Standards for practical management of drug hypersensitivity reactions to intravenous drugs and proactive early allergy involvement before referral: A WAO Statement

Abstract

Hypersensitivity reactions to intravenous therapies—including antibiotics, chemotherapeutics, biologics, anesthesia agents, and contrast media—pose significant challenges in acute care settings. These reactions often occur outside the purview of allergy specialists, leading to delays in recognition, suboptimal management, and inconsistent documentation. This article underscores the imperative for proactive, multidisciplinary collaboration to enhance patient safety and treatment continuity. We examine the spectrum of intravenous reactions, including anaphylaxis, highlighting the pivotal role of allergists in both acute intervention and long-term care planning. Emphasis is placed on the development of standardized protocols, the establishment of inpatient allergy consult teams, and the implementation of penicillin allergy delabeling strategies. Supplemental materials provide real-world examples from leading institutions that have successfully integrated multidisciplinary approaches, demonstrating improved outcomes through coordinated care. By proactively engaging in the creation of safety protocols, referral pathways, and joint models of care, allergy specialists can contribute significantly to safer patient environments, even before reactions occur, ensuring timely diagnosis, effective management, and optimal outcomes.

Introduction

Drug hypersensitivity reactions (DHRs) to intravenous therapies are among the few medical emergencies that simultaneously threaten patient safety, interrupt essential treatment, and require coordinated action across multiple specialties. These reactions often manifest during drug administration by non-allergy specialists or healthcare professionals who may lack specialized training in allergy recognition and management. Consequently, initial responses to DHRs may be delayed or inadequate, leading to increased morbidity and potential treatment discontinuation.^1,2

The traditional model of post-reaction allergy referral is insufficient in addressing the immediate needs of patients experiencing DHRs. There is a pressing need for integrated, multidisciplinary approaches that involve allergists from the outset. Collaborative initiatives, including the formation of inpatient allergy consult teams and the designation of “allergy champions" within various departments, have shown promise in bridging this gap. These models facilitate real-time assessment, ensure accurate documentation, and enable the implementation of rapid access to allergy investigations, advice, delabeling, or desensitization in the context of a structured and safety-oriented framework.^1,2

Framed around intravenous DHRs, this article extends to the wider inpatient drug allergy landscape, highlighting patient complexity and proposing actionable multidisciplinary strategies, emphasizing a proactive role for allergy departments within the hospital ecosystem, including early engagement before formal referral. We explore the roles of various healthcare professionals in recognizing and responding to DHRs, underscoring the importance of standardized protocols and continuous education. Additionally, we present supplemental materials featuring case studies from institutions that have successfully implemented integrated care models, providing practical insights into effective DHR management.

This Statement was developed by members of the Drug Hypersensitivity Reactions Committee of the World Allergy Organization (WAO) and underwent iterative internal review and revision within the Committee before receiving approval from both the Committee and the WAO Board of Directors. While many of the practical examples and supplemental materials are based on real-world institutional experience, the recommendations are informed by the available literature and are intended to provide practical guidance that can be adapted to local resources, healthcare systems, and national regulations. Throughout this Statement, we advocate a shift from the traditional reactive referral or consultation model towards proactively integrating allergy services as essential partners within hospital care pathways.

Management of hypersensitivity reactions to intravenous antibiotics

Adverse Drug Reactions affect approximately 10%–15% of hospitalized patients, with DHRs accounting for an estimated 10%–20% of these events.³ Antibiotics remain the most common cause of immune-mediated DHRs, including both anaphylaxis and severe cutaneous adverse reactions (SCARs).⁴ Among antibiotic classes, beta-lactams are the leading culprits, responsible for approximately 19% of DHRs, followed by quinolones at 7%.⁵

The risk of DHRs increases with repeated and parenteral exposures.⁶ Intravenous administration is associated with a more rapid onset and increased severity of anaphylaxis, occasionally leading to cardiac arrest in as little as 5 min after administration.^7,8 These findings underscore the need for all healthcare personnel involved in antibiotic administration to be adequately trained in the recognition and management of DHRs.

Despite this, training in drug allergy and anaphylaxis management is often restricted to select subgroups. For instance, outpatient parenteral antimicrobial therapy (OPAT) guidelines typically recommend observation during the first infusion and acknowledge that hypersensitivity reactions may occur.⁹ Consequently, some protocols mandate that nurses administering these therapies are trained and equipped to recognize and treat anaphylaxis.¹⁰

Standardized inpatient protocols addressing antibiotic-related hypersensitivity reactions are still a critical unmet need. Targeted research and uniform policies are warranted. In the interim, proactive leadership from allergy departments to develop multidisciplinary pathways and training programs is essential to improving patient safety and reducing associated morbidity and mortality.

Immediate reactions

The cornerstone of effective anaphylaxis management is timely and accurate recognition.¹¹ Anaphylaxis represents the most severe form of immediate allergic reaction. Delayed or missed diagnosis can lead to undertreatment and, in some cases, fatal outcomes. Therefore, all healthcare professionals involved in patient care—whether in general wards, emergency departments, or operating rooms—should undergo regular training in the recognition and management of anaphylaxis.

Anaphylaxis treatment should follow established international and regional guidelines.^8,12 Recent guidance underscores the central role of epinephrine (adrenaline) and fluids as first-line therapy, with antihistamines and corticosteroids serving only supportive roles, which must be clearly understood across clinical teams to avoid delays in appropriate treatment.⁸

Adequate documentation and standardized assessment of DHR severity remain complex. Nomenclature can be confusing, no universally accepted severity grading system exists, and current classifications vary across professional societies, clinical settings, patient populations (eg, pediatric vs adult), and even by the specific drug trigger.^1,13, 14, 15 Many experts have called for improved documentation, and the development of a simplified, standardized system.14, 15, 16, 17 WAO has recently published a guidance document on anaphylaxis with a more encompassing severity classification.¹² However, it remains debatable whether a single universal scoring system is either feasible or clinically beneficial.¹⁸ In acute care settings, focusing on assigning a severity grade may delay epinephrine administration and inadvertently increase patient risk.¹⁸

The measurement of biomarkers during or shortly after anaphylaxis—particularly serum tryptase—can aid in clarifying the underlying mechanism.^19,20 Tryptase typically becomes detectable within minutes of symptom onset, β-tryptase levels reach peak circulating concentrations approximately 15–120 min after symptom onset and return to baseline within 6–48 h.^21,22 Current guidelines recommend obtaining an acute serum tryptase sample as soon as feasible after the reaction (without delaying treatment, ideally not earlier than 30 min after symptom onset), followed by a second sample at 1–2 h (up to 4 h), and a baseline sample at least 24 h after complete resolution of symptoms.⁸ Interpretation should be based on comparison with the patient's baseline value, with mast cell activation supported by an acute tryptase concentration exceeding (1.2 × baseline tryptase) + 2 μg/L.^8,19,20

To support timely and accurate management, every inpatient unit should ideally be equipped with a dedicated anaphylaxis kit containing essential medications, visual management algorithms, appropriately labeled blood collection tubes for tryptase sampling, and an electronic test order set labeled “anaphylaxis.” Liaison with laboratories is essential to ensure processing of all tryptase samples sent rather than just the first. Such preparation facilitates optimal acute care and enhances diagnostic accuracy during follow-up. However, implementation requires regular review for medication expiration and restocking, and some institutions could raise concerns regarding cost and sustainability. These practical barriers should be acknowledged when considering widespread adoption beyond a few selected areas of the hospital.

