WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Efficacy and safety of sublingual versus subcutaneous immunotherapy in children with allergic rhinitis: a systematic review and meta-analysis
Yang J, Lei S
Frontiers in Immunology 2023;14:1274241 (15 December)
https://doi.org/10.3389/fimmu.2023.1274241

In this article, the authors systematically compare the efficacy and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in children with allergic rhinitis (AR), exploring multiple outcomes including: symptom scores (SSs), medication scores (MSs), symptom and medication scores (SMSs), new sensitizations, development of asthma, and improvement, as well as  treatment-related adverse events (TRAEs). The quality of the included studies was assessed by the modified Jadad scale and Newcastle-Ottawa scale (NOS) and meta-regression was carried out to explore the source of heterogeneity. Subgroup analysis was further conducted in terms of study design (randomized controlled trials [RCTs], cohort studies), allergen (house dust mites [HDMs], grass pollen), treatment duration (≥ 24, 12-23 or < 12 months), allergen immunotherapy (AIT) modality (drops or tablets), and AIT protocol (continuous, pre-seasonal, co-seasonal, or after the grass pollen season [GPS]). Sensitivity analysis was conducted for all outcomes. A Bayesian framework and a Monte Carlo Markov Chain (MCMC) model were developed for indirect comparison. Through their analysis, they found 50 studies with 10813 AR children included, of which 4122 were treated with SLIT, 1852 treated with SCIT, and 4839 treated with non-SLIT or non-SCIT therapy. For direct comparison, the SLIT group had a similar SS to the SCIT group (pooled standardized mean difference [SMD]: 0.41, 95% confidence interval [CI]: -0.46, 1.28, P = 0.353). Comparable MSs were observed in the SLIT and SCIT groups (pooled SMD: 0.82, 95%CI: -0.88, 2.53, P = 0.344). For indirect comparison, no significant differences were found in SSs (pooled SMD: 1.20, 95% credibility interval, CrI: -1.70, 4.10), MSs (pooled SMD: 0.57, 95%CrI: -1.20, 2.30), SMSs (pooled SMD: 1.80, 95%CrI: -0.005, 3.60), new sensitizations (pooled relative risk [RR)]: 0.34, 95%CrI: 0.03, 3.58), and development of asthma (pooled RR: 0.68, 95%CrI: 0.01, 26.33) between the SLIT and SCIT groups; the SLIT group illustrated a significantly lower incidence of TRAEs than the SCIT group (pooled RR: 0.17, 95%CrI: 0.11, 0.26).

Regulation of macrophage polarization in allergy by noncoding RNAs
Ishibashi O, Muljo SA, Islam Z
Noncoding RNA 2023;9(6):75 (11 December)
https://doi.org/10.3390/ncrna9060075

This review summarizes the current knowledge regarding regulation of macrophage polarization in allergy by noncoding RNAs. Allergy is a type 2 immune reaction triggered by a variety of allergens, including food and environmental substances such as peanuts, plant pollen, fungal spores, and the feces and debris of mites and insects. Macrophages are myeloid immune cells with phagocytic abilities that process exogenous and endogenous antigens. Upon activation, they can produce effector molecules such as cytokines as well as anti-inflammatory molecules. The dysregulation of macrophage function can lead to excessive type 1 inflammation as well as type 2 inflammation, which includes allergic reactions. Thus, it is important to better understand how macrophages are regulated in the pathogenesis of allergies. Emerging evidence highlights the role of noncoding RNAs (ncRNAs) in macrophage polarization, which in turn can modify the pathogenesis of various immune-mediated diseases, including allergies. The authors stress that understanding the roles of these ncRNAs in macrophage polarization will provide new insights into the pathogenesis of allergies and identify potential novel therapeutic targets

Telehealth interventions for transition to self-management in adolescents with allergic conditions: A systematic review
Sullivan MO, Curtin M, Flynn R et al
Allergy 2023; Published online ahead of print (1 December)
https://doi.org/10.1111/all.15963

Telehealth is an emerging approach that uses technology to provide healthcare remotely. Recent publications have outlined the importance of supporting the transition to self-management of adolescents with allergic conditions. However, no synthesis of the evidence base on the use and impact of telehealth interventions for this purpose has been conducted to date. This review explores these interventions, and their implementation. Four databases were searched systematically. References were independently screened by two reviewers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was undertaken. Eighteen articles were found, reporting on 15 telehealth interventions. A total of 86% targeted adolescents with asthma. Mobile applications were the most common telehealth modality used, followed by video-conferencing, web-based, virtual reality and artificial intelligence. Five intervention content categories were identified; educational, monitoring, behavioral, psychosocial, and healthcare navigational. Peer and/or healthcare professional interaction, gamification and tailoring may increase engagement. Overall, these studies showed positive effects of the interventions or no difference from active controls, in self-management outcomes such as knowledge, health outcomes such as quality-of-life, and economic outcomes such as healthcare utilization. The most common implementation outcomes reported were acceptability, appropriateness, feasibility and fidelity. Certainly, Telehealth will be more often used in the care of our patients over time. Thus, better understanding of the literature is essential to aid us in optimization.

Home monitoring of asthma exacerbations in children and adults with use of an AI-aided stethoscope
Emeryk A, Derom E, Janeczek K et al
Annals of Family Medicine 2023;21(6):517-525
https://doi.org/10.1370/afm.3039

With the advent of new medical devices, patients with asthma are now able to self-monitor at home, providing potentially a more complete picture of their disease than occasional in-person clinic visits. This raises a pertinent question: which devices and parameters perform best in exacerbation detection? One hundred forty-nine patients with asthma (90 children, 59 adults) participated in a 6-month observational study. Participants (or parents) regularly (daily for the first 2 weeks and weekly for the next 5.5 months, with increased frequency during exacerbations) performed self-examinations using 3 devices: an artificial intelligence (AI)-aided home stethoscope (providing wheezes, rhonchi, and coarse and fine crackles intensity; respiratory and heart rate; and inspiration-to-expiration ratio), a peripheral capillary oxygen saturation (SpO2) meter, and a peak expiratory flow (PEF) meter and also filled out a health state survey. The resulting 6029 examinations were evaluated by physicians for the presence of exacerbations. For each registered parameter, a machine learning model was trained, and the area under the receiver operating characteristic curve (AUC) was calculated to assess its utility in exacerbation detection. They found that the best single-parameter discriminators of exacerbations were wheeze intensity for young children (AUC 84% [95% CI, 82%-85%]), rhonchi intensity for older children (AUC 81% [95% CI, 79%-84%]), and survey answers for adults (AUC 92% [95% CI, 89%-95%]). The greatest efficacy (in terms of AUC) was observed for a combination of several parameters. The authors suggested that introduction of this tool to the health care system might enhance asthma exacerbation detection substantially and make remote monitoring of patients easier.

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms
Yepes-Nuñez JJ, Guyatt GH, Gómez-Escobar LG et al
Journal of Allergy and Clinical Immunology 2024;151(1):147-158
https://doi.org/10.1016/j.jaci.2022.09.020

Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. To better understand this potential relationship, the authors systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD as part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline Update on Atopic Dermatitis. Raters independently screened, extracted data, and assessed risk of bias in duplicate, then synthesized intervention effects using frequentist and Bayesian random effects models. The GRADE approach determined the quality of evidence. They found  23 randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite and showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT’s effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations
AAAAI/ACAAI JTF Atopic Dermatitis Guideline Panel; Chu DK, Schneider L, Asiniwasis RN et al
Annals of Allergy Asthma & Immunology 2023;S1081-1206(23)01455-2 Published online ahead of print (17 December)
https://doi.org/10.1016/j.anai.2023.11.009

The Joint Task Force (AAAAI and ACAAI) produced an updated evidence-based guideline to support optimal treatment of atopic dermatitis (AD) by convening a multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing). The Evidence in Allergy Group supported guideline development through performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD, exploring optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical Janus kinase [JAK] inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, and maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, and JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy). They also provide an Appendix which provides practical information and implementation considerations in 1–2-page patient-friendly handouts. This document is a great resource for the practicing clinician.

Allergen-specific immunotherapy and evidence: A European regulatory perspective
Bartel D, Bonertz A, Hartenstein D et al
Allergologie select 2023;7(1):198-210 (12 December)
https://doi.org/10.5414/ALX02413E

In this article, the authors explore the regulatory standards and challenges based on scientific evidence regarding allergy immunotherapy (AIT). Most crucial and timely aspects concerning AIT are addressed from the regulatory perspective through authors who are employees of a national competent authority in Europe. There are several aspects reviewed, including: (1) product specificity; (2) clinical efficacy; (3) treatment for adults and children (needs for extrapolation); (4) allergen exposure chambers; (5) biomarkers; (6) standardization; (7) real-world evidence; (8) independent official batch release (benefit and challenges); and (9) harmonization on the European Union (EU) level.

Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting β₂-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy
Roche N, Yorgancıoğlu A, Cruz AA et al
Respiratory Medicine 2024;221:107478 (23 November)
https://doi.org/10.1016/j.rmed.2023.107478

It is well known that treatment based solely on a diagnostic label do not benefit asthmatic patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting β2-agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted to best aid in optimizing therapy using standardized network meta-analysis techniques. Through this analysis, the authors identified 39 randomized controlled trials (RCTs) of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV1, smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were explored in these meta-analyses. Unfortunately, inconsistent reporting of traits and outcomes, as well as subgroup analyses was observed between RCTs. As a result, the authors could not provide clear answers and recommend more consistent and comparable reporting of clinically important traits and outcomes in respiratory RCTs to aid future analyses.

Development of the Rapid Cough Questionnaire (RCQ): Key Item Identification
Koo HK, Moon JY, Kim JW et al
Annals of Allergy Asthma & Immunology 2023; Published online ahead of print (27 December)
https://doi.org/10.1016/j.anai.2023.12.025

While the Leicester Cough Questionnaire (LCQ) is a reliable tool for measuring the multidimensional impact of cough on patients’ quality of life, its scoring algorithm is very lengthy and complex making it difficult to utilize in routine clinical practice. This study aimed to develop a simplified version of the LCQ, the Rapid Cough Questionnaire (RCQ), to be utilized in clinical practice and to validate the RCQ using an independent cohort. To select items for the RCQ score, a correlation network was used to determine the items from each domain that were strongly correlated with the total LCQ score. The final items for the RCQ were selected based on the centrality of the node degree, betweenness, and closeness in the correlation network. The RCQ score was derived from only three items: tiredness (LCQ3) in the physical domain, the feeling of being fed up (LCQ13) in the psychological domain, and annoyance with partner/family/friends (LCQ19) in the social domain. The correlation between the LCQ and RCQ was high, with a coefficient of 0.93 (P<0.001). The mean score of the RCQ was 11.2 ± 3.2, with scores range from 5.15 to 19.55. The minimal clinically important difference in the RCQ score was calculated to be 1.6 using a distribution-based method. The concurrent validity of the LCQ and the RCQ with cough numeric rating scale was similar. In the validation cohort, the correlation between the LCQ and RCQ scores was consistent regardless of sex and etiology. Overall, this study indicated that the RCQ score, which is concise, reliable, and valid, can be a valuable tool for patient assessment, particularly in clinical practice.

Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs
Müller S, Maintz L, Bieber T
Allergy 2024; Published online ahead of print (8 January)
https://doi.org/10.1111/all.16009

Atopic dermatitis (AD) represents the most common skin disease characterized by heterogeneous endophenotypes and a high disease burden. In Europe, six new systemic therapies for AD have been approved: the biologics dupilumab (anti- interleukin- 4 receptor (IL- 4R) α in 2017), tralokinumab (anti- IL- 13 in 2021), lebrikizumab (anti- IL- 13 in 2023), and the oral Janus kinase (JAK) inhibitors (JAKi) targeting JAK1/2 (baricitinib in 2020 in the EU) or JAK1 (upadacitinib in 2021 and abrocitinib in 2022). In this review, the authors examine these new approvals, focusing on long- term safety, and efficacy. They note that Upadacitinib and abrocitinib have the highest short- term efficacy among the approved systemic therapies. In responders, dupilumab and tralokinumab “catch up” regarding long- term efficacy and incremental clinical benefit within continuous use. Recently, the European Medicines Agency (EMA) has released recommendations for the use of JAKi in patients at risk (cardiovascular and thromboembolic diseases, malignancies, (former) smoking, and age ≥65 years). Furthermore, the authors provide an overview on emerging therapies currently in Phase III trials. With regard to the topical therapies, tapinarof (aryl hydrocarbon receptor), ruxolitinib (JAK1/2i), delgocitinib (pan- JAKi), asivatrep (anti- transient receptor potential vanilloid), and phosphodiesterase- 4- inhibitors (roflumilast, difamilast) are discussed. Among systemic therapies, current data on cord- blood- derived mesenchymal stem cells, CM310 (anti IL- 4Rα), nemolizumab (anti- IL- 31RA), anti- OX40/OX40L- antibodies, neurokinin- receptor- 1- antagonists, and difelikefalin (κ-o p i o i d-R) are also examined.  The therapeutic options for AD are exploding and this review provides a great discussion on both approved options as well as compounds presently being investigated.

In light of the “elusiveness” of biomarkers in chronic spontaneous urticaria (CSU) this study explored the role of C5a, IL-9, and apo A-IV as potential biomarkers in predicting disease severity and antihistamine response in CSU patients through a prospective observational study of 95 patients and 42 controls. Serum analysis of C5a, IL-9, and apo A-IV was performed using enzyme linked immunosorbent assay kits. Also, serum IgE and anti-thyroid peroxidase (TPO) levels were assessed in all patients. All patients were begun on oral levocetirizine 5 mg at baseline and the dose was titrated upwards to maximum of 20 mg based on response. Patients were categorized into antihistamine responders or non-responders, as per their disease response. Serological markers, serum IgE, and anti-TPO were correlated with baseline disease severity and antihistamine response. They found that C5a levels were significantly higher in cases as compared to controls (P = 0.004). Significantly higher IL-9 levels were observed in antihistamine responders than non-responders (P = 0.008). Baseline urticaria severity demonstrated a statistically significant positive and negative correlations with IL-9 (ρ = 0.277, P = 0.007) and apo A-IV (ρ = −0.271, P = 0.008) levels, respectively. Levels of serum IgE (P = 0.031) and anti-TPO (P = 0.039) were significantly higher in antihistamine non-responders compared to responders. Overall indicating that IL-9 and apo A-IV might be potential novel biomarkers to predict urticaria severity. Higher IL-9 might be a predictor of antihistamine response. While elevated anti-TPO and serum IgE might predict poor antihistamine response.

ChatGPT in healthcare: A taxonomy and systematic review
Li J, Dada A, Puladi B, Kleesiek J et al
Computer Methods and Programs in Biomedicine 2024;245:108013
https://doi.org/10.1016/j.cmpb.2024.108013

This article provides a systematic review of existing publications on the use of ChatGPT in healthcare, elucidating the “status quo” of ChatGPT in medical applications, for general readers and healthcare professionals as well as natural language processing (NLP) scientists. The recent release of ChatGPT, a chat bot research project∕product of NLP by OpenAI, stirs up a sensation among both the general public and medical professionals, amassing a phenomenally large user base in a short time. This is a typical example of the “productization” of cutting-edge technologies, which allows the general public without a technical background to gain firsthand experience in artificial intelligence (AI), similar to the AI hype created by AlphaGo (DeepMind Technologies, UK) and self-driving cars (Google, Tesla, etc.). However, it is crucial, especially for healthcare researchers, to remain prudent amidst the hype. The large biomedical literature database PubMed is used to retrieve published works on this topic using the keyword “ChatGPT”. An inclusion criterion and a taxonomy are further proposed to filter the search results and categorize the selected publications, respectively. It is found through this review that the current release of ChatGPT has achieved only moderate or “passing” performance in a variety of tests, and is unreliable for actual clinical deployment, since it is not intended for clinical applications by design. The authors conclude that specialized NLP models trained on (bio)medical datasets still represent the right direction to pursue for critical clinical applications.

