Hypersensitivity reactions are common and can present across virtually all medical specialities. The diagnostic label of “allergy” is often applied when patients present with rashes, respiratory symptoms, or systemic reactions following exposure to drugs, foods, or environmental agents. However, not all such reactions are truly immunoglobulin E (IgE)-mediated. Understanding the mechanisms, clinical presentations, and management of non-IgE hypersensitivity reactions and their mimics is essential for accurate diagnosis and safe, targeted care.

Originally coined to describe altered reactivity to a stimulus, it has historically encompassed both immune responses to external allergens—such as foods, venoms, or drugs, and immune dysregulation against self-antigens, as seen in autoimmune diseases.

In modern clinical practice, allergy is frequently equated with IgE-mediated (Type I) hypersensitivity reactions [1], which are rapid in onset and can be life-threatening. However, IgE-mediated responses represent just one of several immune pathways capable of causing symptoms that mimic allergy. These mechanisms were first categorised by Gell and Coombs [2], who proposed four types (I–IV) of hypersensitivity based on the underlying pathophysiology. Recently, the European Academy of Allergy and Clinical Immunology (EAACI) expanded on the Gell and Coombs classification to include types V–VII [3]. See Table 1 for a summary.

This review will focus on Type I reactions and their mimics, their clinical presentations, diagnostic challenges, and management strategies, particularly using mast cell mediators such as serum tryptase for diagnosis. The goal is to offer clarity on how to accurately differentiate between these hypersensitivity types, ensuring that patients receive targeted, safe, and effective care. We begin by briefly outlining the different types of hypersensitivity before focusing on IgE-mediated mechanisms and their clinical expression. The subsequent sections explore diagnostic tools, the role of cofactors and hidden allergens, and emergency and long-term management. The review then turns to common and rare mimics of Type I reactions, including urticaria variants, bradykinin-mediated angioedema, and mast cell disorders. We conclude by highlighting key clinical points and proposing directions for future research and improved clinical pathways.

Type I reactions are immediate and IgE-mediated. In this type, allergen-specific IgE antibodies bind to mast cells and basophils. Upon re-exposure to the allergen, these antibodies cross-link, triggering degranulation and the release of mediators like histamine. Symptoms usually appear within seconds to minutes and include anaphylaxis, urticaria, allergic asthma, rhinitis, diarrhoea and vomiting. Diagnosis often involves skin testing, specific IgE measurement, and assessment of serum tryptase levels. Acute management focuses on adrenaline for anaphylaxis, antihistamines, corticosteroids, and allergen avoidance. Longer-term options for specific cases can include allergen immunotherapy (AIT) and biologics such as omalizumab [3].

Type II reactions are cytotoxic, mediated by IgG or IgM antibodies. These antibodies bind to cell surface antigens, leading to complement activation, phagocytosis, or antibody-dependent cellular cytotoxicity (ADCC), resulting in cell destruction, functional alteration if directed against cell surface receptors, or tissue damage. The onset of these reactions typically occurs within hours to days and includes conditions such as autoimmune haemolytic anaemia, thrombocytopenia, Goodpasture syndrome, and transfusion reactions. Diagnosis involves tests like the Coombs test and detection of autoantibodies. Treatment aims to remove the trigger, using immunosuppressive drugs, transfusion support, or plasmapheresis as necessary [3].

Type III reactions are immune complex-mediated. Soluble antigen-antibody complexes deposit in tissues, activating complement and neutrophils, causing inflammation. These reactions usually appear over days to weeks and are seen in conditions such as serum sickness, lupus nephritis, and hypersensitivity pneumonitis. Diagnosis is based on low complement levels, biopsy to identify immune complexes, and inflammatory markers. Management includes antigen avoidance, corticosteroid, and immunosuppressive treatments [3].

