Allergy clinics in times of the SARS‑CoV‑2 pandemic: an integrated model
Giacomo Malipiero, Enrico Heffler, Corrado Pelaia, Francesca Puggioni, Francesca Racca, Sebastian Ferri, Lina Spinello, Morena Merigo, Donatella Lamacchia, Giuseppe Cataldo, Melissa Sansonna, Giorgio Walter Canonica and Giovanni Paoletti
Background: Almost the entire World is experiencing the Coronavirus-Disease-2019 (COVID-19) pandemic, responsible, at the end of May 2020, of more than five million people infected worldwide and about 350,000 deaths. In this context, a deep reorganization of allergy clinics, in order to ensure proper diagnosis and care despite of social distancing measures expose, is needed.
Main text: The reorganization of allergy clinics should include programmed checks for severe and poorly controlled patients, application of digital medicine service for mild-to-moderate disease in well-controlled ones, postponement of non urgent diagnostic work-ups and domiciliation of therapies, whenever possible. As far as therapies, allergen immunotherapy (AIT) should not be stopped and sublingual immunotherapy (SLIT) fits perfectly for this purpose, since a drug home-delivery service can be activated for the entire pandemic duration. Moreover, biologic agents for severe asthma, chronic spontaneous urticaria and atopic dermatitis should be particularly encouraged to achieve best control possible of severe disease in times of COVID-19 and, whenever possible, home-delivery and self-administration should be the preferred choice.
Conclusion: During COVID-19 pandemic, allergists have the responsibility of balancing individual patients’ needs with public health issues, and innovative tools, such as telemedicine and digital medicine services, can be helpful to reduce the risk of viral spreading while delivering up-to-date personalized care.
Biomarkers of severity and threshold of allergic reactions during oral peanut challenges
Alexandra F. Santos, MD, PhD, George Du Toit, MD, FRCPCH, Colin O’Rourke, MS, Natalia Becares, PhD, Natalia Couto-Francisco, MSc, Suzana Radulovic, MD, Ekaterina Khaleva, MD, Monica Basting, MA, Kristina M. Harris, PhD, David Larson, PhD, Peter Sayre, MD, PhD, Marshall Plaut, MD, Graham Roberts, DM,FRCPCH, Henry T. Bahnson, MPH, and Gideon Lack, MD,FRCPCH
Background: Oral food challenge (OFC) is the criterion standard to assess peanut allergy (PA), but it involves a risk of allergic reactions of unpredictable severity.
Objective: Our aim was to identify biomarkers for risk of severe reactions or low dose threshold during OFC to peanut.
Methods: We assessed Learning Early about Peanut Allergy study, Persistance of Oral Tolerance to Peanut study, and Peanut Allergy Sensitization study participants by administering the basophil activation test (BAT) and the skin prick test (SPT) and measuring the levels of peanut-specific IgE, Arachis hypogaea 2–specific IgE, and peanut-specific IgG4, and we analyzed the utility of the different biomarkers in relation to PA status, severity, and threshold dose of allergic reactions to peanut during OFC.
Results: When a previously defined optimal cutoff was used, the BAT diagnosed PAwith 98% specificity and 75% sensitivity. The BAT identified severe reactions with 97% specificity and 100% sensitivity. The SPT, level of Arachis hypogaea 2–specific IgE, level of peanut-specific IgE, and IgG4/IgE ratio also had 100% sensitivity but slightly lower specificity (92%, 93%, 90%, and 88%, respectively) to predict severity. Participants with lower thresholds of reactivity had higher basophil activation to peanut in vitro. The SPT and the BAT were the best individual predictors of threshold. Multivariate models were superior to individual biomarkers and were used to generate nomograms to calculate the probability of serious adverse events during OFC for individual patients. Conclusions: The BAT diagnosed PA with high specificity and identified severe reactors and low threshold with high specificity and high sensitivity. The BAT was the best biomarker for severity, surpassed only by the SPT in predicting threshold. Nomograms can help estimate the likelihood of severe reactions and reactions to a low dose of allergen in individual patients with PA. (J Allergy Clin Immunol 2020;146:344-55.)
Butyrate inhibits human mast cell activation via epigenetic regulation of FcεRI-mediated signaling
Jelle Folkerts, Frank Redegeld, Gert Folkerts, Bart Blokhuis, Mariska P. M. van den Berg, Marjolein J. W. de Bruijn, Wilfred F. J. van IJcken, Tobias Junt, See-Ying Tam, Stephen J. Galli, Rudi W. Hendriks, Ralph Stadhouders, Marcus Maurer
Background: Short-chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health, and suppress mast cell–mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs (acetate, propionate, and butyrate) on mast cell–mediated pathology and human mast cell activation, including the molecular mechanisms involved.
