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Suggested by
LIGHTING
July 23, 2019 9:00 AM
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In daily practice, one-third of sesame allergic patients, confirmed by clinical history or food challenge, do not show any detectable specific IgE using current diagnostics. Currently used sesame extracts are water-based and therefore lacking hydrophobic proteins like oleosins. Oleosins, the stabilizer of lipid droplets in plants, are described as allergens in sesame, peanut and hazelnut. In this study, we examine the role of oleosins in sesame allergy and their potential cross-reactivity between sesame and (pea)nuts. Specific IgE and IgG sensitisation to native and heterologously expressed sesame components and oleosins from other nuts, free of seed storage proteins, was assessed by line blot and sera from 17 sesame allergic patients without detectable specific IgE sensitisation to sesame, and compared to 18 sesame allergic and 13 tolerant patients with specific IgE sensitisation to sesame. Sesame allergic patients without sensitisation showed no specific IgE to the tested sesame oleosins or components. Low levels of specific IgE to sesame oleosins were detected in 17% of sesame allergic and 15% of tolerant patients with sIgE sensitisation. Oleosins were recognised by serum IgG from multiple patients confirming immune reactivity and excluding technical issues leading to lack of specific IgE-binding to oleosins. Sesame oleosins are minor allergens and appear to have no additonal value in diagnosing sesame allergy in adults based on sIgE and sIgG detection. There is a high need for additional diagnostic tools in those patients to minimize the number of required food challenges.
Food allergies are a growing public health concern. New work may help pave the way for a therapeutic that reduces or stops allergies.| Microbiology...
Via Krishan Maggon
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Scooped by
Gilbert C FAURE
June 2, 2019 4:36 AM
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Summary Assessment and management of asthma is complicated by the heterogeneous pathophysiological mechanisms that underlie its clinical presentation, which are not necessarily reflected in standardized management paradigms and which necessitate an individualized approach to treatment. This is particularly important with the emerging availability of a variety of targeted forms of therapy that may only be appropriate for use in particular patient subgroups. The identification of biomarkers can potentially aid diagnosis and inform prognosis, help guide treatment decisions and allow clinicians to predict and monitor response to treatment. Biomarkers for asthma have been identified from a variety of sources, including airway, exhaled breath and blood. Biomarkers from exhaled breath include fractional exhaled nitric oxide, measurement of which can help identify patients most likely to benefit from inhaled corticosteroids and targeted anti‐immunoglobulin E therapy. Biomarkers measured in blood are relatively non‐invasive and technically more straightforward than those measured from exhaled breath or directly from the airway. The most well established of these are the blood eosinophil count and serum periostin, both of which have demonstrated utility in identifying patients most likely to benefit from targeted anti‐interleukin and anti‐immunoglobulin E therapies, and in monitoring subsequent treatment response. For example, serum periostin appears to be a biomarker for responsiveness to inhaled corticosteroid therapy and may help identify patients as suitable candidates for anti‐IL‐13 treatment. The use of biomarkers can therefore potentially help avoid unnecessary morbidity from high‐dose corticosteroid therapy and allow the most appropriate and cost‐effective use of targeted therapies. Ongoing clinical trials are helping to further elucidate the role of established biomarkers in routine clinical practice, and a range of other circulating novel potential biomarkers are currently being investigated in the research setting. Introduction Asthma is a heterogeneous disease that is usually characterized by chronic airway inflammation and structural change with associated airway dysfunction 1. It is defined by a history of respiratory symptoms (such as wheeze, shortness of breath, chest tightness and cough), which vary over time and in intensity, together with variable expiratory airflow limitation 1. Asthma affects approximately 300 million individuals worldwide, with prevalence rates ranging from 1% to 16% in different countries 2. In the UK, 5.4 million people currently receive treatment for asthma (1.1 million children [1 in 11] and 4.3 million adults [1 in 12]) and, on average, three people per day die from asthma 3. It is now clear that asthma comprises various disease subtypes with similar clinical manifestations, but with differing underlying pathophysiological mechanisms 1. The classification of asthma has consequently evolved as understanding regarding its pathophysiology has increased. Having initially been categorized in terms of ‘allergic’ or ‘non‐allergic’ asthma, a distinction was then made between ‘eosinophilic’ (‘type 2 high’) and ‘non‐eosinophilic’ (‘type 2 low’) asthma. Advances in disease understanding subsequently indicated that there may be subgroups of type 2 high asthma that differ in terms of both the presence of underlying allergy and the potential source of type 2 cytokines. This led to the current concept of ‘type 2 (T2) asthma’, which is characterized by high levels of type 2 interleukins (ILs), such as IL‐4, IL‐5 and IL‐13, and involves type 2 helper T cells (Th2 cells), mast cells, basophils, B cells and type 2 innate lymphoid cells (ILC2s) 4-6. It is currently believed that Th2 cells and ILC2s are primarily responsible for the production of the majority of type 2 cytokines in the airway, including IL‐4, IL‐5, IL‐9 and IL‐13 5, 7. The prolonged presence of activated inflammatory cells leads to chronic inflammation and airway remodelling 8. Since the 1990s, efforts to characterize asthma in terms of clinical, physiological and pathological parameters have led to the concept of asthma ‘phenotypes’ and ‘endotypes’ 9-13. The term ‘phenotype’ is used to denote a recognizable cluster of similar clinically observable characteristics, which can be identified using statistical methods (e.g. cluster analysis) without establishing an underlying aetiology or pathophysiology 12, 14, 15. By contrast, the term ‘endotype’ is used to describe a disease subtype with a clearly elucidated pathophysiology 15. Current approaches to asthma stratification primarily rely on identifying phenotypes, as the level of understanding required to establish endotypes has, in general, not yet been achieved 15. Asthma can be stratified in many ways: in terms of clinical history, physiology, inflammatory phenotype profile or biomarkers, and also in terms of therapeutic response to individual treatments. Stratification is central to the effective management of asthma, as it facilitates the personalization of treatment tailored to the individual's specific needs. This is particularly important with the emergence of targeted forms of asthma therapy, such as those targeting specific pro‐inflammatory cytokines 16. Asthma management in the UK is currently based on empirical stepwise treatment, with inhaled corticosteroids being standard of care for mild asthma, and combinations of inhaled corticosteroids and long‐acting beta agonist therapy plus further add‐on therapies, as required, for more severe asthma 17. International guidelines define severe asthma as ‘asthma that requires treatment with high‐dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled,” or that remains ‘uncontrolled’ despite this therapy’ 18. Approximately 3–5% of asthma sufferers are unresponsive to available treatments and severe, therapy‐resistant asthma has become increasingly recognized as a major unmet need 18, 19. Moreover, severe refractory asthma is associated with a substantial burden in terms of healthcare costs. In the UK, the direct treatment costs from a National Health Service perspective, based on data from the British Thoracic Difficult Asthma Registry, were estimated to be £2912–4217 per patient per year 20. Identification of therapy resistance in difficult‐to‐treat asthma is hampered by poor adherence to treatment, which is known to be a problem in many asthma patients 21, 22. However, there is also a subset of patients who have poorly controlled asthma with persistent type 2 inflammation, despite adherence with high‐dose inhaled steroids. These patients often progress to systemic steroid treatment, which is associated with significant morbidity 23, and some of the new therapies targeting type 2 inflammation are likely to be of value for treating such patients in the future. It is therefore important to identify patient subgroups likely to benefit from targeted forms of treatment 19, 24. As the diagnosis of asthma is usually based on reported symptomatology and lung function tests 25, which are unable to assess airway inflammation and stratify the disease into discriminated phenotypes, there is a need for biomarkers to help with the accurate identification of clinically relevant phenotypes, not only to potentially aid diagnosis and inform prognosis, but also to guide treatment decisions, and predict and monitor treatment response. A biomarker is defined as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention’ 26. The ideal characteristics of a biomarker are outlined in Table 1 15, 27-29. Essentially, the ideal biomarker should be easily measurable, have the ability to identify a mechanism known to be important in the pathogenesis of the disease, be reliable and reproducible in the clinical setting and be cost‐effective. It should ideally be mechanistically linked to the therapeutic target and responsive to intervention 15, 27-29. Biomarkers for asthma have been identified from a variety of sources, including the airway, exhaled breath and blood. The primary focus of this article is the role of T2 biomarkers in asthma management. Characteristic Details Easily measurable Non‐invasive Not requiring complex or potentially dangerous interventions Easy to collect in the ‘real‐world’ setting Ability to distinguish a mechanism causally linked to important clinical outcome High sensitivity, specificity, and positive and negative predictive values Correlation with treatment responses (e.g. to allow treatment adjustment) ’Normalization’ with successful treatment Reliable and reproducible in the clinical setting Little or no day‐to‐day variation (unless the variation is meaningful) Ability to provide information about disease prognosis and clinical outcomes Able to help inform disease management Mechanistically linked to the therapeutic target Able to provide better understanding of underlying pathophysiology Cost‐effective Airway biomarkers Bronchial biopsy has been considered the ‘gold standard’ for investigating airway inflammation and tissue remodelling, but it is invasive, costly, complex to perform and not readily accessible in clinics or research centres 28. Bronchoalveolar lavage also involves bronchoscopy, is often poorly tolerated by patients with asthma and also has to be conducted in a specialized hospital, preventing its widespread use in routine clinical practice 15. Sputum induction is less invasive and more cost‐effective than bronchoalveolar lavage, but it is still invasive and too technically complex and difficult to standardize for routine practice, and therefore generally only used in specialized centres and usually in a research setting 15, 25. Induced sputum and bronchoalveolar lavage contain cells (such as eosinophils and neutrophils) and supernatant containing cytokines, which can be used to predict asthma severity