Although there is a considerable body of knowledge about allergen immunotherapy (AIT), there is a lack of data on the reliability of real-world evidence (RWE) in AIT and consequently, a lack of information on how AIT effectively works in real life. To address the current unmet need for an appraisal of the quality of RWE in AIT, the European Academy of Allergy and Clinical Immunology Methodology Committee recently initiated a systematic review of observational studies of AIT, which will use the RELEVANT tool and the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE) to rate the quality of the evidence base as a whole. The next step will be to develop a broadly applicable, pragmatic “real-world” database using systematic data collection. Based on the current RWE base, and perspectives and recommendations of authorities and scientific societies, a hierarchy of RWE in AIT is proposed, which places pragmatic trials and registry data at the positions of highest level of evidence. There is a need to establish more AIT registries that collect data in a cohesive way, using standardised protocols. This will provide an essential source of real-world data that can be easily shared, promoting evidence-based research and quality improvement in study design and clinical decision-making.
Letter to EditorTo the EditorEgg-allergic children have higher ovomucoid (OVM)-specific IgD (sIgD) levels compared to the atopic controls.1 Within the egg-allergic group, children with higher levels of OVM-sIgD have a decreased risk of anaphylactic reactions. Ovalbumin (OVA)-sIgD increases in egg-allergic children desensitized by oral immunotherapy (OIT) but not in children unresponsive to OIT or with sustained unresponsiveness to OVA challenge.2 The natural development of tolerance and the acquisition of sustained unresponsiveness by OIT in egg-allergic children are associated with an increase in OVM-specific IgG4 (sIgG4) levels and a decrease in OVM-specific IgE (sIgE) levels.3 To elucidate the potential role of IgD in the outgrowing of egg allergy, we analyzed levels of egg white (EW)-, OVM-, and OVA-sIgD and sIgG4 in sera from 57 egg-allergic children (28 avoided all forms of egg in the diet (complete avoidance of egg: CAE), 18 were able to ingest at least 1/32 cooked whole egg but not one cooked whole egg (partial avoidance of egg: PAE), and 11 outgrew egg allergy (OGE)) and 23 healthy non-egg allergic children (non-egg allergy: NEA) (Table S1). The study was approved by The Research Ethics Committee of University of Fukui (#20110052), and written informed consent was obtained from the parent or guardians.EW-, and OVM-sIgE levels measured using ImmunoCAP (Thermo-Fisher Inc., MA) were higher in the CAE group, followed by the PAE, OGE, and NEA groups (Fig 1, Fig S1). The CAE group exhibited lower serum levels of EW- and OVA-sIgD compared to the NEA group and the PAE group, respectively, and had the lowest OVM-sIgD serum levels among all groups, suggesting that OVM-sIgD levels are associated with outgrowing egg allergy. We observed the lowest serum levels of EW-, OVA-, and OVM-sIgG4 in the CAE group, followed by the PAE and OGE groups. The ratio of OVM-sIgD to OVA-sIgD increased as children outgrew egg allergy, whereas the ratio of OVM-sIgG4 to OVA-sIgG4 did not change. Thus, the production of OVM-sIgD differs from OVM-sIgG4 as children naturally outgrow egg allergy.High-affinity, but not low-affinity, IgE is known to cause anaphylaxis.4 High-affinity IgE is derived from memory IgG1+ B cells, whereas low-affinity IgE is derived from naïve IgM+IgD+ B cells. Considering class switching pathways, switching direction from IgM to IgD, and from IgG1 to IgE or IgG4, elevated OVM-sIgD levels might be associated with low-affinity OVM-sIgE levels as children outgrow egg allergy, resulting in hypo-responsiveness to OVM.A recent study found that OVM-sIgE avidity was more effective at differentiating clinically reactive egg-allergic patients from those tolerant of heated egg compared to EW-sIgE.5 The ratio of OVM-sIgE to OVM-sIgD or sIgG4 in the CAE group was significantly higher compared to the PAE, OGE, and NEA groups (Fig 2). Receiver operating analysis revealed that the ratio of OVM-sIgE to OVM-sIgD discriminated non-tolerant from partially-tolerant egg-allergic patients with the largest area under the curve (AUC = 0.965) compared with levels of OVM-sIgE or the ratio of OVM-sIgE to OVM-sIgG4. The optimal cutoff for the ratio of OVM-sIgE to OVM-sIgD had 86.5% sensitivity and 96.4% specificity to identify high-risk subjects (Table S2).There are several limitations to this study. First, there was a small number of patients. Second, all children were only challenged with heated egg and were instructed to avoid egg of any form if they tested positive with less than 1/32 cooked whole egg. Finally, there was a lack of trajectory of sIgD levels during natural tolerance development.In conclusion, the ratio of OVM-sIgE to OVM-sIgD is a useful marker to identify high-risk egg-allergic patients capable of ingesting a low-dose of cooked whole egg who might be a good candidate for low-dose OIT.