Type IV reactions are delayed and T cell mediated. These reactions involve antigen-specific T lymphocytes that trigger inflammation. There are several subtypes of Type IV reactions. Type IVa involves T helper 1 (Th1) cells and macrophages, causing conditions like contact dermatitis and coeliac disease. Type IVb involves Th2 cells and eosinophils, contributing to chronic asthma, atopic dermatitis, and eosinophilic esophagitis. Type IVc reactions are mediated by cytotoxic T cells and include severe conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Type IVd reactions are neutrophilic, as seen in acute generalized exanthematous pustulosis (AGEP). AGEP reactions have a typical onset 24–72 hours after exposure. Diagnosis is often through patch testing, biopsy, or cautiously conducted drug provocation tests. Treatment strategies include antigen avoidance, corticosteroids, immunosuppressive agents, and biologics in severe cases [3].

Type V hypersensitivity is characterised by epithelial barrier defects that impair immune regulation, leading to chronic inflammation. The breakdown of the skin or mucosal barrier allows allergens and microbes to trigger immune responses, involving T helper cells (Th1, Th2, Th17) and the loss of regulatory cells, resulting in tissue damage. Conditions like asthma, chronic allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food protein-induced enterocolitis syndrome are linked to this mechanism. Environmental factors such as pollutants, chemicals, and allergens can disrupt the barrier, exacerbating symptoms. Clinical features include inflammation, hypersensitivity, and tissue damage in affected organs. Management focuses on allergen avoidance, corticosteroid, immunosuppressants, and biologic treatments targeting immune pathways like alarmins [3].

Type VI hypersensitivity involves metabolic-induced immune dysregulation, where conditions like obesity and diabetes influence immune responses. Obesity, particularly in asthmatic patients, exacerbates inflammation due to altered inflammatory mediators from adipose tissue and metabolic dysfunction. Increased circulating cytokines, chemokines, and reactive oxygen species contribute to airway inflammation, and gut and lung microbiome alterations are also implicated. This leads to chronic low-grade inflammation, impaired epithelial barriers, and enhanced immune responses. Clinical manifestations include obesity-associated asthma, increased airway remodelling, and systemic inflammation. Management focuses on weight control, addressing metabolic dysfunction, and targeting inflammatory pathways, with potential treatments including corticosteroid and biologics [3].

Type VII hypersensitivity involves direct cellular and inflammatory responses to chemical substances, particularly in conditions like allergic rhinitis, allergic conjunctivitis, asthma, atopic dermatitis, acute urticaria/angioedema, and drug allergies. A key example is aspirin-exacerbated respiratory disease (AERD), where non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase enzymes, leading to an overproduction of inflammatory mediators like cysteinyl leukotrienes, resulting in asthma, nasal polyps, and hypersensitivity. Another example involves NSAID reactions, where cross-reactivity causes respiratory or cutaneous symptoms. Recent research highlights a possible role of Mas-related G protein-coupled receptor X2 (MRGPRX2) in mediating anaphylactoid reactions to drugs like neuromuscular blockers and fluoroquinolones. A group of cationic peptidergic drugs, including icatibant, a bradykinin B2 receptor antagonist used in the management of hereditary angioedema, has been found to cause mast cell degranulation via MRGPRX2, leading to local injection site reactions [4]. Management includes avoiding triggering substances, managing symptoms with corticosteroid and leukotriene modifiers, and targeting specific immune pathways [3].

Some reactions, particularly cytokine release syndrome or ‘cytokine release reactions’, seen in drug reactions such as those triggered by biologics, exhibit mixed features that do not neatly fit into the established types. These reactions can present with chills, fever, malaise, flushing and hypotension. They can be associated with elevation in mast cell tryptase and interleukin (IL)-6, and require tailored diagnostic and therapeutic approaches [5].

IgE-mediated allergic reactions are Type I hypersensitivity reactions that develop as a consequence of a coordinated adaptive immune response, involving both T and B lymphocytes. For T cell activation to occur, antigens must first be processed and presented by professional antigen-presenting cells (APCs), which display antigenic peptides via major-histocompatibility-complex (MHC) class II molecules to the T cell receptor (TCR). This antigen-specific interaction alone is insufficient; a second, co-stimulatory signal is also required to achieve full T cell activation. Once activated, T cells proliferate and differentiate into effector subsets with specialised immune functions.