and exacerbations 25, 28. Indeed, the discernment of distinct inflammatory phenotypes through analysis of the cellular component of induced sputum is an early example of how biomarkers can be used to achieve asthma stratification 30, although the utility of these particular biomarkers in the personalization of treatment is unclear 15. Biomarkers in exhaled breath Fractional exhaled nitric oxide (FeNO) The measurement of FeNO is a relatively simple, fast, non‐invasive and reproducible technique that has been used as a surrogate measure of airway inflammation in asthma 15, 29. The American Thoracic Society and European Respiratory Society have standardized a method to measure FeNO 31, providing a simple, fast, non‐invasive and reproducible technique in asthma management 15. Findings from the Isle of Wight birth cohort study indicated that FeNO may be a useful biomarker for atopic asthma (where atopy was defined as having ≥ 1 positive skin prick test to either a food or aeroallergen) 32. High FeNO levels (> 47 ppb) have been shown to be associated with airway eosinophilia and corticosteroid responsiveness 33 and also to be prognostic for asthma exacerbations 34. Similarly, high (≥ 19.5 ppb) vs. low (< 19.5 ppb) FeNO levels have been associated with greater treatment effects with omalizumab, a targeted anti‐immunoglobulin E (IgE) therapy 35. Indeed, of the three potential biomarkers investigated in this study (FeNO, blood eosinophil count, serum periostin level), a high level of FeNO was the strongest predictor of response to omalizumab therapy 35. The degree of suppression of FeNO resulting from inhaled corticosteroid therapy has been used to identify non‐adherence to this treatment in a difficult‐to‐treat asthma population 36, and it has been suggested that this test could be used to help identify patients who are truly refractory to corticosteroid treatment, before considering dose escalation or the introduction of more costly targeted forms of therapy 22. In addition, a treatment algorithm in which FeNO concentrations were used to adjust patients’ inhaled corticosteroid dose during pregnancy was shown to significantly reduce the frequency of asthma exacerbations 37. However, the clinical utility of FeNO measurement in asthma is not clear‐cut, as studies investigating the association between asthma control and FeNO have yielded inconsistent results 25, perhaps partly because FeNO levels can be influenced by factors other than asthma, including age, medication use, smoking status and dietary factors 38. Controversy over the clinical utility of FeNO as biomarker for asthma is reflected in current treatment guidelines. In the UK, the National Institute of Health and Care Excellence Diagnostics Draft Guidance 12 (due for formal publication in 2017) advocates the use of FeNO testing to help diagnose asthma in adults and children 39; however, the Global Initiative for Asthma has concluded that FeNO cannot be recommended for asthma diagnosis and therapy monitoring 1. Volatile organic compounds (VOCs) VOCs can be measured in exhaled breath and their profile patterns might potentially be used to diagnose and distinguish between asthma and other conditions (e.g. chronic obstructive pulmonary disease), and discriminate between different asthma phenotypes 15, 40. ‘Electronic nose’ technology provides a means of studying VOCs in individual patients, by utilizing an array of sensors that react with different VOCs to generate a specific ‘breath print’ 41. This approach has demonstrated high sensitivity and specificity for discriminating between asthma, chronic obstructive pulmonary disease and healthy patients 42, and has been used in a clinical setting to discriminate between different inflammatory asthma phenotypes (eosinophilic, neutrophilic, paucigranulocytic) in patients with persistent asthma 40. It has also shown greater accuracy than measurement of FeNO or eosinophils for predicting responsiveness to corticosteroids 43. However, it does not appear to be able to distinguish mild asthma from severe asthma 44. The clinical utility of VOC measurement needs to be validated in a large asthma cohort; longitudinal data and guidelines for VOC measurement are also lacking 25. Exhaled breath condensate Exhaled breath condensate collection is an easy, non‐invasive, reproducible technique that can be used to measure several asthma biomarkers, including pH, markers of oxidative stress (including hydrogen peroxide), microRNA profiles, lipoxins, cytokines and leukotrienes 25, 28, 45. However, the technique is still in the research phase; a standardized methodology for exhaled breath condensate collection is required and reference values need to be established. Exhaled breath temperature Exhaled breath temperature is another potential biomarker for asthma, as blood flow in asthmatic airways is increased, resulting in a measurable increase in exhaled breath temperature 46, 47. Exhaled breath temperature is unlikely to be able to distinguish between asthma phenotypes, but it could potentially be used to monitor efficacy of asthma treatment, although this requires further research 15. Biomarkers in blood Biomarkers measured in blood are relatively non‐invasive, and less technically demanding than the assessment of biomarkers from exhaled breath. Several blood biomarkers are clinically well established and already used to help characterize asthma subtypes and monitor response to treatment. Certain novel blood biomarkers have also been identified, which may impact asthma management in the future. Eosinophil counts Peripheral blood eosinophil counts have been extensively studied as a potential biomarker for asthma. Eosinophils are important drivers of severe exacerbations in asthma 13, and blood eosinophil counts reflect inflammation in the asthmatic airway, being useful in the early detection of exacerbations and the regulation of steroid dosage 48. Mepolizumab, a humanized monoclonal antibody against IL‐5, is a selective and effective inhibitor of eosinophilic inflammation 49. Mepolizumab treatment has been shown to significantly decrease the frequency of exacerbations in patients with refractory asthma and evidence of eosinophilic airway inflammation, despite treatment with high doses of corticosteroids 13. These findings have been further supported by more recent trials of mepolizumab treatment in patients with eosinophilic asthma 50, 51. The benefits of treatment are closely associated with the blood eosinophil count, and the clinical response is marked in patients with pre‐treatment eosinophilia and absent in patients with a count < 150/μL 50. Similarly, Phase II trials of the anti‐IL‐5 agent, benralizumab, have demonstrated its effectiveness in reducing asthma exacerbation and improving lung function and asthma control in patients with uncontrolled eosinophilic asthma and acute asthma 52-54, and Phase III trials of the anti‐IL‐5 agent, reslizumab, have demonstrated its effectiveness in improving asthma control and symptoms, lung function and quality of life in patients with inadequately controlled asthma and elevated blood eosinophil counts 55-57. Blood eosinophil levels have also been shown to predict treatment benefit from biological therapies targeting IgE, IL‐4 and IL‐13 in patients with asthma 35, 58, 59. For example, in the EXTRA study, in which patients with uncontrolled severe persistent allergic asthma received 48 weeks of omalizumab treatment, patients with pre‐defined high baseline levels of peripheral blood eosinophil counts (≥ 260/μL) experienced a significant reduction in protocol‐defined exacerbations (–32%; P = 0.005), whereas those with pre‐defined low baseline levels (< 260/μL) did not (–9%; P = 0.54) 35. In a randomized, double‐blind, placebo‐controlled study of lebrikizumab (a monoclonal antibody to IL‐13), conducted in adults with asthma who were inadequately controlled despite inhaled glucocorticoid therapy, there was a trend towards a lower rate of protocol‐defined exacerbations in patients treated with lebrikizumab, compared with those treated with placebo, after 24 weeks (P = 0.16) 58. However, in the pre‐specified ‘Th2 high’ subgroup, defined on the basis of baseline peripheral blood eosinophil count and serum IgE level, the rate of exacerbations was 60% lower in the lebrikizumab group than in the placebo group (P = 0.03) 58. Although peripheral blood eosinophil data are readily available from a standard complete blood count, the clinical utility of the blood eosinophil count as a biomarker for asthma may be limited in some situations by its low specificity for eosinophilic airway inflammation, as a raised count can also be caused by other allergies, autoimmune disease and parasitic infections 25. In addition, the sensitivity of blood eosinophil levels as a biomarker for asthma is likely to decrease with the use of anti‐IL‐5 treatment, due to the differential effect of such treatment on eosinophilic inflammation in different tissue compartments. Consequently, a suppressed peripheral blood eosinophil count in patients receiving anti‐IL‐5 therapy does not reliably inform the level of underlying eosinophilic airway inflammation required to determine therapy response when symptoms and/or exacerbations remain persistent. Activation profile of eosinophils Changes in the activation profile of eosinophils in peripheral blood reflect their response to pro‐ and anti‐inflammatory signals; for example, membrane‐bound integrins become activated when eosinophils are primed to leave the circulation and enter tissue 60. Such changes have been used to diagnose the type and severity of allergic asthma 25. In a double‐blind, placebo‐controlled study of inhaled corticosteroid withdrawal in patients with mild asthma, activation of β1 integrins (identified using a monoclonal antibody) predicted decreased forced expiratory volume in 1 s more effectively than either FeNO or the percentage of eosinophils in sputum, and correlated with FeNO following inhaled corticosteroid withdrawal 61, 62. However, such differences in the activation profile of eosinophils are likely to be too subtle for routine application 25. Periostin Genomewide gene expression studies in bronchial epithelial cells identified two subsets of patients, ‘Th2 high’ and ‘Th2 low’ patients 63. This terminology was based on the observation that the highest expressed genes in the ‘Th2 high’ population were all inducible by IL‐13. Moreover, an analysis of gene expression in bronchial biopsies from the same patients demonstrated differences in IL‐13 gene expression levels between patients with ‘Th2‐high’ and ‘Th2‐low’ asthma or healthy controls 63. However, even with highly sensitive assays, differences in serum IL‐13 levels cannot reliably be detected 64. There is therefore a need for a surrogate systemic biomarker of Th2‐driven asthma (recently recognized as T2 asthma) that is mechanistically linked to IL‐13. Periostin, the gene for which was one of those most highly expressed in the Th2 high population in the study by Woodruff et al. 63, is induced by IL‐4 and IL‐13 in airway epithelial cells and lung fibroblasts 65. Periostin is a matricellular protein that has been identified as a component of subepithelial fibrosis in bronchial asthma 65, 66 and which has a potential role in eosinophilic airway inflammation 67 and regulation of mucus production 68. These mechanisms suggest that periostin is a potential mediator of asthma 69. Importantly, periostin has been shown to be a systemic biomarker of T2, IL‐13‐driven, corticosteroid‐responsive asthma 63, 66. In the BOBCAT study, conducted in patients with asthma who remained symptomatic despite maximal inhaled corticosteroid treatment, serum periostin was found to predict eosinophilic airway inflammation (defined as ≥ 22 tissue eosinophils/mm2 on bronchial biopsy or sputum eosinophilia ≥ 3%) better than FeNO levels, blood eosinophil counts or serum IgE