Management of non-immediate reactions

Patients receiving antibiotics in inpatient settings may also develop spontaneous cutaneous eruptions. When such rashes are attributed to antibiotics, it can lead to premature or unnecessary discontinuation of therapy.²³ Accurate morphological description is essential to correctly classify the skin reaction, assess its probability of being drug-related, and guide appropriate management.²⁴ However, a lack of training in dermatologic terminology among non-specialists often results in imprecise documentation and mislabeling. Tools such as the European guidance on how to classify cutaneous reactions to drugs, or targeted educational interventions, could improve diagnostic accuracy and antimicrobial stewardship in this context.^24,25

The majority of supposed drug eruptions encountered by allergists on the wards consist of spontaneous (non-specific) exanthems or urticaria/angioedema. Spontaneous exanthems typically present as widespread erythematous maculopapular rashes, sometimes accompanied by low-grade fever, pruritus, and peripheral eosinophilia. Acute spontaneous urticaria may appear in localized or generalized distributions and may or may not be associated with angioedema. These presentations are generally self-limited, lasting a few days, and do not involve other systemic symptoms or other end organ involvement.²⁴ Duration is a defining feature: an episode of urticaria/angioedema lasting >1 day is virtually always spontaneous (this refers to the overall duration of the urticarial presentation, even if individual wheals last <24 h), whereas spontaneous exanthems are more likely to last <4 days.²⁶ Importantly, although they are among the most frequently reported cutaneous reactions, these spontaneous eruptions are unlikely to be consistent with true drug hypersensitivity.²⁴ European guidance highlights that the risk of true hypersensitivity is higher in the context of severe exanthema, which is defined as a widespread rash that may become confluent and develop into erythroderma; duration >7 days, with systemic involvement (eg, fever, eosinophilia); rarely, with minimal vesicles or pustules.²⁷ A recent study of 872 adults with non-immediate penicillin reactions found eruption duration to be especially relevant: maculopapular exanthems lasting >4 days showed a higher rate of positive delayed-reading intradermal testing, and this rate escalated to 75% when lasting >7 days, irrespective of the interval to testing, warranting delayed-reading intradermal tests before drug challenges in these cases.²⁶ No patients with urticaria (with or without angioedema) whose overall urticarial episode lasted >1 day tested positive, supporting that urticaria persisting or recurring over more than 1 day is highly likely to be spontaneous rather than allergic in nature.²⁶ This distinction is nuanced: individual wheals in urticaria characteristically resolve within 24 h, while the overall urticarial episode may persist or recur over several days.²⁴ Accurate recognition of urticaria and its characteristic morphology and time course is therefore essential to avoid confusion with other cutaneous eruptions.²⁴ Expert evaluation by clinicians with experience in drug allergy is essential to determine whether treatment discontinuation is warranted or if a ‘treat-through' approach can be safely employed.²³

It is critical, however, to promptly recognize SCARs, which, although rare, carry significant morbidity and mortality. These include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and acute generalized exanthematous pustulosis (AGEP).²⁴ Accurate clinical history-taking and detailed morphological assessment are essential for diagnosis.^28,29 These syndromes require urgent multidisciplinary evaluation and management in accordance with established clinical guidelines.30, 31, 32, 33

Practice pearls on allergy-led short-term and long-term management

Identifying the culprit drug can be particularly challenging in acutely ill, polymedicated patients with multiple comorbidities.²⁰ Diagnostic testing is often unreliable in the immediate aftermath of a DHR, and the acute phase is generally not optimal for evaluation due to the heightened risk of false-negative and false-positive results, and potentially life-threatening reactions during in vivo testing, especially in acutely ill patients.^6,27,34, 35, 36

When patients require urgent re-exposure to the same agent—or to a cross-reactive drug—collaborative decision-making is essential. Allergy specialists must work closely with the referring team and infectious disease specialists to optimize antibiotic selection and ensure patient safety.³⁷ In urgent cases, where immediate hypersensitivity is suspected but not definitively diagnosed, empirical rapid drug desensitization (RDD) may be appropriate, with confirmatory testing deferred until the patient is clinically stable.¹

RDD is a highly specialized procedure that, when performed by trained allergists, can induce temporary tolerance and allow the safe administration of a necessary drug to a sensitized patient.^1,38,39 RDD is indicated in immediate reactions with a Type I hypersensitivity endophenotype (ie, reactions involving mast cells/basophils such as urticaria, angioedema, or anaphylaxis), and both for IgE-mediated and non-IgE-mediated immediate DHRs.¹ While its use in non-immediate DHRs remains controversial, empirical RDD may be a pragmatic solution in selected cases involving mild or uncertain presentations.^1,40 RDD is especially relevant for patients who require repeated courses of antibiotics, notably individuals with cystic fibrosis.^41,42 However, it is contraindicated in patients with a history of SCARs, organ-specific immune responses, or hematologic abnormalities.^1,6,40,43,44

The evaluation of SCARs is especially complex and should ideally take place in liaison with specialized centers with multidisciplinary teams comprising experts in allergy, dermatology, immunology, pharmacy, and critical care.^28,29,44,45

When equally effective alternatives are available and there is no pressing need for the implicated drug during hospitalization, patients should be referred for outpatient allergy assessment.^1,35

In the short term, the allergist's role includes documenting the reaction comprehensively, ensuring appropriate biomarker collection, educating and reassuring the patient, coordinating across disciplines, and establishing a contingency plan for urgent RDD where appropriate and indicated. In the long term, the allergist must ensure clear documentation—including electronic allergy labels, written discharge summaries, and patient education materials—and arrange timely outpatient follow-up for formal diagnostic workup and delabeling when appropriate.^20,35,37,46 Timely evaluation of immediate beta-lactam reactions is essential, as increasing the interval between the index reaction and allergy workup reduces the likelihood of positive findings.^47,48 See Fig. 1 for a schematic summary.

Fig. 1.

Algorithm for managing hypersensitivity reactions to intravenous antibiotics in inpatients. LEGEND: IV, Intravenous. This algorithm illustrates the ideal management pathway in centers with access to allergy services. Where an allergist is not available on-site, hospitals should establish referral pathways to a regional allergy center, using hub-and-spoke networks, tele-allergy support, or local allergy champions where available

From a systems-level perspective, allergy teams have a responsibility to provide high-quality, patient-centered care, promote patient and staff safety, and lead institutional initiatives to improve drug allergy care.¹ Ideally, this includes the development of a rapid-access inpatient allergy “mobile team”—comprising, for example, an allergist and a trained allergy nurse or equivalent adequate staff—capable of timely evaluation and management planning. In larger hospitals, where referral volume may exceed the capacity of a central allergy team, a network of trained “allergy champions” (non-allergist clinicians with a special interest in drug allergy) can help triage and manage lower-complexity cases.

However, we recognize that many hospitals worldwide do not have direct access to an allergist. In these settings, hospitals should establish close collaboration with regional allergy centers whenever feasible. Depending on local resources, practical models may include hub-and-spoke networks with an allergy center acting as the hub, tele-allergy support, trained “allergy champions" as mentioned above, and agreed transfer pathways for patients requiring highly specialized care (eg, RDD or acute SCARs).⁴⁹

Patients with SCARs should ideally be managed in liaison with specialized tertiary centers with appropriate multidisciplinary expertise. Allergy departments should lead in involving the relevant specialties and establishing dedicated multidisciplinary rapid-response teams with clear referral pathways and locally endorsed protocols.

RDD services require robust infrastructure and allergy-led interdisciplinary collaboration to meet the time-sensitive needs of hospitalized patients requiring continued treatment with the implicated agent.¹

All services involved in inpatient drug allergy care should be subject to regular auditing, with ongoing quality improvement initiatives informed by outcome data.¹

The active leadership of allergy departments in educational programs, interdepartmental case reviews, and morbidity and mortality meetings is critical to sustaining high standards of care and raising institutional awareness of the importance of drug allergy.¹

Penicillin delabeling in inpatients

Penicillin allergy labels are reported in 8%–25% of hospitalized patients, yet fewer than 5% of those assessed by allergy specialists are found to have true drug hypersensitivity.⁵⁰ This high rate of mislabeling is multifactorial, often stemming from limited training in drug allergy, inadequate documentation, and restricted access to specialist allergy services.^14,51, 52, 53, 54 Inaccurate labels are associated with increased use of second-line antibiotics, unnecessary broader-spectrum antibiotic exposure, suboptimal treatment outcomes, and higher healthcare costs.^50,51 Delabeling low-risk patients can optimize antimicrobial prescribing and reduce unnecessary expenditures, with reported cost savings ranging from $1145 to $4254 per patient.^51,55,56