In the context of allergic sensitisation, Cluster of differentiation 4-positive (CD4⁺) T helper cells—particularly the Th2 subset—produce cytokines such as interleukin (IL)-4 and IL-13, which together are the first signal to promote immunoglobulin class switching in B cells, leading to their differentiation into IgE-producing plasma cells. The second signal is provided by accessory pairs of molecules, such as $\alpha$_L $\beta$₂ integrin and intercellular adhesion molecule 1 and cluster of differentiation 40 (CD40) and its ligand (see Fig. 1, Ref. [6]). Additional cytokines, including IL-3 and IL-5, support the maturation and mobilisation of eosinophils from the bone marrow. These cells migrate into peripheral tissues and contribute to the propagation of allergic inflammation [6]. IgE antibodies secreted by plasma cells circulate in the serum and also bind to high-affinity IgE receptors (Fc$ϵ$RI) on the surface of mast cells and basophils, and to a lesser extent on other cell types such as platelets. Mast cells, in particular, play a central role in the effector phase of the allergic response by storing and releasing inflammatory mediators upon allergen re-exposure (see Fig. 1, Ref. [6]).

Fig. 1.

Interactions between cluster of differentiation 4 (CD4) T cells and B cells that are important in IgE synthesis. Interleukin-4 and interleukin-13 provide the first signal to B cells to switch to the production of the IgE isotype. The second signal is provided by accessory pairs of molecules, such as $\alpha$_L $\beta$₂ integrin and intercellular adhesion molecule 1 and CD40 and its ligand. The engagement of allergen by the complex of the T cell receptor and CD3 on major-histocompatibility-complex (MHC) class II B cells results in the rapid expression of the CD40 ligand. Once formed, IgE antibody circulates in the blood, eventually binding to both high-affinity IgE receptors (Fc$ϵ$RI) and low-affinity IgE receptor (Fc$ϵ$RII, or CD23). After subsequent encounters with antigens, binding of the high-affinity IgE receptors produces the release of preformed and newly generated mediators. Once present in various tissues, mediators may produce various physiological effects, depending on the target organ [6]. From Busse WW, Lemanske RF Jr. Asthma. New Engl J Med. 2001; 334: 350–362. Copyright © (2001) Massachusetts Medical Society. Reprinted with permission from Busse et al. [6], Massachusetts Medical Society.

This sensitisation phase establishes the immunological basis for immediate hypersensitivity reactions upon subsequent contact with the relevant allergen.

In the absence of allergen, IgE bound to the surface of mast cells, basophils, or other effector cells remains inert and does not cause harm. However, when the corresponding allergen is present and binds to the surface-bound IgE, it induces cross-linking of adjacent IgE molecules. This cross-linking triggers cellular activation and initiates the allergic cascade.

Mast cells contain preformed granules packed with potent mediators, including enzymes such as tryptase and chymase, and vasoactive substances like histamine. Upon activation, these granules are rapidly released, resulting in acute physiological changes such as increased vascular permeability and smooth muscle contraction—hallmarks of the immediate phase of IgE-mediated allergy [1, 6].

In addition to releasing preformed mediators, activated mast cells secrete cytokines, including interleukin-4 (IL-4), IL-5, and IL-13, which contribute to the amplification and maintenance of the allergic response. A more delayed process involves enzymatic degradation of the mast cell lipid membrane, leading to the production of lipid-derived mediators such as leukotrienes. These further enhance vascular permeability and bronchoconstriction, contributing to the late-phase response [1, 6]. Common allergens capable of inducing such reactions include peanut, bee and wasp venom, and certain drugs.