House dust mite SCIT reduces asthma risk and significantly improves long-term rhinitis and asthma control – A RWE study
Jutel M, Klimek L, Richter H et al
Allergy 2024;79(4):1042-1051 (2 March)
https://doi.org/10.1111/all.16052

The German Therapy Allergen Ordinance (TAO) triggered an ongoing upheaval in the market for house dust mite (HDM) allergen immunotherapy (AIT) products. Three HDM subcutaneous immunotherapy (SCIT) products hold approval in Germany and therefore will be available after the scheduled completion of the TAO procedure in 2026. In general, data from clinical trials on the long- term effectiveness of HDM AIT are rare. Thus, the authors evaluated real- world data (RWD) in a retrospective, observational cohort study based on a longitudinal claims database including 60% of all German statutory healthcare prescriptions to show the long- term effectiveness of one of these products in daily life. The aim of this analysis was to provide a per-product analysis on effectiveness of mite AIT as it is demanded by international guidelines on AIT. To do so, the authors examined subjects between 5 and 70 years receiving their first (index) prescription of SCIT with a native HDM product (SCIT group) between 2009 and 2013 with a 3:1 matched control group who received prescriptions for only symptomatic allergic rhinitis (AR) medication (non- AIT group); the evaluation period for up to 6 years of follow- up ended in February 2017. Study endpoints were the progression of AR and asthma, asthma occurrence, and time to the onset of asthma after at least 2 treatment years. In total, 892 subjects (608 adults and 284 children/adolescents) were included in the SCIT group and 2676 subjects (1824 adults and 852 children/adolescents) in the non- AIT group. During the follow- up period after at least 2 years of SCIT, the number of prescriptions in the SCIT group was reduced by 62.8% (p =.0010) for AR medication and by 42.4% for asthma medication (p = .0003). New- onset asthma risk was significantly reduced in the SCIT vs non- AIT group by 27.0% (p = .0212). The asthma-preventive effect of SCIT occurred 15 months after start of the treatment. In the SCIT group, the time to onset of asthma was prolonged compared to the non- AIT group (p = .0010).  Overall, demonstrating in this RWD analysis on SCIT with a native HDM product, patients aged 5 to 70 years benefited from AIT in the long term in terms of reduced progression of AR and asthma after at least 2 years of treatment and the effects seemed to last for up to 6 years after treatment termination.

The autologous serum skin test (ASST) predicts the response to anti-IgE treatment in Chronic Spontaneous Urticaria patients: A prospective study

Palladino A, Villani F, Pinter E et al
European Annals of Allergy and Clinical Immunology 2024; Published online ahead of print (14 March)
https://doi.org/10.23822/EurAnnACI.1764-1489.337

Chronic spontaneous urticaria (CSU), characterized by recurrent itchy wheals and angioedema for > 6 weeks, is a quite common disease that may heavily impair a patient’s quality of life. Omalizumab, an anti-IgE mAb, has much improved the management of CSU but patients’ response to the drug may vary and predictive markers are still largely missing. In this study, the authors investigated the predictive value of the autologous serum skin test (ASST) on omalizumab response by examining 15 patients with severe CSU eligible for Omalizumab treatment were prospectively studied submitting them to ASST and to complete blood count, D-dimer, anti-thyroid peroxidase antibodies, and total IgE measurement before the start of the treatment. They found that 14/15 (93%) responded well to omalizumab at 3 months assessment, 7 responded in less than 1 month (“early responders”), and 7 only after multiple administrations (“late responders"). Of 9 patients scoring positive on ASST, 7 (78%) were late, and 2 (22%) early responders to omalizumab (p= 0.021). Of 6 patients scoring negative on ASST, 5 were early omalizumab responders and 1 did not respond. The PPV and NPV of the ASST for a “late” response to omalizumab were 78% and 100%, respectively. Total IgE were significantly higher in early responders. The authors note that although larger prospective studies are needed to confirm these results, this study confirms previous retrospective investigations that the positive ASST appears to predict a slow response to omalizumab in CSU patients.

Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity
Hurrell BP, Shen S, Li X et al
Journal of Experimental Medicine 2024;221(5):e2023185 (6 May)
https://doi.org/10.1084/jem.20231835

Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. In this article by Hurrell and colleagues the authors found that Piezo1 channels repress group 2 innate lymphoid cell (ILC2)–driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, the Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, and Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human-circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. These studies define Piezo1 as a critical regulator of ILC2s and for this reason, the authors propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.

WAO Reviews – Editors’ Choice
The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI, select articles monthly for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.


The airway epithelium: an orchestrator of inflammation, a key structural barrier and a therapeutic target in severe asthma
Russell RJ, Boulet L-P, Brightling CE, et al European Respiratory Journal 2024; 63: 2301397
https://doi.org/10.1183/13993003.01397-2023

Asthma is a disease of heterogeneous pathology, typically characterized by excessive inflammatory and bronchoconstrictor responses to the environment. The clinical expression of the disease is a consequence of the interaction between environmental factors and host factors over time, including genetic susceptibility, immune dysregulation, and airway remodelling. As a critical interface between the host and the environment, the airway epithelium plays an important role in maintaining homeostasis in the face of environmental challenges. Disruption of epithelial integrity is a key factor contributing to multiple processes underlying asthma pathology. In this review, the authors explore the unmet need in asthma management and provide an overview of the structure and function of the airway epithelium. They specifically focus on key pathophysiological changes that occur in the airway epithelium, including epithelial barrier disruption, immune hyperreactivity, remodelling, mucus hypersecretion and mucus plugging, highlighting how these processes manifest clinically and how they might be targeted by current and novel therapeutics.


Rhinoconjunctivitis severity induced by cat exposure influences early and late asthmatic responses: Evidence from an environmental exposure chamber
Piotin A, Godet J, Domis N, de Blay F
Clinical &amp; Experimental Allergy 2024; Published online ahead of print (25 April)
https://doi.org//10.1111/cea.14485

In this study, Piotin and colleagues aimed to assess predictive factors of the early (EAR) and late (LAR) asthmatic response and to evaluate the relation between rhinitis, conjunctivitis, and asthma induced by cat allergen exposure in an environmental exposure chamber (EEC). To do so, they examined data from two cohort studies involving asthmatic patients with cat allergy who performed a cat allergen exposure challenge. Spirometry, visual analogue scale (VAS) for asthma, VAS for rhinitis, Total Nasal Symptoms Score (TNSS), Total Ocular Symptoms Score (TOSS), Rhinoconjunctivitis Total Symptoms Score (RTSS), and Abelson score were used to assess asthma, rhinitis, and conjunctivitis during and after exposure. They found that an EAR occurred in 65.1% of patients, 32.1% of whom had an LAR. The diameter of the prick test to cat allergens and non-specific bronchial hypersensitivity level were independent risk factors for EAR (p< .05). No independent risk factors for LAR were identified. Rhinoconjunctivitis severity during exposure correlated with the VAS during EAR and LAR (p< .05). Allergen exposure time needed to trigger an EAR correlated with the Abelson score during exposure (p< .05). The asthma VAS and TOSS during exposure correlated with faster LAR occurrence (p< .05). Overall, they conclude that prick skin test size and non-specific bronchial hypersensitivity level as independent predictive factors of EAR during allergen exposure in an EEC and demonstrated the relation between the severity of rhinitis, conjunctivitis and asthma induced by allergen exposure for both EAR and LAR.

Digitally-enabled, person-centred care (PCC) in allergen immunotherapy: An ARIA-EAACI
Position Paper
Pfaar O, Sousa-Pinto B, Papadopoulos NG, et al
Allergy 2024; Published online ahead of print (3-May)
https://doi.org/10.1111/all.16135

In rhinitis and asthma, several mHealth apps have been developed but only a few have been validated.
Such apps have a high potential for improving person-centered care (PCC), especially in allergen
immunotherapy (AIT). They can provide support in AIT initiation by selecting the appropriate patient and
allergen shared decision-making. They can also help in (i) the evaluation of (early) efficacy, (ii) early and
late stopping rules, and (iii) the evaluation of (carried-over) efficacy after cessation of the treatment
course. Future perspectives have been formulated in the first report of a joint task force (TF)—Allergic
Rhinitis and Its Impact on Asthma (ARIA) and the European Academy of Allergy and Clinical Immunology
(EAACI)—on digital biomarkers. In this document the TF on AIT share their aims to (i) outline the
potential of the clinical applications of mHealth solutions, (ii) express their current limitations, (iii) make
proposals regarding further developments for both clinical practice and scientific purpose, and (iv)
suggest which of the tools might best comply with the purpose of digitally-enabled PCC in AIT.


An integrated molecular risk score early in life for subsequent childhood asthma risk
Böck A, Urner K, Eckert J K et al Clinical &amp; Experimental Allergy 2024; 54(4): 314-328 (31-March)
https://doi.org/10.1111/cea.14475

Numerous children present with early wheeze symptoms, yet only a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, this group aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). To do so, they mined 3 longitudinal birth cohorts (PAULINA/PAULCHEN, n= 190 + 93 = 283, PASTURE, n= 1133) to predict childhood asthma (age 5–11) including epidemiological
characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) were assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high dimensional logistic regression models (LASSO). They found that asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (up to ocAUC = 0.68). They found that the greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p= .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r= .59, p< .001, 4.5–6 years).


Emerging and novel elicitors of anaphylaxis: Collegium Internationale Allergologicum Update 2024
Treudler R International Archives of Allergy and Immunology 2024 (25-March)
https://doi.org/10.1159/000537958

As we all know frequent elicitors of anaphylaxis are insects, foods, and drugs. In this review by Treudler examines recent developments regarding emerging and novel elicitors of anaphylaxis.: Food allergens on the rise include pulses (like pea, chickpea), seeds (hemp, chia), nuts (cashew), pseudograins (buckwheat, quinoa), fruits, and microalgae. Furthermore, the author notes that novel foods are foods that were not consumed to any significant extent in the European Union before May 1997, which includes four edible insects (mealworm, migratory locust, house cricket, and buffalo worm). Recent investigations have pointed out the risk of anaphylaxis associated with the consumption of yellow mealworm for people allergic to shellfish and house dust mites. In Europe, fire ants (mostly Solenopsis invicta) and Vespa velutina nigrithorax represent invasive species, which also account for increasing numbers of anaphylactic reactions. Finally, several new drugs, especially biological therapeutics, have been associated with anaphylaxis.

WAO Reviews – Editors’ Choice
The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI, select articles monthly for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.


Baseline characteristics and ICS/LAMA/LABA response in asthma; Analyses from the CAPTAIN study
Boulet LP, Abbott C, Brusselle G et al
Journal of Allergy and Clinical Immunology: In Practice 2024;12(5):1244-1253 (1 February)
https://doi.org/10.1016/j.jaip.2024.01.039 

In this study, Boulet and colleagues explored the phase 3 CAPTAIN study to determine the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist umeclidinium (UMEC) to inhaled corticosteroid/long-acting b2-agonist combination FF/VI, or doubling the FF dose. Specifically, they analyzed categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI. They found that adding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics.


Hereditary angioedema with normal C1 esterase inhibitor: Current paradigms and clinical dilemmas
Radojicic C, Anderson J
Allergy and Asthma Proceedings 2024;45(3):147-157 (1 May)
https://doi.org/10.2500/aap.2024.45.240010

A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging, and pharmacologic management is not well defined. Thus, the objective of this article was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and address select challenges. The authors stress that symptoms of HAE-nl-C1-INH overlap with HAE types I and II, thus making the heterogeneity of presentation and symptom burden a diagnostic challenge. It is important when considering patient history to pay particular attention to whether urticaria or other symptoms of mast cell mediator release are present, as such symptoms would strongly suggest a mast cell–mediated pathway. A family history of angioedema is informative, but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations and most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell–targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines.
Response to medications approved for HAE types I/ II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE.


Immunotherapy and biologics in the management of IgE-mediated food allergy:
Systematic review and meta-analyses of efficacy and safety
Riggioni C, Oton T, Carmona L et al
Allergy 2024; Published online ahead of print (15 May)
https://doi.org/10.1111/all.16129

In this article, the European Academy of Allergy and Clinical Immunology (EAACI) Food Allergy Guidelines Expert Group and the EAACI Research and Outreach Committee Food Allergy Group perform a systematic review (SR) to inform the development of clinical recommendations on the treatment of IgE-mediated FA with biologic therapies and/or immunotherapy (IT) for the update of the EAACI guidelines. Studies were identified via comprehensive search strategies in Medline, Embase, and Cochrane Library, up to April 2022. This included a population of adults, children, and adolescents with IgE-mediated FA, undergoing therapy with IT and/or biologics, compared to placebo or standard-of-care (allergen avoidance), exploring outcomes including efficacy (desensitization, sustained unresponsiveness [SU], remission), quality of life, and safety (systemic and local adverse reactions [AR]). The Cochrane RoB tool was used to assess the risk of bias. It was reported according to PRISMA and registered in PROSPERO CRD4202229828.

After screening, 121 studies were included (111 for IT and 10 for biologics). Most studies had a high risk of bias and showed high heterogeneity in design and results. Metanalysis showed a positive effect of biologics and IT in terms of relative risk (RR) for achieving tolerance to the culprit food compared to avoidance or placebo. Omalizumab for any FA showed a RR of 2.17 [95% confidence interval: 1.22, 3.85]. For peanut allergy, oral IT (OIT) had a RR of 11.94 [1.76, 80.84] versus avoidance or placebo, sublingual IT (SLIT) had a RR of 3.00 [1.04, 8.66], and epicutaneous IT (EPIT) of 2.16 [1.56, 3.00]. OIT had a RR of 5.88 [2.27, 15.18] for cow&#39;s milk allergy, and of 3.43 [2.24, 5.27] for egg allergy. There was insufficient data on SLIT or EPIT for the treatment of egg and milk allergies. Most ARs reported were mild. For OIT the most common AR involved the gastrointestinal system, and for EPIT ARs most affected the skin. There were limited data on severe or life-threatening ARs. There was limited evidence for long- term efficacy and quality of life. The authors concluded that biologics and IT, alone or in combination, are effective in achieving desensitization while on active treatment, but more evidence is needed on long-term tolerance as current evidence is not of high quality. ARs while on therapy are generally mild to moderate but a long-term comprehensive safety profile is missing. There is a critical need to optimize and standardize desensitization protocols and outcome measures to facilitate our understanding of the efficacy and safety as well as to allow for comparison between interventions.


The Multiple Trajectories of the Allergic March de Las Vecillas L, Quirce S
Journal of Investigative Allergology and Clinical Immunology 2024;34(2):75-84 (15 May)
https://doi.org10.18176/jiaci.0983 

In this narrative review, the authors provide an overview of the current data regarding the allergic march, including clinical observations, omics data, risk factors, and measures aimed at modifying its course or even preventing its onset. As the authors of this review point out, the allergic march comprises the sequential appearance of a series of allergic comorbidities. However, variability in the onset and progression of allergic diseases generates a heterogeneous scenario that does not follow a linear and single trajectory. The authors note that almost half of the pediatric population presents at least 1 allergy symptom; however, only 4%-6% present multimorbidity, with several allergic diseases co- occurring. It has recently been shown that, although they share etiological mechanisms and risk factors, allergic diseases arise independently. In most cases, progression is not consecutive, or at least not the same in all patients. TH2-mediated inflammation, epithelial barrier dysfunction, and genetic predisposition play a fundamental role in the etiology of allergic diseases, on which the interaction with the exposome acts decisively. Therefore, studying diseases from an omics point of view is essential when attempting to describe the various trajectories of allergic progression and to propose effective interventions to prevent multimorbidity.


Usage prevalence of angioedema patient-reported outcome measures: Results from the UCARE and ACARE PROMUSE study
Cherrez-Ojeda I, Bousquet J, Giménez-Arnau A et al Journal of Allergy and Clinical Immunology: In Practice 2024; Article in press (9 May)
https://doi.org/10.1016/j.jaip.2024.04.056 

In angioedema, the three most widely used patient-reported outcome measures (PROMs) are the Angioedema Activity Score (AAS, the Angioedema Quality of Life Questionnaire (AE-QoL), and the Angioedema Control Test (AECT). These tools are validated, recommended by current guidelines, and freely available in many languages, yet the rate of their use in angioedema management is currently unknown. To address this gap, the global networks of Urticaria Centers of Reference and Excellence (UCAREs) and Angioedema Centers of Reference and Excellence (ACAREs) performed a cross-sectional study, PROMUSE to assess which and how often PROMs are used by physicians who treat patients with angioedema, and to identify what physicians perceive as barriers to the use of PROMs. In total, 370 angioedema-treating physicians from 39 countries completed the PROMUSE 53-item questionnaire. Of 370 physicians who treat patients with angioedema, only 32 (9%) used all three PROMs, i.e. the AAS, the AE-QoL, and the AECT. Two and one of these PROMs were used by 82 and 105 of 370 physicians, i.e. 22% and 28%, respectively, and 151 physicians (41%) did not use any of them. The AAS was the most commonly used angioedema PROM (48%; n=180), followed by the AE-QoL (43%; n=161/370) and the AECT (28%; n=102/370). Of physicians who use the AAS, the AE-QoL, and the AECT, only 19%, 19%, and 23%, respectively, reported using it “always”.
The findings of this study demonstrate that PROMs are very much underused in the management of patients with angioedema, even though many participating physicians practice in highly specialized allergy and dermatology facilities. The authors point out that this paper lays the groundwork for identifying the gaps in PROM usage in angioedema, a disorder which substantially impacts patients’ quality of life. They recommend that medical societies consider these findings to overcome barriers and enhance the provision of continuing medical education on patient-reported outcome measures (PROMs). Furthermore, they suggest that clinicians should consider incorporating additional objective biomarkers into PROMs to optimize the monitoring and follow-up tools for this condition.

