug-specific.47, 48 In conclusion, the updated medical algorithm for managing HSRs to biologicals delineates a sophisticated blend of old and new strategies tailored to the evolving landscape of biological therapeutics. The expansion of the definition of biologicals to include a broader array of therapeutic molecules like hormones, vaccines, and nanobodies represents significant advancement in the field. The inclusion of diagnostic tools such as ST and DPT, the future promise of BAT moving beyond a research tool, alongside the strategic implementation of RDD underscores a multifaceted approach to safely managing and potentially continuing first-line therapy in patients experiencing HSRs. This comprehensive algorithm not only addresses the immediate needs of managing adverse reactions but also highlights the importance of phenotypic and endotypic assessment to tailor premedication and desensitization protocols, ensuring patient safety and treatment efficacy. Moreover, the emphasis on desensitization protocols specific to children and the importance of phenotype switching during RDD provide essential insights into the personalized nature of treating HSRs. The allergy community's ongoing commitment to refining these protocols and expanding therapeutic options through research is crucial for enhancing patient outcomes and minimizing the burden of biological therapy-related hypersensitivity. There was no financial or material support for this publication. The authors have nothing to disclose. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.