Respiratory Diseases Associated With Organic Dust Exposure.

Organic dusts are complex bioaerosol mixtures comprised of dust and par ticulate matter of organic origin. These include components from bacteria, fungi, pollen, and viruses to fragments of animals and plants commonplace to several environmental/occupational settings encompassing agriculture/farming, grain processing, waste/recycling, textile, cotton, woodworking, bird breeding, and more. Organic dust exposures are linked to development of chronic bronchitis, chronic obstructive pulmonary disease, asthma, asthma-like syndrome, byssinosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. Risk factors of disease development include cumulative dust exposure, smoking, atopy, timing/duration, and nutritional factors. The immunopathogenesis predominantly involves Toll-like receptor signaling cascade, T-helper 1/T-helper 17 lymphocyte responses, neutrophil influx, and potentiation of manifestations associated with allergy. The true prevalence of airway disease directly attributed to organic dust, especially in a workplace setting, remains challenging. Diagnostic confirmation can be difficult and complicated by hesitancy from workers to seek medical care, driven by fears of potential labor-related consequence. Clinical respiratory and systemic presentations coupled with allergy testing, lung function patterns of obstructive versus restrictive disease, and radiological characteristics are typically utilized to delineate these various organic dust-associated respiratory diseases. Prevention, risk reduction, and management primarily focus on reducing exposure to the offending dust, managing symptoms, and preventing disease progression.

The impact of indoor pollution on asthma-related outcomes: A systematic review for the EAACI guidelines on environmental science for allergic diseases and asthma.

Systematic review using GRADE of the impact of exposure to volatile organic compounds (VOCs), cleaning agents, mould/damp, pesticides on the risk of (i) new-onset asthma (incidence) and (ii) adverse asthma-related outcomes (impact). MEDLINE, EMBASE and Web of Science were searched for indoor pollutant exposure studies reporting on new-onset asthma and critical and important asthma-related outcomes. Ninety four studies were included: 11 for VOCs (7 for incidenceand 4 for impact), 25 for cleaning agents (7 for incidenceand 8 for impact), 48 for damp/mould (26 for incidence and 22 for impact) and 10 for pesticides (8 for incidence and 2 for impact). Exposure to damp/mould increases the risk of new-onset wheeze (moderate certainty evidence). Exposure to cleaning agents may be associated with a higher risk of new-onset asthma and with asthma severity (low level of certainty). Exposure to pesticides and VOCs may increase the risk of new-onset asthma (very low certainty evidence). The impact on asthma-related outcomes of all major indoor pollutants is uncertain. As the level of certainty is low or very low for most of the available evidence on the impact of indoor pollutants on asthma-related outcomes more rigorous research in the field is warranted.

AllergoOncology: Biomarkers and refined classification for research in the allergy and glioma nexus-A joint EAACI-EANO position paper.

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival.

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.

Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions.

Drug hypersensitivity reactions are a serious concern in clinical practice because they can be severe and result in lifelong sequelae. An accurate diagnosis and identification of the culprit drug is essential to prevent future reactions as well as for the identification of safe treatment alternatives. Nonetheless, the diagnosis can be challenging. In vivo and in vitro tests can be helpful, although none are conclusive; therefore, the tests are not usually performed in isolation but as part of a diagnostic algorithm. In addition, some in vitro tests are only available in research laboratories, and standardization has not been fully accomplished. Collaborating research is needed to improve drug hypersensitivity reaction diagnosis. In this review, we update the current available in vivo and in vitro tools with their pros and cons and propose an algorithm to integrate them into clinical practice.

EAACI Molecular Allergology User's Guide 2.0.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Multistep IgE Mast Cell Desensitization Is a Dose- and Time-Dependent Process Partially Regulated by SHIP-1.

Multistep mast cell desensitization blocks the release of mediators following IgE crosslinking with increasing doses of Ag. Although its in vivo application has led to the safe reintroduction of drugs and foods in IgE-sensitized patients at risk for anaphylaxis, the mechanisms of the inhibitory process have remained elusive. We sought to investigate the kinetics, membrane, and cytoskeletal changes and to identify molecular targets. IgE-sensitized wild-type murine (WT) and FcεRIα humanized (h) bone marrow mast cells were activated and desensitized with DNP, nitrophenyl, dust mites, and peanut Ags. The movements of membrane receptors, FcεRI/IgE/Ag, actin, and tubulin and the phosphorylation of Syk, Lyn, P38-MAPK, and SHIP-1 were assessed. Silencing SHIP-1 protein was used to dissect the SHIP-1 role. Multistep IgE desensitization of WT and transgenic human bone marrow mast cells blocked the release of ß-hexosaminidase in an Ag-specific fashion and prevented actin and tubulin movements. Desensitization was regulated by the initial Ag dose, number of doses, and time between doses. FcεRI, IgE, Ags, and surface receptors were not internalized during desensitization. Phosphorylation of Syk, Lyn, p38 MAPK, and SHIP-1 increased in a dose-response manner during activation; in contrast, only SHIP-1 phosphorylation increased in early desensitization. SHIP-1 phosphatase function had no impact on desensitization, but silencing SHIP-1 increased ß-hexoxaminidase release, preventing desensitization. Multistep IgE mast cell desensitization is a dose- and time-regulated process that blocks ß-hexosaminidase, impacting membrane and cytoskeletal movements. Signal transduction is uncoupled, favoring early phosphorylation of SHIP-1. Silencing SHIP-1 impairs desensitization without implicating its phosphatase function.