WAO Reviews – Editors’ Choice
The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI, select articles monthly for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Impact of comorbidities on EQ5D quality of life index in severe asthma
Pfeffer PE, Brown T, Chaudhuri R et al Journal of Allergy and Clinical Immunology: Global 2024; 3(3):100286 (31 May 2024)
https://doi.org/10.1016/j.jacig.2024.100286

Severe asthma pathology encompasses a wide range of pulmonary and extra-pulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health related quality of life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), may prove better at capturing the impact of comorbidities. To confirm this, the authors examined the impact of pulmonary and extra-pulmonary treatable traits on quality of life at initial severe asthma assessment, and compared the characteristics of those patients whose quality of life did vs. did not improve during follow-up at severe asthma centres. Patient characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. They found that patients in the quartiles with worst disutility at baseline were observed to exhibit more treatable traits and in particular extra-pulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms and requirement for maintenance oral corticosteroids (OCS) was observed.

Contribution of MASK-air® as a mHealth tool for digitally-enabled person-centred care in rhinitis and asthma
Sousa-Pinto B, Fonseca JA, Bousquet J
Journal of Investigational Allergology and Clinical Immunology 2024;34(3):148-156
https://doi.org/10.18176/jiaci.0994

This review discusses the clinical and scientific contributions of MASK-air to person-centred care of rhinitis and asthma, providing an illustrative example on the use of mHealth data in chronic diseases. In chronic diseases, mHealth apps help to improve clinical management and provide valuable real-world scientific evidence. In allergic rhinitis, a market research study identified only 4 mHealth apps that were multilingual, resulted in scientific publications, and displayed a comprehensive list of medications. The authors note that of these 4 apps, MASK-air® had the most robust scientific publications. MASK-air was launched in 2015 and is currently available in 30 countries, with data collected from more than 30 000 users. It comprises a daily monitoring questionnaire, enabling patients to register their daily allergy symptoms by means of visual analog scales and their medication use. The achievements of MASK-air include the development of 2 digital biomarkers for daily monitoring of rhinitis and asthma (combined symptom-medication score and electronic daily asthma control score). MASK-air data have also made it possible to assess patients’ behavior, suggesting that patients do not follow guideline recommendations, but rather treat themselves (and often use comedication) when they feel worse. Using MASK-air data, we quantified the impact of allergic diseases on quality of life and school and work productivity. Real-world MASK-air data are being used as a source of evidence for the Allergic Rhinitis and its Impact on Asthma 2024 guidelines in an innovative process of incorporation of mobile health data into guidelines.

Risk of anaphylaxis associated with cold urticaria
Bizjak M, Rutkowski K, Asero R
Current Treatment Options in Allergy 2024; (20 June)
https://doi.org/10.1007/s40521-024-00366-9

Cold-induced anaphylaxis (ColdA) is a poorly understood form of anaphylaxis that occurs in patients with cold urticaria (ColdU). This comprehensive review explores our understanding of ColdA. It emphasizes the identification of high-risk ColdU patients susceptible to ColdA and provides recommendations for their effective management. Specifically, recent studies including the large international COLD-CE study, have identified clinical features of ColdU patients associated with increased ColdA risk. These individuals can now be recognized through routine clinical assessments. Key diagnostic indicators for assessing ColdU and the risk of ColdA include oropharyngeal/laryngeal symptoms and positive standard local cold provocation tests. ColdA has been defined as acute cold-induced involvement of the skin and/or visible mucosal tissue accompanied by cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms, but a universally accepted definition is lacking. Additionally, ColdA has recently been recognized as an indication for prescribing adrenaline (epinephrine) autoinjectors, marking a significant advancement in disease management. Summary ColdA is a major and potentially life-threatening concern for a subset of ColdU patients. Early recognition of high-risk patients, coupled with education and preparedness of both patients and healthcare providers, is crucial for effectively managing this challenging condition. The authors note that further research is needed to expand understanding of the underlying pathophysiological mechanisms of ColdA, identify potential cofactors influencing ColdA, and improve disease-management strategies.

Predicting the daily number of patients for allergic diseases using PM10 concentration based on spatiotemporal graph convolutional networks
Jeon HJ, Jeon HJ, Jeon SH
PLoS One 2024;19(6):e0304106 (13 June)
https://doi.org/10.1371/journal.pone.0304106

Air pollution causes and exacerbates allergic diseases including asthma, allergic rhinitis, and atopic dermatitis. Precise prediction of the number of patients afflicted with these diseases and analysis of the environmental conditions that contribute to disease outbreaks play crucial roles in the effective management of hospital services. To better understand this association, the authors explored the daily number of patients with these allergic diseases and determine the impact of particulate matter (PM10) on each disease. To analyze the spatiotemporal correlations between allergic diseases (asthma, atopic dermatitis, and allergic rhinitis) and PM10 concentrations, they proposed a multi-variable spatiotemporal graph convolutional network (MST-GCN)-based disease prediction model. Data on the number of patients were collected from the National Health Insurance Service from January 2013 to December 2017, and the PM10 data were collected from Airkorea during the same period. This proposed disease prediction model showed higher performance (R2 0.87) than the other deep-learning baseline methods. The synergic effect of spatial and temporal analyses improved the prediction performance of the number of patients. The prediction accuracies for allergic rhinitis, asthma, and atopic dermatitis achieved R2 scores of 0.96, 0.92, and 0.86, respectively. In the ablation study of environmental factors, PM10 improved the prediction accuracy by 10.13%, based on the R2 score.

Allergic Conjunctivitis Management: Update on Ophthalmic Solutions
Leonardi A, Quintieri L, Presa IJ et al
Current Allergy and Asthma Reports 2024;24:347-360 (13 June)
https://doi.org/10.1007/s11882-024-01150-0

In this excellent review, Leonardi and colleagues present an updated review of topical management for seasonal and perennial conjunctivitis (SAC and PAC), based on the available scientific evidence and focused on the impact of ophthalmic solution formulations on eye surface. They point out that physicians treating ocular allergy (OA) should be aware of tear film and tear film disruption in SAC and PAC, and how eye drop composition and additives affect the physiology of the allergic eye. SAC and PAC are the most frequent causes of ocular allergy, and both conditions are underdiagnosed and undertreated. The additional tear film disruption caused by the release of inflammatory mediators increases and exacerbates the impact of signs and symptoms and may trigger damage of the ocular surface. Comorbidities are frequent, and dry eye disease in particular must be considered. Clinical guidelines for the management of SAC and PAC recommend topical therapy with antihistamines, mast cells stabilizers or dual action agents as first-line treatment. The authors stress that care should be taken, as many medications contain other compounds that may contribute to ocular surface damage.

WAO Reviews – Editors’ Choice
The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI, select articles monthly for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Improving allergy management and treatment: a proposed algorithm and curriculum for prescribing allergen immunotherapy in the primary care setting
Bustos G, Sanchez-Gonzalez MA, Grogan T. et al npj Primary Care Respiratory Medicine 2024; 34:22 (1 August)
https://doi.org/10.1038/s41533-024-00380-z 

Allergic rhinitis (AR), is a consequence of sensitivity to allergens leading to poor quality of life, including disrupted sleep, reduced vitality, lowered mood, changes in blood pressure, limited frustration tolerance, impaired focus, decreased performance in academic and professional settings, and millions of missed work and school days every year. Approximately 20–40% of individuals in the United States are affected by AR, which carries notable clinical and financial burdens. Interestingly, there is a strong link between AR and asthma to the extent that countries with a high prevalence of rhinitis have asthma rates ranging from 10% to 25%. Research has indicated that Allergen Immunotherapy (AIT) is associated with improved AR symptoms, as well as potential to: resolve the AR over time, and decrease the likelihood of asthma exacerbations and incidence of pneumonia in individuals with concurrent asthma, which are advantages that persist for years even after the cessation of treatment. 

This article clearly points out the impediment of optimal care, noting that patients presenting with allergies are first seen and treated in the primary care setting. Gaps in training and the lack of available guidance for primary care practitioners have significantly impacted the quality of care for these patients with persistent AR symptoms, resulting in inefficient use of healthcare resources. To complicate matters, there is an insufficient number of allergists and immunologists, which impedes the ability to provide next-level care to the number of AR patients who could benefit from AIT. Hence, the authors suggest that there is a need to equip primary care providers with educational experience – essentially focusing on concepts related to immune responses in allergies and asthma, recognizing the significance of the common airway in treating these entities, and familiarizing with the scientific evidence-supporting various options for AIT. The development and implementation of medical education and algorithms designed to assess diverse patients’ symptoms, pharmacotherapy approaches, and situations where AIT can be initiated or sustained are warranted. 

The present commentary proposes a workflow model of the critical steps for managing and treating mild to moderate respiratory allergies via AIT in primary care settings. The authors highlight the initial development of medical education programs to minimize the burden on allergy-specialized care while, importantly, actively improving patient outcomes.

Childhood infections, asthma and allergy trajectories, and chronic rhinosinusitis in middle age: A prospective cohort study across six decades
Perret JL, Idrose NS, Walters EH et al Allergy 2024; Early view (10 August)
https://doi.org/10.1111/all.16184

Evidence regarding the early life risk factors of adult chronic rhinosinusitis (CRS), and the history of asthma and allergies across the life course, is limited. Thus, in the study, the authors investigated relationships between respiratory infective/allergic conditions in childhood, and asthma and allergies across the life course and CRS in middle age. To do so, they mined data from the population-based Tasmanian Longitudinal Health Study (TAHS) cohort, first studied in 1968 when aged 6–7 years (n= 8583) and serially followed the group into middle age (n= 3609). Using a well-accepted epidemiological definition, participants were assigned a CRS-severity subtype at age 53: no sinusitis/CRS (reference); past doctor diagnosis only; current symptoms without doctor diagnosis; and doctor-diagnosed CRS with current symptoms. Relationships with infective/allergic respiratory illnesses at age 7, and previously published asthma-allergy trajectories from 7 to 53 years, were examined using multinominal regression. They found that in middle age, 5.8% reported current CRS symptoms with 2.5% doctor-diagnosed.

Childhood conditions associated with symptomatic doctor-diagnosed CRS included frequent head colds (multinomial odds ratio [mOR] = 2.04; 95% confidence interval [95% CI]: 1.24, 3.37), frequent tonsillitis (mOR = 1.61 [95% CI: 1.00, 2.59]) and current childhood asthma (mOR = 2.23 [95% CI: 1.25, 3.98]). Life course trajectories that featured late-onset or persistent asthma and allergies were associated with all CRS subtypes in middle age; early-onset persistent asthma and allergies (mOR = 6.74, 95% CI: 2.76, 16.4); late-onset asthma allergies (mOR = 15.9, 95% CI: 8.06, 31.4), and late-onset hay fever (mOR = 3.02, 95% CI: 1.51, 6.06) were associated with symptomatic doctor-diagnosed. Overall, they conclude that current asthma, frequent head colds, and tonsillitis at age 7 could signal a susceptible child who is at higher risk for CRS in mid-adult life and who might benefit from closer monitoring and/or proactive management. Concurrent asthma and allergies were strongly associated and are potential treatable traits of adult CRS.

Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment
Zuberbier T, Ensina LF, Giménez-Arnau A et al The Lancet 2024; 404(10450): 393-404 (27 July)
https://doi.org/10.1016/S0140-6736(24)00852-3

Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angioedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab or ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging, which is based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton’s tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This “therapeutics” article focuses on the evidence for these novel drugs and their role in addressing an unmet need for the personalised management of patients with chronic urticaria.

Systemic Immunomodulatory Treatments for Atopic Dermatitis: Living Systematic Review and Network Meta-Analysis Update
Drucker AM, Lam M, Prieto-Merino D et al JAMA Dermatology 2024; e242192 (17 July)
https://doi.org/10.1001/jamadermatol.2024.2192 

Presently, there are several approved systemic treatments for atopic dermatitis. Lebrikizumab is a newly licensed biologic medication that has been compared to placebo in clinical trials but not to other systemic treatments. In this study, the authors compare reported measures of efficacy and safety of lebrikizumab to other systemic treatments for atopic dermatitis via a living systematic review and network meta-analysis examining Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Latin American and Caribbean Health Science Information database, the Global Resource of Eczema Trials database, and trial registries. Randomized clinical trials evaluated 8 or more weeks of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis. Titles, abstracts, and full texts were screened in duplicate and then data were abstracted in duplicate and random-effects Bayesian network meta-analyses were performed. Minimal important differences were used to define important differences between medications. Certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). The updated analysis was completed from December 13, 2023, to February 20, 2024. Efficacy outcomes were the Eczema Area and Severity Index (EASI), the Patient Oriented Eczema Measure (POEM) Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS) and were compared using mean difference (MD) with 95% credible intervals (CrI). Safety outcomes were serious adverse events and withdrawal due to adverse events. Other outcomes included the proportion of participants with 50%, 75%, and 90% improvement in EASI (EASI-50, -75, -90) and the proportion with success on the Investigator Global Assessment compared using odds ratios with 95% CrI. The study sample included 98 eligible trials, with a total of 24 707 patients. 

The authors found that Lebrikizumab was associated with no important difference in change in EASI (MD, −2.0; 95% CrI, −4.5 to 0.3; moderate certainty), POEM (MD, −1.1; 95% CrI −2.5 to 0.2; moderate certainty), DLQI (MD, −0.2; 95% CrI −2.1 to 1.6; moderate certainty), or PP-NRS (MD, 0.1; 95% CrI −0.4, 0.6; high certainty) compared to dupilumab among adults with atopic dermatitis who were treated for up to 16 weeks. Dupilumab was associated with higher odds of efficacy in binary outcomes compared with lebrikizumab. The relative efficacy of other approved systemic medications was similar to that found by previous updates of this living study, with high-dose upadacitinib and abrocitinib demonstrating numerically highest relative efficacy. For safety outcomes, low event rates limited useful comparisons. Overall demonstrating that in this living systematic review and network meta-analysis, lebrikizumab was similarly effective to dupilumab for the short-term treatment of atopic dermatitis in adults

Atopic diseases-Diagnostics, mechanisms, and exposures
Schoos AM
Pediatric Allergy and Immunology 2024;35(7):314198 (17 July)
https://doi.org/10.1111/pai.14198 

Epidemiological data suggest that atopic diseases begin in early life and that most cases present clinically during early childhood. The diseases are highly prevalent and increase as communities adopt western lifestyles. Disentangling the pathophysiological mechanisms leading to disease debut is necessary to identify beneficial/harmful exposures so that successful prevention and treatment can be achieved. The objective of this review was to explore the definition of atopy and mechanisms of atopic diseases, and to investigate the importance of environmental factors in early life, prior to disease development. First, the distribution of sIgE levels in children was investigated, as this is one of the main criteria for the definition of atopy. Specifically, the authors explored how studies of parental atopic status, sensitization patterns, and early onset and severity of atopic dermatitis have substantiated the theory of an early-life window of opportunity for intervention that precedes the development of atopic diseases in childhood. They then examined whether early-life exposures such as breastfeeding, dogs, cats, and house dust mites in the home perinatally constitute important influencers in this crucial time of life. Finally, they discussed how these findings could be validated in randomized controlled trials, which might prepare the ground for improved diagnostics and prevention strategies to mitigate the current atopic pandemic.