Additional Features of Food Induced Immediate Reaction in the Esophagus (FIRE) in a Series of Adult Patients with Eosinophilic EsophagitisTo the EditorEosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil predominant inflammation. The predominant symptom in adults with active EoE is solid food dysphagia due to the high incidence of esophageal stricture formation. A quantitative tool has been developed to characterize the nature of these symptoms (1). Most typically patients complain of food going down slowly, food getting stuck and pain. These symptoms are most likely to occur during the passage of dense solid foods such as meats, bread and rice.Recently a phenomenon with a different symptom referred to as FIRE (food induced immediate reaction in the esophagus) has been described in adults with EoE. (2). Patients with eosinophilic esophagitis describe these esophageal symptoms as distinct from dysphagia. The symptoms typically occur after the food has been swallowed with rapid onset esophageal discomfort often described as tightening or pressure but without the sense of dysphagia. A large series of Swiss patients with eosinophilic esophagitis were queried via a form mailed to their homes or in clinics concerning symptoms related an immediate reaction in the esophagus distinct from dysphagia (2). A significant portion (49%) reported some form of esophageal discomfort related to eating. Although certain subject characteristics in this study such as younger age of onset of EoE and higher prevalence of allergies was noted, detailed clinical information on each subject was not available for review. Here in we described a series of patients with biopsy proven eosinophilic esophagitis who describe characteristic symptoms of FIRE following a specific food ingestion. For each selected FIRE patient a detailed chart review was conducted characterizing their demographics and EoE history (Table 1) as well as characteristics of their FIRE profile (Table 2). A number of features were noted in this group of 8 EoE patients as a previously unrecognized symptom complex. The onset of symptoms most often occurred within 1-60 minutes (median 3.5 minutes) after ingestion of the food. The duration of symptoms lasted from <10 minutes to > 6 hours (median 120 minutes). Among the patients the description of discomfort was often similar consisting of a tightening or pressure in the mid sternum. The most common foods inducing symptoms were beans, melon and beer. The symptoms were significant enough that patients attempted to subsequently avoid these foods. All patients were able to distinguish between symptoms related to their pollen food allergy syndrome and FIRE.The exact mechanism of this esophageal discomfort has not been elucidated. It appears distinct from pollen food allergy syndrome. It also appears different from EoE as uncommon foods such as banana, melon and avocado were capable of invoking symptoms, notably foods more commonly associated with oral allergy syndrome. However the strong association with atopy, the rapid onset of symptoms and symptoms distinct from dysphagia suggest a local possibly immunologic factor causing an immediate esophageal mucosal response. A careful history of FIRE symptoms should be part of the routine evaluation of patients with eosinophilic esophagitis. Further investigations will be required to help better understand the frequency and mechanism of this newly described phenomenon.Conflicts of InterestMH no conflicts, AS no conflictsMark Holbreich M.D.Alex Straumann M.D.1. Schoepfer AM, Straumann A, Panczak R, et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology 2014;147:1255–1266.2. Biedermann, L, Holbreich, M, Atkins, D, et al. Food‐induced immediate response of the esophagus—A newly identified syndrome in patients with eosinophilic esophagitis. Allergy . 2020; 00: 1– 9.Corresponding authorMark Holbreich M.D.Allergy and Asthma ConsultantsIndianapolis IN USAmholbreich@comcast.net