Inpatient penicillin delabeling is particularly suited to patients with clearly low-risk histories—for example, those who report vague or non-specific childhood rashes without features suggestive of anaphylaxis or SCARs.57, 58, 59, 60, 61 In these cases, ward-based history-taking and, where appropriate, direct oral challenge can be performed safely under structured local guidelines and robust governance by the allergy department.57, 58, 59, 60, 61 However, patients who are acutely unwell, have uncontrolled comorbidities, or present with features suggestive of higher-risk reactions should not routinely undergo direct delabeling in the inpatient setting without expert input.57, 58, 59, 60, 61 These patients may benefit from a more cautious approach balancing skin testing, alternatives, or testing on discharge. Although there are reports of successful delabeling initiatives even in ICU settings,⁶² fatalities have occurred during allergy testing in clinically unstable patients.³⁶ Patients who cannot be delabeled from their penicillin allergy during admission should be referred before discharge for allergy evaluation, to minimize the risk of ongoing mislabeling and ensure future access to appropriate first-line antibiotics.⁵³

Non-allergist clinicians are often the first to assess patients with presumed antibiotic allergies, yet many report limited confidence, competing priorities, and structural barriers to delabeling during acute care episodes.⁶³ Educational interventions and clear workflows are therefore essential, particularly when embedded within multidisciplinary pathways. Recent initiatives have demonstrated that hospital-wide or healthcare system-level programs involving allergists can significantly improve diagnostic accuracy, antibiotic stewardship, and patient outcomes.57, 58, 59, 60, 61 Allergy-led models, including pragmatic approaches such as “allergy mobile teams” and “allergy champions” (see previous section entitled "Practice pearls on allergy-led short-term and long-term management"), may facilitate long-term implementation by mitigating organizational barriers and resistance to institutional change. Key advantages of allergy-led models include governance oversight by allergy departments, protocol standardization, procedural consistency, safer triage of higher-risk cases, equitable and streamlined access, integration with electronic health records, and promotion of institutional learning. Centralizing delabeling within allergy services facilitates broader hospital-wide access and ensures continuity across care settings, rather than confining such efforts to isolated and time-limited departmental initiatives (eg, quality improvement or research) that often encounter multi-factorial barriers or lose momentum when key personnel move on.⁶³

Given the resource limitations in many allergy departments, collaboration across specialties has proven vital.^64,65 Supplemental Material 1 provides a real-life, practical example of a Trust-wide Standard Operating Procedure (SOP) for inpatient penicillin allergy delabeling in adult patients recently implemented at Barts Health NHS Trust in London, United Kingdom. This SOP supports 5 hospitals and 2 partner institutions, serving a population of approximately 2 million people.⁶⁶ When supported by robust infrastructure, these models can offer a cost-effective approach that enhances diagnostic accuracy, strengthens antimicrobial stewardship, improves patient safety, and promotes consistency in care and timely responsiveness.^64,65

Chemotherapy and biologics

Approximately 2.5–5% of all cancer patients receiving chemotherapy will experience an infusion reaction to their potentially life-saving treatment.^67,68 Chemotherapy and biologics can trigger a wide range of infusion reactions, many of which can be severe, potentially disrupting treatment continuity and compromising survival outcomes.^1,69,70 As cancer survival improves and novel antineoplastic agents proliferate, the number of patients exposed to agents with potential for infusion reactions is rising.¹ This epidemiological shift necessitates stronger systems to recognize and manage DHRs.

Recent data indicate that up to 45% of patients with chemotherapy-related DHRs may discontinue treatment unnecessarily when allergy evaluation is not integrated into routine care pathways.⁶⁸ An estimated 1.1% of all patients receiving antineoplastic therapies are affected by this gap, with a disproportionate impact on women, particularly those treated for gynecological malignancies.⁶⁸

Allergists play a key role in evaluating these patients and identifying safe pathways for re-exposure.^1,2,49 Some patients can be safely delabeled from their chemotherapy or biologics allergy labels.^37,71, 72, 73, 74, 75, 76, 77 Other patients may require RDD to induce temporary tolerance to the culprit drug.^{1,2,49,73,74,76,78} Beyond reactive management, preventive approaches—such as skin testing for platinum agents prior to administration in selected patients—could be considered to reduce risk.^49,79, 80, 81 These strategies highlight the essential role of allergists in ensuring patient safety and continuity of care.^1,2,49,82

RDD is an allergy-specific, cost-effective intervention that enables reactive patients to continue first-choice treatments and maintain the same survival rates as their non-reactive counterparts.83, 84, 85, 86, 87 RDD is most efficacious and safe in the hands of expert allergists leading a multidisciplinary team with dedicated spaces and resources.^1,88

Regrettably, allergists are not usually present at the time of the index reaction, and only a small proportion of patients are subsequently referred for allergy evaluation, with referral absent altogether in some settings.^1,67,68 However, some allergy departments have on-call allergists who assess all the initial infusion reactions that patients experience in infusion centers.^89,90 This allergy-led multidisciplinary work ensures homogeneity in patient management for all the patients in the infusion center, regardless of specialty, as the same allergy team will take care of patients from oncology, hematology, and other specialties.

The effective management of chemotherapy-related DHRs begins well before the allergist's involvement.⁸² Timely recognition and appropriate treatment during the acute phase are critical to ensuring patient safety and treatment continuity. Since nurses are often the first responders during infusion reactions, structured training in recognizing and managing anaphylaxis is essential. Allergy-led on-site simulation-based training can help teams build confidence and competence in high-stakes scenarios, potentially avoiding delays in life-saving treatments like adrenaline.¹

Misclassifying or undertreating severe reactions risks patient deterioration or inappropriate treatment suspension.¹ Hospitals without allergy-led protocols may see inconsistent approaches, including inappropriate re-exposures or premature abandonment of therapies.^1,91, 92, 93 In some cases, clinicians unfamiliar with the principles and protocols of RDD may attempt desensitization independently, risking patient safety.^1,91 Early specialist involvement and referral ensure adherence to validated desensitization protocols and appropriate risk stratification.^1,82

Detailed documentation of the reaction phenotype, timeline, and initial management—shared across teams—helps ensure appropriate follow-up and avoids repetition of errors or delays.^1,91,94 Even when infusion reactions are appropriately managed at onset, the absence of structured referral pathways to allergy services may lead to missed or misattributed diagnoses, delays in optimal treatment planning, and unnecessary switching to less effective or more toxic alternatives.⁹¹ For example, recent data indicate that a substantial proportion of patients labeled as having DHRs to biologics were ultimately found to have chronic spontaneous urticaria, illustrating how limited allergy input may allow common alternative diagnoses to be overlooked.⁷⁷

Involving expert allergists in the initial management of these reactive patients can be beneficial, as it ensures adequate management of anaphylaxis and other reactions, proper documentation of the reaction, collection of the relevant biomarkers, opportunities for training non-allergy teams, and a streamlined and fast-tracked referral process to the allergy department to avoid delays.⁶⁷

Whenever feasible, biomarker sampling should also be undertaken during the acute phase. At a minimum, serum tryptase should be obtained according to current anaphylaxis guidelines. Where available and when appropriate, additional biomarkers such as interleukin-6 (IL-6) may further aid endophenotyping of immediate infusion reactions and subsequent allergy evaluation.^1,82

In addition, allergists can even help ensure that reactive patients receive their treatments safely on the same day.^67,89 Borras Cuartero et al developed an innovative model in which an allergist assesses all infusion reactions on-site in the oncology infusion center and coordinates empirical same-day RDD—allowing patients to continue treatment despite reactions, including during their first episode, and avoiding treatment waste.^89,90

Similarly, at the Drug Hypersensitivity &Desensitisation Centre of the Catalan Institute of Oncology (ICO), Barcelona, Spain, allergists directly assess and characterize reactions occurring within the oncology infusion center, with this close involvement associated with marked improvements in management planning and patient outcomes. As outlined in Fig. 2, patient safety improved through more effective anaphylaxis management and increased access to on-site, allergy-led same-day re-challenge.⁹⁵ Additionally, efficiency increased notably since this involvement with a reduction in unnecessary RDDs following the introduction of structured delabeling approaches.^71,72 A real-life example of a unified, multidisciplinary SOP used to optimize the management of infusion reactions to chemotherapy and biologics is provided in Supplementary Material 2, with Fig. 3 summarizing its practical algorithm for the recognition and initial management of suspected hypersensitivity reactions.