Although IgE cross-linking is a classical activation pathway, mast cells can also be triggered via alternative mechanisms. These include engagement of Fc gamma (Fc$\gamma$) receptors by IgG, complement receptors by activated complement components—particularly relevant in contrast media hypersensitivity—and MRGPRX2 [7], as illustrated in Fig. 2 (Ref. [8]). MRGPRX2 can be directly activated by a range of pharmacological agents, including vancomycin, quinolones, and certain neuromuscular blocking agents. Importantly, mast cell activation via MRGPRX2 does not require prior sensitisation and may clinically mimic IgE-mediated reactions. Some drugs may activate mast cells through more than one of these pathways, underscoring the complexity of drug-induced hypersensitivity.

Fig. 2.

Main receptor systems and examples of ligands involved in mast cell activation. Mast cells can be activated by a number of receptor—ligand interactions, including allergen binding to IgE as depicted in red, complement components binding to complement receptors as depicted on the right of the figure, pathogen specific IgG binding to IgG receptors and binding of drugs or endogenous peptides to the transmembrane MRGPRX2 receptor, depicted in blue at the top of the figure. Some drugs may activate mast cells by more than 1 mechanism. Reprinted from Porebski et al. [8], available under the terms of the CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Fc$ϵ$RI, high-affinity IgE receptors; MRGPRX2, Mas-related G protein-coupled receptor X2; CR, complement receptor; CysLT1R/2R, cysteinyl leukotriene receptor 1/receptor 2; Fc$\gamma$RII, Fc gamma receptor 2 (IgG receptor); GM-CSF, granulocyte/macrophage colony-stimulating factor; IL, interleukin; KIT, mast/stem cell growth factor receptor (CD117); LPS, lipopolysaccharide; LTC4, leukotriene C4; mAbs, monoclonal antibodies; NMBA, neuromuscular blocking agents; PAR2, protease-activated receptor 2; PGN, peptidoglycan; SCF, stem cell factor; sIgE, specific IgE; TLR, Toll-like receptor; TNF, tumor-necrosis factor; QWF, tripeptide (the glutaminyl-D-tryptophylphenylalanine); VIP, vasoactive intestinal peptide; PAF, platelet activating factor; AutoAbs, autoantibody; IL-6, interleukin 6. Note: LL-37 is a 37-amino-acid peptide and the active form of the human cathelicidin antimicrobial peptide. The “LL” refers to the two leucine residues at the N-terminus.

The clinical history is of paramount importance in determining what is and what is not allergy (Type I hypersensitivity). When taking an allergy history, there are a few key features that should be included:

Symptoms: Are symptoms consistent with acute mast cell degranulation? Typical manifestations include urticaria, angioedema, flushing, nasal congestion, bronchospasm, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea), and hypotension.

Timing: IgE-mediated reactions are typically rapid in onset from allergen exposure, often within minutes, and not usually delayed by more than 1–2 hours.

Attributable allergen: Are symptoms attributable to a possible allergen?

Reproducible: Symptoms should be reproducible on repeat exposure, however, this can be modified by co-factors, see below.

Biomarkers can be of help in determining whether acute symptoms are a result of mast cell activation. Measurement of mast cell tryptase may confirm an acute mast cell degranulating event and may identify those rare patients with an underlying mast cell disorder [9]. Unlike histamine, which has a short half-life, making it an impractical biomarker in the context of acute allergy, mast cell tryptase has a half-life of approximately 2.5 hours. It is stable in serum at room temperature and does not require any special sample handling. An isolated normal mast cell tryptase result does not exclude allergy. A mast cell tryptase series is most helpful, with the first sample taken after any necessary resuscitation, with further samples at 1–2 and 24 hours or in convalescence [10]. A dynamic change, defined as the baseline mast cell tryptase $\times$ 1.2 + 2 $\mu$g/L [9], confirms mast cell activation. For example, if a patient has an acute mast cell tryptase of 11 $\mu$g/L (usual reference range 2–14), that could be misinterpreted as normal, but if their baseline is 3 $\mu$g/L, then the 11 $\mu$g/L result suggests acute mast cell degranulation. It may not be possible to measure a baseline level if a patient is discharged in a short time frame, but efforts should be made to do this in convalescence in primary care, or on referral to the allergy clinic.