Method: Precision-cut lung slices (PCLS) of allergen-exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co-cultured with SCFAs and assessed for degranulation after IgE- or non–IgE-mediated stimulation. The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays.
Results: Butyrate treatment inhibited allergen-induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE- and non–IgE-mediated human or mouse mast cell degranulation in a concentration- dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43, or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate-induced downregulation of the tyrosine kinases BTK, SYK, and LAT, critical transducers of FcεRI-mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK, and LAT promoter regions.
Conclusion: Known health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation.
How to compare the efficacy of biologic agents in asthma
Ravi K. Viswanathan, MD; William W. Busse, MD
Objective: The use of biologics in severe asthma has made substantial strides in disease management and fostered a personalized medicine approach; however, how, when, and which biologic to choose are unresolved issues, which form the focus of this review.
Data Sources: The data sources were published literature, including current guidelines, available through PubMed searches and online resources.
Study Selections: Studies and randomized controlled trials pertaining to the use of biologics in various phenotypes and/or endotypes of asthma and comparative analyses between biologics in asthma were included.
Results: Inflammatory constructs in asthma are complex and translate differentially into clinical practice for both disease severity and treatment responsiveness. The utilization of biologics, which target selected components of inflammation, has begun to dramatically improve the course of management for many patients with severe asthma. A retuning of our approach into selecting appropriate patient cohorts or phenotypes for studies and selection of clinically relevant outcomes,which are reflected byexisting and novel emerging biomarkers, is enabling a paradigm shift in asthmamanagement. Comparing the efficacy of the available biologics for asthma is challenging as no direct head-to-head studies are available, and indirect comparisons to this query provide varying results.
Conclusion: Significant progress has been achieved in the management of severe asthma with treatment of target-specific biologics. Sophisticated algorithms and trial designs, using a combination of available biomarker profiles and clinical characteristics to stratify patient populations into more precise subphenotypes and endotypes to guide our choice of a biologic or therapy, are critically needed but currently not formulated.
IgE autoantibodies and autoreactive T cells and their role in children and adults with atopic dermatitis
Fariza Mishaal Saiema Badloe, Shauni De Vriese, Katarina Coolens, Carsten B. Schmidt‑Weber, Johannes Ring, Jan Gutermuth1 and Inge Kortekaas Krohn
The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and selfreactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self-reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self-reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies.
Molecular approach to a patient’s tailored diagnosis of the oral allergy syndrome
Claudia Alessandri, Rosetta Ferrara1, Maria Livia Bernardi1, Danila Zennaro, Lisa Tuppo, Ivana Giangrieco, Teresa Ricciardi, Maurizio Tamburrini, Maria Antonietta Ciardiello and Adriano Mari1
Oral allergy syndrome (OAS) is one of the most common IgE-mediated allergic reactions. It is characterized by a number of symptoms induced by the exposure of the oral and pharyngeal mucosa to allergenic proteins belonging to class 1 or to class 2 food allergens. OAS occurring when patients sensitized to pollens are exposed to some fresh plant foods has been called pollen food allergy syndrome (PFAS). In the wake of PFAS, several different associations of allergenic sources have been progressively proposed and called syndromes. Molecular allergology has shown that these associations are based on IgE co-recognition taking place between homologous allergens present in different allergenic sources. In addition, the molecular approach reveals that some allergens involved in OAS are also responsible for systemic reactions, as in the case of some food Bet v 1-related proteins, lipid transfer proteins and gibberellin regulated proteins. Therefore, in the presence of a convincing history of OAS, it becomes crucial to perform a patient’s tailored molecule-based diagnosis in order to identify the individual IgE sensitization profile. This information allows the prediction of possible cross-reactions with homologous molecules contained in other sources. In addition, it allows the assessment of the risk of developing more severe symptoms on the basis of the features of the allergenic proteins to which the patient is sensitized. In this context, we aimed to provide an overview of the features of relevant plant allergenic molecules and their involvement in the clinical onset of OAS. The value of a personalized moleculebased approach to OAS diagnosis is also analyzed and discussed.