A compilation answering 50 questions on monkeypox virus and the current monkeypox outbreak.

The current monkeypox disease (MPX) outbreak constitutes a new threat and challenge for our society. With more than 55,000 confirmed cases in 103 countries, World Health Organization declared the ongoing MPX outbreak a Public Health Emergency of International Concern (PHEIC) on July 23, 2022. The current MPX outbreak is the largest, most widespread, and most serious since the diagnosis of the first case of MPX in 1970 in the Democratic Republic of the Congo (DRC), a country where MPX is an endemic disease. Throughout history, there have only been sporadic and self-limiting outbreaks of MPX outside Africa, with a total of 58 cases described from 2003 to 2021. This figure contrasts with the current outbreak of 2022, in which more than 55,000 cases have been confirmed in just 4 months. MPX is, in most cases, self-limiting; however, severe clinical manifestations and complications have been reported. Complications are usually related to the extent of virus exposure and patient health status, generally affecting children, pregnant women, and immunocompromised patients. The expansive nature of the current outbreak leaves many questions that the scientific community should investigate and answer in order to understand this phenomenon better and prevent new threats in the future. In this review, 50 questions regarding monkeypox virus (MPXV) and the current MPX outbreak were answered in order to provide the most updated scientific information and to explore the potential causes and consequences of this new health threat.

IgE-mediated Anisakis allergy in children

Anisakids are nematodes responsible for different clinical patterns in humans. The well-known human-infecting Anisakis species include members of the Anisakis simplex (AS) complex. Humans usually contract anisakiasis through ingestion of raw or undercooked seafood containing Anisakis larvae. Once Anisakis has been ingested, patients may develop disease driven directly by Anisakis larvae and/or by allergic reaction due to this nematode. The capability of inducing allergic reactions depends on the expression of specific antigens by nematodes and host factors. This study aims to resume actual knowledge about AS and Anisakiasis with regard to epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment. Particular attention is paid to Anisakis allergens and their cross-reactivity on available diagnostic methods, and defining a diagnostic pathway for Anisakis allergy. Because only a few data are available in the literature about pediatric population, we focus on this group of patients specifically (AU)

Hypersensitivity reactions to biologics in children.

INTRODUCTION: Hypersensitivity reactions (HSRs) have been observed with the use of biologics in children. The management of HSRs in children is mainly based on experiences from the adult population. Recently, data from different centers experienced in managing these reactions, including desensitization in children, have been published, allowing clinicians to have an appropriate global overview and compare results. AREAS COVERED: This review highlights the published data on hypersensitivity reactions to biologics in children and drug desensitization protocols adapted to the pediatric population. EXPERT OPINION: With regard to HSRs to biologics in children, few data are available. Compared with the adult population, there is a lack of knowledge in the endophenotypes, management and the standardization of protocols including premedication regimens in children. An international consensus is needed to provide clinicians with new insight on how to apply personalized management and to perform tailored desensitization protocols in pediatric populations. Various specialists including allergists, pediatricians, oncologists, hematologists, rheumatologists, and pharmacists, should build a multidisciplinary management team to keep pediatric patients on their best treatment options in the safest manner.

Landscape of short-acting beta-agonists (SABA) overuse in Europe.

This review article provides an overview of short-acting beta-agonist (SABA) use and prescribing trends in Europe, summarizing updated data on the results from the industry-funded SABINA program (SABA use IN asthma) and other studies on this matter. SABA use continues to increase worldwide. Overuse has been defined as ≥3 canisters/year. Almost a third of European patients with asthma, at all severity levels, overuse SABA. Guidelines recommend close monitoring of patients who overuse SABA and avoiding over-reliance on SABA monotherapy. SABA overuse is associated with increased risk of asthma exacerbations and mortality, increased use of health services and negative physical and mental health outcomes. Reliance on SABA monotherapy can be unsafe and therefore it is necessary to change asthma treatment approaches and policies. Changes in physician and patient behaviours towards SABA use are required to ensure that patients with asthma are not over-reliant on SABA monotherapy. Notwithstanding, the limitations of the studies on the use of SABA should be considered, taking into account that the prescription/purchase of medication canisters does not always represent the actual use of the medication and that associations between SABA overuse and poor asthma outcomes may not be directly causal. National health systems and asthma guidelines must align asthma management with global recommendations and adjust them to local needs.

