Increasing introduction of novel foods, especially from alternative protein sources, increases the need for reliable tools to assess allergenicity, particularly for assessing de novo sensitising capacity. Currently, there are no tools to predict de novo sensitisation, and as in silico and in vitro approaches cannot capture the complexity of the sensitisation process nor the associate clinical relevance, in vivo animal models remain the best option for developing such predictive tool. Thus, in this study, an adjuvant-free intraperitoneal Brown Norway rat model was developed to evaluate allergenicity and rank the sensitising capacity of six different well-known foods according to their allergenicity in humans and subsequently transferred to a CBA/J mouse model. Using a reference set of foods, ranging from low- to medium- to high-allergenicity, the rat model demonstrated clear and reproducible differentiation between foods, particularly when optimal dose and immunisation regimes were selected. Integration of multiple endpoints, including humoral (IgG1, IgE), functional (basophil activation), and clinical responses (ear swelling test and oral food challenge), enabled the assessment of sensitisation and supported the development of a composite sensitisation capacity ranking system with machine learning. Overall, the Brown Norway rat model was shown to be sensitive, with reproducible responses capable of distinguishing between foods with varying allergenicity. This study highlights the importance of selecting an appropriate experimental design and suitable endpoint parameters for assessing sensitisation and provides a promising step towards developing predictive tools for evaluating sensitising capacity of novel foods, although further validation using a larger set of reference foods is required.

Poly(ethylene glycol) (PEG) is a cornerstone excipient in drug delivery, widely used to prolong circulation duration and improve the therapeutic efficacy of protein therapeutics and nanomedicines. However, both pre-existing and treatment-induced anti-PEG antibodies have been increasingly recognized during clinical applications, raising concerns regarding the safety, efficacy, and translational reliability of PEGylated therapeutics. In this review, we summarize the origins and prevalence of anti-PEG antibodies, critically evaluate current detection methodologies, and analyze antibody-PEG binding patterns and downstream biological effects, including complement activation, accelerated blood clearance, hypersensitivity reactions, and tissue-specific toxicities, while emphasizing the context-dependent impact of anti-PEG immunity on therapeutic efficacy. We also discuss the emerging strategies to mitigate anti-PEG-mediated risks and outline the key challenges and future directions. This integrated framework aims to facilitate functional interpretation of anti-PEG immunity and support the rational design and clinical translation of next-generation PEGylated drug delivery systems.

Infectious mononucleosis caused by Epstein-Barr virus (EBV) commonly presents with pharyngitis, lymphadenopathy, and fever. Cutaneous eruptions may occur, particularly following antibiotic exposure. We report a case of a man in his late 20s who developed a widespread maculopapular rash following sequential exposure to multiple antibiotics in the setting of acute EBV infection. The rash progressed to involve the palms and soles, raising concern for secondary syphilis and a possible drug hypersensitivity reaction. Investigations demonstrated marked lymphocytosis, elevated inflammatory markers and deranged liver enzymes. Throat culture was negative for beta-haemolytic streptococci and the antistreptolysin O titre did not suggest recent streptococcal infection. Treponema pallidum antibody testing and measles polymerase chain reaction (PCR) were negative. Subsequent EBV PCR and repeat serology supported acute EBV infection. The patient improved with conservative management, with resolution of the rash and normalization of the white cell count and liver enzymes at follow-up. Retrospective review also identified prior intravenous amoxicillin exposure during admission for appendicitis, adding further uncertainty regarding the cause of the eruption. This case highlights the diagnostic complexity of rash occurring during acute EBV infection following multiple antibiotic exposures and the importance of considering both EBV-associated exanthem and drug hypersensitivity in the differential diagnosis. Accurate assessment of suspected penicillin allergy is important to guide future antibiotic prescribing.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe delayed hypersensitivity reaction most commonly associated with anticonvulsants and antibiotics. We describe a 50-year-old woman with chronic polymicrobial prosthetic joint infection (PJI) whose course was complicated by refractory DRESS attributed to vancomycin. Despite discontinuation of systemic vancomycin, disease activity persisted for months and required high-dose corticosteroids, mycophenolate mofetil, intravenous immunoglobulin, benralizumab, and cyclosporine. Ongoing antigen exposure from vancomycin-containing orthopedic cement and an antibiotic-coated intramedullary nail was suspected. Her prolonged hospitalization was complicated by cytomegalovirus (CMV) reactivation, steroid-induced hyperglycemia, acute kidney injury, severe edema, chronic pain, and recurrent infection. Ultimate management required removal of antibiotic cement and hardware, prolonged antimicrobial therapy, and multidisciplinary coordination. This case suggests that implanted antibiotic-containing orthopedic materials may perpetuate DRESS despite cessation of systemic drug exposure.