Cofactors can exacerbate allergy, and in some circumstances, are necessary for the development of allergic symptoms. A good example is wheat-dependent, exercise induced allergy/anaphylaxis, where the combination of exercise and wheat consumption are required to elicit an allergic response [11]. Such patients are often seen in the emergency department in advance of allergy referral having presented with systemic symptoms. Additional cofactors such as NSAID use, or alcohol consumption may modify reactions. Another example of where cofactors, including exercise and NSAID use, can exacerbate allergic symptoms is in patients with lipid transfer protein (LTP) allergy, where patients have hypersensitivity to lipid transfer proteins of plant-derived foods [12]. Unlike the oral allergy syndrome, where patients usually have mild oral allergic symptoms on exposure to certain raw fruits, raw vegetables, and some nuts in the context of pollen allergy, LTP hypersensitivity can lead to anaphylaxis. Other cofactors modifying an allergic response include stress and infection. These types of food reactions could also lead to confusion about possible NSAID hypersensitivity, if NSAID is not recognised as a cofactor.

A number of hidden allergens can lead to more atypical presentations of IgE-mediated allergy. For example, in the medical setting, chlorhexidine allergy is a consideration in patients having otherwise unexplained allergic reactions in the operating theatre or following vascular or urinary catheterisation [13]. Alpha-gal syndrome refers to hypersensitivity to non-primate mammalian meat proteins in patients with a history of tick bite [14]. Tick bites can sensitise the human host to the oligosaccharide galactose-$\alpha$-1-3 galactose, derived from the non-primate animal. Allergic symptoms are typically delayed by 4–6 hours after eating non-primate mammalian meat (beef, pork, lamb) and predominantly affect the gastrointestinal system. Cofactors can also have a modifying role in alpha-gal-related reaction. This syndrome is important to recognise not only for management of acute episodes, but also to guide long-term avoidance, including advice with respect to surgery and anaesthesia, where mammalian products may otherwise be used, for example gelofusin.

Anaphylaxis is a severe, potentially life-threatening allergic reaction that occurs rapidly after exposure to an allergen. It is characterised by systemic mast cell and basophil activation, leading to the release of histamine and other mediators. Anaphylaxis is difficult to define, but common symptoms include hypotension, airway obstruction, urticaria, angioedema, and bronchospasm, with rapid onset within minutes to hours of exposure to the trigger. Anaphylaxis can progress quickly to cardiovascular collapse and respiratory failure, necessitating urgent treatment to prevent fatal outcomes [10].

The UK Resuscitation Council’s 2021 guidelines emphasise the rapid and systematic approach required to manage anaphylaxis, and are the recommended management pathway in the UK. The first-line treatment is intramuscular adrenaline, administered as soon as anaphylaxis is suspected. Adrenaline acts on alpha- and beta-receptors, leading to vasoconstriction, improved myocardial contractility, bronchodilation, and reduced mediator release, thus reversing the most dangerous effects of anaphylaxis. The recommended dose is 500 micrograms for adults, with a repeat dose after 5 minutes if necessary. Once adrenaline has been administered, the patient should be monitored closely, ideally in a hospital setting, as further reactions may occur. Patients must be placed in a comfortable position, which may vary depending on specific factors like pregnancy, and must not walk or stand during acute reactions [10]. See Fig. 3 (Ref. [10]).

Fig. 3.

Resuscitation Council UK anaphylaxis algorithm. Reproduced from Resuscitation Council UK [10], with the kind permission of Resuscitation Council UK. IV, intravenous; ECG, electrocardiogram; SpO; Peripheral Capillary Oxygen Saturation.

The 2023 guideline for the management of anaphylaxis in the peri-operative setting emphasises early intravenous adrenaline administration in this context [15], but this is beyond the scope of this review.