Following the emergency use authorization of the vaccine mRNA-1273 on 18th December 2020 in the US and the vaccine BNT162b2 one week earlier, two mRNA vaccines are in currently used for the prevention of coronavirus disease 2019 (COVID-19). Phase 3 pivotal trials on both vaccines excluded individuals with a history of allergy to vaccine components. Immediately after the initiation of vaccination in the United Kingdom, Canada, and in the US, anaphylactic reactions have been reported. While the culprit trigger requires investigation, initial reports suggested the excipient polyethylene glycol 2000 (PEG-2000), which is contained in both vaccines as PEG-micellar carrier system as the potential culprit. Surface PEG chains form a hydrate shell to increase stability and prevent opsonization. Allergic reactions to such PEG-ylated lipids are rarely IgE-mediated, but may result from complement activation-related pseudoallergy (CARPA) that has been described to similar liposomes. In addition, mRNA-1273 also contains tromethamine (trometamol), which has been reported to cause anaphylaxis to e.g. gadolinium-based or iodinated contrast media. Skin prick-, intradermal-, epicutaneous- tests, in vitro sIgE assessment, evaluation of sIgG/IgM, as well as basophil activation test are in use to demonstrate allergic reactions to various components of the vaccines.
Coronavirus disease 2019 (COVID-19) vaccine BNT162b2 received approval and within the first few days of public vaccination several severe anaphylaxis cases occurred. An investigation is taking place to understand the cases and their triggers. The vaccine will be administered to a large number of individuals worldwide and concerns raised for severe adverse events might occur. With the current information, the European Academy of Allergy and Clinical Immunology (EAACI) states its position for the following preliminary recommendations that are to be revised as soon as more data emerges. To minimize the risk of severe allergic reactions in vaccinated individuals, it is urgently required to understand the specific nature of the reported severe allergic reactions, including the background medical history of the individuals affected and the mechanisms involved. To achieve this goal all clinical and laboratory information should be collected and reported. Mild and moderate allergic patients should not be excluded from the vaccine as the exclusion of all these patients from vaccination may have a significant impact on reaching the goal of population immunity. Health care practitioners vaccinating against COVID-19 are required to be sufficiently prepared to recognise and treat anaphylaxis properly with the ability to administer adrenaline. A mandatory observation period after vaccine administration of at least 15 minutes for all individuals should be followed. The current guidelines, which exclude patients with severe allergies from vaccination with BNT162b2, should be re-evaluated after more information and experience with the new vaccine develops.
Background: Hereditary angioedema (HAE) attacks can be provoked with psychological factors. The aim of this study was to assess the effects of anxiety, depression and stress related to COVID-19 pandemic on disease activity of HAE patients during the quarantine period (QP) and the return to normal period (RTNP). Methods: This prospective study was conducted between March 2020 and September 2020 in four allergy centres. Demographic, clinical features and mental health status were evaluated in QP (from March to the beginning of June) and RTNP (from June to the beginning of September) was applied by the government. The 10-point visual analogue scale (VAS10) was used to define the severity of HAE attacks. Depression-Anxiety- Stress Scale-21 (DASS-21) and Fear of Covid-19 (FC-19) scales were performed to assess mental health status. Results: 139 HAE patients were included in the study. In QP, median attack numbers and median VAS10 scores were 5 (min-max: 0-45) and 6 (min-max: 0-10), respectively. HAE attack numbers, DASS-21 stress, anxiety, depression and total DASS-21 scores, as well as FC-19 scores were higher in QP than RTNP (p= 0.001, p <0,001, p = 0,001, p <0,001, p <0.001, p<0.001, respectively). However, there was no difference in attack severity scores between the two periods (p>0.05). Conclusions: This study revealed that the restriction measures during Covid-19 outbreak causes an increase in the number of HAE attacks in relation to anxiety, depression, stress and fear of Covid-19 pandemic. Therefore, it is important to provide psychological support to HAE patients during the pandemic.