Mas-related G protein-coupled receptor X2 (MRGPRX2) is a mast-cell-enriched receptor that mediates immunoglobulin E-independent activation by structurally diverse neuropeptides, host-defense peptides, microbial products, and selected cationic drugs. Its biology links tissue stress and neuroimmune signaling to degranulation, vascular responses, pruritus, barrier dysfunction, and inflammatory amplification, but the extent to which individual diseases depend on this pathway remains uncertain. The strongest clinical rationale begins with non-IgE-mediated immediate drug hypersensitivity, for which MRGPRX2 provides a direct mechanistic framework, although rocuronium illustrates the need to distinguish human MRGPRX2 pharmacology from murine Mrgprb2 and from IgE-mediated perioperative allergy. In atopic dermatitis, preclinical and human skin data support a potential amplifier role in type 2 inflammation and itch, but a randomized phase 2b study of EVO756 did not demonstrate efficacy in an unselected population. In chronic urticaria, challenge, biomarker, and genetic studies suggest an MRGPRX2-responsive subgroup within a heterogeneous disease, whereas a randomized phase 2b study of EVO756 in unselected chronic spontaneous urticaria was also negative despite earlier pharmacodynamic activity. Ulcerative colitis provides additional human tissue evidence for an MRGPRX2-associated mast-cell circuit, although murine Mrgprb2 studies show context-dependent protective and pathogenic effects. Emerging evidence in chronic prurigo, allergic contact dermatitis, asthma, mastocytosis, rheumatoid arthritis, synovial inflammation, and neurogenic inflammation is also considered, with explicit separation of human observations from mouse-model evidence. We integrate these findings with receptor pharmacology and early clinical development, emphasizing evidence hierarchy, validated biomarker needs, patient selection, tissue target engagement, safety, and trial design. Current data support MRGPRX2 as an investigational endotype-defining pathway rather than a universal driver of allergic or immune-mediated disease.

Complement activation-related pseudoallergy (CARPA) describes a proposed non-IgE-mediated hypersensitivity mechanism in which complement activation contributes causally, often through generation of the anaphylatoxins C3a and C5a. These mediators may activate responsive effector cells and contribute to systemic inflammatory responses that clinically resemble anaphylaxis. Complement activation and complement-associated immediate reactions have been reported with several therapeutic agents and drug-delivery systems, including micelle-solubilized formulations, liposomal drugs, nanoparticle-based therapeutics, PEGylated agents, and biologic therapies; however, the strength of causal evidence varies among products. Importantly, reactions may be driven not only by the active pharmaceutical ingredient but also by formulation components, such as surfactants, solubilizing agents, lipid carriers, and other drug vehicles. As compounded injectable therapies, including intralesional dutasteride, become increasingly used in dermatology, clinicians should recognize that formulation vehicles vary among manufacturers and compounding pharmacies. Certain formulations may contain complement-activating excipients, such as Cremophor EL (polyoxyethylated castor oil), which has been implicated in immediate pseudoallergic reactions. Although CARPA has been widely discussed in oncology, immunology, and nanomedicine, its relevance to a broader range of infusion and injectable therapies remains underrecognized. This narrative review summarizes the mechanisms, clinical features, drug classes, and formulation-related risk factors associated with complement activation and complement-associated reactions, with particular attention to injectables and compounded therapies. Greater awareness of complement-activating formulations may help recognize pseudoallergic reactions, evaluate excipients more carefully, and improve the safe administration of infusion and injectable therapies.

