Granulocytes and mast cells in AllergoOncology-Bridging allergy to cancer: An EAACI position paper.

Derived from the myeloid lineage, granulocytes, including basophils, eosinophils, and neutrophils, along with mast cells, play important, often disparate, roles across the allergic disease spectrum. While these cells and their mediators are commonly associated with allergic inflammation, they also exhibit several functions either promoting or restricting tumor growth. In this Position Paper we discuss common granulocyte and mast cell features relating to immunomodulatory functions in allergy and in cancer. We highlight key mechanisms which may inform cancer treatment and propose pertinent areas for future research. We suggest areas where understanding the communication between granulocytes, mast cells, and the tumor microenvironment, will be crucial for identifying immune mechanisms that may be harnessed to counteract tumor development. For example, a comprehensive understanding of allergic and immune factors driving distinct neutrophil states and those mechanisms that link mast cells with immunotherapy resistance, might enable targeted manipulation of specific subpopulations, leading to precision immunotherapy in cancer. We recommend specific areas of investigation in AllergoOncology and knowledge exchange across disease contexts to uncover pertinent reciprocal functions in allergy and cancer and allow therapeutic manipulation of these powerful cell populations. These will help address the unmet needs in stratifying and managing patients with allergic diseases and cancer.

NCCN Guidelines® Insights: Systemic Mastocytosis, Version 3.2024.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Drug allergy awareness and perspectives with the implementation of the International Classification of Diseases-11.

PURPOSE OF REVIEW: To understand the current global scale of drug hypersensitivity (DH) and drug allergy (DA), and to identify possible strategies to increase the accuracy of epidemiological data. RECENT FINDINGS: Global patterns of DH/DA seem to be changing and increasing worldwide, but there are still great challenges in capturing quality DH/DA mortality and morbidity statistics (MMS). DH/DA MMS may gain new perspectives with the global implementation of the International Classification of Diseases (ICD)-11. Improving the quality of epidemiological data related to DH/DA should clarify areas of uncertainty, which would lead to better strategies to reduce the burden of these conditions. SUMMARY: DH/DA remains a complex and unaddressed problem globally that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. DH/DA labels should contribute to people well being, by protecting true allergic individuals from being re-exposed to their allergic drugs and providing needed medications to individuals wrongly labeled as allergic or who have lost allergic sensitivity. The true rate of DH/DA is in fact unknown due to a number of factors, such as misdiagnosis, miscoding and under- and over-notification, among others. Moreover, there is lack of data about DH/DA epidemiology in many countries. Difficulties on collecting accurate and comparable data should be acknowledged, with great impact in the correct labeling DH/DA in electronic health records and official statistics. More accurate definitions, classification and coding may contribute to a better-quality MMS thanks to the ICD-11, under implementation worldwide. Improving the quality of epidemiological data related to DH/DA should clarify areas of uncertainty, which would lead to better strategies to reduce the burden of these conditions. As knowledge derived from populations is key information for more realistic decision-making, the construction of the new section addressed to DH/DA in the ICD-11 will allow the collection of more accurate epidemiological data to support quality management of patients, and facilitate healthcare planning to implement public health measures to prevent and reduce the morbidity and mortality attributable to these conditions.

Mast cell activation syndrome: Current understanding and research needs.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

Case Report: Mast cell anergy: absence of symptoms after accidental re-exposure to amoxicillin/clavulanic acid 3 days after anaphylaxis.

Empty mast cell syndrome, also named post anaphylaxis mast cell anergy (PAMA), is a temporary state of loss of mast cell responsiveness after a severe immediate hypersensitivity reaction. In this study, we describe a case of PAMA after accidental re-exposure to amoxicillin in a patient who developed severe anaphylaxis to this drug three days earlier in the operating room. To our knowledge, this report is the second to document this phenomenon.

Recent findings on drug hypersensitivity in children.