levels (Fig. 1) 70. However, in another study, serum periostin was unable to distinguish eosinophilic asthma (defined as sputum eosinophils ≥ 3%) from non‐eosinophilic airway inflammation, whereas blood eosinophil count and FeNO level were able to do so 71. Serum periostin levels in patients with asthma have been shown to be significantly higher than those in healthy subjects, and to correlate positively with blood eosinophil counts, serum IgE and eosinophil cationic protein levels (P < 0.05) 72. High serum periostin levels have also been shown to predict asthmatic activity after reduction in inhaled corticosteroids in patients with apparently stable, well‐controlled asthma 73. Similarly, serum periostin appears to be a useful biomarker for the development of airflow limitation in patients with asthma on prolonged treatment with inhaled corticosteroids 74. These findings indicate that serum periostin may be a biomarker for responsiveness to inhaled corticosteroid therapy, which may therefore be useful in helping to identify patients as suitable candidates for alternative targeted forms of therapy 75. Serum periostin has also been investigated as a biomarker for predicting treatment response to targeted asthma therapies. For example, patients with asthma with high baseline levels of serum periostin reportedly benefit most from anti‐IL‐13 therapy with lebrikizumab and tralokinumab 58, 76, 77. Recently, topline results from 2 Phase III, randomized, double‐blind, placebo‐controlled studies evaluating the efficacy and safety of lebrikizumab in patients with severe asthma were released (LAVOLTA I and II) 78. LAVOLTA I met its primary endpoint by demonstrating a significant reduction in the rate of asthma exacerbations in patients with high levels of serum periostin or blood eosinophils. However, the exacerbation reduction results observed in LAVOLTA II did not attain statistical significance 78. The potential prognostic role of periostin as a biomarker to predict exacerbations and to help guide asthma therapy is being further investigated in ongoing clinical trials, such as the UK Refractory Asthma Stratification Programme (RASP‐UK; see ‘Implications of biomarkers of type 2 inflammation for current clinical practice’ section) 24. Current evidence suggests that periostin can help identify patients with T2 asthma, but additional biomarkers are likely to be required in order to further subdifferentiate this phenotype 15. The use of periostin as a biomarker in asthma management is currently limited by the need for well‐established and validated cut‐off values for high and low serum periostin levels, and thus the need for standardized measurement techniques. In addition, the specificity of periostin for asthma may be confounded by the presence of several factors, including comorbidities in which it is also known to be involved, such as metastatic cancer, renal injury, bone fracture and osteoporosis 79-81. Chitinase‐like protein YKL‐40 Serum levels of the chitinase‐like protein, YKL‐40, have been shown to be significantly elevated in patients with asthma vs. controls 82-84. However, reports regarding correlations between serum YKL‐40 levels and asthma severity or other asthma biomarker levels (eosinophils, total serum IgE, FeNO) have been inconsistent 70, 82-85. YKL‐40 polymorphisms have been shown to be associated with asthma, bronchial hyperresponsiveness and reduced lung function 86. It remains to be determined whether YKL‐40 is involved in the pathophysiology of asthma or is simply a marker of extracellular tissue remodelling 87, and its clinical utility in asthma management remains to be established. ILC2S Emerging evidence has indicated that activated ILC2s are capable of producing large amounts of inflammatory cytokines and may play a crucial role in T2 asthma 88. In a recent study conducted in 150 patients with mild‐to‐moderate asthma and 42 healthy controls, the percentage of ILC2s in peripheral blood was shown to correlate significantly with sputum eosinophil counts (P < 0.001), and to have a sensitivity of 67.7% and a specificity of 95.3% when used to distinguish eosinophilic from non‐eosinophilic patients with asthma 89. The percentage of ILC2s in peripheral blood therefore appears to be a surrogate marker of airway eosinophilic inflammation 89, although the clinical utility of this as a potential biomarker in asthma management is likely to be limited by difficulties in measuring ILC2 counts. IgE Serum levels of total and allergen‐specific IgE have been considered as potential biomarkers for study population characterization and for the assessment of effectiveness in intervention studies in asthma 90. However, in clinical trials of the anti‐IgE therapy, omalizumab, pre‐treatment levels of total IgE or antigen‐specific IgE were inconsistent in predicting response to treatment 91, 92. The clinical utility of measuring IgE serum levels may be limited by low specificity 25. Other circulating biomarkers Many other circulating molecules and proteins have been investigated as potential biomarkers for asthma (Table 2). Whilst some of these are related to clinically important features cross‐sectionally, we do not currently have evidence that they are prognostic or capable of predicting treatment responses. Potential biomarker Details ECP Component of eosinophil secondary granules, released during degranulation Increased serum ECP levels are indicative of systemic eosinophilic inflammation 93 Serum ECP levels are often increased in patients with asthma 94 and correlate well with airway inflammation 95 May have an advantage as a marker of activated eosinophils, although there is little evidence that ECP is more informative than blood eosinophil counts Serum ECP levels are affected by other factors, in particular smoking 95 Eotaxin (CCL11) Potent and selective chemoattractant for human eosinophils 93 Serum eotaxin levels correlate with ECP levels in asthma patients 96 Has been used to predict symptom severity during tapering of inhaled corticosteroid treatment 97 DPP‐4 Glycoprotein induced from bronchial epithelial cells by IL‐13 stimulation; highly expressed in bronchial epithelial cells of untreated asthma patients 98 In a Phase IIb study of tralokinumab therapy in severe uncontrolled asthma, patients with baseline serum DPP‐4 levels higher than the population median experienced improvements in FEV1 and asthma quality of life questionnaire scores 77 RANTES Chemokine at sites of allergic inflammation Serum levels significantly increased in asthma patients vs. controls; and in moderate and severe vs. mild asthma 99 Serum levels correlate positively with absolute eosinophil counts and total serum IgE, and negatively with FEV1 99 Osteopontin Plays a role in Th2‐mediated inflammation Serum levels shown to be elevated in patients with asthma vs. healthy controls, but do not appear to correlate with disease severity 100, 101 Thymus and activation‐regulated chemokine (TARC; CCL17) Thought to be involved in type 2‐mediated inflammation Serum levels shown to be significantly higher in patients with asthma vs. healthy controls and to correlate with eotaxin levels in patients with asthma 102 Serum levels are also increased in other allergic conditions; in particular, atopic dermatitis 103 Appetite‐modulating factors: visfatin and ghrelin Visfatin is an appetite‐modulating pro‐inflammatory adipokine and ghrelin primarily exerts anti‐inflammatory effects Serum levels of visfatin and ghrelin found to be significantly increased in patients with asthma vs. healthy controls 104 Other cytokines and growth factors IL‐3, IL‐18, fibroblast growth factor, hepatocyte growth factor and stem cell growth factor‐β shown to be significantly higher in patients with poorly controlled asthma vs. healthy controls 105 IL‐3 and IL‐18 levels found to be significantly higher in patients with poorly controlled asthma vs. those with well‐controlled asthma 105 Levels of IL‐18, fibroblast growth factor, hepatocyte growth factor and stem cell growth factor‐β shown to correlate positively with poor asthma control and negatively with quality of life scores 105 IL‐23 may be involved in modulating Th17 cells, which are thought to have a pathogenic role in T2 asthma 106 IL‐23 levels found to be significantly higher in children with asthma vs. healthy controls and to have a strong inverse relationship with FEV1 107 Acute‐phase proteins: α(2)‐macroglobulin, haptoglobin, ceruloplasmin and hemopexin Shown to be capable of discriminating between patients with asthma, patients with COPD and healthy controls, using two‐dimensional gel electrophoresis 108 Complement components C3 and C4 Serum levels of C3, but not C4, shown to be elevated in children with stable asthma, with a positive correlation between serum C3 and the severity of asthma 109 Serum levels of C3 and/or C4 found to be elevated in the majority of patients with intermittent atopic asthma vs. healthy controls 110 CRP Non‐specific marker of systemic inflammation that can be routinely measured in clinical practice 111 CRP levels shown to be increased in patients with asthma vs. controls 112 Correlations found between CRP levels and airway obstruction (FEV1/forced vital capacity ratio) 113 and the risk of severe asthma 114 However, CRP is highly non‐specific and has not shown consistent correlation with asthma control 111 Neutrophil chemotaxis velocity Neutrophils obtained from patients with asthma migrate significantly more slowly than those from patients with non‐asthmatic allergic rhinitis 115 Chemotaxis velocity of 1.55 μm/min may represent a threshold that can identify asthma with diagnostic sensitivity and specificity of 96% and 73%, respectively 115 COPD, chronic obstructive pulmonary disease; CRP, C‐reactive protein; DPP‐4, dipeptidyl peptidase‐4; ECP, eosinophil cationic protein; FEV1, forced expiratory volume in 1 s; IgE, immunoglobulin E; IL, interleukin; RANTES, regulated upon activation, normal T‐cell expressed and secreted; Th2, type 2 helper T cell; T2, type 2. Implications of biomarkers of type 2 inflammation for current clinical practice The management of severe asthma remains a daily challenge as we currently have no gold standard diagnostic test, easy measure of adherence to prescribed therapies or accurate predictor of future risk. Failure to respond to high‐dose inhaled corticosteroids in difficult‐to‐control asthma may either be due to non‐adherence to treatment (which occurs in 30–50% of patients) or may be due to persistent type 2 inflammation, which is relatively resistant to corticosteroid therapy. This latter group of patients requires additional treatment with agents that specifically target type 2 mechanisms (such as anti‐IL‐5 and anti‐IL‐13 treatments) 24. Conversely, patients with severe asthma frequently suffer from multiple comorbidities and may continue to be symptomatic even when their underlying airway inflammation is well controlled. RASP‐UK is currently conducting an objective assessment of corticosteroid adherence in patients with severe asthma and investigating the use of novel biomarker stratification strategies to improve clinical management 24. Specifically, the study will identify patients with high levels of T2 asthma biomarkers (periostin, eosinophils, FeNO) when adherent to high‐dose corticosteroid therapy as appropriate candidates for novel biological treatments that target the T2 cytokine axis 24. It is hoped that such stratification will enable patients to receive the most appropriate treatment, thus optimizing the use of relatively expensive targeted therapies. RASP‐UK will also compare the use of a composite biomarker score, comprising FeNO, serum periostin and blood eosinophils, to guide corticosteroid therapy vs. conventional symptom‐based guidelines, thereby potentially helping to avoid unnecessary morbidity due to excessive corticosteroid exposure 24. U‐BIOPRED (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes) is a 5‐year European‐wide project that aims to identify biomarkers for severe asthma 116. It will make use of multi‐dimensional phenotyping using a series of ‘omics platforms’, in which a large number of parameters will be assessed at one time, allowing researchers to develop a ‘handprint’ of severe asthma subtypes 116. It is hoped that the project will help refine diagnostic criteria for asthma phenotypes and establish whether these can predict responsiveness to new and existing treatments 116, thereby providing a template for asthma stratification and personalization of treatment. Hopefully, these and other ongoing clinical studies will allow the use of blood biomarkers in asthma to move from the research setting to routine clinical practice. The emergence of a multiplicity of novel biomarkers for asthma, including those developed as companion diagnostics for targeted therapies, could lead to confusion and over‐complexity in clinical practice. It is hoped that studies such as RASP‐UK and U‐BIOPRED will provide the strength of data required to enable the development of evidence‐based guidelines detailing how and when specific biomarkers should be used, in terms of guiding prognosis, informing treatment decisions and monitoring subsequent response to therapy. To date, research has predominantly focussed on the characterization of biomarkers for T2 asthma. However, T2 asthma represents only one of the currently recognized asthma phenotypes. Non‐eosinophilic airway inflammation occurs in approximately 50% of patients with asthma, and non‐eosinophilic asthma has been further subdivided into neutrophilic, mixed granulocytic and pauci‐granulocytic (or pauci‐immune) subtypes 30, 117, 118. The proportions of these subtypes are currently unclear, due to variations in the cut‐offs used to define them 117. For example, non‐eosinophilic asthma has been defined as asthma associated with a sputum eosinophil count of either ≤ 2% or ≤ 3%, whilst neutrophilic asthma has been defined using sputum neutrophil cut‐offs ranging from ≥ 60% to > 76% 119. Crucially, non‐eosinophilic asthma is insensitive to corticosteroid therapy 9. To date, biological agents developed to target mediators of non‐eosinophilic inflammation (e.g. IL‐17) and novel small molecules targeting neutrophilic inflammation (e.g. chemokine receptor 2 antagonists) have failed to show convincing beneficial effects in clinical trials 117, 120, 121. There is therefore an ongoing need for research to further identify and characterize biomarkers of non‐T2 asthma, to aid diagnosis, inform prognosis and help guide the development of effective targeted therapies. The characterization of non‐T2 biomarkers is also important for the characterization and management of T2 asthma, as the absence of expression of a T2 biomarker does not necessarily imply a non‐T2 status, and biomarkers for non‐T2 asthma will therefore aid the differential diagnosis of both non‐T2 and T2 phenotypes. Conclusions The clinical management of airway diseases is not straightforward and is confounded by the use of diagnostic labels implying a probable natural history, which can result in suboptimal management paradigms and unhelpfully influence expectations about treatment outcomes 122, 123. Asthma is now known to be heterogeneous with a number of underlying pathophysiological mechanisms, which may require very different treatment approaches. Consequently, there has been an increasing focus on identifying specific, well‐defined and treatable aspects of disease 123, 124. The identification and evidence‐based clinical application of reliable biomarkers that: (1) assist in the diagnosis of asthma, (2) provide prognostic information and (3) identify underlying pathophysiological disease mechanism(s) to target treatment will be major areas of advance in coming years. Several biomarkers are currently available that assist in these areas (Table 3) but ongoing research will help clarify further the potential use of these and other biomarkers in routine practice, and provide greater understanding and evidence for the clinical utility of a range of emerging novel potential biomarkers. Biomarker Ideal characteristics of biomarker Easily measurable Ability to distinguish a mechanism causally linked to important clinical outcome Reliable and reproducible in the clinical setting Ability to provide information about disease prognosis and clinical outcomes Mechanistically linked to the therapeutic target Cost‐effective Bronchial biopsy − ++ − − ++ − Bronchoalveolar lavage − ++ − − ++ − Sputum induction + ++ − +++ + + FeNO ++ ++ +++ ++ ++ ++ VOCs ++ +++ + − ++ ? Exhaled breath condensate +++ + − ++ ++ ? Exhaled breath temperature +++ − − + + +++ Blood eosinophil counts +++ +++ +++ ++ +++ +++ Activation profile of eosinophils + ++ − − +++ ? Serum periostin +++ +++ +++ +++ +++ +++ Chitinase‐like protein YKL‐40 + − − − + ? Blood ILC2s − +++ − ++ ++ ? Serum IgE +++ − − + + ? FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; ILC2s, type 2 innate lymphoid cells; VOCs, volatile organic compounds. Acknowledgements Third‐party medical writing assistance for this review paper was provided by John Scopes, mXm Medical Communications, and was funded by Roche Products Ltd. Author contributions All authors were involved in the analysis and interpretation of data included in this article, in the writing of the article and in the decision to submit the article for publication. All authors have reviewed and approved the final version for publication. Conflict of interests In the last 5 years, IDP has received speaker's honoraria from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis and GlaxoSmithKline, and a payment for organizing an educational event from AstraZeneca. He has also received honoraria for attending advisory panels with Almirall, Genentech, Regeneron, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Schering‐Plough, Novartis, Dey, Napp and Respivert, and sponsorship to attend international scientific meetings from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca and Napp. SA is an employee of Roche Products Ltd. AMG has attended advisory boards for Roche, AstraZeneca, Teva and Novartis; has received lecture fees from Roche, AstraZeneca, Teva, Novartis, Chiesi, Boehringer Ingelheim and Napp; has attended international conferences with Napp and Boehringer Ingelheim; and has participated in clinical trials with GlaxoSmithKline, Roche and Boehringer Ingelheim, for which his institution has been remunerated. LGH has received grant funding from MedImmune, Novartis UK, Hoffmann‐La Roche/Genentech Inc., AstraZeneca and GlaxoSmithKline; has taken part in advisory boards and given lectures at meetings supported by GlaxoSmithKline, Respivert, Merck Sharp & Dohme, Nycomed, Boehringer Ingelheim, Vectura, Novartis and AstraZeneca; has received funding support to attend international respiratory meetings (AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim and GlaxoSmithKline); and has taken part in asthma clinical trials (GlaxoSmithKline, Schering‐Plough, Synairgen and Hoffmann‐La Roche/Genentech), for which his institution was remunerated. He is also Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with Amgen, Genentech/Hoffman‐La Roche, AstraZeneca, Medimmune, Aerocrine and Vitalograph. References Citing Literature Number of times cited according to CrossRef: 10 G. Roberts, Asthma and oral immunotherapy biomarkers, Clinical & Experimental Allergy, 49, 2, (140-141), (2019). Wiley Online Library Hitasha Rupani and Anoop J Chauhan, Measurement of FeNO in asthma: what the hospital doctor needs to know, British Journal of Hospital Medicine, 10.12968/hmed.2019.80.2.99, 80, 2, (99-104), (2019). Crossref Ian D. Pavord and Nicola A. Hanania, Controversies in Allergy: Should Severe Asthma with Eosinophilic Phenotype Always Be Treated with Anti-IL-5 Therapies, The Journal of Allergy and Clinical Immunology: In Practice, 10.1016/j.jaip.2019.03.010, (2019). Crossref Sun-Hye Lee, Pureun-Haneul Lee, Byeong-Gon Kim, Jisu Hong and An-Soo Jang, Annexin A5 Protein as a Potential Biomarker for the Diagnosis of Asthma, Lung, 10.1007/s00408-018-0159-x, 196, 6, (681-689), (2018). Crossref S. Diver, R. J. Russell and C. E. Brightling, New and emerging drug treatments for severe asthma, Clinical & Experimental Allergy, 48, 3, (241-252), (2018). Wiley Online Library Yunus Çolak, Shoaib Afzal, Børge G. Nordestgaard, Jacob L. Marott and Peter Lange, Combined value of exhaled nitric oxide and blood eosinophils in chronic airway disease: the Copenhagen General Population Study, European Respiratory Journal, 10.1183/13993003.00616-2018, 52, 2, (1800616), (2018). Crossref Lisa Giovannini-Chami, Agnès Paquet, Céline Sanfiorenzo, Nicolas Pons, Julie Cazareth, Virginie Magnone, Kévin Lebrigand, Benoit Chevalier, Ambre Vallauri, Valérie Julia, Charles-Hugo Marquette, Brice Marcet, Sylvie Leroy and Pascal Barbry, The “one airway, one disease” concept in light of Th2 inflammation, European Respiratory Journal, 10.1183/13993003.00437-2018, 52, 4, (1800437), (2018). Crossref Reynold A Panettieri, Ulf Sjöbring, AnnaMaria Péterffy, Peter Wessman, Karin Bowen, Edward Piper, Gene Colice and Christopher E Brightling, Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials, The Lancet Respiratory Medicine, 10.1016/S2213-2600(18)30184-X, 6, 7, (511-525), (2018). Crossref Joo-Hee Kim, Serum vascular endothelial growth factor as a marker of asthma exacerbation, The Korean Journal of Internal Medicine, 32, 2, (258), (2017). Crossref Giovanni Passalacqua, Anti-interleukin 5 therapies in severe asthma, The Lancet Respiratory Medicine, 5, 7, (537), (2017). Crossref
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Gilbert C FAURE
April 1, 2019 2:24 PM
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This Medical News feature discusses findings from a recent study on the prevalence of adult-onset food allergies and the potential reasons behind them.
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Gilbert C FAURE
March 13, 2019 10:01 AM
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Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen–driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.
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Gilbert C FAURE
February 27, 2019 9:31 AM
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Review Series 10.1172/JCI124610 Influences on allergic mechanisms through gut, lung, and skin microbiome exposures Andrea M. Kemter and Cathryn R. Nagler First published February 25, 2019 - More info In industrialized societies the incidence of allergic diseases like atopic dermatitis, food allergies, and asthma has risen alarmingly over the last few decades. This increase has been attributed, in part, to lifestyle changes that alter the composition and function of the microbes that colonize the skin and mucosal surfaces. Strategies that reverse these changes to establish and maintain a healthy microbiome show promise for the prevention and treatment of allergic disease. In this Review, we will discuss evidence from preclinical and clinical studies that gives insights into how the microbiota of skin, intestinal tract, and airways influence immune responses in the context of allergic sensitization. PREVIEW PAGES Reset NextPage 0Back Continue reading with a subscription. A subscription is required for you to read this article in full. If you are a subscriber, you may sign in to continue reading. Already subscribed? Click here to sign into your account. Don't have a subscription? Please select one of the subscription options, which includes a low-cost option just for this article. At an institution or library? If you are at an institution or library and believe you should have access, please check with your librarian or administrator (more information). Problems? Please try these troubleshooting tips.