Following initial resuscitation, the management focuses on stabilisation and preventing recurrence. Oxygen should be provided if necessary, and intravenous fluids may be required to manage hypotension. Antihistamines and corticosteroids are now considered second-line treatments, as they do not provide immediate benefit in reversing the acute symptoms of anaphylaxis. These medications are used to reduce symptoms like urticaria or angioedema and prevent delayed-phase reactions, but they are not life-saving in the acute setting. Steroids, while helpful for inflammation (especially in the context of asthma exacerbation and anaphylaxis), take several hours to take effect and should not delay the administration of adrenaline [10].

In the emergency department (A&E), after initial treatment with adrenaline, patients should be observed for at least 4–6 hours. Fast-tracked discharge after 2 hours can be considered for patients with good response (within 5–10 minutes) to a single dose of adrenaline given within 30 minutes of onset of reaction, who have experienced complete resolution of symptoms, have access to unused adrenaline auto-injectors and appropriate training, and have adequate supervision following discharge. The patient’s clinical history, the severity of the reaction, and the allergen involved should be reviewed to guide further management, including specialist referral to an allergy department. Ensuring the patient has an adrenaline autoinjector for future use and providing appropriate education are crucial for long-term management [10].

All patients with systemic allergy should be issued with an allergy action plan and adrenaline autoinjectors with appropriate training. Patients should be advised regarding appropriate avoidance measures, to record their allergy within their mobile medical information, carry a medical emblem confirming the allergy, and electronic patient records should be updated at the time of allergy diagnosis [10].

Patients often present for medical attention with clinical features that resemble allergy but are not allergy-related. Depending on clinical context, common pathologies such as sepsis, haemorrhage, embolus, arrhythmia, or airway manipulation need to be considered in the differential diagnosis of hypotension and/or bronchospasm [16].

Other allergy mimics presenting to the emergency department include acute exacerbation of asthma or anxiety disorder, although other features of acute systemic allergy will be absent [16]. Vocal cord dysfunction, with involuntary paradoxical adduction of the vocal cords during inspiration, can present with dyspnoea, cough, wheeze and or inspiratory stridor [17]. A careful clinical history may differentiate this from anaphylaxis. The diagnosis is confirmed by direct observation of the vocal cords by laryngoscopy.

Flushing with medication or alcohol may be diagnosed from the clinical history.

A minority of patients presenting with allergic symptoms will have an underlying mast cell disorder, identified by mast cell tryptase assessment at the time of an acute event. Mast cell activation disorders is an umbrella term that describes typical clinical signs of severe, recurrent, episodic acute systemic mast cell activation, with objective evidence of mast cell mediator release on biochemical testing, with a dynamic rise in serum tryptase [9], and symptoms that respond to mast cell targeted therapy [33]. Mast cell activation disorders can be further subdivided into primary disorders, with KIT(KIT receptor tyrosine kinase) D816V mutated, clonal mast cells, with or without an underlying diagnosis of mastocytosis; secondary, where clonal disease is absent, but an IgE dependent allergy or other hypersensitivity reaction is detected; and idiopathic, where no KIT mutation or hypersensitivity trigger can be found [33]. Patients can have more than one type, for example, mastocytosis and IgE-mediated venom allergy. Patients with combined primary and secondary forms are at high risk for life-threatening anaphylaxis. Patients with a persistently elevated baseline mast cell tryptase with additional clinical features, such as skin lesions, musculoskeletal abnormalities or organomegaly, may have underlying mastocytosis. The classification of systemic mastocytosis has recently been updated [34], and there are a number of scoring systems that can be used to determine a patient’s risk, such as the Red Española de Mastocitosis score (REMA) score [35]. These patients can be complex and require expert, multidisciplinary assessment, and management. Other haematological malignancies, particularly myeloid malignancies, can also be associated with mastocytosis [36].