AllergoOncology: Danger signals in allergology and oncology: A European Academy of Allergy and Clinical Immunology (EAACI) Position Paper.

The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes.

Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity.

INTRODUCTION: Nivolumab is a fully human IgG4 monoclonal antibody (moAb) against programmed cell death protein 1, approved for the treatment of over ten types of cancer. The use of this and other moAbs has augmented considerably in recent years and this in turn has caused an increase of hypersensitivity reactions (HSR). CASE REPORT: We present the case of a patient with metastatic renal cell cancer (RCC) who developed a grade 3 cytokine release reaction (CRR) to nivolumab. The maintenance of the symptoms despite of the administration of symptomatic treatment and slowing down the infusion rate of nivolumab during the 1st and 2nd reaction required an allergy evaluation of our patient. MANAGEMENT AND OUTCOME: Skin testing to Nivolumab with negative results and baseline tryptase within the normal range were observed during the allergy workout. A desensitization protocol with specific premedication was applied to reintroduce the moAb, with no further issues. Moreover, a follow up of the patient in the oncology setting was done showing disease stabilization. DISCUSSION: The CRR should be treated by desensitization, in contrast to infusion reactions. The diagnosis of CRR phenotype is based on the clinical presentation and recently, and elevation of IL-6 levels has been shown to be a useful biomarker along with negative skin testing. We can conclude that after a HSR and an appropriate allergy diagnosis of CRR, nivolumab can be safely reintroduced by desensitization without reducing the target dose or the appropriate dilution concentration.

Allergenicity to worldwide invasive grass Cortaderia selloana as environmental risk to public health.

Allergies to grass pollen affects about 20% of the population worldwide. In the last few decades, the South American grass Cortaderia selloana (CS, Pampas grass) has expanded worldwide in a variety of countries including the USA, Australia and Western Europe. In many of these locations, CS has strikingly spread and has now been classified an invasive species. Many pernicious consequences of CS have been reported for local biodiversity, landscape and structures. However, the effect on human health has not been studied. To investigate this issue, we have chosen a European region on the northern cost of Spain where CS spread is overwhelming, Cantabria. We obtained CS pollen extract and analysed the allergenic reaction of 98 patients that were allergic to pollen of local grasses. We determined the skin reaction and the presence of specific IgE antibodies (sIgE) to CS or to a typical autochthonous grass, Phleum pratense. We also compared the seasonal symptoms with reported grass pollen counts in the area. The results strongly suggest that CS can cause respiratory allergies at a similar extent to the local grasses. Given that CS pollinises later than the local grasses, this would extend the period of grass allergies in the region for about three months every year, as stated by most of the patients. This is the first study reported on the effects of the striking expansion of CS on human health. Considering the strong impact that respiratory allergies have on the population, our results suggest that CS can currently constitute a relevant environmental health issue.

Author Correction: Analysis of Ani s 7 and Ani s 1 allergens as biomarkers of sensitization and allergy severity in human anisakiasis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Analysis of Ani s 7 and Ani s 1 allergens as biomarkers of sensitization and allergy severity in human anisakiasis.

The high frequency of infection by Anisakis simplex (A. simplex) has led to an increase in IgE sensitization, turning allergy to this parasite a relevant contemporary health problem. Improving the lack of conventional diagnosis test specificity is crucial to better understand these clinical scenarios. Specific IgE (sIgE) to A. simplex extract by ImmunoCAP (Anisakis-sIgE) was determined in sera from 403 blood donors (BD) from Cantabria (North of Spain) of which 51 subjects resulted sensitized. Among these latter, 47 were asymptomatic (sABD). The values of total IgE, prick-test, Anisakis-sIgE, and sIgE to Ani s 1 (anti-rAni s 1) and Ani s 7 (anti-rAni s 7) were compared between 46 sABD and 49 A. simplex allergic patients. The IgE seroprevalence by ImmunoCAP among BD was 12.65%. Allergic patients and sABD showed significant differences in all serum biomarkers evaluated. The area under the curve was assessed for Anisakis-sIgE (0.892), sIgE-rAni s 1 (0.672) and sIgE-rAni s 7 (0.668). After a severe reaction, significantly higher levels of Anisakis-sIgE and sIgE anti-rAni s 1 were detected. Determinations of sIgE by ImmunoCAP, Ani s 1 and Ani s 7 presented different sensitization patterns between allergic and asymptomatic individuals. The Ani s 1 allergen arises as a possible biomarker to detect patients at risk of suffering severe allergic reactions.