Involvement of small airways, those of less than 2 mm in internal diameter, is present in all stages of asthma and contributes substantially to the pathophysiologic expression of asthma. Therefore, small airways are increasingly viewed as a potential target in optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post-synaptically on airway smooth muscle (ASM). In small airways, M3 mAChRs are expressed, but there is no vagal innervation. Non-neuronal ACh released from the epithelial cells that may express choline acetyltransferase (ChAT) in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate these receptors. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be affected. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long-acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma.
Background: Early-life exposures to geohelminths may protect against the development of wheeze/asthma and atopy. Objective: Study effect of maternal geohelminths and infections in children during the first 5 years of life on atopy, wheeze/asthma, and airways reactivity/inflammation at 8 years. Methods: Birth cohort of 2,404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO), and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy. Results: 1,933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and in 45.5% of children to 5 years. Frequencies of outcomes at 8 years were: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%), and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced prevalence of SPT (OR 0.72). Childhood T. trichiura infections were associated with reduced wheeze (OR 0.57) but greater parasite burdens with A. lumbricoides were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children. Conclusions: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086).
Background: Few and small studies have described the management of immunomodulant/immunosuppressive therapies or phototherapy in atopic dermatitis (AD) patients during coronavirus disease 2019 (COVID-19) pandemic. Methods: A national registry, named DA-COVID-19 and involving 35 Italian dermatology units, was established in order to evaluate the impact of COVID-19 pandemic on the management of adult AD patients treated with systemic immunomodulant/immunosuppressive medications or phototherapy. Demographic and clinical data were obtained at different timepoints by teledermatology during COVID-19 pandemic, when regular visits were not allowed due to sanitary restrictions. Disease severity was assessed by both physician- and patient-reported assessment scores evaluating itch intensity, sleep disturbances, and AD severity. Results: A total of 1831 patients were included, with 1580/1831 (86.3%) continuing therapy during pandemic. Most patients were treated with dupilumab (86.1%, 1576/1831) that was interrupted in only 9.9% (156/1576) of cases, while systemic immunosuppressive compounds were more frequently withdrawn. Treatment interruption was due to decision of the patient, general practitioner or dermatologist in 39.9% (114/286), 5.6% (16/286), and 30.1% (86/286) of cases, respectively. Fear of increased susceptibility to SARS-CoV-2 infection (24.8%, 71/286) was one of the main causes of interruption. Sixteen patients (0.9%) resulted positive to SARS-CoV-2 infection, 3 of them (0.2%) were hospitalized but no cases of COVID-related death occurred. Conclusions: Most AD patients continued systemic treatments during COVID pandemic and lockdown period, without high impact on disease control, particularly dupilumab-treated patients.
Interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), rhinitis and airway hyperreactivity. In AD, IL-31 has been identified as one of the main ‘drivers’ of its cardinal symptom pruritus. Here, we aim to summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2-produced cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, and stimulating itch and neuronal outgrowth through activation of the heterodimer receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor β. IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well as various innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31 downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo nodularis. For example, whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.