WAO Reviews – Editors’ Choice
The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI, select articles monthly for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Indoor air pollution and airway health
Radbel J, Rebuli ME, Kipen H, Brigham E
Journal of Allergy and Clinical Immunology 2024; Accepted article (20 August)
https://doi.org/10.1016/j.jaci.2024.08.013

Due to the disproportionate amount of time people spend indoors, and the complexities of air pollutant exposures found there, indoor air pollution is rightfully a growing concern for airway health. Both infiltration of outdoor air pollution into the indoor space, and indoor sources (such as smoke from tobacco products, cooking or heating practices and combustion of associated fuels, household materials) can contribute to unique exposure mixtures. The authors of this review explore the extensive literature regarding the chemistry of indoor air pollution, noting that research focused on health effects is only beginning to emerge and remains an important area of need to protect public health. They also examine both the impact of individual pollutant exposures as well as common combustion sources on the lower airways. Factors defining susceptibility and/or vulnerability are also reviewed, with attention to modifiable risk factors that may be targeted to advance health equity. 

The circadian rhythm of itching among 241 Adults with atopic dermatitis: A cross-sectional study

Sang X, Lu J, Tan L, Zeng J, Wang D et al
Acta Dermato-Venereologica 2024;104: adv35427
https://doi.org/10.2340/actadv.v104.35427

The pattern of itching in patients with atopic dermatitis has not been systematically studied. Therefore, this study aimed to assess the pattern of itching in adults with atopic dermatitis using questionnaires to assess for a circadian rhythm of itching in participating patients at a single institution (n=241). To do so, they relied upon a self-report questionnaire to assess circadian rhythm and intensity of itching in patients. In addition, the patients’ disease severity (Eczema Area and Severity Index [EASI]) and quality of life (Dermatology Life Quality Index [DLQI]) were assessed. Itching occurred most frequently (74.69%) and with the greatest severity (62.66%) between 20:00 and 00:00, and the least number of patients (25.31%) experienced itching between 04:00 and 08:00. The DLQI and EASI scores both correlated with the average and maximum itch intensity (r=0.582, r=0.533, respectively; r=0.539, r=0.517, respectively; p<0.001). The DLQI and EASI scores were associated with average itch intensity (B=0.179, B=0.204, respectively; 95% CI: 0.112 to 0.246, 95% CI: 0.096 to 0.313, respectively; p < 0.001), and the EASI score was associated with males and family history (B = 0.285, B = 0.287, respectively; 95% CI: 0.094 to 0.476, 95% CI: 0.096 to 0.478, respectively; p = 0.003). This study highlights that adult patients with atopic dermatitis exhibited a circadian rhythm of itching.

Innate lymphoid cells in immunoglobulin E-mediated food allergy
Ilangovan J, Neves JF, Santos AF
Current Opinion in Allergy and Clinical Immunology 2024;24(5):419-425
https://doi.org/10.1097/ACI.0000000000001018

Recognition of the importance of innate lymphoid cells (ILCs) in the immune mechanisms of food allergy has grown in recent years. This review summarizes recent findings of ILCs in immunoglobulin E (IgE)- mediated food allergy. New research on ILCs in the context of the microbiome and other atopic diseases are also considered with respect to how they can inform understanding of the role of ILCs in food allergy. 

Impact on food allergy should be of no surprise as ILCs can mediate allergic and tolerogenic responses through multiple pathways. A subset of interleukin (IL)-10 producing ILC2s are associated with tolerance following immunotherapy to grass pollen, house dust mite allergy and lipid transfer protein allergy. Likewise, ILC2s can drive food allergen-specific T cell responses in an antigen-specific manner. A memory subset of ILC2s has been identified through studies of other atopic diseases and is associated with effectiveness of response to therapy. 

First-generation antihistamines and seizures in young children
Kim JH, Ha EK, Han B, Han T, Shin J et al
JAMA Network Open 2024; 7(8):e2429654 (28 August)
https://doi.org/10.1001/jamanetworkopen.2024.29654

The use of antihistamine therapy in children for treatment of the common cold is well known to be associated with central nervous system effects, like drowsiness. To assess the potential for other side effects the authors examined the association of their use and seizures in children using a comprehensive and nationwide dataset. The odds ratios (ORs) for seizure events were estimated using a conditional logistic regression model, comparing first-generation antihistamine prescription 1 to 15 days before seizure (hazard period) against control period 1 (31-45 days before the event) and control period 2 (61-75 days before the event) using the same period windows. Stratified analyses were conducted to examine the association with individual participant characteristics. Of 11,729 children who had a seizure event, 3178 (1776 [55.9%] boys) were identified as having been prescribed antihistamines during the hazard or the control period, but not both. Seizure events were predominantly observed in children aged 6 to 24 months (985 [31.0%]) and 25 months to 6 years (1445 [45.5%]). During the hazard period, 1476 first-generation antihistamine prescriptions were recorded, in contrast to 1239 and 1278 prescriptions during control periods 1 and 2, respectively. After multiple confounder adjustments, first-generation antihistamine prescription was associated with an increased seizure event risk during the hazard period (adjusted OR [AOR], 1.22 [95% CI, 1.13-1.31]). Stratified subgroup analyses showed consistent results, particularly in children aged 6 to 24 months who were prescribed first-generation antihistamines having a higher risk (AOR, 1.49 [95% CI, 1.31-1.70]) than children aged 25 months to 6 years (AOR, 1.11 [95% CI, 1.00- 1.24]; P = .04 for interaction). Furthermore, sensitivity analyses, including adjustment for exposure window periods, evaluation of new first-generation antihistamine prescriptions, comparison of control points from the same period 1 year prior, and exclusion of individuals using combination drugs, confirmed a similarly high risk. Overall this indicates that prescriptions for first-generation antihistamines were associated with a 22.0% higher seizure risk in children, especially in those aged 6 to 24 months. The authors point out that these findings emphasize the need for careful and judicious prescription of first- generation antihistamines in young children and underline the need for further research to elucidate associations between antihistamine prescriptions and seizure risk. 

ChatGPT in medicine: A cross-disciplinary systematic review of ChatGPT's (artificial intelligence) role in research, clinical practice, education, and patient interaction
Fatima A, Shafique MA, Alam K, Fadlalla Ahmed TK, Mustafa MS 
Medicine 2024;103(320):329250 (9 August)
https://doi.org/10.1097/MD.0000000000039250

ChatGPT, a powerful artificial intelligence language model, has gained increasing prominence in medicine, offering potential applications in healthcare, clinical decision support, patient communication, and medical research. This systematic review comprehensively explores the applications of ChatGPT in healthcare education, research, writing, patient communication, and practice while also delineating potential limitations and areas for improvement. 

To do so, the authors performed a comprehensive database search finding 83 studies that met the inclusion criteria. This review includes original studies comprising case reports, analytical studies, and editorials with original findings. They found that ChatGPT is useful for scientific research and academic writing, and assists with grammar, clarity, and coherence. Furthermore, it aids non-English speakers and improves accessibility by breaking down linguistic barriers. However, its limitations include probable inaccuracy and ethical issues, such as bias and plagiarism. ChatGPT streamlines workflows and offers diagnostic and educational potential in healthcare but exhibits biases and lacks emotional sensitivity. It is useful in inpatient communication but requires up-to-date data and faces concerns regarding the accuracy of information and “hallucinatory” responses. 

The authors conclude that despite the potential for ChatGPT to transform healthcare education, research, and practice, it is essential to approach its adoption in these areas with caution with understanding of its inherent limitations.

WAO Reviews – Editors’ Choice
The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI, select articles monthly for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Emerging Biologic Therapies for the Treatment of Atopic Dermatitis
Alvarenga, J.M., Bieber, T. & Torres, T
Drugs 2024; (4 October)
https://doi.org/10.1007/s40265-024-02095-4 

Atopic dermatitis (AD) is a prevalent inflammatory skin disease having a significant impact on the quality of life of patients. The authors of this review stress that conventional treatments, including topical therapies and systemic immunosuppressants, often have limited efficacy and long-term safety concerns. Emerging biologic therapies target specific immune pathways implicated in AD pathogenesis, offering new therapeutic options in a disease known for its complex immune pathomechanisms. This review focuses on novel biologics under investigation, particularly those targeting specific immune pathways, including interleukin-4 (IL-4), IL-13, IL-22, IL-31, thymic stromal lymphopoietin (TSLP), and OX40-OX40L axis. Interleukin-4 and IL-13 inhibitors aim to reduce Th2-driven inflammation, while IL-22 inhibitors focus on restoring skin barrier function. Interleukin-31 inhibitors help alleviate pruritus, a major symptom in AD. OX40-OX40L pathway inhibitors can selectively suppress the activity of pathogenic T cells, without inducing significant immunosuppression. Bispecific antibodies targeting both IL-4 and IL-31 pathways are emerging as potential dual-action treatment for AD. Thymic stromal lymphopoietin inhibitors offer a novel strategy to control inflammation. While many of these therapies offer promising safety and efficacy profiles, long-term studies and real-world data are essential to confirm their lasting impact. This review highlights the potential of these emerging systemic therapies to continue transforming AD management and improve patient outcomes.

Consensus on a Patient-Centered Definition of Atopic Dermatitis Flare
Drucker AM, Thibau IJC, Mantell B et al
JAMA Dermatology 2024; Published online 11 September
https://doi.org/10.1001/jamadermatol.2024.3054 

Flare is a commonly used in atopic dermatitis (AD) care settings and clinical research, but little consensus exists on what it means. Meanwhile, flare management is an important unmet research and treatment need. Understanding how various therapies might comparatively improve AD flares as a measure of treatment effectiveness may facilitate shared decision-making and enable assessment of effectiveness within and outside clinical settings. Thus, identifying patient-reported attributes associated with an AD flare is sentinel and highlights the importance of a patient-centered, consensus-based working definition. To do so, the authors relied upon a consensus survey study used a modified Delphi method involving consensus-building focus groups and a survey.  Following this, focus groups were conducted virtually, and the online survey was advertised to National Eczema Association members. Adults in the  United States aged 18 years or older with AD were recruited via convenience sampling. The main outcome was consensus on which attributes of AD to include in a patient-centric definition of flare. Using a rating scale (range, 1-9), consensus for the modified Delphi statement rating was defined as at least 70% of participants rating a statement as 7 to 9 (critical to a flare definition) and less than 15% rating it as 1 to 3(not important). Twenty-six participants with AD who completed focus group activities (24 aged 18-44years [92.3%]and 2 aged 45-64 years [7.7%]; 18 women [69.2%]) and 631 participants with AD (mean [SD] age,45.5[18.1] years; 533 women [84.5%]) who completed the survey were included in this analysis. Fifteen statements reached consensus from these focus groups, and of those, 12 reached consensus from survey participants. More than half (334 of 631 [52.9%]) of survey participants reported alignment with their health care practitioner on what a flare is, and most (478 of 616 [77.6%]) reported that a patient-centered definition would be useful when communicating with their health care practitioner about their condition.

Risk of Anaphylaxis Associated with Cold Urticaria
Bizjak, M., Rutkowski, K. & Asero, R
Current Treatment Options in Allergy 2024; 11:167-175
https://doi.org/10.1007/s40521-024-00366-9 

Cold-induced anaphylaxis (ColdA) is a poorly understood form of anaphylaxis that occurs in patients with cold urticaria (ColdU). This comprehensive review aims to deepen our understanding of ColdA. It emphasizes the identification of high-risk ColdU patients susceptible to ColdA and provides recommendations for their effective management. The authors highlight several recent studies, including the large international COLD-CE study, which identified clinical features of ColdU patients associated with increased ColdA risk. These individuals can now be recognized through routine clinical assessments. Key diagnostic indicators for assessing ColdU and the risk of ColdA include oropharyngeal/laryngeal symptoms and positive standard local cold provocation tests. ColdA has been defined as acute cold-induced involvement of the skin and/or visible mucosal tissue accompanied by cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms, but a universally accepted definition is lacking. Additionally, ColdA has recently been recognized as an indication for prescribing adrenaline (epinephrine) autoinjectors, marking a significant advancement in disease management.

A Practical Guide to Using Oral JAK Inhibitors for Atopic Dermatitis from the International Eczema Council
Haag C, Alexis A, Aoki Vet al
British Journal of Dermatology 2024; Corrected proof, published online 10 September
https://doi.org/10.1093/bjd/ljae342

This consensus expert opinion statement from the International Eczema Council (IEC) provides a pragmatic approach to prescribing JAK inhibitors, including choosing appropriate patients, dosing, clinical and lab monitoring, as well as optimizing long-term use.  Specifically, the authors recommend JAKinibs be considered in patients with moderate to severe AD seeking the benefits of rapid reduction in disease burden and itch, oral administration, and the potential for flexible dosing. Baseline risk factors should be assessed prior to prescribing JAKinibs, including increasing age, venous thromboembolisms, malignancy, cardiovascular health, kidney/liver function, pregnancy and lactation, and immunocompetence. Patients being considered for JAKinib therapy should be current on vaccinations and in this statement the experts provide a generalized framework for laboratory monitoring, though clinicians should consult individual product labels for recommendations as there are variations among the JAKinib class. The experts stress that patients who achieve disease control should be maintained on the lowest possible dose, as many of the observed AEs occurred in a dose-dependent manner. Future studies are needed in AD patients to assess the durability and safety of continuous long-term use of JAKinibs, combination medication regimens, and the effects of flexible, episodic treatment over time.

Asthma management in the digital age
Bocian IY, Chin AR, Rodriguez A et al
Frontiers in Allergy 2024; 5: 1451768 (3 September)
https://doi.org/10.3389/falgy.2024.1451768

Asthma affects 25 million people in the United States, and its prevalence is increasing. As noted in this review, access to care and adherence to prescribed asthma-treatment programs remain the principal formidable challenges for asthma management. One innovation, Telemedicine offers substantial opportunities for improved asthma care of patients across the full range of socioeconomic strata. Furthermore, ever-improving digital tools for asthma assessment and treatment are key components of telemedicine platforms for asthma management. This article reviews the variety of remote patient-monitoring devices, digital inhaler systems, and mobile-health applications that facilitate ongoing assessment and adherence to treatment protocols. Digital tools for monitoring treatment focus on tracking medication use, inhalation technique, and physiological markers such as peak-flow rate and pulse-oximetry. Telemedicine visits allow for elements of assessment via video, approximating or duplicating many aspects of in-person visits, such as evaluating a patient’s general appearance, breathing effort, and cough. Unfortunately, despite these innovations, challenges remain in ensuring equitable access to these technologies, especially in rural and low-income areas, and in maintaining patient privacy and data security in digital platforms.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Immediate hypersensitivity reactions to iodinated contrast media: The diagnosis of allergy by skin testing
Caron J, Graf S, Delebarre-Sauvage C
Clinical and Translational Allergy 2022;12(12):e12214 (4 December)
https://doi.org/10.1002/clt2.12214

In the retrospective analysis by Caron et al, they found that among 74 patients with an immediate hypersensitivity reaction (IHR) to iodinated contrast media (ICM), the rate of allergic patients confirmed by positive prick test or diluted intradermal test was 8.1%. They also found that 12.5% of re‐exposed patients had a recurrent IHR despite negative skin tests.  The authors conclude that evaluation with IDT to ICM and development of DPT may provide an additional “safety net” to uncover recurrent ICM reactors.

Role of chemokines and inflammatory cells in respiratory allergy
Bao Y, Zhu X
Journal of Asthma and Allergy 2022;15:1805-1822 (21 December)
https://doi.org/10.2147/JAA.S395490

In the review Bao and colleagues explore the role of the chemokine system in the respiratory immune response and discuss how respiratory disease modulates overall chemokines to shape the type and outcome of the immune response to the treatment of respiratory allergic disease so that we can further deepen our knowledge of chemokines and their role in respiratory allergy. The concept of “one airway, one disease” has been espoused for some time, whereby in the upper and lower airways, allergic mechanisms interact with each other. In the initial stage of respiratory allergic inflammation, allergens contact the respiratory epithelium, which produces chemokines and inflammatory factors, which cause allergic reactions by binding to the corresponding receptors and chemotactic various inflammatory cells to reach the epithelium and tissues. It also drives inflammatory cells to activate and produce more inflammatory factors, thus producing an amplification effect. Inflammatory cell aggregation and activation are very complex and interact with each other in a lattice structure. By blocking the action of various chemokines, inflammatory cell aggregation is reduced, and ultimately the symptoms of respiratory allergy are alleviated. Chemokines can serve as cues for coordinated recruitment of immune cells into and out of tissues, as well as directing the spatial organization of immune cells within tissues and cellular interactions. Chemokines are critical in directing immune cell migration and thus have an important role in the direction of respiratory allergy: however, chemokines are also involved in the production and recruitment of immune cells that contribute to respiratory allergy. The authors conclude by suggesting that future drug research and development should consider this network structure in their new research directions.