Drug hypersensitivity reactions (DHR) in children have a significant impact on clinical practice and public health. Both under-diagnosis (due to under-reporting) and over-diagnosis (due to the overuse of the term "allergy") are potential issues. The aim of this narrative review is to describe the most recent findings of DHR in children/adolescents and gaps regarding epidemiology, antibiotic allergy, antiepileptic hypersensitivity, vaccine allergy, and severe cutaneous adverse reactions (SCAR) in this age group.

Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Challenges in Drug and Hymenoptera Venom Hypersensitivity Diagnosis and Management in Mastocytosis.

Mastocytosis is a myeloproliferative neoplasm characterized by abnormal proliferation and activation of clonal mast cells typically bearing the KITD816V mutation. Symptoms manifest due to the release of bioactive mediators and the tissue infiltration by neoplastic mast cells. Mast cell activation symptoms include flushing, pruritus, urticaria, abdominal cramping, diarrhea, wheezing, neuropsychiatric symptoms, and anaphylaxis. Up to 50% of patients with mastocytosis report a history of provoked and unprovoked anaphylaxis, with Hymenoptera venom and drugs the most common culprits. NSAIDs, antibiotics, vaccines, perioperative medications, and radiocontrast media are often empirically avoided without evidence of reactions, depriving patients of needed medications and placing them at risk for unfavorable outcomes. The purpose of this review is to highlight the most common agents responsible for adverse drug reactions in patients with mastocytosis, with a review of current epidemiology, diagnosis, and management of drug hypersensitivity and Hymenoptera venom allergy.

Differential presentation of hypersensitivity reactions to carboplatin and oxaliplatin: Phenotypes, endotypes, and management with desensitization.

BACKGROUND: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. METHODS: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. RESULTS: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. CONCLUSION: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.

Changing patterns in the epidemiology of drug allergy.

Drug allergy (DA) remains a complex and unaddressed problem worldwide that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. Underdiagnosis and overdiagnosis are common and due to the lack of standardized definitions and biomarkers. The true burden of DA is unknown, and recent efforts in data gathering through electronic medical records are starting to provide emerging patterns around the world. Ten percent of the general population engaged in health care claim to have a DA, and the most common label is penicillin allergy. Up to 20% of emergency room visits for anaphylaxis are due to DA and 15%-20% of hospitalized patients report DA. It is estimated that DA will increase based on the availability and use of new and targeted antibiotics, vaccines, chemotherapies, biologicals, and small molecules, which are aimed at improving patient's options and quality of life. Global and regional variations in the prevalence of diseases such as human immunodeficiency virus and mycobacterial diseases, and the drugs used to treat these infections have an impact on DA. The aim of this review is to provide an update on the global impact of DA by presenting emerging data on drug epidemiology in adult and pediatric populations.

Development of a Pipeline for Removing Allergy Labels in Patients Undergoing Hematopoietic Stem Cell Transplantation.