Fig. 2.

Optimizing acute reaction management in an oncology infusion center through allergist involvement in on-call teams. Modified with permission from: Vazquez-Revuelta PG, Celine; Molina, Gustavo J; Perez Gonzalez, Dolores; Pamias Nogue M; Lleonart Bellfill, Ramon. Adrenaline in Anaphylaxis: a Must, Not Only a Priority. Managing Anaphylaxis in an Oncology Infusion Center. XXXIV Congreso Nacional de la Sociedad Española de Alergologia e Inmunologia Clinica; Santiago de Compostela, Spain 2023

Fig. 3.

Recognition and initial management of immediate hypersensitivity reactions during antineoplastic infusions. LEGEND: Practical algorithm for the recognition and immediate management of suspected immediate hypersensitivity reactions (iHSRs) occurring during antineoplastic infusions. The figure summarizes the clinical criteria for recognizing anaphylaxis, the initial measures common to all suspected reactions (including interruption of the infusion, ABCDE assessment, monitoring, and supportive care), and a severity-based management pathway distinguishing patients requiring immediate intramuscular adrenaline from those with non-severe reactions receiving symptom-directed treatment. The algorithm is intended as a practical frontline tool for healthcare professionals managing acute infusion reactions before specialist allergy assessment. Adapted from the Standard Operating Procedure of the Drug Hypersensitivity and Desensitisation Centre, Catalan Institute of Oncology, Barcelona, Spain (Supplementary Material 2)

Although this section focuses primarily on immediate infusion reactions, delayed DHRs should also be recognized. Patients developing delayed cutaneous eruptions or other suspected delayed immune-mediated reactions should undergo careful documentation of the morphology, chronology, duration, systemic features, and concomitant medications, with clinical photographs obtained whenever possible, as mentioned in the section of this manuscript entitled "Practice pearls on allergy-led short-term and long-term management". Patients with features suggestive of SCARs require immediate multidisciplinary assessment and referral, whereas milder delayed reactions should be referred for outpatient allergy evaluation once clinically stable.¹

A comprehensive management model for infusion reactions should integrate allergy departments throughout the care pathway for patients experiencing reactions to chemotherapy and biologics.^1,82This end-to-end approach ensures patient-centered care and treatment continuity. This includes early-stage involvement, such as allergy-led initiatives to manage initial infusion reactions in real-time as the on-call first point of contact, which have demonstrated significant clinical benefits.^89,90,95 Institutional multidisciplinary initiatives should encompass early recognition, frontline treatment protocols, fast-track allergy referral, standardized evaluation, allergy-validated safe re-exposure planning, robust allergy-led governance, and regular training and auditing.^1,49,82Recent WAO guidance outlines practical strategies to implement these multidisciplinary collaborations.¹ In addition, acknowledging the diversity of institutional realities and resource availability, several organizational models have been proposed to optimize allergy care in oncology infusion centers.^49,82 These include centralized services, hub-and-spoke networks, and specialized satellite units, each offering distinct advantages depending on local resources and patient needs.⁴⁹

Perioperative anaphylaxis

Perioperative hypersensitivity reactions (POH), including perioperative anaphylaxis (POA), are rare, potentially life-threatening and may have severe consequences for patients. Anesthetists often have limited allergy knowledge and may refuse to anaesthetize patients with suspected POH. If POH is overlooked or not taken seriously, patients risk re-exposure to the culprit and subsequent POH/POA. On the other hand, allergists usually have limited knowledge of the perioperative setting. They are unfamiliar with the potent drugs used and may not feel confident in investigating patients with anaphylaxis to specific perioperative intravenous medications. These shortcomings challenge subsequent allergy investigation and the fact that reactions occur in a setting where numerous drugs and substances are used simultaneously, and symptoms of anaphylaxis may be difficult to distinguish from normal events during anesthesia and surgery. Therefore, the optimal management of patients with suspected POH is best achieved by close collaboration between anesthetists and allergists.

In recent years, national and international working groups have recommended such collaborations in the management of POH. In France, collaborations have taken place for many years in the GERAP network.⁹⁶ In Spain and Brazil, national societies of allergology and anesthesiology have worked together to produce joint guidelines.97, 98, 99 In the United Kingdom, the National Audit Project 6 (NAP6) on POA included crucial recommendations such as identifying a departmental lead for POA in all anesthetic departments and having a clear pathway for referral to an allergy clinic.^100,101 A multidisciplinary UK Perioperative Allergy Network has been established, formally involving allergy, anesthesiology, and immunology societies at a national level.¹⁰² European guidelines on the investigation of POH from 2019 strongly recommended collaboration between anesthetists and allergists to provide the best patient care.¹⁰³ The International Suspected Perioperative Allergic Reactions (ISPAR) Group is a multidisciplinary global network aiming to facilitate collaborations.¹⁰⁴

Services are organized differently in different countries. In some places, collaborations take place on an ad hoc basis, and some have regular multidisciplinary clinics. A few centers, for example the Danish Anesthesia Allergy Center (DAAC), are national reference with a completely integrated collaboration between allergists and anesthetists.¹⁰⁵ In Australia and New Zealand, POH investigation is driven by a very active national network of anesthetists, the Australian and New Zealand Anesthetic Allergy Group (ANZAAG).¹⁰⁶

Anesthetists play a critical initial role in POH investigation, and they need to be able to: (1) recognize and (2) treat anaphylaxis, (3) take serum tryptase, and (4) send a detailed referral for allergy investigation.

Recognizing anaphylaxis in the perioperative setting is challenging as symptoms such as tachycardia, bronchospasm and hypotension regularly occur during routine anesthesia, and skin symptoms may be hidden by drapes.^107,108 In addition, POH/POA occur rarely and unexpectedly, and as a result, treatment may be delayed and inadequate if the anesthetist is not familiar with the acute management of anaphylaxis.^100,101,109 Simulation training using a scenario of perioperative anaphylaxis is an effective way to raise awareness of diagnosing and treating anaphylaxis according to up-to-date guidelines, including correct dilution and dosing of intravenous adrenaline.^109,110 The specifics of managing anaphylaxis during anesthesia are not usually considered in general anaphylaxis guidelines, and only Scandinavian and UK guidance have addressed this directly.^111,112 In Denmark, the national curriculum for trainee anesthetists includes both lectures and full-scale simulations of a POA scenario taught by anesthetists from DAAC with special expertise in POH.

When the patient has been treated and stabilized, the anesthetist should take a blood sample for serum tryptase. In a busy operating room, the logistics of this can be challenging, and to overcome this, “anaphylaxis packs” are used in some countries. Originally these were recommended in Scandinavia and included a treatment algorithm, blood forms, referral forms and information about where to send referrals and blood samples.¹¹² More recently, the NAP6 report recommended both treatment packs including medication and investigation packs.^100,101

The success of an allergy investigation depends on a detailed referral from the anesthetist. A referral letter stating which drugs were used is not sufficient.¹⁰³ In some countries, standardized referral forms are included in anaphylaxis packs. See supplemental material 3 for an example based on the DAAC referral form that was published as a supplement to recent European guidelines.¹⁰³ See supplemental material 4 for a practical local adaptation based on the NAP6 anesthetic anaphylaxis investigation pack.¹⁰¹ Information about symptoms, such as timing, duration and response to treatment, should be recorded on these standardized referral forms. Detailed account of all drugs given, with time of administration, is essential for allergists when trying to establish potential culprits. Documentation of all non-IV drugs and substances used is also important, as disinfectants, latex, sterilizing agents, gels, sprays, bone cement, hemostatic agents, blue dyes, or radiocontrast media may be allergens themselves or contain excipients that are potential culprits.^103,113 Timing of the tryptase sample in relation to symptom onset is crucial for correctly interpreting tryptase results.⁸ A brief free-text narrative of the sequence of events is often helpful, and information on relevant medical history, drug history and previous allergies should be included. Lastly, copies of anesthetic and recovery room charts, surgical notes, theatre care plans, drug charts, and medical notes should be included with the referral.^100,101,103 Patient consent might be required if the allergist needs to retrieve other relevant source documents upon receiving the referral. In the DAAC referral form, a consent form for the retrieval and exchange of medical information and storage of the tryptase blood sample is included for the anesthetist to obtain consent and send it together with the referral form. The anesthetist involved in the event should ensure timely referral to the allergy department. They should also inform the patient before discharge, providing reassurance, written information, and ideally a clear follow-up plan with a named point of contact.