Molecular mechanisms and epidemiology of COVID-19 from an allergist’s perspective
Koa Hosoki, MD, PhD, Abhijit Chakraborty, PhD, and Sanjiv Sur, MD
The global pandemic caused by the newly described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused worldwide suffering and death of unimaginable magnitude from coronavirus disease 2019 (COVID-19). The virus is transmitted through aerosol droplets, and causes severe acute respiratory syndrome. SARS-CoV-2 uses the receptorbinding domain of its spike protein S1 to attach to the host angiotensin-converting enzyme 2 receptor in lung and airway cells. Binding requires the help of another host protein, transmembrane protease serine S1 member 2. Several factors likely contribute to the efficient transmission of SARS-CoV-2. The receptor-binding domain of SARS-CoV-2 has a 10- to 20- fold higher receptor-binding capacity compared with previous pandemic coronaviruses. In addition, because asymptomatic persons infected with SARS-CoV-2 have high viral loads in their nasal secretions, they can silently and efficiently spread the disease. PCR-based tests have emerged as the criterion standard for the diagnosis of infection. Caution must be exercised in interpreting antibody-based tests because they have not yet been validated, and may give a false sense of security of being ‘‘immune’’ to SARS-CoV-2. We discuss how the development of some symptoms in allergic rhinitis can serve as clues for newonset COVID-19. There are mixed reports that asthma is a risk factor for severe COVID-19, possibly due to differences in asthma endotypes. The rapid spread of COVID-19 has focused the efforts of scientists on repurposing existing Food and Drug Administration–approved drugs that inhibit viral entry, endocytosis, genome assembly, translation, and replication. Numerous clinical trials have been launched to identify effective treatments for COVID-19. Initial data from a placebocontrolled study suggest faster time to recovery in patients on remdesivir; it is now being evaluated in additional controlled studies. As discussed in this review, till effective vaccines and treatments emerge, it is important to understand the scientific rationale of pandemic-mitigation strategies such as wearing facemasks and social distancing, and implement them. (J Allergy Clin Immunol 2020;146:285-99.)
Prevention and treatment of recurrent viral-induced wheezing in the preschool child
Jeffrey R. Stokes, MD; Leonard Benjamin Bacharier, MD
Objective: To summarize the recent evidence in the treatment of viral-induced wheezing in the infant and preschool aged child.
Data Sources: Published literature obtained through PubMed database searches.
Study Selections: Studies relevant to phenotypes and treatment of wheezing illnesses in infants and preschool children were included.
Results: Recurrent wheezing in preschool children is common and is frequently triggered by viral respiratory tract infections. Certain phenotypes may respond to treatments differently, depending on the risk factors identified. Inhaled corticosteroids, administered continuously or intermittently, reduce the risk of virus-induced wheezing episodes. The use of leukotriene modifying agents may have a role in wheezing episodes in a select group of preschool children. Early administration of azithromycin reduces the risk of severe lower respiratory tract illnesses in children. The effect of oral corticosteroids on wheezing episodes in young children varies by degree of episode severity.
Conclusion: Recurrent viral-induced wheezing illnesses has been the focus of many clinical trials, which now provide an increasingly robust evidence base for management. Additional research is needed to define optimal strategies, to best match therapies to specific phenotypes and endotypes, and will eventually begin to include therapies directed specifically at the viral triggers.
Real-world evidence of subcutaneous allergoid immunotherapy in house dust mite-induced allergic rhinitis and asthma
Marek Jutel, Bernd Brüggenjürgen, Hartmut Richter, Christian Vogelberg
Background: The objective of this study was to analyze the effectiveness of allergen immunotherapy (AIT) with an allergoid in the treatment of house dust mites (HDM)- induced allergic rhinitis and/or asthma based on recent real-life data. The outcomes were measured using asthma incidence and consumption of corresponding medications as the indicator of persisting symptoms.
Methods: In this retrospective cohort analysis of a German longitudinal prescription database, patients who received at least two relevant mite AIT prescriptions in two different successive seasonal cycles were compared with non-AIT patients who received at least three symptomatic allergic rhinitis (AR) prescriptions in successive mite seasons. Study endpoints included AR progression, asthma progression, asthma occurrence, and therapy adherence. We used multivariate regression analyses to estimate the effects of AIT, adjusting for relevant variables.
Results: This study included 2350 patients receiving a mite allergoid and 64 740 control patients. After up to 6 years of follow-up, patients treated with mite allergoid required significantly fewer AR and asthma prescriptions (59.7% vs 10.8%) than the control group, and the probability of asthma development was significantly lower. The adherence of patients receiving allergoid was 63.8% at the end of the second year and 38.6% at the end of the third year.
Conclusions: This real-world evidence confirms the good efficacy of subcutaneous AIT with HDM mite allergoid in the treatment of allergic rhinitis and/or asthma. Up to 6 years of follow-up revealed significant effects in allergic rhinitis by measuring the number of AR medications and demonstrating significant reductions in asthma medications.