Penicillin allergy is reported by 10% to 20 % of patients, but when evaluated only 1% to 2% may have a true allergy. Patients undergoing hematopoietic stem cell transplantation (HSCT) have a high likelihood of requiring beta-lactam antibiotics due to increased infection risk, which can be limited by a penicillin allergy label. When a penicillin allergy is recorded, alternatives are needed, including more expensive broader-spectrum antibiotics, with increases in drug-resistant bacteria, longer hospital stays, higher expenditures, and increases in nosocomial infections, such as Clostridium difficile colitis. This group of patients already undergoes extensive pretreatment testing and would especially benefit from allergy delabeling. This study aimed to develop a self-sustaining, low-cost pipeline between an HSCT clinic and an allergy clinic to identify and successfully delabel low-risk patients who endorse an allergy to penicillin, amoxicillin, amoxicillin-clavulanate, piperacillin-tazobactam, or ampicillin before admission to the hospital. We developed a survey to triage allergy risk, identified key stakeholders in building the pipeline, and underwent 4 plan, do, study, act (PDSA) cycles. Changes were made in each of the PDSA cycles to minimize cost and uncompensated provider time, as well as to increase patient retention throughout the pipeline by increasing appointment availability and decreasing reliance on patients to independently progress through the pathway. Of the 410 patients with planned HSCT who were screened over 11 months, 89 (21.7%) were listed as having a penicillin and/or beta lactam allergy. All but 1 (66 of 67; 98.5%) of the participants completed the survey accurately when confirmed by an allergist, and the survey was 100% accurate in predicting delabeling success in low-risk patients. Of eligible patients, 43.8% (n = 39) were successfully delabeled before their transplant date, and 97.4% of these (n = 38) have undergone HSCT to date. This pipeline is maintained by approximately 5 hours of work per week (1 hour of allergy physician time, 4 hours of nurse and/or clinical coordinator time), with no other direct costs. There is an estimated direct savings of at least $1914.93 per patient delabeled. We successfully designed and implemented a pipeline between the HSCT clinic and the allergy clinic as a quality improvement initiative to identify and address high rates of reported beta-lactam allergies. We identified and addressed patient-based factors, logistical, temporal, and financial barriers that impacted patient retention and sustainability. This model is expected to yield significant and sustained cost savings for the healthcare system as well as to improve patient outcomes, and this hypothesis is currently undergoing formal analysis. We anticipate that this model can be used to create a similar pipeline in other healthcare systems for HSCT recipients, as well as patients in other clinical settings, such as oncology and chimeric antigen receptor T cell therapy.

Multisite Oral Amoxicillin Challenges During Pediatric Emergency Department Visits.

This cohort study assesses differences in children's allergy risk level designation and results of a direct oral challenge via a penicillin allergy delabeling process.

The Long Road of Long COVID: Specific Considerations for the Allergist/Immunologist.

Long COVID (coronavirus disease 2019) syndrome, also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a new disorder that can develop after an acute infection with the SARS-CoV-2 virus. The condition is characterized by multiorgan system involvement with a wide range of symptoms that can vary in severity from mild to debilitating. Some of the common symptoms associated with long COVID syndrome include cardiovascular issues such as heart palpitations and chest pain; thrombotic events (eg, blood clotting disorders); metabolic problems (eg, type 2 diabetes); dysautonomia; paroxysmal orthostatic tachycardia syndrome; myalgic encephalomyelitis/chronic fatigue syndrome; reactivation of the Epstein-Barr virus; the presence of autoantibodies; chronic spontaneous urticaria (hives); and connective tissue diseases. Whereas long COVID syndrome can affect individuals from various backgrounds, certain populations may be at higher risk such as individuals of Hispanic and Latino heritage, as well as those with low socioeconomic status, although approximately one-third of affected patients have no known risk factors or preexisting conditions. Many survivors of COVID-19 struggle with multiple symptoms, increased disability, reduced function, and poor quality of life. Whereas vaccination has been the most significant intervention able to decrease the severity of acute SARS-Cov2 infection and curtail deaths, limited data are available related to its modulating effect on long COVID necessitating the need for further investigation. Furthermore, several inflammatory pathways have been proposed for the pathogenesis of long COVID that are the targets for ongoing clinical studies evaluating novel pharmacological agents. The purpose of the present report is to review the many factors associated with long COVID with a focus on those aspects that have relevance to the allergist-immunologist.

Drug and Venom Allergy in Mastocytosis.

Patients with mastocytosis have an increased risk for mast cell activation events including anaphylaxis when exposed to certain drugs and Hymenoptera venom. Hypotension and cardiovascular collapse without skin or other systemic manifestations can occur after Hymenoptera stings, during the perioperative period, and after exposure to nonsteroidal ntiinflammatory drugs, opioids, and other mast cell activating medications, including vancomycin and quinolones. This chapter reviews the epidemiology, mechanisms, diagnosis, management, and treatment options for Hymenoptera venom and drug-induced reactions in patients with mastocytosis.