A sputum bioassay for airway eosinophilia using an eosinophil peroxidase aptamer
Ali MM, Wolfe MG, Mukherjee M et al
Science Reports 2022;12:22476 (28 December)
https://doi.org/10.1038/s41598-022-26949-7

Eosinophils are well known to play a significant role in the pathogenesis of asthma and other airway diseases. Directing patient treatment based on the level of eosinophilia has been shown to be extremely effective in reducing exacerbations and therefore has tremendous potential as a routine clinical test. In this manuscript Ali et al. describe the in vitro selection and optimization of DNA aptamers that bind to eosinophil peroxidase (EPX). Fifteen rounds of magnetic bead aptamer selection were performed prior to high throughput DNA sequencing. The top 10 aptamer candidates were assessed for EPX binding using a mobility shift assay. This process identified a lead aptamer candidate termed EAP1-05 with low nanomolar affinity and high specificity for EPX over other common sputum proteins. This aptamer sequence was further optimized through truncation and used to develop an easy-to-use colourimetric pull-down assay that can detect EPX over a concentration range from 1 – 100 nM in processed sputum. Following this, 46 clinical samples were processed using a new sputum dispersal method, appropriate for a rapid assessment assay, which avoids centrifugation and lengthy processing times. The assay demonstrated 89% sensitivity and 96% specificity in detecting eosinophilia (compared to gold standard sputum cytometry), with results being available in under an hour. The authors suggest that this assay could allow for an easy assessment of eosinophil activity in the airway to guide anti-inflammatory therapy for several airway diseases.

Resistant Chronic Spontaneous Urticaria - A Case Series Narrative Review of Treatment Options
Khan S, Chopra C, Mitchell A et al
Allergy & Rhinology 2022;13 (21 December)
https://doi.org/10.1177/21526575221144951

Chronic spontaneous urticaria (CSU) can be extremely debilitating to sufferers and challenging for the treating clinician. The National Institute of Health and Clinical Excellence (NICE) in the United Kingdom (UK) recommendation of omalizumab for patients who fail to respond to high-dose anti-histamines has improved treatment options and quality of life; however, there is still a lack of clear guidelines for treatment of patients resistant to standard and anti-IgE therapies. In this paper, Khan et al. explore the therapeutic strategies available by examining nine extremely resistant CSU cases, highlighting the heterogeneity between guidelines from different societies. Patients with anti-histamine-resistant urticaria either remained on omalizumab or were started on immunosuppressive drugs (dapsone or ciclosporin) when they stopped responding to omalizumab. Clinical assessment, skin biopsies (when available) and previously published reports were considered before using dapsone (for predominantly neutrophilic infiltration), or ciclosporin at doses between 2 and 4 mg/kg/day. One patient with ciclosporin-resistant urticaria responded to mycophenolate mofetil. Two patients remained on long-term omalizumab due to its relative safety and efficacy. Its safety was especially important in one patient with underlying antibody deficiency where omalizumab was preferred over risks of using immunosuppressive medications. The authors stress that these case studies highlight the real-world difficulties in managing patients with resistant CSU and the need for generating evidence-based recommendations regarding alternative therapeutic options, including consideration of the use of biologics in tandem with immunosuppressive drugs.

Peanut-Induced Anaphylaxis in Children: A Literature Review
Alshajarah HA, Alghamdi HA, Alberi ZA et al
Cureus 2022;14(12): e32946 (26 December)
https://doi.org/10.7759/cureus.32946

Peanut allergy has become more common among children and is considered one of the most common triggers for fatal anaphylaxis. Treatment of symptoms during a reaction is only one aspect of managing anaphylaxis; other elements include rigorous dietary avoidance and education about settings that could put the patient at a high risk of unintentional exposure. In this review, the authors examine the prevalence, mechanism, diagnosis, treatment, and emergency action of peanut-induced anaphylaxis among children. Peanuts are the most common food to cause fatal anaphylaxis and a common cause of food allergies. The research cited in this review, demonstrates that the peanut allergy prevalence differs across cultures, and that while early oral peanut exposure may reduce the occurrence of peanut allergy, early non-oral exposure may have the opposite effect. They close by stressing that research involving oral immunotherapy, anti-IgE antibody, and herbal formulations have all demonstrated promise, but more research is needed. To conclude, peanut allergies have increased frequently during the past 10 years, especially in Westernized nations. Given that peanut allergy poses a danger for fatal anaphylaxis, response management is crucial. The current standard of care for those with nut allergies comprises complete food avoidance and the administration of injectable epinephrine to treat systemic symptoms.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Allergy: Mechanistic insights into new methods of prevention and therapy
Akdis CA, Akdis M, Boyd SD et al
Science Translational Medicine 2023;15(679):eadd2563
https://doi.org/10.1126/scitranslmed.add2563

In this review, Akdis and colleagues explore the etiology and pathophysiology of allergic diseases, including the role of the epithelial barrier, the immune system, climate change, and pollutants. The authors note that our current understanding of the impact of early life and infancy; diverse diet; skin, respiratory, and gut barriers; and microbiome in building immune tolerance to common environmental allergens has led to changes in prevention guidelines. Recent developments regarding the mechanisms involved in allergic diseases have been translated to effective treatments, particularly in the past 5 years, with additional treatments now in advanced clinical trials.

Skin care interventions in infants for preventing eczema and food allergy
Kelleher MM, Cro S, Cornelius V et al
Cochrane Database of Systemic Reviews 2021;2(2):CD013534
https://doi.org/10.10.1002/14651858.CD013534.pub2

In the Cochrane analysis, Kelleher et al evaluate the efficacy of skin care interventions such as emollients for primary prevention of eczema and food allergy in infants. Applying standard Cochrane methods, they found that skin care treatments in babies, specifically using moisturizers on the skin during the first year of life, probably do not prevent babies from developing eczema; may increase the chance of food allergy; and probably increase the chance of skin infection. The authors note that this review looked at the prevention of eczema and food allergy only and that such interventions are still important to treat eczema.

Digitally-enabled, patient-centred care in rhinitis and asthma multimorbidity: The ARIA-MASK-air^® approach
Bousquet J, Anto JM, Sousa-Pinto B et al
Clinical and Translational Allergy 2023;13(1):e12215
https://doi.org/10.1002/clt2.12215

MASK‐air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK‐air® data has enabled novel phenotype discovery and characterization, as well as insights into the management of allergic rhinitis. MASK‐air® data show that most rhinitis patients: (i) are not adherent and do not follow guidelines, (ii) use as‐needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms, and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, and educational performance) is not always improved by medications. A combined symptom‐medication score (ARIA‐EAACI‐CSMS) has been validated for clinical practice and trials. The authors note that the implications of this app results should lead to change management in rhinitis and asthma.

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms
Yepes-Nuñez JJ, Guyatt GH, Gómez-Escobar LG et al
Journal of Allergy and Clinical Immunology 2023 151(1):147-158
https://doi.org/10.1016/j.jaci.2022.09.020

It is known that atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens in triggering AD remains unclear. Thus the objective of this study was to systematically examine the evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD utilizing the GRADE approach to determine the quality of the evidence. The authors found 23 randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and quality of life (QoL), defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT’s effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. Overall, they found that SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL, but SCIT increases adverse effects more than SLIT.

Cutaneous manifestations of COVID-19 and COVID-19 vaccination
Nakashima C, Kato M, Otsuka A
Journal of Dermatology 2023; Published online ahead of print
https://doi.org/10.1111/1346-8138.16651

Although this new COVID-19 infection is known to cause primarily interstitial pneumonia and respiratory failure, it is often associated with cutaneous manifestations as well. The authors note that the manifestations of COVID-19 can be classified into seven categories: (i) chilblain-like skin eruption (e.g., COVID toes), (ii) urticaria-like skin eruption, (iii) maculopapular lesions, (iv) vesicular eruptions, (v) purpura, (vi) livedo reticularis and necrotic lesions, (vii) urticarial vasculitis, and others such as alopecia and herpes zoster.

In this review Nakashima and colleagues examine the various cutaneous adverse reactions that have been observed with COVID-19 infection and after COVID-19 mRNA vaccination. The major cutaneous adverse reactions are type I hypersensitivity (urticaria and anaphylaxis) and type IV hypersensitivity (COVID arm and erythema multiform). Autoimmune-mediated reactions including bullous pemphigus, vasculitis, vitiligo, and alopecia areata have also been reported. Several cases with chilblain-like lesions and herpes zoster after COVID-19 mRNA vaccination have been reported, and the mechanism has been partly elucidated. The authors note that some COVID-19-associated skin reactions are indistinguishable from drug eruptions and close by stressing that in the future, the mechanisms of COVID-19 infection- or COVID-19 vaccine-associated skin reactions need to be elucidated and verification of causal relationships is required.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Epithelial barrier in the nasal mucosa, related risk factors and diseases
Zhang R, Zhang L, Li P et al
International Archives of Allergy and Immunology 2023 (1 February)
https://doi.org/10.1159/000528969

This review by Zhang examines the epithelial barrier of the nose. We know the importance of this barrier, as it is the first line of defense against risk factors and maintains homeostasis in the nasal mucosa. The composition of this barrier contains physical, chemical, immune, and microbiological barriers. Together, these barriers form the nasal defense against irritations. Risk factors from both internal and external environments can disrupt them. Furthermore, external risk factors contain allergen containing proteases, bacteria, virus, particulate matter, diesel exhaust particles, and cigarette smoke.

Considering the epithelial barrier's role in the nasal mucosa, several studies have focused on the treatment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) to restore the epithelial barrier. Among the therapeutic approaches, histone deacetylase (HDAC) inhibitor and corticosteroids are two of the more studied interventions. The underlying mechanism of HDAC inhibitor may be related to the transcription factor p63. And the protection of corticosteroids may be associated with the allergic disease susceptibility gene, protocadherin-1. Notably, manipulation of the microbiological barrier also has a positive effect on AR and CRS. Also in this review, the authors examine the utility of probiotics as well as several promising novel approaches that attempt to restore the defective barrier in nasal allergic diseases.

Associations between outdoor air pollutants and non-viral asthma exacerbations and airway inflammatory responses in children and adolescents living in urban areas in the USA: a retrospective secondary analysis
Altman MC, Kattan M, O’Connor GT et al
Lancet Planet Health 2023;7(1):e33-e44 (January)
https://doi.org/10.1016/S2542-5196(22)00302-3

Previous research has demonstrated that asthma prevalence and severity have markedly increased with urbanization, and children in low-income urban centers have among the greatest asthma morbidity. Not surprisingly, outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. Thus, the aim of this study was to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus.

To do so, the authors performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6–17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The ICATA cohort was composed of 419 participants aged 6–20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008.

The authors used air quality index values and air pollutant concentrations for PM2·5, PM10, O3, NO2, SO2, CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant and investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalized additive models, case crossover analyses, and generalized linear mixed-effects models.

Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in their analysis. The authors found that increased air quality index values, driven predominantly by increased PM2·5 and O3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection.

Furthermore, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O3 with increased type-2 inflammation.

Overall, these findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway.

Benchmarking omics-based prediction of asthma development in children
Wang XW, Wang T, Schaub D et al
Respiratory Research 2023;24(1):63 (26-February)
https://doi.org/10.1186/s12931-023-02368-8

It is well known that asthma is a heterogeneous disease with high morbidity. Advancement in high-throughput multi-omics approaches has enabled the collection of molecular assessments at different layers, providing a complementary perspective of complex diseases such as asthma. While numerous computational methods have been developed for the omics-based patient classification or disease outcome prediction in other illnesses, systematic benchmarking of those methods using various combinations of omics data for the prediction of asthma development is still lacking.

Thus, the goal of this study was to investigate the computational methods in disease status prediction using multi-omics data by systematically benchmarked 18 computational methods using all the 63 combinations of six omics data (GWAS, miRNA, mRNA, microbiome, metabolome, and DNA methylation) collected in The Vitamin D Antenatal Asthma Reduction Trial (VDAART) cohort. The authors evaluated each method using standard performance metrics for each of the 63 omics combinations finding that overall Logistic Regression, Multi-Layer Perceptron, and MOGONET display demonstrated superior performance, and the combination of transcriptional, genomic and microbiome data achieves the best prediction. They also found that including the clinical data can further improve the prediction performance for some but not all the omics combinations.

The authors conclude that omic combinations can reach the optimal prediction of asthma development in children with certain computational methods demonstrating superior performance compared with other methods. This is the beginning of a new age of further precision in our care of asthmatic patients.

Allergic march in children: The significance of precision allergy molecular diagnosis (PAMD@) in predicting atopy development and planning allergen-specific immunotherapy
Knyziak-Mędrzycka I, Majsiak E, Cukrowska B
Nutrients 2023;15(4):978 (15-February)
https://doi.org/10.3390/nu15040978

In this paper, Knyziak-Medrzycka et al explore the literature regarding the allergic march, which they described with age. The classic allergic march typically begins in infancy manifesting in the form of atopic dermatitis and food allergy. As immune tolerance develops over time, these conditions may resolve by the age of 3–5 years; however, they may evolve into allergic illnesses, including allergic rhinitis and bronchial asthma. Traditional diagnostic assessments, such as skin prick testing or serum allergen-specific immunoglobulin E (sIgE) level testing, are conducted to introduce effective treatment. Recently the utilization of precision allergy molecular diagnosis (PAMD@), which assesses sIgE against allergenic molecules has been introduced. This recent technology helps more accurately evaluate the patient’s allergy profile, which helps create more precise dietary specifications and personalize allergen-specific immunotherapy. The focus of this review highlights possible predictors regarding the allergic march and the means of controlling it, based on PAMD@ results.

New Indications of Biological Drugs in Allergic and Immunological Disorders: Beyond Asthma, Urticaria, and Atopic Dermatitis
Russo D, Di Filippo P, Di Pillo S et al
Biomedicines 2023;11(2):236 (17-Jan)
https://doi.org/10.3390/biomedicines11020236

Asthma, chronic urticaria, and atopic dermatitis are some of the most common allergic illnesses affecting children. Recent advances in the understanding of their specific intracellular molecular pathways have led to the approval of monoclonal antibodies which target specific inflammatory molecules associated with the illness, to control symptoms and improve quality of life. Less is known about other allergic and immunologic disorders such as rhinosinusitis with nasal polyps, eosinophilic esophagitis, anaphylaxis, and food allergy. With the increasing evidence regarding the molecular mechanisms underlying their pathogeneses it is now possible to find, in the pediatric population, new indications for existing biological drugs, such as omalizumab and dupilumab, as well as novel compounds with even more specificity. In this review, the authors explore the latest evidence regarding the safety, and efficacy of biologic agents to treat allergic and immunologic diseases in children.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Cross-sectional study to describe allergic rhinitis flare-ups and associated airways phenotype in house dust mite sensitization
de Gabory L, Amet S, Le Maux A et al
PLoS One 2023;18(3):e0283246
https://doi.org/10.1371/journal.pone.0283246

In this observational, multicenter, cross-sectional study of patients aged > 5 years with house dust mite allergic rhinitis (HDM-AR) eligible for allergen immunotherapy (AIT) and without prior AIT for at least 12 months, the authors examined flare-ups that occurred during the preceding 12 months. Data were collected using medical records and patient questionnaires examining variables that were associated with the occurrence of > 2 AR flare-ups. Included were 1701 patients (average age: 23 years, 51.5% males, 30.4% children, 17.7% adolescents, and 51.9% adults). Severe and persistent AR affected 70.9% of them and 53.7% showed polysensitization. Asthma was associated with AR in 34.4% and was well-controlled in 58.5%. The occurrence of at least one AR flare-up in the year was reported by 77.7%, with an annual rate in the whole population of 2.6 ± 3.9 and a duration of 14.1 ± 17.1days. Deeply or moderately AR-related degraded quality of life (QoL) was experienced by 39.5% and 64.6%, respectively. The occurrence of > 2 AR flare-ups was reported by 54.5% and was associated with polysensitization, AR intermittence, and severity of underlying disease.