Institutional collaboration between anesthesia and allergy departments is essential to ensure safe, timely, and consistent investigation of POH/POA. Patients with perioperative hypersensitivity represent some of the most complex cases in drug allergy, and their optimal care requires close coordination across specialties. Both departments should jointly develop and regularly update SOPs covering acute management, the routine use of anaphylaxis investigation packs, documentation, standardized referral forms and processes, and follow-up. Establishing a joint perioperative anaphylaxis multidisciplinary team—with a designated lead in each department and scheduled regular meetings—promotes good practice, shared learning, ensures bidirectional communication, and supports continuity of care. Formal collaboration at local, regional, and national levels will also be key to achieving consistency, sustainability, and excellence in the care of these high-risk patients.

Contrast media

Although the relative incidence of DHRs to contrast media (CM) is low, the increasing frequency of their use has led to a significant number of reported reactions, posing a relevant clinical issue for allergy departments.¹¹⁴ CM DHRs are categorized into immediate IgE-mediated and non-IgE-mediated DHRs (such as urticaria, angioedema, and anaphylaxis) and non-immediate (delayed) T cell-mediated allergic DHRs (eg, exanthems).¹¹⁵ Non-allergic reactions can also occur.¹¹⁶

Allergy workup, including clinical history, skin testing, laboratory tests, and drug challenge, is essential in confirming an allergic mechanism and identifying skin testing-negative alternative CMs for future procedures.¹¹⁷ In cases where urgent re-administration is required and allergy assessment is not possible, the decision to either avoid or cautiously re-administer CM (with appropriate risk management strategies) is based on the details of the clinical history, the allergy test results, the severity of the initial reaction, and the patient's comorbidities.^114,117 Of note, skin testing and drug challenge are not routinely performed in certain countries like the USA.¹¹⁸

Iodinated contrast media differ in their physicochemical properties, including ionic versus non-ionic structure, monomeric versus dimeric composition, osmolality, and viscosity, all of which may influence tolerability. Modern low-osmolar and iso-osmolar non-ionic contrast media are associated with substantially lower rates of acute adverse reactions than the older high-osmolar ionic agents, although hypersensitivity reactions can still occur with any preparation.114, 115, 116, 117 Knowledge of the specific contrast medium administered is therefore essential for subsequent allergy evaluation and selection of suitable alternatives.

The management of patients is often hindered by a lack of communication and missing information between radiologists, general practitioners, dermatologists, and allergists. Immediate DHRs are initially encountered and treated by radiologists, while non-immediate DHRs are typically addressed by dermatologists or general practitioners. Later, sometimes years after the initial reaction, allergists become involved, requiring specific information to develop an appropriate testing plan. In many cases, a subsequent contrast-enhanced examination is needed, prompting the radiologist to seek management recommendations and feedback from the allergist. When designing a coordinated management approach for patients with prior DHRs to CM, the following fundamental considerations should be taken into account.

For the radiologist

Necessity of anaphylaxis training

As an illustrative example, in this section's author's radiology department, the clinical director dismissed the relevance of DHRs to CM, with senior doctors suggesting severe reactions were rare, while fellows reported DHRs occurred occasionally. Thus, although most DHRs had been mild and managed by fellows or senior doctors, a skewed perception of DHRs frequency may result in neglecting training on how to manage acute CM DHRs. A telephone survey conducted across radiology departments assessed radiologists' knowledge of severe acute CM DHRs management.¹¹⁹ In a case scenario involving a severe CM-induced HR, none of the radiologists selected the best treatment option, and only 41% chose an acceptable adrenaline administration route, concentration, and dose. Similarly, a simulation involving pediatric radiology residents found that only 1 out of 19 residents identified the correct sequence of interventions.¹²⁰ Furthermore, a radiology practice reviewing medical data over a five-year period found that adrenaline was used in only 9 out of 457,000 cases, primarily in patients with laryngeal edema (n = 6).¹²¹ Of these 9 patients, 4 experienced cardiovascular side effects due to intravenous adrenaline administration instead of the recommended intramuscular route.

These studies highlight the critical need for radiologists and radiology staff to receive training in anaphylaxis management. Although the treatment for CM hypersensitivity does not differ from standard guidelines, the rapid onset of severe reactions—typically within 1–5 min of intravenous administration—requires swift intervention.^8,122, 123, 124 We recommend a 30-min observation period following CM administration.

Additionally, regular training for radiologists should include periodic on-site anaphylaxis simulation focusing on recognizing anaphylaxis, administering both pharmacological and non-pharmacological treatments, and testing pathways, with an emphasis on task distribution, positioning, calling for help, administering adrenaline, fluids, providing oxygen, and monitoring respiratory and cardiovascular function.^8,125 Exploring clear emergency protocols within the pathway is also essential: What is the exact procedure in an emergency? Who is responsible for what? Where is the emergency equipment stored? A written, easily accessible emergency plan detailing necessary drugs and dosages is critical (see Fig. 4). Emergency equipment for anaphylaxis treatment must be readily available (Table 1).

Fig. 4.

EAACI schematic illustration of the initial management of anaphylaxis. With permission from: Muraro A, Worm M, Alviani C, Cardona V, DunnGalvin A, Garvey LH et al. EAACI guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357–77

Table 1.

Essential emergency preparedness and post-reaction documentation for acute drug hypersensitivity reactions in radiology and other intravenous infusion services.

Emergency preparedness
Monitoring equipment	Stethoscope; blood pressure monitor; pulse oximeter (and, where available, blood glucose meter).
Intravenous access	Tourniquet; intravenous catheters (various sizes); syringes; infusion set; adhesive tape for catheter fixation.
Airway and oxygen equipment	Oxygen supply; nebulizer set with oxygen masks (various sizes); bag-valve-mask (various sizes); suction device; guedel airway where appropriate.
Circulatory support	Intravenous fluids (eg, balanced electrolyte solution).
Emergency medication	Adrenaline (epinephrine); glucocorticoid; H1-antihistamine; short-acting β2-agonist (eg, inhaled salbutamol, preferably via nebulizer, or metered-dose inhaler with spacer).
Resuscitation equipment	Automated external defibrillator.
Essential clinical documentation following a hypersensitivity reaction
Patient and exposure details	•Date of reaction(s) •Name of culprit contrast medium (trade and international non-proprietary name) •Indication for contrast administration •Dose and route of administration
Clinical presentation	•Manifestations, symptoms and severity •Reaction kinetics (time of onset, progression and course) •Duration of symptoms
Management	•Treatment administered and response to treatment
Relevant background	•Possible cofactors and comorbidities •Previous hypersensitivity reactions •Previous tolerance of alternative contrast media
Future planning	•Alternative contrast media available within the institution for future imaging studies

Recommended emergency equipment and minimum clinical documentation following an acute drug hypersensitivity reaction. The emergency equipment list is adapted from the German anaphylaxis guideline and should be modified according to local resources and institutional protocols. Standardized documentation facilitates subsequent allergy evaluation, optimization of future management, and prevents the loss of clinically relevant information following the acute event

Documentation of hypersensitivity reactions

Critical clinical information may be lost if DHRs are not promptly and adequately documented. This applies particularly to dermatologists, emergency physicians, general hospitalists, or general practitioners who may evaluate patients days after CM exposure. Specific clinical details are essential for later allergy workup (Table 1), and failure to document them compromises future care. Identifying and recording the exact name of the CM involved is crucial for planning skin testing; unfortunately, in many institutions where multiple CM agents are in use, this information is often missing. From a pharmacovigilance and clinical governance perspective, failure to record the specific CM administered is inappropriate, as it compromises patient safety, impedes allergy investigation, and contravenes standards for drug accountability and traceability. Allergy departments should formally raise concerns with radiology teams and, where necessary, escalate the issue to hospital leadership if CM are not consistently documented.