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Gilbert C FAURE
from Immunology and Biotherapies
February 18, 2019 2:03 AM
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IgE‐mediated food allergy (FA) is a potentially life‐threatening condition with a negative impact on quality of life and an increasing prevalence in westernized countries in the recent two decades. A strict avoidance of the triggering food(s) represents the current standard approach. However, an elimination diet may be difficult and frustrating, in particular for common foods, (e.g. milk, egg, and peanut). Food allergy immunotherapy (FA‐AIT) may provide an active treatment that enables to increase the amount of food that the patient can intake without reaction during treatment (i.e. desensitization), and reduces the risk of potential life‐threatening allergic reaction in the event of accidental ingestion. However, several gaps need still to be filled. A memorable Latin orator stated: “Est modus in rebus” (Horace, Sermones I, 1, 106‐07). This sentence remembers that there is a measure in everything to a proper proportion of therapy. The common sense of measure should find application in each stage of treatment. A personalized approaching should consider the specific willing and features of each patient. Efforts are devoted to improve the efficacy, the safety but also the quality of life of patients suffering from FA. In the near future it will be important to clarify immunological pathways of FA‐AIT, and to identify reliable biomarkers in order to recognize the most suitable candidates to FA‐AIT and algorithms for treatments tailored on well‐characterized subpopulations of patients. This article is protected by copyright. All rights reserved.
Via Krishan Maggon
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Société Francaise d'Immunologie
February 3, 2019 5:31 AM
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Background Food allergy (FA) is an adverse health effect produced by the exposure to a given food. Currently, there is no optimal animal model of FA for the screening of immunotherapies or for testing the allergenicity of new foods.
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Gilbert C FAURE
January 30, 2019 11:29 AM
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US study finds some people needlessly avoid foods while others do not have life-saving medication
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Gilbert C FAURE
January 29, 2019 5:00 AM
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Suspected food allergies should always be evaluated, diagnosed, and treated by a qualified medical professional, such as a board-certified allergist. Your primary care provider may refer you to an allergist. You may also search the physician directory maintained by the American Academy of Allergy, Asthma & Immunology. Avoid Self-Diagnosis and Unproven Tests Do not diagnose a food allergy on your own. Self-diagnosis can lead to unnecessary dietary restrictions and inadequate nutrition, especially in children. Additionally, some people think they are allergic to a food when they actually have another type of food disorder, and treatment may differ. Some methods of food allergy testing are unproven and are considered controversial, since no definitive studies have shown that they can effectively diagnose food allergies. Some may even increase the risk of an allergic reaction. Learn more about unproven diagnostic food allergy testing. Diagnosing Food Allergies The first step an allergist will take to diagnose a food allergy is a thorough medical history. The allergist will ask questions to determine if food allergy may be causing your symptoms and to identify the culprit food(s), and will then perform a physical exam. Next, the allergist may conduct tests to help identify a food allergy. While these tests alone do not always provide clear-cut answers, the allergist will combine your test results with the information given in your medical history to provide a diagnosis. These tests may include: These tests are all proven diagnostic methods. Depending on your medical history and initial test results, you may have to take more than one test before receiving your diagnosis. Guidelines for the Diagnosis and Management of Food Allergy in the United States, published by the National Institute of Allergy and Infectious Diseases (NIAID), is an excellent resource. Developed by a panel of prominent food allergy experts, along with 34 professional organizations, federal agencies and patient advocacy groups, this document provides the most up-to-date clinical advice on caring for people with food allergies.
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Gilbert C FAURE
January 9, 2019 12:32 PM
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This survey study provides nationally representative estimates of the distribution, severity, and factors associated with adult food allergy in the United States.
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Suggested by
Société Francaise d'Immunologie
January 3, 2019 2:53 PM
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The Atopic march denotes the progression from atopic dermatitis (AD) to the development of other allergic disorders such as immunoglobulin (Ig) E-mediated food allergy, allergic rhinitis and asthma in later childhood.
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Gilbert C FAURE
December 20, 2018 8:23 AM
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The prevalence of food allergy has increased over recent decades and is now recognized as a substantial public health burden, particularly in developed countries. This Primer provides a comprehensive overview of advances in the field of food allergies, covering mechanistic understanding, diagnostics, prevention and management.
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Gilbert C FAURE
July 15, 2019 2:29 AM
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Allergic diseases, such as respiratory, cutaneous and food allergy, have dramatically increased in prevalence over the last few decades. Recent research points to a central role of the microbiome, which is highly influenced by multiple environmental and dietary factors. It is well established that the microbiome can modulate the immune response, from cellular development to organ and tissue formation exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. It has been described at some extent changes in environment and nutrition produce dysbiosis in the gut but also in the skin, and lung microbiome, inducing qualitative and quantitative changes in composition and metabolic activity. Here we review the potential role of the skin, respiratory and gastrointestinal tract microbiomes in allergic diseases.In the gastrointestinal tract, the microbiome has been proven to be important in developing either effector or tolerant responses to different antigens by balancing the activities of Th1 and Th2 cells. In the lung, the microbiome may play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns. Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis and psoriasis. Thus, the microbiome can be considered a therapeutical target for treating inflammatory diseases, such as allergy. Despite some limitations, intervention
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Société Francaise d'Immunologie
June 8, 2019 1:58 PM
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Services on Demand Journal Article Indicators Cited by SciELO Access statistics Related links Cited by Google Similars in SciELO Similars in Google Share Anais Brasileiros de Dermatologia Print version ISSN 0365-0596On-line version ISSN 1806-4841 An. Bras. Dermatol. vol.94 no.2 supl.1 Rio de Janeiro Mar./Apr. 2019 Epub June 03, 2019 http://dx.doi.org/10.1590/abd1806-4841.2019940210 ; ATOPIC DERMATITIS Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology* 1Department of Dermatology, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP), Brazil. 2Dermatology Service, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre (RS), Brazil. 3Dermatology Service, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre (RS), Brazil. 4Dermatology Service, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre (RS), Brazil. 5Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brazil. 6Medical Dermatology Residency Program, Instituto de Ensino e Pesquisa, Hospital Sírio-Libanês, São Paulo (SP), Brazil. 7Clinic of Dermatology, Department of Medicine, Faculdade de Medicina da Santa Casa de São Paulo, São Paulo (SP), Brazil. 8Dermatology Service, Universidade do Estado do Pará, Belém (PA), Brazil. 9Dermatology Service, Hospital Municipal Jesus, Rio de Janeiro (RJ), Brazil. 10Dermatology Outpatient Clinic, Discipline of Dermatology, Faculdade de Medicina do ABC, Santo André (SP), Brazil. 11Dermatology Service, Hospital do Servidor Público Estadual, São Paulo (SP), Brazil. 12Dermatology Service, Complexo Hospitalar Padre Bento, Guarulhos (SP), Brazil. ABSTRACT: BACKGROUND: Atopic dermatitis is a highly prevalent inflammatory and pruritic dermatosis with a multifactorial etiology, which includes skin barrier defects, immune dysfunction, and microbiome alterations. Atopic dermatitis is mediated by genetic, environmental, and psychological factors and requires therapeutic management that covers all the aspects of its complex pathogenesis. OBJECTIVES: The aim of this article is to present the experience, opinions, and recommendations of Brazilian dermatology experts regarding the therapeutic management of atopic dermatitis. METHODS: Eighteen experts from 10 university hospitals with experience in atopic dermatitis were appointed by the Brazilian Society of Dermatology to organize a consensus on the therapeutic management of atopic dermatitis. The 18 experts answered an online questionnaire with 14 questions related to the treatment of atopic dermatitis. Afterwards, they analyzed the recent international guidelines on atopic dermatitis of the American Academy of Dermatology, published in 2014, and of the European Academy of Dermatology and Venereology, published in 2018. Consensus was defined as approval by at least 70% of the panel. RESULTS/CONCLUSION: The experts stated that the therapeutic management of atopic dermatitis is based on skin hydration, topical anti-inflammatory agents, avoidance of triggering factors, and educational programs. Systemic therapy, based on immunosuppressive agents, is only indicated for severe refractory disease and after failure of topical therapy. Early detection and treatment of secondary bacterial and viral infections is mandatory, and hospitalization may be needed to control atopic dermatitis flares. Novel target-oriented drugs such as immunobiologicals are invaluable therapeutic agents for atopic dermatitis. Keywords: Atopic dermatitis; Interleukins; Inflammation; Keratinocytes; Skin barrier INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory skin disease, with lesions showing typical morphology and distribution, and whose hallmark is intense pruritus. AD presents in patients with a personal or family history of atopic diseases such as asthma, rhinitis, or AD itself. It is one of the most frequent diseases of childhood, and its prevalence reaches up to 20% in infants and 2.1 to 4.9% in adults in Europe, North America, and Japan.1-3 Annual incidence of new cases of AD in patients below the age of 17 in the US is 11%; 85% of AD patients first manifest the disease before the age of 5, but 20-40% of children with AD persist with the skin disease in adulthood. 4,5 In the Brazilian population, prevalence of AD symptoms according to Solé et al. was 8.2% in children and 5.0% in adolescents. 6 Due to the complex pathogenesis of AD, which involves skin barrier defects, immune dysfunction, and microbiome alterations mediated by genetic, environmental, and psychological triggers, a single therapeutic approach is hardly capable of achieving disease control. 7 Increased transepidermal water loss (TEWL), decreased stratum corneum water content, and reduced expression of skin barrier proteins such as filaggrin and claudin 1 are the main alterations of the skin barrier in individuals with AD. 8-10 Of note is the cytokine dysregulation, leading to Th2, Th1, Th17, and Th22 polarization, which varies according to age, ethnicity, and AD phase. 11-13 Skin microbiome plays a crucial role in AD; about 90% of the skin of atopic individuals is colonized by Staphylococcus aureus (S. aureus). 14 The diversity of skin microbiome of AD patients shows temporal shifts, with a predominance of S. aureus during flares and Streptococcus, Propionibacterium, and Corynebacterium after treatment. 