Pathogenesis of allergic diseases and implications for therapeutic interventions
Wang J, Zhou Y, Zhang H et al
Signal Transduction and Targeted Therapy 2023;8:138 (24 March)
https://doi.org/10.1038/s41392-023-01344-4

Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema are systemic diseases caused by an impaired immune system. This review aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD, and FA. Accompanied by high recurrence rates, the steadily rising incidence rates of these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors, including maternal-fetal environment, living environment, genetics, epigenetics, and the body’s immune status. It exhibits a marked heterogeneity, with phenotype and endotype defining visible features and associated molecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, many new biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), anti-interleukin (IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becoming more and more important to understand the influencing factors, pathogenesis, and treatment progress of allergic diseases.

International consensus statement on allergy and rhinology: Allergic rhinitis – 2023
Wise SK, Damask C, Roland LT, et al
International Forum of Allergy and Rhinology 2023;13(4):293-859
https://doi.org/10.1002/alr.23090

In this ICAR-Allergic Rhinitis 2023 update the expert panel present 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the previous 2018 document. Originally presented topics from 2018 have also been reviewed and updated. ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic, with stepwise iterative peer review and consensus performed for each topic. Through this approach the authors provide a comprehensive evaluation of AR based upon the currently available evidence. This is a wonderful resource for the practicing allergist as well as ENT.

Allergen challenge tests in allergen immunotherapy: State of the art
Zieglmayer P, Zieglmayer R, Lemell P
Allergologie Select 2023;7:25-32
https://www.doi.org/10.5414/ALX02322E

Allergen challenge tests, such as conjunctival (CAC) nasal (NAC), or bronchial (BAC) challenge tests, or challenges in allergen exposure chambers (AEC) are accepted by regulatory agencies for allergy immunotherapy (AIT) phase II studies. In light of the use of these challenge procedures in the approval process, it is important that allergist be familiar with these techniques. This article provides a great review of the available allergen challenge test methods, summarizing the safety and limitations for each, and discusses their potential for use in AIT trials.

Stepping down treatment in chronic spontaneous urticaria: What we know and what we don't know
Terhorst-Molawi D, Fox L, Siebenhaar F, Metz M, Maurer M
American Journal of Clinical Dermatology 2023; Published online ahead of print
https://doi.org/10.1007/s40257-023-00761-z

In chronic spontaneous urticaria (CSU), wheals, angioedema, or both appear spontaneously for > 6 weeks. Current recommended treatment options for urticaria target mast cell mediators such as histamine, or activators, such as autoantibodies. The goal of CSU treatment is to treat the disease until it is gone as effectively and safely as possible. As at present no cure is available, the treatment is aimed at continuously suppressing disease activity, with complete control of the disease and a normalization of quality of life. To achieve this, pharmacological treatment should be continued until no longer needed.

CSU directed therapy should follow the basic principles of treating as much as needed and as little as possible taking into consideration that the activity of the disease may vary. Since CSU is a disease with spontaneous remission, it is hard to tell in patients with complete control and no signs or symptoms, when medication is no longer needed. The current international guideline for urticaria suggests that the treatment can be stepped down once a patient is free of signs and symptoms; yet, as of now, it is unclear over which period, with what intervals and with which dosages CSU treatment should be stepped down. Guidance on this is needed for all recommended therapies. However, there is a lack of controlled trials which focus on the step down and discontinuation of these treatments. In this review, the authors explore what is known and what needs to be investigated through further studies to aid in optimizing the step-down process.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Timing of allergenic food introduction and risk of immunoglobulin E-mediated food allergy: A systematic review and meta-analysis
Scarpone R, Kimkool P, Ierodiakonou D et al
JAMA Pediatrics 2023;177(5):489-497
https://doi.org/10.1001/jamapediatrics.2023.0142

Earlier egg and peanut introduction probably reduce the risk of egg and peanut allergy, respectively, but it is uncertain whether food allergy as a whole can be prevented using earlier allergenic food introduction. Thus, the objective of this study was to investigate associations between timing of allergenic food introduction to the infant diet and risk of food allergy. To do so, the authors performed a systematic review and meta-analysis, searching for articles from database inception to December 29, 2022, including search terms of: infant, randomized controlled trial, and terms for common allergenic foods and allergic outcomes. Screening was conducted independently by multiple authors, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISM) guideline, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess certainty of evidence. The primary outcomes were risk of IgE-mediated allergy to any food from 1 to 5 years of age and withdrawal from the intervention. Secondary outcomes included allergy to specific foods.

Of 9283 titles screened, data were extracted from 23 eligible trials (56 articles, 13,794 randomized participants). There was moderate-certainty evidence from 4 trials (3295 participants) that introduction of multiple allergenic foods from 2 to 12 months of age (median age, 3-4 months) was associated with reduced risk of food allergy (risk ratio [RR], 0.49; 95% CI, 0.33-0.74; I ² = 49%). Absolute risk difference for a population with 5% incidence of food allergy was −26 cases (95% CI, −34 to −13 cases) per 1000 population. There was moderate-certainty evidence from 5 trials (4703 participants) that introduction of multiple allergenic foods from 2 to 12 months of age was associated with increased withdrawal from the intervention (RR, 2.29; 95% CI, 1.45-3.63; I ² = 89%). Absolute risk difference for a population with 20% withdrawal from the intervention was 258 cases (95% CI, 90-526 cases) per 1000 population. There was high-certainty evidence from 9 trials (4811 participants) that introduction of egg from 3 to 6 months of age was associated with reduced risk of egg allergy (RR, 0.60; 95% CI, 0.46-0.77; I ² = 0%) and high-certainty evidence from 4 trials (3796 participants) that introduction of peanut from 3 to 10 months of age was associated with reduced risk of peanut allergy (RR, 0.31; 95% CI, 0.19-0.51; I ² = 21%). Evidence for timing of introduction of cow’s milk and risk of cow’s milk allergy was very low certainty.

Overall, the results indicated through this systematic review and meta-analysis that earlier introduction of multiple allergenic foods in the first year of life was associated with lower risk of developing food allergy, but a high rate of withdrawal from the intervention was seen.

Severe asthmatic responses: The impact of TSLP
Theofani E, Tsitsopoulou A, Morianos I, Semitekolou M
International Journal of Molecular Sciences 2023;24(8):7581
https://doi.org/10.3390/ijms24087581

It is well known that patients with severe asthma (SA) represent a group of asthmatics that are poorly responsive to medium-to-high doses of inhaled corticosteroids and additional controllers, thus leading in some cases to life-threatening disease exacerbations. To elaborate on SA heterogeneity, the concept of asthma endotypes has been developed, with the latter being characterized as T2-high or low, depending on the type of inflammation implicated in disease pathogenesis. As SA patients exhibit curtailed responses to standard-of-care treatment, biologic therapies are prescribed as adjunctive treatments. To date, several biologics that target specific downstream effector molecules involved in disease pathophysiology have displayed superior efficacy only in patients with T2-high, eosinophilic inflammation.  This is not surprising, as until recently, all of the biologic therapies available targeted T2 mediators, including IgE, IL5, and IL4/13. In the case of the T2 low subset of SA, upstream mediators of the inflammatory cascade could constitute an attractive therapeutic approach for difficult-to-treat asthma. One such appealing therapeutic target is thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine with critical functions in allergic diseases, including asthma. This review explores the numerous studies in both humans and mice that provided major insights pertinent to the role of TSLP in the initiation and propagation of the asthmatic responses.

Associations between fetal or infancy pet exposure and food allergies: The Japan Environment and Children’s Study (JECS)
Okabe H, Hashimoto K, Yamada M et al
PLoS One 2023;18(3):e0282725
https://doi.org/10.1371/journal.pone.0282725

The hygiene hypothesis suggests that pet exposure is effective in preventing allergic disease, and some studies have reported the beneficial effects of dog exposure during fetal development or early infancy on food allergy. However, the effects of exposure to pets other than dogs on the impact of food allergies remains unaddressed. This study aimed to explore the effect of exposure to various species of pets on the risk of food allergies. To do so, Okabe and colleagues obtained information on pet exposure and food allergy from the Japan Environment and Children’s Study (JECS), a nationwide, prospective birth cohort study that included 97,413 mothers and their children and examined the associations between exposure to various species of pets during fetal development or early infancy and the incidence risk of food allergies. They then applied logistic regression analysis for each pet species, causative food, and timing of exposure.

They found that exposure to dogs or cats during fetal development or early infancy was estimated to reduce the incidence risk of food allergies until the age of 3 years. Dog exposure was estimated to reduce the incidence risk of egg, milk, and nut allergies, and cat exposure was estimated to reduce the incidence risk of egg, wheat, and soybean allergies. However, hamster exposure was estimated to increase the incidence risk of nut allergy.

The authors conclude that the association between pet exposure and food allergies might differ depending on the pet species and causative food. Continued dog and cat exposure from fetal development to infancy was estimated to reduce the incidence risk of food allergies.

EAACI Molecular Allergology User’s Guide 2.0
Dramburg S, Hilger C, Santos AF et al
Pediatric Allergy and Immunology 2023; 34(28):e13854
https://doi.org/10.1111/pai.13854

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

Development and validation of a respiratory-responsive vocal biomarker-based tool for generalizable detection of respiratory impairment: Independent case-control studies in multiple respiratory conditions including asthma, chronic obstructive pulmonary disease, and COVID-19
Kaur S, Larsen E, Harper J, Purandare B et al
Journal of Medical Internet Research 2023;25:e44410 (14 Apr)
https://doi.org/10.2196/44410

The use of vocal biomarker–based machine learning approaches have shown promising results in the detection of various health conditions, including respiratory diseases, such as asthma. In this study by Kaur and colleagues, the authors aimed to determine whether a respiratory-responsive vocal biomarker (RRVB) model platform initially trained on an asthma and healthy volunteer (HV) data set could differentiate patients with active COVID-19 infection from asymptomatic HVs by assessing its sensitivity, specificity, and odds ratio (OR). The authors relied upon a logistic regression model using a weighted sum of voice acoustic features was previously trained and validated on a data set of approximately 1700 patients with a confirmed asthma diagnosis and a similar number of healthy controls. The same model has shown generalizability to patients with chronic obstructive pulmonary disease, interstitial lung disease, and cough. In this study, 497 participants (female: n=268, 53.9%; <65 years old: n=467, 94%; Marathi speakers: n=253, 50.9%; English speakers: n=223, 44.9%; Spanish speakers: n=25, 5%) were enrolled across 4 clinical sites in the United States and India and provided voice samples and symptom reports on their personal smartphones. The participants included patients who are symptomatic COVID-19 positive and negative as well as asymptomatic HVs. The RRVB model performance was assessed by comparing it with the clinical diagnosis of COVID-19 confirmed by reverse transcriptase–polymerase chain reaction.

The ability of the RRVB model to differentiate patients with respiratory conditions from healthy controls was previously demonstrated on validation data in asthma, chronic obstructive pulmonary disease, interstitial lung disease, and cough, with ORs of 4.3, 9.1, 3.1, and 3.9, respectively. The same RRVB model in this study in COVID-19 performed with a sensitivity of 73.2%, specificity of 62.9%, and OR of 4.64 (P<.001). Patients who experienced respiratory symptoms were detected more frequently than those who did not experience respiratory symptoms and completely asymptomatic patients (sensitivity: 78.4% vs 67.4% vs 68%, respectively) than those who did not experience respiratory symptoms and completely asymptomatic patients (sensitivity: 78.4% vs 67.4% vs 68%, respectively).

The authors conclude that the generalizability of this model for detecting respiratory symptoms across different linguistic and geographic contexts suggests a potential path for the development and validation of voice-based tools for broader disease surveillance and monitoring applications in the future.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

T helper 2 cells in asthma
Harker JA, Lloyd CM
Journal of Experimental Medicine 2023; 220(6):e20221094 (10 May)
https://doi.org/10.1084/jem.20221094

In this review, the authors provide an update of our current understanding of Th2 cells in human asthma, highlighting their many functions in asthma, both pathogenic and regulatory, and how these are influenced by the tissue location and disease stage and severity. It also explores how biologics targeting type 2 immune pathways impact asthma, and how they have the potential to reveal hitherto underappreciated roles for Th2 cells in lung inflammation.

Allergy to stings and bites from rare or locally important arthropods: Worldwide distribution, available diagnostics and treatment
Sturm GJ, Boni E, Antolín-Amérigo D et al
Allergy 2023; Published online ahead of print (16 May)
https://doi.org/10.1111/all.15769

This Task Force position paper from the European Academy of Allergy and Clinical Immunology (EAACI) aims to identify either rare or locally important insects causing systemic sting reactions (SSR). Insect venom allergy is the most frequent cause of anaphylaxis in Europe and possibly worldwide. It is known that most systemic allergic reactions after insect stings are caused by Hymenoptera and among these, vespid genera induce most of the SSRs. Honeybees are the second leading cause of SSR. Depending on the global region, other Hymenoptera such as different ant genera are responsible for SSR. Widely distributed hornets and bumblebees or local vespid or bee genera rarely induce SSR. Hematophagous insects such as mosquitoes and horse flies usually cause large local reactions while SSR rarely occur. In this paper, the authors summarize relevant venom or saliva allergens and intend to identify possible cross-reactivities between the insect allergens. Moreover, they explore diagnostic tests both for research and routine diagnosis, as well as treatment.

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Choi YJ, Yoo JS, Jung K et al
Nature Communications 2023;14:2045 (11 April)
https://doi.org/10.1038/s41467-023-37873-3

It is known that lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT–stem cell factor (SCF) and FcεRI–immunoglobulin E interactions have been shown to be critical for the proliferation and activation of mast cells, respectively. In this report Choi and colleagues demonstrate that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. Overall, this study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation.

A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma
Alladina J, Smith NP, Kooistra T et al
Science Immunology 2023;8(83):eabq6352 (5 May)
https://doi.org/10.1126/sciimmunol.abq6352

Asthma is a chronic disease most commonly associated with allergies and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, the authors compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. They found that in response to allergen exposure, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9-expressing pathogenic TH2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C) and CCR2-expressing monocyte-derived cells (MCs) were enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a TH2-mononuclear phagocyte-basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Overall, that authors note that their study suggests that pathogenic effector circuits and the absence of pro-resolution programs drive structural airway disease in response to type 2 inflammation.

Quantitative proteomics profiling of plasma from children with asthma
Zhou Y, Kuai S, Pan R et al
International Immunopharmacology 2023;119:110249 (3 May)
https://doi.org/10.1016/j.intimp.2023.110249

Zhou and colleagues suggest that a lack of validated blood diagnostic markers presents an obstacle to asthma control. They thus sought to profile the plasma proteins of children with asthma to attempt to find potential biomarkers. Plasma samples from children in acute exacerbation (n = 4), in clinical remission (n = 4), and from healthy children (n = 4, control) were analyzed using a tandem mass tag (TMT)-labeling quantitative proteomics and the candidate biomarkers were validated using liquid chromatography-parallel reaction monitoring (PRM)/mass spectrometry (MS) with enzyme-linked immunosorbent assay (ELISA). They identified 347 proteins with differential expression between groups: 125 (50 upregulated, 75 downregulated) between acute exacerbation and control, 142 (72 upregulated, 70 downregulated) between clinical remission and control, and 55 (22 upregulated, 33 downregulated) between acute and remission groups (all between-group fold changes > 1.2; P < 0.05 by Student’s t-test). Gene ontology analysis implicated differentially expressed proteins among children with asthma in immune response, the extracellular region, and protein binding. Further, KEGG pathway analysis of differentially expressed proteins identified complement and coagulation cascades and Staphylococcus aureus infection pathways as having the highest protein aggregation. Analysis of protein interactions identified potentially important node proteins, particularly KRT10. Among 11 differentially expressed proteins, seven proteins (IgHD, IgHG4, AACT, IgHA1, SAA, HBB, and HBA1) were verified through PRM/MS. Protein levels of AACT, IgA, SAA, and HBB were verified through ELISA and may be useful as biomarkers to identify individuals with asthma. The authors conclude that this study presents a novel comprehensive analysis of changes in plasma proteins in children with asthma and identifies a potential panel for accessory diagnosis of pediatric asthma.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Exposure frequency, intensity, and duration: What we know about work-related asthma risks for healthcare workers from cleaning and disinfection
Wilson AM, Ogunseye O, Fingesi T et al
Journal of Occupational and Environmental Hygiene 2023; Published online ahead of print (6 July)
https://doi.org/10.1080/15459624.2023.2221712

In this review the authors explore the current evidence related to three exposure assessment concepts: frequency, intensity, and duration (latency) for cleaning and disinfection exposures in healthcare and subsequent work-related asthma risks. Three databases were searched: Embase, PubMed, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) database. Data were extracted related to three main components of risk assessment. They found that the latency periods for occupational asthma were exponentially distributed, with a mean waiting time (1/λ) of 4.55 years. No extracted concentration data were above occupational exposure limits except for some formaldehyde and glutaraldehyde concentrations. Data from included sources also indicated some evidence for a dose-response relationship regarding increased frequency yielding increased risk, but this relationship was unclear due to potential confounders (differences in role/task and associated exposure) and the healthy worker effect. The authors stress that more data are needed to understand how demographic variables; and task, role, as well as chemical type vary this distribution. Furthermore, they note that contributions of latency to risk will inform work-related asthma monitoring efforts and risk perception research that has the potential for connecting exposure intensity, frequency, and duration to probabilities of work-related asthma outcomes.