For cutaneous reactions, photographs—ideally taken by the patient using their mobile phone—should be encouraged, with instructions to retain them for later review by the allergist. High-quality clinical images can assist allergists in distinguishing between urticaria, exanthems, and other lesions, enhancing diagnostic accuracy and assessment of plausibility and risk.

In cases of urticaria or anaphylaxis, at least 1 serum tryptase level should be obtained 0.5–2 h after symptom onset (or postmortem, if applicable), in addition to appropriate acute treatment.^126,127 Comparing the acute value with the patient's baseline tryptase helps identify mast cell activation, which is supported by an acute tryptase concentration exceeding (1.2 × baseline tryptase) + 2 μg/L, although the absence of such an increase does not exclude a clinical reaction. See section entitled "Management of hypersensitivity reactions to intravenous antibiotics" for further information on tryptase determination.

Referral to an allergy department

Because sensitization on skin testing to CM may wane over time (but not necessarily clinical hypersensitivity)—and future CM administration is often required—patients should be referred to an allergist as soon as possible following a DHR.¹²⁴ For this reason, testing should occur ideally within 6 months of the reaction, when skin testing results are most informative for selecting safe alternatives.

Non-immediate reactions may occur up to 10 days after CM administration—often after the patient has left the radiology department.¹²⁸ These reactions are frequently underreported, misdiagnosed (eg, confused with spontaneous exanthema or attributed to a different drug), and insufficiently documented, resulting in a limited understanding of their true epidemiology. While their management lies outside the radiologist's scope, radiologists should advise patients who develop delayed rashes (eg, maculopapular exanthems) to take photographs, document symptom chronology, and seek evaluation by an allergist or dermatologist for appropriate diagnosis and reporting. This could easily be achieved, for example, through the systematic use of aftercare information leaflets, which could also include the name of the CM used.

For the radiologist and the allergist

Prevention of future reactions

Radiologists and allergists should not rely solely on premedication to prevent CM–related DHRs, particularly in severe cases, as evidence shows it is often insufficient and current guidelines increasingly discourage its use in such scenarios.129, 130, 131 The efficacy of premedication for non-ionic CM is not well established, and glucocorticosteroids themselves can induce adverse effects.¹³² Antihistamine premedication may be considered for mild non-allergic immediate DHR, but it is not appropriate for preventing severe reactions.^118,133

Instead, changing the CM for the next examination and skin testing is recommended in patients who have experienced anaphylaxis or features suggestive of anaphylaxis (eg, urticaria) to CM, especially in more severe cases. It has been demonstrated that changing the CM was much more effective than premedication in preventing future reactions.¹³⁴ This preventive effect was greater when the alternative CM had a different side chain from the culprit.¹³⁵ Thus, in all patients with previous moderate to severe reactions, a CM should be chosen with a different side chain for future examinations.¹¹⁶

Furthermore, positive skin testing results to the culprit CM can help validate the selection of alternative CM agents that test negative, as these are more likely to be tolerated in future procedures.¹¹⁵ Even if not readily available within the hospital formulary, radiologists should make efforts to use a skin-test-negative CM, even if it involves additional logistical or financial burden.

Positive skin testing results in immediate DHRs are relatively uncommon—reported in approximately 17% of cases—but are strongly correlated with reaction severity.¹³⁶ The relatively low positivity rate likely reflects, at least in part, the heterogeneous mechanisms underlying immediate CM reactions, not all of which are IgE-mediated, together with reduced skin test sensitivity as the interval between the index reaction and allergy evaluation increases.^124,136 Patients with negative skin testing results generally have milder initial reactions and may be safely managed with adequate emergency preparedness and antihistamine premedication if re-exposure is required.¹³⁷ However, we must keep in mind that false negatives are possible when a long interval has elapsed between the reaction and testing.¹²⁴

Importantly, regardless of whether the DHR was immediate or non-immediate, the original culprit CM should not be re-administered unless hypersensitivity has been definitively ruled out through a negative drug challenge or an uneventful monitored re-exposure. Avoiding the culprit agent is more effective at preventing recurrence than premedication alone.¹³³

Because of their limited sensitivity and specificity, skin testing is not a suitable strategy for pre-screening patients with no prior history of CM hypersensitivity.¹³⁸ However, reducing the contrast dose and slowing the injection rate during computed tomography procedures has been associated with a decreased incidence of HR and may be considered as a preventive measure.¹³⁹

Urgency and setting for reexposure

Severe immediate DHRs are more likely to be allergic in nature and associated with positive skin testing results.^136,137 For patients experiencing mild immediate DHRs (eg, urticaria/angioedema) or non-immediate DHRs (eg, uncomplicated maculopapular exanthem), and with an urgent need for CM, a non-culprit CM may be administered without prior allergy testing, provided the radiology setting is well-prepared for anaphylaxis management, ideally with direct access to an intensive care unit.^114,115 In cases of anaphylaxis, CM should be avoided unless deemed essential following a favorable risk-benefit assessment, and its administration should be conducted with anesthesiology on standby.¹¹⁴ Multidisciplinary SOPs and pathways should be approved between allergy and radiology to ensure consistency of safe care.

Following allergy evaluation with skin testing, patients with a history of mild immediate or non-immediate DHR may undergo reexposure to a non-culprit CM (ie, 1 with negative ST or no positive reaction to any CM) in a radiology setting. For those who have experienced severe anaphylaxis, a drug challenge should be considered, typically using a skin testing-negative alternative.

For the allergist

Intradermal & patch tests with undiluted CM

Skin testing should first be conducted using the culprit CM, if known. If the result is positive, or if the culprit is unknown, a panel of CM should be tested, as cross-reactivity between CM can occur.^140,141 The allergist should prioritize testing those CM that are available in the department where the next procedure is planned or those commonly used in clinical practice. Typically, intradermal tests are carried out at a 1:10 dilution for both immediate and non-immediate DHRs, though preparing these dilutions can be time-consuming.^115,124 Patch testing is also helpful for non-immediate DHRs. It is carried out with undiluted CM and is recommended as the initial step skin test in severe cutaneous adverse reactions, before proceeding to delayed-reading intradermal testing if reported negative.^114,142 Patch testing can also be used in fixed drug eruptions via a lesional ‘in situ’ testing approach.¹¹⁴ For non-severe reactions, undiluted CM delayed-reading IDT can be used for non-immediate DHRs with good specificity. Undiluted CM intradermal tests have also been used for immediate DHRs.¹⁴³ However, if a positive reaction occurs, retesting with a 1:10 dilution is necessary to ensure greater specificity.

The diagnostic yield of skin testing depends on the underlying reaction mechanism and varies between IgE-mediated, non-IgE-mediated, and T-cell-mediated reactions; therefore, results should always be interpreted in the context of the clinical history.^114,115

Drug challenge

Drug challenge, as opposed to re-exposure in cases of medical necessity, is usually performed in patients with moderate to severe DHRs, and only in well-equipped centers with trained personnel capable of managing immediate emergency treatment.¹¹⁴ Decisions regarding future avoidance, drug challenge, or re-exposure should be based on a careful risk-benefit analysis for each patient. CM has been associated with kidney damage, and patients with reduced renal function are at a higher risk. Renal contraindications for CM must be excluded, and kidney function should be closely monitored. While available protocols are neither standardized nor validated and vary between centers, we recommend administering 3–4 incremental doses, with intervals of 30–120 min (for immediate reactions), up to a maximum of 1/3 to 2/3 of the dose required for the patient's procedure, as a standard approach. Nevertheless, dosing schemes and intervals may differ between centers or depend on different factors such as pre-test probability, severity, or the type of reaction (eg, immediate vs non-immediate).