15 AD remains a challenging disease. Ideal treatment is targeted to long-term disease control with reduction of flares and maintenance of good quality of life. Moreover, treatment approaches depend on geographic, economic, and genotypic/phenotypic variations. This paper aims to communicate the experience, opinions, and recommendations of Brazilian dermatology experts on atopic dermatitis treatment. METHODS Eighteen faculty members from 10 university hospitals with expertise in AD were appointed by the Brazilian Society of Dermatology. The first step was the application of an online questionnaire with 14 questions regarding the management of AD patients by the experts at university hospitals. Table 1 shows the compiled answers. Table 1 answers/total Number of AD patients seen per month <50 9/18 >50 9/18 Number of patients seen in public institutions < 50 2 / 18 >50 16 / 18 Number of patients seen in private practice < 50 4 / 18 >50 13 / 18 Treatment based on published guidelines (12/18) American 5 / 12 European 5 / 12 Other 2 / 12 Topical therapy: Topical corticosteroids 17 / 18 Calcineurin inhibitors 16 / 18 Topical antibiotics 6 / 18 Other-moisturizers 7 / 18 Systemic therapy: Cyclosporine 14 / 18 Azathioprine 3 / 18 Methotrexate 11 / 18 Mycophenolatemofetil 1 / 18 Oral steroids 5 / 18 Immunobiologicaltherapy 0 / 18 Phototherapy (narrow-band UVB) Yes 15 / 18 No 3 / 18 Use of antimicrobials during flares Topical 10 / 18 Systemic 16 / 18 The second step was the analysis of recent international guidelines (American Academy of Dermatology, published in 2014, and the European Academy of Dermatology and Venereology, published in 2018). 16-21 All sections and recommendations regarding AD treatment were discussed with the 18 experts, and consensus was defined as approval by at least 70% of the panel. This paper expresses their opinions regarding international guidelines for AD treatment and provides practical guidance for dermatologists in Brazil. RESULTS/DISCUSSION Table 1 shows the data obtained from the applied questionnaire. The majority of experts (17/18) who answered the questionnaire work in public and private institutions. About 50% of the specialists see more than 50 AD patients/month, mostly at public hospitals. Twelve out of 18 of the dermatologists follow published consensuses, with emphasis on the American and European guidelines. The most widely used topical treatments are corticosteroids, followed by calcineurin inhibitors. The first choice for systemic therapy was cyclosporin, followed by methotrexate and azathioprine. Baseline therapy and preventive measures The recent guidelines are in accordance regarding baseline therapy. Key steps include maintenance of the skin barrier through the constant use of emollients, which recover the function of the damaged skin barrier in AD and consequently protect the skin from allergen penetration and subsequent inflammation. 22 Skin hydration improves xerosis and reduces pruritus, sparing topical corticosteroid use. Cleansing eliminates crusts and reduces bacterial contamination. The use of substances with physiological pH is recommended, and baths should last no longer than five minutes. 23 Sodium hypochlorite baths (bleach) may not always change the severity of AD but appear to reduce the need for topical anti-inflammatory drugs and antibiotics. 24 Daily bathing is possible for regular skin hydration, and emollients should be applied on slightly wet skin, immediately after drying; application twice daily is usually sufficient. 25 Some emollients have additional ingredients such as urea and propylene glycol, which may lead to skin irritation, and there is still inconclusive evidence about superiority of emollients enhanced with components of the skin barrier such as ceramides. 25,26 Recent concepts regarding the microbiome and the skin highlight that the cutaneous microbiome in AD is not as heterogeneous as in healthy individuals, with the predominance of Staphylococcus aureus (S. aureus). 15,27 Recovery of the skin barrier by adjusting the inflammatory response reestablishes the skin microbiome in AD patients. 28,29 Bacterial lysates or topical application of commensal bacteria are promising, but skin hydration itself is able to recover the skin microbiome. 15,30 There is evidence for early use of emollients in atopic dermatitis-prone children (three months of age and older) in the prevention of AD. 28,29 Recommendations by the dermatology experts for baseline therapy: Daily cleansing for up to 5 minutes with mild agents with adequate pH Emollient application twice daily on slightly wet skin is the main component of baseline therapy Aeroallergens Aeroallergens are relevant triggering factors of AD flares.31-33 Exacerbation of an eczematous lesion after skin contact or inhalation has been reported, but studies are still inconclusive. 32 The skin prick test and specific IgE are routinely utilized but have a low positive predictive value. 32 In the present panel of dermatology experts, 89% do not perform the skin prick test or RAST as part of routine practice. Food allergy One-third of the children with moderate/severe AD have associated food allergy; however, food allergy is not the cause of AD. 34 Restrictive diets should only be prescribed for children with proven food allergy. 34,35 The published guidelines recommend restrictive diets only for those patients with a positive oral challenge test, the gold standard assay for food allergy. 19,34-36 The detection of specific IgE to food through prick or serological tests does not prove food allergy, and their positive predictive value is low. 37 The present panel of dermatology experts does not recommend restrictive diets, but considers that food allergy may be investigated in children with severe, treatment-resistant AD and in those with a history of flares following ingestion of specific foods. Contact dermatitis Contact dermatitis is present in 40-65% of AD patients, usually exacerbating the existing eczema. 38 The patch test is recommended for refractory AD with atypical skin lesions. 39 Patients should be tested for fragrances, preservatives, topical corticosteroids, and other topical components. 38 Patients are more prone to develop occupational dermatoses, since AD exacerbates the irritant effect of allergens in certain professions such as hairdressers, mechanics, metalworkers, janitorial workers, and nurses, in whom hand eczema is commonly reported. 40 Preventive measures should be taken in order to reduce the incidence of AD in such patients. Fifty percent of the expert group recommend patch tests. The main problem is the difficulty in performing the test, since ideal sites are usually limited in AD patients. Topical anti-inflammatory therapy Topical anti-inflammatory therapy is the mainstay of AD treatment. Anti-inflammatory agents must have sufficient potency and should be applied on the skin lesions according to the recommendations and not exceeding the allowed amount per day. 41 Topical corticosteroids (TC) TC are the first line treatment for AD, with strong evidence of their superiority over placebo. 42 They are classified according to their potency based on vasoconstrictive effects, and every clinician should be aware of their potential local and systemic adverse effects, such as cutaneous atrophy and adrenal suppression.43,44 Strategies defining the use of TC vary according to their potency, but the suggested applied amounts of topical corticosteroids follow the fingertip unit rule.19,20 In the European guidelines, the approximate total amount of TC per month is 15g in infants, 30g in children, and 60-90g in adolescents and adults.20 The choice of corticosteroid and its vehicle depend on the affected site, the patients’ age and the severity and clinical phase of AD. Wet-wrap dressings may improve AD flares, and ultrahigh potent topical corticosteroids should be applied for up to two weeks.29,45 TC use depends on the vehicle; as a cream, they should be applied 15 minutes before the moisturizer, and as an ointment, applied 15 minutes prior to the moisturizer.41 Corticosteroid phobia is a relevant matter that should be addressed, especially due to its influence on adherence to treatment; it varies according to the country and culture.46 Topical corticosteroids are the first-line topical treatment for AD, according to the experts. Calcineurin inhibitors (topical immunomodulators or TIM) Tacrolimus and pimecrolimus are second-line non-corticosteroid, anti-inflammatory therapies for AD with proven efficacy.20,47 The most widely reported adverse effect is burning sensation during the initial days of use (especially with tacrolimus); they do not induce skin atrophy, which makes them useful for application on eyelids, perioral lesions, axillae, and genitals.48 Despite a black box warning in the package insert, studies have not reported an increased risk of lymphoma with the topical use of TIM at therapeutic doses.49 Intermittent use of TIM is recommended above two years of age.20 Eighty percent of the Brazilian experts use TIM as a second-line therapy for AD. Proactive treatment Proactive treatment has been proposed in published guidelines. It consists of long-term use of topical anti-inflammatory agents, either TC or TIM (tacrolimus), twice a week in previously affected areas, combined with moisturizers. 29,45,50,51 The rationale for proactive treatment is based on its efficacy and long-term safety (up to one year), reducing the number of flares and improving the quality of life of atopic patients. 50,51 The Brazilian experts recommend proactive treatment with TC or TIM in AD patients. Topical antimicrobial therapy Colonization by S. aureus is frequent on the skin of AD patients and is much higher than in non-atopic individuals (100% vs. 30%). 52-54Fortunately, the skin and nares of AD patients are not frequently colonized by methicillin-resistant S. aureus (MRSA) (7.4 and 4%, respectively). 54 The American Academy of Dermatology does not recommend the use of topical antibiotics, since they do not show clear benefits for AD patients. However, the use of 0.005% sodium chlorine in bathwater may be helpful in children and is recommended by the EADV. 17,20 During flares, 100% of the Brazilian experts use antibiotics. About 1/3 of the experts use topical antibiotics in acute phases of AD for short periods (up to one week). Recommendations for topical therapy in AD: TC are the first-line treatment for AD patients and must be carefully prescribed according to their potency and vehicle. Patient’s age, site, and phase of AD lesions are key factors when choosing TC. TIM constitute the second-line treatment for AD and are suitable for application on areas with high risk of corticosteroid-induced atrophy. Proactive therapy with either TC or TIM is safe, reduces flares and AD severity, and is indicated as long-term maintenance therapy. The use of topical antibiotics and antiseptics is still variable. Topical antibiotics can be used for short periods, and bleachers (0.005% sodium hypochlorite may be useful for pediatric AD). Wet-wrap bandages or occlusive treatment during hospitalization are helpful measures for improving flares. In patients that fail to respond to topical treatment, the following should be considered: -differential diagnoses of AD -lack of adherence -contact dermatitis -secondary infection (bacterial, viral, or fungal) -indication for systemic therapy Systemic treatment Systemic treatment of AD is recommended in moderate to severe cases that fail to respond topical therapies. Before initiating systemic treatment, it is mandatory to avoid aggravating factors, to diagnose and treat secondary infections, and to rule out differential diagnoses. The option for systemic therapy should also include the impact of the disease on the patient’s quality of life and a careful balance of risks and benefits with the chosen medication. 55,56 Phototherapy Phototherapy is a valid adjuvant therapeutic option, especially for chronic AD and in adults. It improves pruritus, thus reducing insomnia. 57 Ultraviolet B (UVB), narrow-band UVB, and psoralen + UVA (PUVA) are the main modalities. 12,57 UVB-NB (311-313nm) is the most widely used form and can be indicated for children. UVA1 (340-400nm) is seldom used in Brazil but is useful for flares. 