A recently recognised cause of a raised baseline tryptase is an increased copy number of the alpha tryptase gene, known as hereditary alpha tryptasaemia (HAT). Whilst this was initially thought to represent a distinct clinical phenotype [37], HAT has a reported prevalence of in the United Kingdom and France of 5–6%. Symptomatic patients can present with a constellation of symptoms, including those associated with mast cell activity, such as flushing, urticaria and pruritus. HAT is more common in patients with systemic mastocytosis [38] and can be a risk factor for anaphylaxis.

Neuroendocrine conditions may present with flushing and systemic symptoms. Carcinoid syndrome, for example, may present with flushing and gastrointestinal symptoms. Other gastrointestinal tumours that produce vasoactive components may mimic clinical features of allergy. Phaeochromocytomas more commonly present with intermittent headache, sweating and tachycardia. Intermittent hypertension rather than hypotension occurs in approximately 50% of patients, but orthostatic hypotension is recognised. Such differentials are considered in the allergy clinic when patients present with unusual, episodic reactions, in the absence of a reproducible trigger. Appropriate assessment, including 24-hour urine testing, may need to be considered, with referral to endocrinology for investigation.

This review highlights the importance of recognising Type I hypersensitivity reactions and differentiating them from a range of mimicking conditions. Accurate diagnosis depends on a thorough clinical history, timely recognition of key symptoms, and appropriate use of biomarkers such as serum tryptase. While IgE-mediated reactions follow well-characterised immunological pathways, overlapping symptoms with non-IgE and non-immune mechanisms—such as bradykinin-mediated angioedema or neuroendocrine tumours—can complicate clinical assessment.

Key messages include the early use of intramuscular adrenaline for anaphylaxis, the utility of the Symptoms, Timing, Attributable allergen, Reproducibility (STAR) approach in history taking, and the necessity of specialist referral in complex or atypical cases. Raising awareness of cofactors, hidden allergens, and pseudoallergic mechanisms also helps to avoid mislabelling and guide safe, individualised care.

Future research should focus on improving diagnostic accuracy through novel biomarkers and point-of-care testing. Clinical practice would benefit from greater interdisciplinary collaboration, particularly in perioperative and emergency contexts. Further guidance is needed on standardised pathways for evaluating suspected allergy and managing patients with overlapping or unclear phenotypes. Ultimately, advancing diagnostic precision will reduce harm, minimise unnecessary avoidance strategies, and improve outcomes for patients presenting with suspected allergic reactions.

$\bullet$ It is essential to differentiate between various types of hypersensitivity reactions, here particularly focusing on Type I, mast cell/IgE-mediated hypersensitivity, while recognising the other mechanisms and their presentations.

$\bullet$ Many conditions can mimic type I allergic reactions, and common medical emergencies associated with hypotension and bronchospasm should be considered in the differential diagnosis, for example, sepsis and asthma exacerbation.

$\bullet$ Early use of adrenaline in systemic allergy can be lifesaving and should not be delayed.

$\bullet$ Comprehensive clinical history is integral to allergy diagnosis, using the STAR method (Symptoms, Timing , Attributable allergen, and Reproducibility).

$\bullet$ Understanding when to refer patients to specialists is critical, especially when dealing with complex cases that may involve hereditary angioedema, clonal mast cell disorders, or other rare conditions.

All the data of this study are included in this article.

SLJ and RMB designed the study. SLJ and RMB contributed equally to the writing of the manuscript. SLJ prepared the figures and obtained the necessary reprint permissions. Both authors contributed to important editorial revisions of the manuscript. Both authors read and approved the final version of the manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Patient consent was confirmed for inclusion of medical imaging (Fig. 5). Ethical approval was not required for this review.

We gratefully acknowledge the patient for consenting to the use of clinical images in this publication.

This research received no external funding.

Neither author has any conflict of interest with respect to this publication. Both authors are members of the Perioperative Allergy Network Steering Committee, a UK-wide network created jointly by the British Society for Allergy and Clinical Immunology, the Association of Anaesthetists and the British Society for Immunology Clinical Immunology Professional Network. Neither author has any financial interests or other biases related to these institutions.