Information for the radiologist

The radiologist relies heavily on the information provided after the allergy evaluation. This information should be clearly documented following a full allergy workup, with a telephone number or email address included for further inquiries.¹⁴⁴ Allergy reports may contain detailed information that could be more specialized than what is typically required in the radiology setting, potentially hindering straightforward interpretation. Therefore, a drug allergy passport should be issued, containing key information on future CM use, including details on CM to be avoided, symptoms of reactions, tests performed, skin testing-negative and/or tolerated alternatives, premedication advice, and any recommended clinical settings for administration.^46,114

Miscellaneous—Infusion reactions to intravenous immunoglobulin

Infusion reactions are not limited to the most common drugs mentioned above. A range of miscellaneous agents—including intravenous immunoglobulin (IVIG), iron preparations, and enzyme replacement therapies—are increasingly used across specialties, as discussed in a recent WAO document.¹ We will focus on IVIG, which plays a central role in both replacement and immunomodulatory therapy and is associated with a spectrum of infusion-related adverse events. Recognizing these reactions, understanding their pathophysiology, and determining when to involve allergy specialists are essential for optimizing patient care and ensuring treatment continuity.

Indications and formulations

IVIG is commercially available in various concentrations (3%–12%) and contains pooled human polyclonal IgG, with a subclass distribution similar to native serum. Small amounts of IgA, IgE, and IgM are also present, but IgE and IgM are essentially eliminated during the manufacturing process. Most IVIG preparations contain only 1 excipient, ie, l-proline, glycine, maltose, or glucose, with only Iqymune® containing glycine and polysorbate, but there might be differences in osmolarity and pH between formulations. Clinical indications for IVIG include immunoglobulin replacement in primary or secondary immunodeficiencies (typically 200–600 mg/kg every 3–4 weeks), as well as immunomodulatory therapy for autoimmune or inflammatory disorders, where high-dose regimens such as 2 g/kg, administered within 1–5 days (0.4 g/kg/day in protocols of 5 days), every 4–6 weeks, are often used.145, 146, 147, 148, 149

Infusion-related adverse reactions

Although rates can vary depending on the product, underlying condition, and infusion protocol used, adverse reactions occur in approximately 5–10% of patients, most often during the first infusion. These are usually mild and relate to a combination of product-specific and patient-specific factors. Product characteristics that influence tolerability include infusion volume and rate, osmolarity, pH, excipients (eg, sugars or stabilizers), and IgA content. On the patient side, age, comorbid conditions (especially renal or cardiac disease), diabetes, and IgA deficiency can modulate risk.145, 146, 147, 148, 149

Common reactions

The most frequent adverse effects are mild to moderate and include headache, myalgia, arthralgia, chills, nausea, vomiting, flushing, urticaria, bronchospasm, and transient blood pressure changes. These reactions typically arise within the first hour of infusion and are managed by temporarily halting or slowing the infusion rate. Premedication with paracetamol, antihistamines, or non-steroidal anti-inflammatory drugs (NSAIDs) may help prevent recurrence, particularly in patients receiving high-dose regimens or those with prior symptoms.145, 146, 147, 148, 149

Severe reactions

Although rare, severe reactions may occur and merit particular attention. Aseptic meningitis is more likely in patients with a history of migraines and can often be avoided by slow infusion and NSAID premedication. Acute kidney injury, typically linked to the currently abandoned sucrose-containing or hyperosmolar preparations, underscores the importance of using low-osmolarity formulations and assessing renal function before administration, especially in high-risk patients. Myocardial infarction and thromboembolic events (eg, DVT, stroke) have also been described, potentially linked to hyperviscosity or activated factor XI in some preparations. In such cases, preventive measures such as low-dose aspirin (eg, 325 mg orally) and mobility assessments are advisable. Anaphylaxis, while extremely rare, is of particular concern in IgA-deficient individuals sensitized to trace amounts of IgA and may require the use of more extensively IgA-depleted products.145, 146, 147, 148, 149

Referral and investigations

In the event of suspected anaphylaxis, serum tryptase should be collected to aid diagnosis. Referral to an allergy specialist is recommended after severe reactions, unclear reaction mechanisms, or when IVIG remains clinically necessary despite adverse events. In clinical practice, evaluation often includes assessment for alternative triggers—such as chlorhexidine, latex, or other hidden allergens—although in many cases no definitive cause is identified. Pragmatic strategies may involve switching to a different IVIG brand, considering batch-to-batch variability, or altering the administration route (eg, IV to SC) when feasible. The occurrence of marked acute tryptase elevation despite a negative subsequent allergy work-up, sometimes including a negative drug challenge, highlights that, although an acute tryptase rise provides important evidence of mast-cell activation and may support a diagnosis of allergy, it does not necessarily establish an IgE-mediated mechanism or confirm the suspected drug as the trigger. Such findings should therefore be interpreted cautiously in the context of the clinical phenotype and subsequent allergy investigation, with consideration of non-IgE-mediated or other incompletely understood mechanisms of mast-cell activation. Collaboration with allergy services therefore remains essential to develop personalized management plans, including biomarker sampling, skin testing, drug challenge, or RDD, as appropriate. See supplemental material 5 for a real-life local protocol for adult patients receiving IVIG replacement therapy at the Hospital Clinico Universidad de Chile.145, 146, 147, 148, 149

Pediatric aspects

In the pediatric population, the primary indication for intravenous medication use is the treatment of infectious diseases. Although immediate DHRs are rare, they can be severe and warrant prompt allergy evaluation. A major challenge in this age group is the high prevalence of viral-induced exanthems, which often mimic drug hypersensitivity reactions and contribute to frequent overdiagnosis of antibiotic allergy.150, 151, 152 Other spontaneous cutaneous eruptions, including urticaria, are common in children in the context of infections, further complicating clinical assessment.^150,153 In the context of short-term management, a detailed clinical history is essential to establish an accurate reaction profile and inform risk stratification, as selected reactions may be managed by “treating through” following appropriate assessment, thereby avoiding unnecessary interruption of effective therapy.^23,151,153, 154, 155 To support optimal long-term management, referral to allergy services at discharge is essential, enabling comprehensive evaluation—most critically including drug challenge to establish an accurate diagnosis and reduce unnecessary drug allergy labeling in children.^2,27,155, 156, 157 In cases of benign, non-immediate cutaneous reactions to beta-lactams and most oral antibiotics, skin testing offers limited diagnostic utility, and recent evidence supports the use of direct drug challenge without prior skin testing in selected children.^2,158, 159, 160 The evidence base for diagnosis and management of DHRs to intravenous drugs in children remains limited, owing to infrequent use and the smaller number of tests conducted in pediatric allergy departments when compared to adults.

It is crucial that general pediatricians maintain a foundational understanding of drug allergy to enable timely referral following a suspected reaction. Ideally, involvement of a pediatric allergy team during the acute phase can ensure thorough documentation of the episode—including the implicated drug(s), timing, and symptom profile—thereby optimizing subsequent diagnostic workup. Early specialist input can also help guide acute management, support selection of safe alternatives, or implement RDD when the index drug remains clinically indispensable.^1,2

Children with cystic fibrosis represent a distinct pediatric population that frequently receives intravenous antibiotic therapy, particularly beta-lactams. Although studies suggest an increased prevalence of suspected DHRs in these patients, recent data—including systematic allergy workup with drug challenge—indicate that the rate of confirmed beta-lactam allergy is comparable to that of the general pediatric population, suggesting that most reactions do not represent true allergy.^2,161,162

Children with primary and secondary immunodeficiencies, particularly those affected by HIV, constitute an additional high-risk population. In these patients, the infectious burden is markedly elevated, necessitating frequent administration of parenteral antibiotics, antivirals, antifungals, and trimethoprim-sulfamethoxazole, in conjunction with IVIG.¹⁶³ Variable anaphylaxis rates (0.3% vs 10.6%), predominantly triggered by drugs and food, reinforce the findings of El-Sayed et al. that allergic manifestations are integral to inborn errors of immunity and demand close immunologist–allergist collaboration.¹⁶⁴

Infusion-related hypersensitivity reactions can also occur with enzyme replacement therapies, such as those used for mucopolysaccharidoses, including anaphylaxis.^165,166

These findings reinforce the critical role of comprehensive allergy assessment to accurately confirm or exclude drug hypersensitivity. Effective coordination between pulmonologists, gastroenterologists, pediatricians, and infectious disease specialists is essential—not only to guide the timing and components of the allergy workup, but also to ensure optimal antibiotic management during acute illness. This is particularly important when RDD may be required to enable continued use of a first-line agent. In pediatric practice, weight-based dosing adds an additional layer of complexity, underscoring the need for close collaboration between ward-based pediatricians and allergy specialists to minimize the risk of dosing errors and ensure, for example, safe and effective implementation of RDD, which need to be adapted individually to the patient's age and characteristics.^1,2,167,168 Because younger children may struggle to report symptoms accurately, and clinical history is frequently obtained from parents; this process benefits from the guidance of an experienced pediatric allergist.