21,57 In the Brazilian consensus group, 83% recommend this treatment modality, especially for the chronic phase of AD. Phototherapy improves clinical signs and reduces pruritus and bacterial colonization, thus being a steroid-sparing measure. It is important to avoid this treatment in patients with recurrent herpes simplex infection or history of eczema herpeticum. A limiting factor for this therapeutic modality is lack of adherence to long-term treatment. Antihistamines Oral antihistamines that block the histamine 1 receptor (H1R) have been prescribed for AD patients for decades; however, there are few randomized studies that evaluate their real efficacy in AD. 21 The aim of systemic antihistamines in AD is to allow better quality of sleep, since their role as anti-inflammatory agents in AD is controversial. There is no evidence of improvement of severity scores in randomized studies, and first-generation drugs are prescribed due to their sedative effect and to the relief of other conditions related to AD, such as asthma, rhinoconjunctivitis, dermographism, and urticaria. 21,58 However, our group stresses that the quality of sleep induced by anti-H1R drugs is not ideal, since they do not alter the REM phase. 21,58 Our group recommends the use of first-generation antihistamines (hydroxyzine and chlorpheniramine) based only on their sedative effect. Anti-inflammatory agents Cyclosporin A (CyA) Cyclosporin A is approved in many European countries and in Brazil for severe AD. The U.S. FDA approves it for psoriasis. The initial dose for children and adults varies from 3 to 5 mg/kg/day, and the maintenance dose is from 2.5 to 3 mg/kg/day. 55,59-61 Clinical improvement can be observed after 2-8 weeks; CyA is recommended for up to 2 years with constant monitoring of blood pressure and kidney function. 55,59-61 Periodic intervals of 3-6 months off therapy decreases the occurrence of side effects. 62 The average length of treatment with CyA is 3-12 months, and the drug is usually considered first-line treatment for treatment-resistant AD and in acute flares. 63 Pregnancy is not a contraindication to CyA use. 63 Although CyA leads to prompt improvement in severity scores after 2 weeks from the initial dose, reactivation of AD after the drug’s suspension is equally rapid, occurring in 2 weeks. 63 Methotrexate (MTX) MTX can be indicated as initial treatment for moderate/severe AD, recalcitrant to topical treatment with corticosteroids. The drug has a good safety profile and is indicated for long-term maintenance; clinical efficacy is reached after 8-12 weeks of administration.21,61,63 The therapeutic dose varies from 15 to 25mg/week for adults and 10-15mg/m2/week for children (oral, intravenous, or subcutaneous), and folate should be added to the treatment, usually 1-2 days after MTX. 21,61,63 Average length of treatment ranges from 6 to 12 months, and clinical improvement is seen at 8-12 weeks from the initial dose. Side effects include hematological disorders, liver enzyme alterations, and gastrointestinal discomfort. Its use is recommended for up to 2 years, with constant monitoring of bone marrow and liver function. 21,61,63,64 Contraception is mandatory, since the drug is considered category X. 61,63 Azathioprine (AZA) AZA can be indicated as systemic treatment for refractory AD. Peak efficacy of AZA is reached after 8-12 weeks of use. 63 The initial dose is usually 50 mg/day for 1-2 weeks, increased thereafter to 2-3 mg/kg/day. 63,65 It can increase the risk of non-melanoma skin cancer and lymphoma. 66,67 Thiopurine methyltransferase enzyme (TPMT) levels should be measured whenever possible, since TPMT deficiency while in use of AZA can lead to bone marrow aplasia. 65 It can be prescribed for children (off label for AD) and is subject to restricted indication during pregnancy. 63,68 Mycophenolate mofetil (MMF) Clinical efficacy of MMF is reached after 8-12 weeks of use (off label in AD), and the drug has a good safety profile. 21,63 The recommended doses in adults are 1-2g/day (starting dose) and 2-3g/ day (maintenance); the pediatric doses are 20-50mg/kg/day (starting dose) and 30-50mg/kg/day (maintenance).21,68 Gastrointestinal and hematological side effects have been reported. 21,63 Systemic corticosteroids (SC) There are few randomized controlled studies regarding the use of systemic corticosteroids in AD. In the 2018 European consensus, SC are used in exceptional cases of AD, but only for one week.21 There is a rapid clear up of skin lesions , but severe rebound tends to occur in 2 weeks. 21 One controlled trial indicates lower efficacy of systemic prednisolone in comparison to CyA in severe AD.21,69 Position/recommendations for the use of systemic anti-inflammatory drugs in AD: CyA and MTX are the most widely used systemic drugs for severe refractory AD. CyA leads to fast improvement of AD severity scores after 2 weeks of initial treatment, but reactivation of AD after drug suspension is equally fast, occurring in 2 weeks. MTX can be used as the initial systemic medication for refractory moderate/severe AD and is indicated for long-term maintenance. Clinical efficacy is reached after 8-12 weeks of administration. Oral corticosteroids are used in exceptional cases for short periods (up to 1 week). Few dermatologists have experience with mycophenolate mofetil or azathioprine. Treatment of secondary infections (bacterial, viral, or fungal) S. aureus and Streptococcus pyogenes are the most common bacterial agents in AD. They are detected in more than 90% of AD lesions.53 Systemic antibiotics are reserved for patients with clinical evidence of infection, and cephalosporins are the first choice of treatment.21,70 Extensive viral infections such as eczema herpeticum (EH) are seen in AD patients. Skin barrier defects, including mutations of the filaggrin and claudin1 genes or abnormalities in IFN-gamma response may increase the risk of EH. 12,71 Risk factors for EH include early severe AD, high IgE levels, eosinophilia, and associated food allergy and asthma.14,45,63,72 Treatment for localized EH is oral acyclovir. Systemic involvement with fever, lethargy, headache, nausea, and dizziness requires hospitalization and intravenous acyclovir. 72 As for fungal infections in patients with AD, Malassezia spp. appears to contribute to skin inflammation during flares, and there is an anti-IgE response to immunogenic proteins released by some Malassezia species. 73 Recommendations by the Brazilian experts: oral antibiotics are indicated when there are signs of bacterial superinfection of the skin; cephalosporins are the first choice, followed by sulfamethoxazole-trimethoprim. Eczema herpeticum must be treated with systemic antiviral drugs; when it is followed by systemic symptoms and signs, hospitalization and intravenous antiviral therapy are indicated. AD patients with head and neck involvement may benefit from treatment with antifungal agents. Education and AD AD has a strong impact on the quality of life of patients and caregivers due to its chronic course and intense pruritus. 21,45,74 Sleep loss, school and work absenteeism, social isolation, depression, and suicidal ideation may be present. 56,74 Low treatment adherence is common in AD, and educational programs are needed to reinforce the patient’s understanding of the disease complexity and therapeutic approaches. 75 Various models focusing on AD education and with multidisciplinary approaches have shown subjective and objective improvement of AD worldwide. 75-79 Future perspectives Immunobiologicals and small molecules are targeted therapies that have been developed for many inflammatory, autoimmune, and oncologic diseases. Crisaborole ointment is a topical phosphodiesterase 4 (PDE4) inhibitor that was approved in the USA in 2017 for patients above the age of 2 years with mild/moderate AD. 80 Dupilumab is a human monoclonal antibody for AD that blocks the alfa-chain receptor for IL-4 and IL-13 (dupilumab) and is approved for adults with moderate/severe AD. 81 Its efficacy after 16 weeks as monotherapy (initial dose: 600 mg, followed by 300 mg every 2 weeks, SC), measured by the reduction of eczema severity scores (EASI) was 82.5% (EASI 50), 60.3% (EASI 75), and 36.5% (EASI 90).81-83 Improvement of skin lesions and reduction of pruritus improved 2 weeks after initiating treatment. 81-83The studies show sustained long-term efficacy (one year) with dupilumab combined with TC in AD patients.84,85 The main adverse event reported with dupilumab was conjunctivitis, detected in 25-50% of AD patients.85,86 There are ongoing studies (phases 2-3) with novel immunobiologicals and small molecules for AD treatment. See Chart 1. 87,88 Chart 1 Agent Target Administration Phase Tralokinumab IL-13 SC 3 Lebrikizumab IL-13 SC 2 Nemolizumab IL-31Ra SC 3 Apremilast PDE4 PO 2 ILV-094 IL-22 IV terminated Secukinumab IL-17 SC 2 Baricitinib JAK1/2 PO 2 Upadacitinib JAK1 SC 2 ZPL389 H4R PO 2 Tezepelumab TSLP SC 2 Serlopitant NKR1 PO 2 IL=interleukin; R=receptor PDE=phosphodiesterase; JAK= janus kinase; H=histamine; TSLP=thymic stromal lymphopoietin; NKR=neurokinin receptor; SC= subcutaneously; PO= per oral; IV= intravenously Source: Wang, et al, 201687 and Lee, et al, 2018.88 Chart 1: New systemic drugs for AD treatment. 87,88 CONCLUSIONS Despite the cultural and economic differences between Brazil, USA, and Europe, including in access to immunobiological therapies, the ideal management of AD is based on a better understanding of disease pathogenesis and knowledge of treatment strategies. 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Immunologic Targets in Atopic Dermatitis and Emerging Therapies: An Update. Am J Clin Dermatol. 2016;17:425-43. [ Links ] 88 Lee DE, Clark AK, Tran KA, Shi VY. New and emerging targeted systemic therapies: a new era for atopic dermatitis. J Dermatolog Treat. 2018;29:364-74. [ Links ] Received: October 22, 2018; Accepted: January 13, 2019 Mailing address: Valeria Aoki. E-mail: valeria.aoki@gmail.com Daniel Lorenzini. E-mail: daniellorenzini@gmail.com Conflict of interest: None. AUTHORS’ CONTRIBUTIONS Valeria Aoki 0000-0003-4256-4413 Approval of the final version of the manuscript; Conception and planning of the study; Elaboration and writing of the manuscript; Obtaining, analyzing and interpreting the data; Critical review of the literature; Critical review of the manuscript Daniel Lorenzini 0000-0002-6850-5799 Approval of the final version of the manuscript; Elaboration and writing of the manuscript; Obtaining, analyzing and interpreting the data; Critical review of the literature; Critical review of the manuscript Raquel Leão Orfali 0000-0002-2807-1404 Approval of the final version of the manuscript; Obtaining, analyzing and interpreting the data; Critical review of the literature; Critical review of the manuscript Mariana Colombini Zaniboni 0000-0002-7830-8668 Approval of the final version of the manuscript; Obtaining, analyzing and interpreting the data; Critical review of the literature; Critical review of the manuscript Zilda Najjar Prado de Oliveira 0000-0002-8596-1999 Approval of the final version of the manuscript; Critical review of the manuscript Maria Cecília Rivitti-Machado 0000-0003-2910-7330 Approval of the final version of the manuscript; Critical review of the manuscript Roberto Takaoka 0000-0003-0952-2641 Approval of the final version of the manuscript; Critical review of the manuscript Magda Blessmann Weber 0000-0001-5885-5851 Approval of the final version of the manuscript; Critical review of the manuscript Tania Cestari 0000-0003-3001-0202 Approval of the final version of the manuscript; Critical review of the manuscript Bernardo Gontijo 0000-0003-1938-5986 Approval of the final version of the manuscript; Critical review of the manuscript Andrea Machado Coelho Ramos 0000-0001-7414-3395 Approval of the final version of the manuscript; Critical review of the manuscript Claudia Marcia de Resende Silva 0000-0002-3250-1227 Approval of the final version of the manuscript; Critical review of the manuscript Silmara da Costa Pereira Cestari 0000-0001-9824-7906 Approval of the final version of the manuscript; Critical review of the manuscript Silvia Souto-Mayor 0000-0001-9335-2758 Approval of the final version of the manuscript; Critical review of the manuscript Francisca Regina Carneiro 0000-0001-6735-4004 Approval of the final version of the manuscript; Critical review of the manuscript Ana Maria Mosca de Cerqueira 0000-0001-8779-834X Approval of the final version of the manuscript; Critical review of the manuscript Cristina Laczynski 0000-0001-7483-5826 Approval of the final version of the manuscript; Critical review of the manuscript Mario Cezar Pires 0000-0001-7587-8932 Approval of the final version of the manuscript; Elaboration and writing of the manuscript; Critical review of the manuscript ©2019 by Anais Brasileiros de Dermatologia This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License which permits unrestricted noncommercial use, distribution, and reproduction in any medium provided the original work is properly cited.