Intrapleural enzyme therapy consisting of tissue plasminogen activator and DNase has become a standard approach to the medical management of pleural space infection. The primary risk of such a strategy is pleural hemorrhage, which is rare but well-described, and this complication normally requires surgical intervention since tissue bleeding cannot be treated with vascular embolization. In this report, we describe the novel and successful use of intrapleural tranexamic acid administered at the bedside through a chest tube to control hemothorax caused by tissue plasminogen activator instillation into the pleural space. The index patient, a 60-year-old man with coagulopathy due to liver cirrhosis, had developed a nosocomial empyema following complex spine surgery. His empyema was being managed medically with intrapleural enzyme therapy when the second instillation of this regimen produced a hemothorax. A single dose of 500 mg of tranexamic acid led to the cessation of bleeding without surgery and enabled the patient to ultimately leave the hospital without experiencing recurrent pleural hemorrhage. Although the administration of tranexamic acid via tube thoracostomy is not unprecedented, our report is the first to document its use in this manner to address hemothorax resulting from intrapleural enzyme therapy, introducing a non-invasive option for this challenging clinical scenario.

Mitragyna speciosa, a tree of the Rubiaceae family native to Southeast Asia, is the plant used in kratom products. Traditional use involves chewing fresh leaves or brewing them into tea, whereas modern products are marketed as loose powders, capsules, tablets, and other formulations. Kratom use has increased in recent years and is an underrecognized cause of hyperpigmentation, which is hypothesized to result from alkaloid-mediated activation of dopamine receptors, leading to melanocyte activation. Recognition of this uncommon adverse effect is increasingly important, as dermatologists should consider kratom use in patients presenting with unexplained photodistributed or drug-induced hyperpigmentation.

Background: Drug hypersensitivity reactions (DHR) exhibit substantial clinical heterogeneity. Although established cardiovascular disease is a known risk factor for severe anaphylaxis, the impact of subclinical cardiovascular risk on DHR severity remains poorly understood. Objective: This study investigated the association between Systematic Coronary Risk Evaluation 2 (SCORE2) estimated cardiovascular risk and the severity of immediate-type DHRs. Methods: This retrospective study included 161 patients ages 40-69 years (median age, 49 years; 79.5% women) with immediate-type DHRs. To assess the subclinical risk, those with known cardiovascular disease, diabetes, or chronic kidney disease were excluded. Reaction severity was graded by using the Brown system, and SCORE2 was calculated by using clinical data from the 12 months preceding the reaction. Results: Reaction severity was graded as mild (35.4%), moderate (34.8%), or severe (29.8%). The median SCORE2 values were significantly higher in the severe group versus the mild group (4.10% versus 2.50%; p = 0.022). The proportion of patients in high or very high SCORE2 risk categories increased stepwise with reaction severity (35.1% in the mild group versus 64.6% in the severe group; p = 0.011). In an univariable ordinal logistic regression, each 1-point increase in SCORE2 percentage was associated with higher odds of greater reaction severity (odds ratio 1.144 [95% confidence interval, 1.041-1.257]; p = 0.005). This association remained significant after adjusting for the culprit drug class (p = 0.008). Conclusion: Higher subclinical cardiovascular risk, as estimated by SCORE2, is significantly associated with increased DHR severity. Analysis of these findings suggests that vascular reserve may modulate the clinical presentation of drug-induced allergic reactions, potentially aiding in clinical risk stratification.