The use of biologics in pediatric populations is steadily increasing across a range of conditions, and with it, the incidence of hypersensitivity reactions is also rising. Despite this trend, data on hypersensitivity to biologics in children remain limited. In particular, current classifications—including clinical endophenotypes—are poorly defined in pediatric patients.^2,169 There is also an urgent need to standardize protocols in children, including premedication strategies and desensitization procedures, which are usually extrapolated from adult practice without pediatric-specific validation.^1,2,167,168 Moreover, the diagnostic utility of available tools—including ST and the basophil activation test—warrants systematic evaluation in pediatric cohorts.^170,171 In pediatric oncology, where intravenous administration of both biologics and chemotherapeutic agents is common, DHRs pose significant therapeutic challenges. As with biologics, large-scale studies are essential to determine the reliability of diagnostic tests and to develop evidence-based, standardized RDD protocols tailored to children.^1,2

Perioperative reactions, while rare in children, can result in severe anaphylaxis and present significant diagnostic challenges.^2,172 Hypersensitivity to intravenous agents administered during surgical procedures is infrequent in the pediatric population, and published data remain limited. As in adults, acute-phase serum tryptase measurement may aid in the diagnosis of POH reactions. Because respiratory symptoms typically predominate in pediatric anaphylaxis, tryptase elevations are less frequently observed. However, as POH in children appears to involve cardiovascular features more often than respiratory ones, further data are needed to determine the diagnostic utility of tryptase in this setting.¹⁷³ Close collaboration between anesthesiologists and pediatric allergists is essential to ensure thorough documentation of the reaction, which informs the design of an individualized allergy workup.^2,101,103 As explored in Section 5 of this article, standardized referral pathways with specific documentation requirements, including detailed proformas with a timeline of all exposures, are fundamental. Importantly, intradermal testing is technically more difficult to perform in young children, and perioperative allergy evaluation often requires multiple such tests conducted by experienced allergists.^2,174 Further pediatric-specific studies are urgently needed to clarify the diagnostic accuracy and predictive value of currently employed testing strategies in this setting.

Conclusions

Hypersensitivity reactions to intravenous agents pose significant challenges across healthcare settings, particularly at the point of infusion, when allergists are often not present. Early management is usually led by professionals from other specialties—including oncology, anesthesia, radiology, or infectious diseases—who may lack the allergy-specific training or protocols necessary for optimal care. Without coordinated systems of care, this can delay diagnosis, compromise patient safety, interrupt essential therapies, and fragment long-term follow-up.

Addressing these challenges requires more than timely referral after a reaction has occurred. Throughout this Statement, we advocate a shift from the traditional reactive referral model towards proactively integrating allergy services as essential partners within multidisciplinary hospital care pathways. Allergy departments should provide proactive leadership through early engagement, shared protocols, joint educational initiatives, robust hospital-wide governance frameworks, and structured referral pathways that enable allergy expertise to support patient care before, during, and after acute reactions, regardless of the organizational model adopted.

Successful examples of this collaborative approach already exist. The multidisciplinary UK Perioperative Allergy Network (PAN), which formally brings together national societies in allergy, anesthesia, and immunology, demonstrates how coordinated leadership across specialties can establish shared standards and improve patient care nationally. Likewise, the real-world service models presented in the supplemental material—including inpatient mobile allergy teams and structured inpatient penicillin delabeling programs—illustrate how these principles can be successfully implemented across different healthcare settings when allergy departments take an active role in designing proactive models of care. Models that integrate allergy departments with hospital-wide governance and multidisciplinary teams are particularly effective in sustaining improvements and ensuring continuity across settings.

As reactions to intravenous medications become increasingly complex, allergy departments should no longer be viewed solely as providers of specialist consultations, but as integral partners in the delivery of safer hospital care. Organizational models will inevitably differ between healthcare systems, but the principles of early specialist involvement, multidisciplinary collaboration, robust governance, innovation in service design, continuous quality improvement, and continuity of care should be universal. The future of inpatient drug hypersensitivity care lies not in reacting better once hypersensitivity has occurred, but in designing healthcare systems in which allergy expertise is embedded before, during, and after the event. Ultimately, the greatest impact of allergy services extends beyond the diagnosis and management of individual hypersensitivity reactions to providing proactive clinical leadership that prevents avoidable harm and delivers safer, more consistent care.

Author contributions

Madrigal-Burgaleta (Lead of the document's Task Force), Ansotegui (Executive Medical Director of the WAO), and Alvarez-Cuesta (Co-Chair of the WAO Drug Hypersensitivity Reactions Committee), contributed to conceiving, designing, editing, and revising the manuscript.

Steering Committee Authors Madrigal-Burgaleta, Alvarez-Cuesta, Brockow, Caubet, Garvey, Guzman-Melendez, Labella Alvarez, Mayorga, Vazquez-Revuelta, and Ansotegui, performed the literature research and drafted their specific sections.

Alvarez-Cuesta, Ansotegui, and Madrigal-Burgaleta co-authored the introduction and conclusion. Labella, Madrigal-Burgaleta, and Mayorga co-authored sections entitled "Management of hypersensitivity reactions to intravenous antibiotics" and "Penicillin delabeling in inpatients". Vazquez-Revuelta, Madrigal-Burgaleta, and Alvarez-Cuesta co-authored "Chemotherapy and biologics". Garvey authored "Perioperative anaphylaxis". Brockow authored "Contrast media". Guzman-Melendez authored "Miscellaneous-Infusion reactions to intravenous immunoglobulin". Caubet authored "Pediatric aspects". All the Steering Committee authors accepted the final version of the manuscript. Any supplementary material was kindly provided individually by the authors of each section.

A Review Panel of experts from all around the globe, all members of the WAO Drug Hypersensitivity Reactions Committee, critically reviewed the manuscript and accepted the final version of the manuscript. All the review panel members sent a review with modifications to the manuscript that were duly implemented and equally contributed to the discussions.

Ethics approval

Ethics approval not applicable.

Consent for publication

All authors gave their consent to publish this work.

Availability of data and material

Not applicable.

Submission declaration

The authors confirm that this manuscript is original, has not been published before, is not currently being considered for publication elsewhere.

Use of generative AI and artificial intelligence technologies declaration

During the preparation of this work the authors used ChatGPT for basic checks of grammar, spelling and punctuation. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Funding

Not applicable

Declaration of competing interest

R. Madrigal-Burgaleta has received research grants from the National Institute for Health and Care Research (NIHR; UK), Junta de Andalucía (Spain), Midlands Asthma and Allergy Research Association (UK), and Leeds Teaching Hospitals NHS Trust Research and Innovation Department (UK), all outside the submitted work. He has received honoraria from Opella for advisory board participation, and from Roxall and Fundacion Martifabra for educational activities. He has received non-financial support, including travel support for scientific and educational activities, from the World Allergy Organization (WAO), the European Academy of Allergy and Clinical Immunology (EAACI), the British Society for Allergy and Clinical Immunology (BSACI), Novartis, and Alergonorte. All these relationships were outside the submitted work.

Appendix A. Supplementary data

The following are the Supplementary data to this article.