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An eight-year hunt for the cells that drive the extreme childhood food allergy eosinophilic esophagitis (EoE) has identified a potential new way to treat the disease while also raising questions about a dietary supplement often taken to reduce bowel inflammation.
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Galactose-α-1,3-galactose (α-Gal) is an oligosaccharide that was first described as a cause of immunoglobulin E-mediated anaphylaxis in case
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San Francisco, CA (PRWEB) February 25, 2019 -- San Francisco, CA – Sesame allergy appears increasingly common among United States children and adults, with...
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Disrupted epithelial barriers are thought to be central to development of allergic disorders such as atopic dermatitis, which is commonly associated with food allergy. Leung et al . performed repeated skin tape stripping on lesional and nonlesional skin of patients with pediatric atopic dermatitis, some of whom also had food allergies. Among other parameters, they measured lipids, proteins, barrier integrity, and the microbiome. They found that nonlesional skin from patients with atopic dermatitis had different characteristics depending on whether the patient also had food allergy. Gene expression analysis also showed elevated type 2 immune signatures in food allergic samples. Their findings reveal unique properties about the epidermis in allergic disease and could lead to the development of biomarkers for food allergy.
Skin barrier dysfunction has been reported in both atopic dermatitis (AD) and food allergy (FA). However, only one-third of patients with AD have FA. The purpose of this study was to use a minimally invasive skin tape strip sampling method and a multiomics approach to determine whether children with AD and FA (AD FA +) have stratum corneum (SC) abnormalities that distinguish them from AD without FA (AD FA −) and nonatopic (NA) controls. Transepidermal water loss was found to be increased in AD FA +. Filaggrin and the proportion of ω-hydroxy fatty acid sphingosine ceramide content in nonlesional skin of children with AD FA + were substantially lower than in AD FA − and NA skin. These abnormalities correlated with morphologic changes in epidermal lamellar bilayer architecture responsible for barrier homeostasis. Shotgun metagenomic studies revealed that the nonlesional skin of AD FA + had increased abundance of Staphylococcus aureus compared to NA. Increased expression of keratins 5, 14, and 16 indicative of hyperproliferative keratinocytes was observed in the SC of AD FA +. The skin transcriptome of AD FA + had increased gene expression for dendritic cells and type 2 immune pathways. A network analysis revealed keratins 5, 14, and 16 were positively correlated with AD FA +, whereas filaggrin breakdown products were negatively correlated with AD FA +. These data suggest that the most superficial compartment of nonlesional skin in AD FA + has unique properties associated with an immature skin barrier and type 2 immune activation.
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These results suggest that sustained desensitization after omalizumab-facilitated
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Adv Exp Med Biol. 2019 Jan 26. doi: 10.1007/5584_2018_316.[Epub ahead of print]...
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Food allergy is a common cause of anaphylaxis, but the incidence of fatal food anaphylaxis is not known. The aim of this study was to estimate the incidence of fatal food anaphylaxis for people with food allergy and relate this to other mortality risks ...
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Gilbert C FAURE
January 8, 2019 5:08 AM
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At least one in 10 American adults have a food allergy, but almost twice that many think they have one, according to new research out today.
In a survey of over 40,000 people conducted between 2015 and 2016, 10.8 percent reported symptoms suggestive of a convincing food allergy.
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Gilbert C FAURE
December 30, 2018 1:54 PM
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Changes in the human environment and activities over the past few decades have caused an epidemic of food allergies ([ 1 ][1]). People suffering from allergies often feel that they live on a cliff edge, as the allergens to which they react are potentially fatal ([ 2 ][2]). For example, tiny amounts of peanut picked up on skin or contaminating other foods can be dangerous to peanut-sensitized individuals ([ 2 ][2]–[ 4 ][3]). Immunoglobulin E (IgE) antibodies mediate the allergic response. They bind to specific receptors on inflammatory immune cells: mast cells in mucosal tissues lining body surfaces and cavities, and basophils in the circulation. These cells mediate allergic responses triggered by specific antigens (allergens) that are recognized by IgE. B cells expressing IgG antibodies have long served as the paradigm for the development of B cells into antibody-secreting plasma cells in the immune response. Until recently, the far less abundant IgE-expressing B cells have proved to be elusive. On page 1306 of this issue, Croote et al. ([ 5 ][4]) have analyzed single B cells from six individuals with peanut allergy, which enabled the identification of the natural Ig heavy- and light-chain pairs from IgE-expressing B cells that are responsible for peanut allergy. With this information they produced recombinant antibodies, identified the peanut allergen–specific antibodies, and used site-directed mutagenesis to suppress their activity. The mutated antibodies could be used to treat peanut allergy.
![Figure][5]
From sensitization to peanut allergy
Dendritic cells in the skin pick up peanut allergens and present them to peanut allergen–specific T helper 2 (TH2) cells, which in turn present them to B cells. Interaction between peanut allergen–specific TH2 cells and B cells solicits help from TH2 cells for B cell proliferation, somatic hypermutation and affinity maturation, class switching to IgE, and plasma cell differentiation. Allergen-specific IgE secreted by plasma cells binds to resident mast cells in the gut, so the ingestion of peanuts triggers an allergic reaction.
GRAPHIC: N. DESAI/ SCIENCE
Whole-exome sequencing of single B cells from peanut-allergic individuals yielded two principal components of gene expression, representing naïve or memory B cells and plasmablasts (the circulating precursors of plasma cells). The majority of Ig-Eexpressing cells were plasmablasts, whereas the majority of cells expressing IgG or IgA (the more abundant antibody classes) were naïve or memory B cells. It has previously been observed that IgE-expressing B cells tend to develop into the plasma cell lineage as opposed to the memory cell lineage. The IgE plasma cells inherit their antigen specificity from B cells of other antibody classes, which have undergone affinity maturation. This is advantageous for their biological function in immediate hypersensitivity to antigens as it cuts out the time that would be required for affinity maturation of IgE memory B cells ([ 6 ][6], [ 7 ][7]).
In immune responses, antigens bind to specific B cells expressing a membrane-bound form of the antibody [the B cell receptor (BCR)], which stimulates B cell maturation through the processes of somatic hypermutation (mutations affecting the antibody affinity for antigen) and affinity maturation (the selection of cells expressing BCRs with the highest affinity for antigen). The cells may also undergo class switching (from IgM to IgG, IgA, or IgE) to the most effective antibody class for a particular location in the body. IgE expression is needed for protection from parasites at barriers to the environment (airways, gut, skin). The cost of this elaborate immune mechanism is frequently the lack of normal tolerance to harmless allergens, causing allergy.
There is compelling clinical and experimental evidence that both IgE class switching and somatic hypermutation in humans occur transiently in the respiratory tract upon allergen stimulation ([ 8 ][8]–[ 10 ][9]). Whether primary contact with peanuts through the skin ([ 3 ][10], [ 4 ][3]) is followed by local class switching to IgE in the aerodigestive tract in food allergy remains to be investigated. Immediate hypersensitivity that is characteristic of allergic reactions mediated by IgE occurs in the gut as it does in the airways (see the figure). The IgE-expressing B cells isolated from blood by Croote et al. may represent peanut-specific cells that have migrated out of the tissue to other sites in the body where they continue to function ([ 10 ][9], [ 11 ][11]).
The authors focused on B cells that were of interest because the variable region sequences in six B cells from two of the six individuals studied were similar. Such similarity between individuals is highly improbable (one in 1014 potential sequences in the far fewer number of B cells that occur in each individual). The similarities suggest that the antigen-binding sequences are convergent or “public” sequences (inherited sequences that are conserved in evolution). Convergent sequences have been observed in infectious disease and in vaccination studies. A rationale is to hand: The relatively small germline gene repertoire encoding the Ig variable region sequences, compared to the repertoire resulting from somatic hypermutation and affinity maturation of the B cells, may have evolved in our ancestors to protect them against commonly encountered pathogens. Whether the conserved sequences serve the same purpose now or allergens are mistaken for the pathogens that affected our ancestors is unclear ([ 12 ][12]).
The six convergent clones were expressed as recombinant antibodies. This revealed high levels of somatic hypermutation, reflecting affinity maturation in the B cells specific for the three most common and clinically relevant peanut allergens, Ara h 1, Ara h 2, and Ara h 3. The coincidence of convergence and peanut specificity here is remarkable. Genetic mutagenesis gave insight into the crucial residues for activity, and this could be further understood through high-resolution crystal structure determination of the allergen-antibody complexes ([ 13 ][13]). One other B cell was shown to express an Ara h 3–specific IgE antibody. This cell was especially interesting because the IgE was related to an IgG4 (an IgG subclass) in the same cell. This confirms previous reports of related IgG4 and IgEs in allergy ([ 10 ][9]). IgG4 is an antibody class that confers tolerance to allergens by competing with IgE for specific antigens ([ 14 ][14], [ 15 ][15]) and is dramatically increased in specific allergen immunotherapy. It is reassuring that the immune system itself can operate a mechanism to prevent or ameliorate allergy, which can be exploited in the clinic.
Further research on these antibodies could lead to modified antibodies or antibody fragments that compete with IgE for allergen binding and prevent the allergic response. Future use of whole-exome sequencing, perhaps comparing the development of IgE-expressing plasma cells with those expressing other antibody classes, may identify genes that regulate IgE plasma cell development and survival that could be counteracted. The work of Croote et al. exemplifies a concerted approach to understanding and potentially intervening in allergic disease.
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