LMAN1 is a receptor for house dust mite allergens
Miller MH, Swaby LG, Vailoces VS et al
Cell Reports 2023;42(3):112208 (3 March)
https://doi.org/10.1016/j.celrep.2023.112208

The development of therapies with the potential to change the allergic asthmatic disease course will require the discovery of targets that play a central role during the initiation of an allergic response, such as those involved in the process of allergen recognition. In attempt to better understand potential targets in house dust mites (HDM), Miller and colleagues utilized the glycocapture technique to screen for house dust mite (HDM) receptors and identified LMAN1 as a candidate. They verified the ability of LMAN1 to directly bind HDM allergens and demonstrated that LMAN1 is expressed on the surface of dendritic cells (DCs) and airway epithelial cells (AECs) in vivo. Overexpression of LMAN1 downregulates NF-kB signaling in response to inflammatory cytokines or HDM. HDM promotes binding of LMAN1 to the FcRg and recruitment of SHP1. They also found that peripheral DCs of asthmatic individuals show a significant reduction in the expression of LMAN1 compared with healthy controls. These findings have potential implications for the development of therapeutic interventions for atopic disease.

Mechanisms of allergen immunotherapy and potential biomarkers for clinical evaluation
Sahiner UM, Giovannini M, Escribese MM et al
Journal of Personalized Medicine 2023;13(5):845 (17 May)
https://doi.org/10.3390/jpm13050845

Allergen-immunotherapy (AIT) is an efficacious and disease-modifying treatment option for IgE-mediated diseases, including allergic rhinitis, insect venom allergy, food allergy, and allergic asthma. AIT gives rise to clinical immunotolerance which may last for years after the treatment cessation. As highlighted in this review, while AITs efficacy is well established, we are not certain of its mechanism of action, but proposed routes include suppression of allergic inflammation in target tissues and stimulation of the production of blocking antibodies, especially IgG4 and IgA. These mechanisms are followed by a reduction of underlying allergen-specific Th2 cell-driven responses to the allergens. Tolerance induction takes place through the desensitization of effector cells and stimulation of regulatory T cells that show their effects by mechanisms involving cell-cell cross-talk, but also other mechanisms, e.g., by the production of immunomodulatory cytokines such as, e.g., IL-10 and TGF-beta. The authors of this review note that there is a need for clinical biomarkers of value in selecting responders and optimizing patient care during AIT, as well as a deeper understanding of underlying mechanistic processes which could improve AIT’s future outcomes.

Finding the Right Biological: Eosinophil Subset Differences in Asthma and COPD
Freeman CM, Curtis JL, Hastie AT
American Journal of Respiratory and Critical Care Medicine 2023; Accepted article, published online ahead of print (13 June)
https://doi.org/10.1164/rccm.202305-0811ED

In this editorial accompanying a recent article by Cabrera Lopez et al., the authors note that the paper provides important new insights into differences in the roles of eosinophils between COPD versus asthma, finding higher inflammatory Eos (high expression of the IL-5 receptor alpha chain [IL5Rα, CD125]) proportions in participants with asthma compared to participants with COPD (25% vs. 0.5%) matched for age, sex, and FEV1%. The editorial stresses that future studies should not simply count eosinophils, but should characterize subsets of eosinophils. Furthermore, they point out that clinical trials of both existing and novel biologics would benefit from in-depth eosinophil phenotyping to identify the best participants for personalized therapies.

Diversity of B cell populations and Ig repertoire in human lungs
Aihara F, Wang Y, Belkina AC et al.
Journal of Immunology 2023; Published online ahead of print (14 June)
https://doi.org/10.4049/jimmunol.2200340

The human lung carries a unique microbiome adapted to the air-filled, mucous-lined environment, specifically having an immune system capable of recognizing harmful populations while preventing reactions toward commensals. B cells in the lung play a key role in pulmonary immunity, generating Ag-specific Abs, as well as cytokine secretion for immune activation and regulation. In this study, Aihara and colleagues compared B cell subsets in human lungs versus circulating cells by analyzing patient-paired lung and blood samples, finding a significantly smaller pool of CD19+, CD20+ B cells in the lung relative to the blood. CD27+, IgD2, class-switched memory B cells (Bmems) composed a larger proportion of the pool of pulmonary B cells. The residency marker CD69 was also significantly higher in the lung. Furthermore, that authors also sequenced the Ig V region genes (IgVRGs) of class-switched Bmems that do, or do not, express CD69, finding the IgVRGs of pulmonary Bmems to be as heavily mutated from the unmutated common ancestor as those in circulation. Overall, their results show the unique proportion of B cell subsets within the lung. The IgVRGs of pulmonary Bmems are as diverse as those in blood, and progenies of Bmems retain the ability to gain or lose residency.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Guidelines of care for the management of atopic dermatitis in adults with topical therapies
Sidbury R, Alikhan A, Bercovitch L et al
Journal of the American Academy of Dermatology 2023;89(1):e1-320 (11 January)
https://doi.org/10.1016/j.jaad.2022.12.029

New evidence has emerged since the 2014 guidelines that further informs the management of atopic dermatitis (AD) with topical therapies. These guidelines update the American Academy of Dermatology 2014 recommendations for management of AD with topical therapies. The author’s document provides evidence-based recommendations related to management of AD in adults using topical treatments via a multidisciplinary workgroup who conducted a systematic review and applied the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for assessing the certainty of evidence and formulating and grading recommendations. They developed 12 recommendations regarding the management of AD in adults with topical therapies, including nonprescription agents and prescription topical corticosteroids (TCS), calcineurin inhibitors (TCIs), Janus kinase (JAK) inhibitors, phosphodiesterase-4 inhibitors (PDE-4), antimicrobials, and antihistamines. This is a great resource for the practicing allergist.

Effect of maternal egg intake during the early neonatal period and risk of infant egg allergy at 12 months among breastfeeding mothers: A randomized clinical trial
Nagakura KI, Sato S, Shinahara W et al
JAMA Network Open 2023;6(7):e2322318 (3 July)
https://doi.org/10.1001/jamanetworkopen.2023.22318

Egg introduction in infants at age 4 to 6 months is associated with a lower risk of immunoglobulin E–mediated egg allergy (EA). However, whether their risk of EA at age 12 months is affected by maternal intake of eggs at birth is unknown. Thus, this study assessed the effect of maternal egg intake during the early neonatal period (0-5 days) on the development of EA in breastfed infants at age 12 month through a multicenter, single-blind (outcome data evaluators), randomized clinical trial at 10 medical facilities in Japan. Newborns with at least 1 of 2 parents having an allergic disease were included. Neonates whose mothers had EA or who were unable to consume breast milk after the age of 2 days were excluded. Data were analyzed on an intention-to-treat basis. Newborns were randomized (1:1) to a maternal egg consumption (MEC) group, wherein the mothers consumed 1 whole egg per day during the first 5 days of the neonate’s life, versus a maternal egg elimination (MEE) group, wherein the mothers eliminated eggs from their diet during the same period. The primary outcome was EA at age 12 months. Egg allergy was defined as sensitization to egg white or ovomucoid plus a positive test result in an oral food challenge or an episode of obvious immediate symptoms after egg ingestion. Three hundred and eighty newborns included (198 [52.1%] female), 367 (MEC: n = 183; MEE: n = 184) were followed up for 12 months. As would be expected, on days 3 and 4 after delivery, the proportions of neonates with ovalbumin and ovomucoid detection in breast milk were higher in the MEC group than in the MEE group (ovalbumin: 10.7% vs 2.0%; risk ratio [RR], 5.23; 95% CI, 1.56-17.56; ovomucoid: 11.3% vs 2.0%; RR, 5.55; 95% CI, 1.66-18.55). At age 12 months, the MEC and MEE groups did not differ significantly in EA (9.3% vs 7.6%; RR, 1.22; 95% CI, 0.62-2.40) or sensitization to egg white (62.8% vs 58.7%; RR, 1.07; 95% CI, 0.91-1.26). Overall it demonstrated that EA development and sensitization to eggs were unaffected by MEC during the early neonatal period.

Clinic versus home spirometry for monitoring lung function in patients with asthma
Oppenheimer J, Hanania NA, Chaudhuri R et al
Chest 2023;S0012-3692(23)00935-2 Published online ahead of print (27 June)
https://doi.org/10.1016/j.chest.2023.06.029

Studies examining agreement between home and clinic spirometry in patients with asthma are limited, with conflicting results. Understanding the strengths and limitations of telehealth and home spirometry has been highlighted following the SARS-CoV-2 pandemic. The purpose of this study was determined how well home and clinic measurements of trough FEV1 agree in patients with uncontrolled asthma via a post hoc analysis from the randomised, double-blind, parallel-group Phase IIIA CAPTAIN (205715; NCT02924688) and phase IIB (205832; NCT03012061) trials in patients with uncontrolled asthma.

Trough FEV1 measurements were collected via home spirometry and supervised in-person spirometry in the research clinic and they examined the time-course analyses of home and clinic trough FEV1, from which they generated post hoc Bland–Altman plots to assess agreement between home and clinic spirometry.  They found that treatment related improvements in FEV1 were observed in both trials using home and clinic spirometry; however, improvements measured by home spirometry were of lower magnitude and less consistent than clinic measurements. Bland–Altman plots suggested poor agreement between home and clinic trough FEV1 at baseline and Week 24. Overall, this indicates that that home spirometry was less consistent than and lacked agreement with clinic spirometry, suggesting that unsupervised home readings are not interchangeable with clinic measurements. The authors do note, however, that these findings may only be applicable to home spirometry using the specific device and coaching methods employed in these studies and that further research to optimise home spirometry use is needed.

Childhood body mass index trajectories and asthma and allergies: A systematic review
Chang CL, Ali GB, Pham J et al
Clinical & Experimental Allergy 2023; Early view (3 July)
https://doi.org/10.1111/cea.14366

Previous systematic reviews have focused on associations between single time point measures of Body Mass Index (BMI) and asthma and allergic diseases. The authors of this study point out that as BMI changes dynamically during childhood, examination of associations between longitudinal trajectories in BMI and allergic diseases is needed to fully understand the nature of these relationships. To understand better this potential association, they conducted a systematic review following the PRISMA guidelines, and two independent reviewers assessed the study quality using the ROBINS-E and GRADE tools. A narrative synthesis was performed as the statistical heterogeneity did not allow a meta-analysis. Their search found 11 studies met the inclusion criteria with a total of 37,690 participants between 0 and 53 years of age. Ten studies examined asthma outcomes, three assessed association with allergic rhinitis, two assessed eczema, and one assessed food allergy. High heterogeneity and high risk of bias were observed. Overall, the quality of evidence was very low. Nevertheless, two consistent findings were identified: (1) a persistently high BMI between 6 and 10 years of age may be associated with an increased risk of asthma at 18 years and (2) a rapid increase in BMI in the first 2 years of life may be associated with subsequent asthma. The authors conclude that maintaining a normal BMI trajectory during childhood may reduce the risk of asthma and suggest further research to confirm this finding.

Is there a rationale for supplementing with vitamin D patients under treatment with allergen immunotherapy?
Mario Di Gioacchino, Claudia Petrarca, Loredana Della Valle et al
Annals of Medicine 2023;55(1):2230864 (30 June)
https://doi.org/10.1080/07853890.2023.2230864

In this commentary, the authors explore the data regarding use of Vitamin D as a modulating agent in allergic disease, finding allergic patients treated with allergen immunotherapy benefit from the simultaneous administration of Vitamin D, while Vitamin alone did not offer benefits in the prevention or treatment of allergies. They suggest that vitamin serum levels should be always evaluated in patients treated with allergen immunotherapy because these patients have the maximum clinical and immunological benefit with accompanying Vitamin D supplementation.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Asthma hospitalisations and heat exposure in England: A case-crossover study during 2002-2019
Konstantinoudis G, Minelli C, Lam HCY et al
Thorax 2023;78(9):875-881
https://doi.org/10.1136/thorax-2022-219901

Previous studies have reported an association between warm temperature and asthma hospitalization, but little is known about cofactors. This study aims to evaluate the association between asthma hospitalization and warm temperature and investigate vulnerabilities by age, sex, time, and space. In this study, the authors explored individual-level data on summer asthma hospitalization at high temporal (daily) and spatial (postcodes) resolutions during 2002–2019 in England from the NHS Digital. Daily mean temperature at 1 km×1 km resolution was retrieved from the UK Met Office. The authors focused on lag 0–3 days and employed a case–crossover study design and fitted Bayesian hierarchical Poisson models accounting for possible confounders (rainfall, relative humidity, wind speed, and national holidays). After accounting for confounding, they found an increase of 1.11% (95% credible interval: 0.88% to 1.34%) in the asthma hospitalization risk for every 1°C increase in the ambient summer temperature. The effect was highest for males aged 16–64 (2.10%, 1.59% to 2.61%) and during the early years of our analysis.  Interestingly, they found evidence of a decreasing linear trend of the effect over time. Overall, this study provides evidence of an association between warm temperature and hospital admission for asthma. The effect has decreased over time with potential explanations including temporal differences in patterns of heat exposure, adaptive mechanisms, asthma management, lifestyle, comorbidities, and occupation.

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases
Metz M, Kolkhir P, Altrichter S, Siebenhaar F et al
Allergy 2023; Published online ahead of print (22 August)
https://doi.org/10.1111/all.15850

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation—including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators—strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, the authors  explore: (1) the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

Distinction between rhinitis alone and rhinitis with asthma using interactomics
Aguilar D, Lemonnier N, Melén E et al
Scientific Reports 2023;13(1):13125 (12 August)
https://doi.org/ 10.1038/s41598-023-39987-6

The concept of “one-airway-one-disease”, coined over 20 years ago, may be an over-simplification of the links between allergic diseases. Genomic studies suggest that rhinitis alone and rhinitis with asthma are operated by distinct pathways. In this Medal (Mechanisms of the Development of Allergy) study, Augilar and colleagues leveraged the information of the human interactome to distinguish the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone and rhinitis with asthma. The authors found significant differences in the topology of the interactomes and in the pathways associated to each phenotype. In rhinitis alone, identified pathways included cell cycle, cytokine signaling, developmental biology, immune system, metabolism of proteins and signal transduction. In rhinitis and asthma multimorbidity, most pathways were related to signal transduction. The remaining few were related to cytokine signaling, immune system or developmental biology. Toll-like receptors and IL-17-mediated signaling were identified in rhinitis alone, while IL-33 was identified in rhinitis in multimorbidity. On the other hand, few pathways were associated with both phenotypes, most being associated with signal transduction pathways including estrogen-stimulated signaling. The only immune system pathway was Fery-mediated MAPK activation. Overall, the authors suggest that rhinitis alone and rhinitis and asthma/multimorbidity should be considered as two distinct diseases.

Food allergen sensitization on a chip: The gut-immune-skin axis
Janssen R, de Kleer JWM, Heming B et al
Trends in Biotechnology 2023; Correct proof (12 August)
https://doi.org/j.tibtech.2023.07.005

The global population is growing, rapidly increasing the demand for sustainable, novel, and safe food proteins with minimal risks of food allergy. In vitro testing of allergy-sensitizing capacity is predominantly based on 2D assays. However, these lack the 3D environment and crosstalk between the gut, skin, and immune cells essential for allergy prediction. Organ-on-a-chip (OoC) technologies are promising to study type 2 immune activation required for sensitization, initiated in the small intestine or skin, in interlinked systems. Increasing the mechanistic understanding and, moreover, finding new strategies to study interorgan communication is of importance to recapitulate food allergen sensitization in vitro. In this paper, Janssen and colleagues outline recently developed OoC platforms and discuss the features needed for reliable prediction of sensitizing allergenicity of proteins.