Background: Diagnostic tests for allergy rely on detecting allergen-specific IgE. Component-resolved diagnostics incorporate multiple defined allergen components to improve the quality of diagnosis and patient care. Objective: To develop a new approach for determining sensitization to specific allergen components that utilizes fluorescent protein tetramers for direct staining of IgE on blood basophils by flow cytometry. Methods: Recombinant forms of Lol_p_1 and Lol_p_5 proteins from ryegrass pollen (RGP) and Api_m_1 from honeybee venom (BV) were produced, biotinylated and tetramerized with streptavidin-fluorophore conjugates. Blood samples from 50 RGP-allergic, 41 BV-allergic and 26 controls were incubated with fluorescent protein tetramers for flow cytometric evaluation of basophil allergen binding and activation. Results: Allergen tetramers bound to and activated basophils from relevant allergic patients but not controls. Direct fluorescence staining of Api_m_1 and Lol_p_1 tetramers had greater positive predictive values than basophil activation for BV and RGP allergy, respectively, as defined with receiver operator characteristics (ROC) curves. Staining intensities of allergen tetramers correlated with allergen-specific IgE levels in serum. Inclusion of multiple allergens coupled with distinct fluorochromes in a single tube assay enabled rapid detection of sensitization to both Lol_p_1 and Lol_p_5 in RGP-allergic patients and discriminated between controls, BV-allergic and RGP-allergic patients. Conclusion: Our novel flow cytometric assay, termed CytoBas, enables rapid and reliable detection of clinically relevant allergic sensitization. The intensity of fluorescent allergen tetramer staining of basophils has a high positive predictive value for disease and the assay can be multiplexed for a component-resolved and differential diagnostic test for allergy.
Background Specific IgE against a peanut 2S albumin (Ara h2 or 6) is the best predictor of clinically relevant peanut sensitization. However, sIgE levels of peanut allergic and those of peanut sensitized but tolerant patients partly overlap, highlighting the need for improved diagnostics to prevent incorrect diagnosis and consequently unnecessary food restrictions. Thus, we sought to explore differences in V(D)J gene transcripts coding for peanut 2S albumin-specific monoclonal antibodies (mAbs) from allergic and sensitized but tolerant donors Methods 2S albumin-binding B-cells were single-cell sorted from peripheral blood of peanut allergic (n=6) and tolerant (n=6) donors sensitized to Ara h2 and/or 6 (≥ 0.1 kU/l) and non-atopic controls (n=5). Corresponding heavy and light chain gene transcripts were heterologously expressed as mAbs and tested for specificity to native Ara h2 and 6. HCDR3 sequence motifs were identified by Levenshtein distances and hierarchically clustering. Results The frequency of 2S albumin-binding B-cells was increased in allergic (median: 0.01%) compared to tolerant (median: 0.006%) and non-atopic donors (median: 0.0015%, p=0.008). The majority of mAbs (74%, 29/39) bound specifically to Ara h2 and/or 6. Non-specific mAbs (9/10) were mainly derived from non-atopic controls. In allergic donors, 89% of heavy chain gene transcripts consisted of VH3-family genes, compared with only 54% in sensitized but tolerant and 63% of non-atopic donors. Additionally, certain HCDR3 sequence motifs were associated with allergy or tolerance upon hierarchical clustering of their Levenshtein distances. Conclusions HCDR3 sequence motifs associated with allergy or tolerance may support correct diagnosis of patients with suspected peanut allergy.
Background: There is controversy whether taking β-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT). Methods: In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking β-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment. Results: In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took β-blockers, 11.9% ACEI, 5.0% β-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43–1.22, p=0.25). The severity of the initial sting reaction was not affected by the intake of β-blockers or ACEI (OR: 1.14, 95% CI: 0.89–1.46, p=0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took β-blockers, none an ACEI. Conclusions: This trial provides robust evidence that taking β-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629)
Background: The interplay between COVID-19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID-19 on childhood asthma outcomes. Methods: The PeARL multinational cohort included 1,054 children with asthma and 505 non-asthmatic children aged between 4-18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID-19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control. Results: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks and hospitalizations due to asthma, in comparison to the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. Conclusion: Childhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.
Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells and epithelial cells. During recent years, clinical and experimental studies on human mast cells as well as experiments using animal models have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity and reactivity. We also highlight the development in our understanding of mast cell driven-diseases and discuss the development of novel strategies to treat such conditions.