Current state and prospects of artificial intelligence in allergy
van Breugel M, Fehrmann RSN, Bügel M et al
Allergy 2023; Published online ahead of print (16 August)
https://doi.org/10.1111/all.15849

As noted by the authors of this paper, van Breugel and colleagues note that the field of medicine is witnessing an exponential growth of interest in artificial intelligence (AI), which enables new research questions and the analysis of larger and new types of data. Nevertheless, applications that go beyond proof of concepts and deliver clinical value remain rare, especially in the field of allergy. In this review the authors explore the fundamental concepts of AI and critically discuss its limitations and open challenges, such as data availability and bias, along with potential directions to surmount them. They provide a conceptual framework to structure AI applications within this field and discuss forefront case examples. Most of these applications of AI and machine learning in allergy concern supervised learning and unsupervised clustering, with a strong emphasis on diagnosis and subtyping. A perspective is shared on guidelines for good AI practice to guide clinicians in applying it effectively and safely, along with prospects of field advancement and initiatives to increase clinical impact. The authors conclude by suggesting that AI can further deepen our knowledge of disease mechanisms and contribute to precision medicine in allergy.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

The immunology of long COVID
Altmann DM, Whettlock EM, Liu S et al
Nature Reviews Immunology 2023;23(10):618-634
https://doi.org/10.1038/s41577-023-00904-7

Estimated numbers of long COVID-19 vary greatly; however, at least 10% of patients infected with COVID appear to develop long COVID. The disease burden spans from mild symptoms to profound disability, making this a huge, new health-care challenge. The authors of this review suggest that long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, including multiorgan, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have also been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic etiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways. This review details the present available data.

Don’t we overestimate drug allergies in children?
E.Podlecka D, Jerzyńska J, Brzozowska A
International Journal of Occupational Medicine and Environmental Health 2023:169848
https://doi.org/10.13075/ijomeh.1896.02227

Approximately 10% of parents report hypersensitivity to at least 1 drug in their children. Yet, few are truly confirmed as drug hypersensitivity reactions. The aim of the study was to assess the real-life prevalence of drug hypersensitivity in children based on drug provocation tests. One hundred thirteen children, aged 4–18 years, referred to Pediatrics and Allergy Clinic in Łódź, Poland, due to an adverse reaction during treatment underwent a history, skin prick tests, intradermal test and drug provocation test. Of the 113 patients suspected of drug allergy, after all diagnostic procedures, the authors proved IgE-mediated allergy to β-lactams, nonsteroid anti-inflammatory drugs, and local anesthetics in only 19 patients (16.8%). The authors found that a previous history of allergy was a risk factor for drug allergy in studied patients (p = 0.001). The most frequent symptoms of allergy were urticaria and erythematous papular rash. Overall, this study reinforces confirming true drug allergy in children presenting with a history of potential drug induced reaction.

Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease
Visca D, Centis R, Pontali E, et al
International Journal of Tuberculosis and Lung Disease 2023;27(10):729-741
https://doi.org/10.5588/ijtld.23.0248

A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified in attempt to develop a “best standard” of care for COVID-19 patients. Relying upon the Delphi process 45 experts completed  a 5-point Likert scale indicated level of agreement with the draft standards resulting in four consensus standards (with 100% agreement). Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ‡4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR program should be based on feasibility, effectiveness and cost-effectiveness criteria, organized according to local health services and tailored to an individual patient’s needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session.

Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for Pediatric Allergology (GPA), the German Contact Dermatitis Research Group (DKG), the German Society for Pneumology (DGP), the German Society of Otorhinolaryngology, Head and Neck Surgery, the Austrian Society of Allergology and Immunology (ÖGAI), the Austrian Society of Dermatology and Venereology (ÖGDV), the German Academy of Allergology and Environmental

Medicine (DAAU), and the German Documentation Center for Severe Skin Reactions (dZh)
Brockow K, Wurpts G, Trautmann A et al
Allergologie Select 2023;7:122-139
https://doi.org/10.5414/ALX02422

In this updated “Guideline for allergological diagnosis of drug hypersensitivity reactions”, the authors conclude that drug hypersensitivity reactions presenting as urticaria/anaphylaxis within 1 (– 6) hours after drug administration (“immediate reactions”) or as exanthem several hours to days later (“delayed reactions”) should be clarified allergologically (strong consensus). Appropriate allergological diagnostics should be used to try to prove the involvement of the immune system (allergy) (strong consensus). The clinical symptoms of an allergic reaction are usually much more severe than those of a non-allergic/intolerance reaction. The experts recommend allergological diagnostics be utilized to identify patients at risk unambiguously in a timely manner to prevent unjustified restrictions in drug therapy. They suggest that allergy diagnostics should be performed within 4 weeks to 6 months after the reaction (strong consensus). The classification of a drug reaction and thus the planning of allergy diagnostics should be based on the clinical picture, the time course (chronology), and the suspected causative drug (strong consensus). If the result of a validated skin and/or laboratory test is clearly positive in conjunction with a matching medical history, the trigger(s) can be considered sufficiently confirmed (strong consensus). If no diagnosis is possible after the skin and laboratory diagnostics, controlled provocation testing should be sought after a risk-benefit assessment (strong consensus). The result of the allergological diagnosis should be explained in detail to the patient (strong consensus). A diagnosed allergic or non-allergic hypersensitivity to one or more drugs should be documented in a drug allergy passport to ensure that this drug(s) will be avoided in the future; in individual cases, if known and considered useful, tolerated alternative drugs can also be mentioned in the allergy passport (strong consensus).

Efficacy of Biologics in Patients with Allergic Severe Asthma, Overall and by Blood Eosinophil Count: A Literature Review
Bernstein JA, Llanos JP, Hunter G et al
Advances in Therapy 2023;40(11):4721-4740
https://doi.org/10.1007/s12325-023-02647-2

Patients with uncontrolled, allergic severe asthma may be prescribed biologic therapies to reduce exacerbations and improve disease control. Unfortunately, randomized controlled trials (RCTs) of these therapies have differed in design, with varying baseline blood eosinophil count (BEC) and not surprisingly divergent results. This study describes published annualized asthma exacerbation rate (AAER) reductions from RCTs in patients with allergic severe asthma, overall and by baseline BEC category. To do so, the authors performed a literature search to identify published phase 3 RCT data of US Food and Drug Administration-approved biologics for severe asthma in patients with severe, uncontrolled asthma and confirmed sensitization to perennial aeroallergens. Analyses focused on AAER reduction versus placebo in the overall population and/or in those with an elevated or low BEC at baseline or screening. It should be noted that baseline serum total immunoglobulin E levels varied between RCT populations. In patients with allergic severe asthma across all BEC categories, data were available for tezepelumab, dupilumab, benralizumab and omalizumab only. In patients with allergic severe asthma and BECs of >260 cells/lL or > 300 cells/lL, AAER reductions were observed with all biologics (tezepelumab, dupilumab, mepolizumab, benralizumab and omalizumab); the greatest AAER reduction was observed with tezepelumab and the smallest AAER reduction was observed with omalizumab. In patients with allergic severe asthma and BECs of <260 cells/lL or <300 cells/lL (regardless of historical BEC), an AAER reduction was observed with tezepelumab but not with benralizumab or omalizumab. The authors suggest that differential mechanisms of action may explain the differences in results observed between biologics. Among patients with allergic severe asthma, the efficacy of biologics in RCTs varied considerably. The authors suggest that these differences can inform provider treatment decisions when selecting biologic treatments for patients with allergic severe asthma.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

The mycobiome in atopic diseases: inducers and triggers
Glatthardt T, van Tilburg Bernardes E, Arrieta M-C
Journal of Allergy and Clinical Immunology 2023: S0091-6749(23)01288-5; Published online ahead of print (19-Oct)
https://doi.org/10.1016/j.jaci.2023.10.006

Atopic diseases are characterized by type 2 inflammation, with high allergen-specific T helper type 2 (Th2) immune responses and elevated immunoglobulin E (IgE) production. These common disorders have increased in incidence around the world, which may be at least partly explained by detrimental disturbances to the early-life intestinal microbiome. While most studies have focused exclusively on bacterial members of the microbiome, intestinal fungi have started to gain an appreciation for their impact on host immune development and atopy pathogenesis. In this perspective, the authors explore recent findings demonstrating the strong interactions between members of the mycobiome and the host immune system early in life, leading to immune tolerance during eubiosis, or inducing sensitization and overt Th2 responses during dysbiosis. This article demonstrates that the current evidence places intestinal fungi as central players in the development of allergic diseases and potential targets for atopy prevention and treatments.

Multifaceted analysis of cross-tissue transcriptomes reveals phenotype-endotype associations in atopic dermatitis
Sekita A, Kawasaki H, Fukushima-Nomura A et al
Nature Communications 2023;14:6133  (2-Oct)
https://doi.org/10.1038/s41467-023-41857-8

It is known that atopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. In this paper, Sekata and colleagues examine integrated RNA sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, to explore specific clinical presentations associated with matching differential molecular signatures. Through a regression model based on transcriptome modules they identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. They further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. The authors’ approach in this study serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases.

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper
Jutel M, Agache I, Zemelka-Wiacek M, Akdis M et al
Allergy 2023; Published online ahead of print (10-Oct)
https://doi.org/10.1111/all.15889

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nanotechnologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The authors note that the clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime.

Breast feeding, obesity, and asthma association: clinical and molecular views
Kian N, Bagheri A, Salmanpour F et al
Clinical and Molecular Allergy 2023;21:8 (3-Oct)
https://doi.org/10.1186/s12948-023-00189-0

Asthma is a chronic condition that affects children worldwide. Numerous studies have reported that the prevalence of pediatric obesity and asthma might be altered through breastfeeding. This article reviews the literature regarding this association.  It has been proposed that Leptin, which exists in human milk, is oppositely associated with weight increase in newborns. It may also influence peripheral immune system by promoting TH1 responses and suppressing TH2 cytokines. Leptin influences body weight and immune responses through complex signaling pathways at molecular level. Although previous studies provide explanations for the protective role of breastfeeding against both obesity and asthma, other factors such as duration of breastfeeding, parental, and prenatal factors may confound this relationship which requires further research.

A nerve-goblet cell association promotes allergic conjunctivitis through the rapid antigen passage
Kimura M, Ando T, Kume Y et al
JCI Insight 2023;8(21)e168596  (11-Oct)
https://doi.org/10.1172/jci.insight.168596

The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although allergic patients manifest symptoms within minutes after pollen exposure, the mechanisms of the rapid allergen transport remain unclear. In the present study, the authors found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by the stromal cells including macrophages and CD11b+ dendritic cells correlated with the surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of the pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. They found that the inducible rapid GAP formation and antigen acquisition was suppressed by topical lidocaine or trigeminal ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a novel therapeutic target for allergic conjunctivitis.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Angiotensin-converting enzyme inhibitors and other medications associated with angioedema
Landry L, Witten T, Anwar A I, et al
Cureus 2023;15(11):e49306 (23 November)
https://doi.org/10.7759/cureus.49306

The present review explores our current knowledge of the pathophysiology, epidemiology, clinical manifestations, predisposing factors, and management of drug-induced angioedema. Angioedema is a localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid extravasation into these tissues. Angioedema is associated with vasoactive molecules and is typically mediated by histamine or bradykinin. It manifests clinically as facial edema, swelling of the extremities and urogenital area, and potential involvement of the larynx, leading to dyspnea and inspiratory stridor, which can become life-threatening. Histamine-mediated angioedema is associated with urticaria and pruritus and will show classic signs of allergic (type 1 hypersensitivity) reactions. Bradykinin-mediated angioedema is often familial (hereditary angioedema) and is more often associated with gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), edema of the extremities and trunk, and a lack of urticaria and pruritus. Angiotensin-converting enzyme inhibitors (ACEIs) are a class of medications commonly prescribed for hypertension, heart failure, and diabetic nephropathy. ACEIs are associated with an increased risk of angioedema, which can range from a mild reaction to severe and life-threatening. ACEI induced angioedema is a bradykinin-mediated reaction that can occur in individuals with a genetic predisposition. Other medications, such as angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, and certain antibiotics, most notably those in the beta-lactam class, can also cause drug-induced angioedema.

Home monitoring of asthma exacerbations in children and adults with use of an AI-aided stethoscope
Emeryk A, Derom E, Janeczek K et al
Annals of Family Medicine 2023;21(6):517-525
https://doi.org/10.1370/afm.3039

The advent of new medical devices allows patients with asthma to self-monitor at home, providing a more complete picture of their disease than occasional in-person clinic visits. This raises a pertinent question: which devices and parameters perform best in exacerbation detection? To better understand the utility of this technology, the authors examine 149 patients with asthma (90 children, 59 adults) in a 6-month observational study. Participants (or parents) regularly (daily for the first 2 weeks and weekly for the next 5.5 months, with increased frequency during exacerbations) performed self-examinations using 3 devices: an artificial intelligence (AI)-aided home stethoscope (providing wheezes, rhonchi, and coarse and fine crackles intensity; respiratory and heart rate; and inspiration-to-expiration ratio), a peripheral capillary oxygen saturation (SpO2) meter, and a peak expiratory flow (PEF) meter and filled out a health state survey. The resulting 6,029 examinations were evaluated by physicians for the presence of exacerbations. For each registered parameter, a machine learning model was trained, and the area under the receiver operating characteristic curve (AUC) was calculated to assess its utility in exacerbation detection. They found that the best single-parameter discriminators of exacerbations were wheezes intensity for young children (AUC 84% [95% CI, 82%-85%]), rhonchi intensity for older children (AUC 81% [95% CI, 79%-84%]), and survey answers for adults (AUC 92% [95% CI, 89%-95%]). The greatest efficacy (in terms of AUC) was observed for a combination of several parameters. Overall, this study demonstrates that an AI-aided home stethoscope provides reliable information on asthma exacerbations. The parameters provided are effective for children, especially those younger than 5 years of age. The authors suggest that the introduction of this tool to the health care system might enhance asthma exacerbation detection substantially and make remote monitoring of patients easier.

Prevalence and socioeconomic impact of allergic rhinitis among ear, nose, and throat patients of a tertiary hospital
Appiah-Thompson P, Amuquandoh A
Cureus 2023;15(12):e49768 (1 December)
https://doi.org/10.7759/cureus.49768

This cross-sectional hospital-based study explored both quantitative and qualitative features of a group of subjects to better understand the common allergens or triggers that lead to the symptoms of allergic rhinitis and to determine the prevalence of other comorbidities associated with allergic rhinitis. The quantitative study involved collecting data on allergic rhinitis patients visiting a tertiary care hospital from March 1, 2021, to June 25, 2021. The quantitative data included the gender and age groups commonly affected, the most common symptom, and the trigger identified. Whilst the qualitative aspect of the study involved the socioeconomic impact of allergic rhinitis on the clients. They found the prevalence of allergic rhinitis was 10% at the ENT clinic of their hospital. It was most common in the age group of 19- to 35-year-olds. Urban residents suffered more from allergic rhinitis than the rural residents. The main presenting complaint was sneezing, and the commonest comorbid condition and trigger associated with allergic rhinitis were sinusitis and dust mites respectively. Twenty-nine percent of respondents had experienced reduced productivity at their workplace and in school. Twenty-one percent had experienced depression, while 26% perceived the cost of treatment to be very expensive. Lastly, they found that the use of face masks was not beneficial in reducing the symptoms of allergic rhinitis in most patients.

The emerging role of digital health in the management of asthma
Kaplan A, Boivin M, Bouchard J et al
Therapeutic Advances in Chronic Disease 2023;14:20406223231209329 (17 November)
https://doi.org/10.1177/20406223231209329

This review examines the literature regarding the utility of digital health in the management of asthma.  The most common reasons seen for lack of asthma control include misconceptions about disease control, low controller treatment adherence, poor inhaler technique, and the resulting underuse of controllers and overuse of short-acting beta2 agonists (SABAs). Reducing these care gaps may be achieved through well-designed patient education that considers the patient’s motivation, beliefs, and capabilities regarding their asthma and its management and empowers the patient to become an active participant in treatment decisions. Digital health technologies (DHTs) and digital therapeutic (DT) devices provide new opportunities to monitor treatment behaviors, improve communication between healthcare providers and patients, and generate data that inform educational interactions. DHT and DT have been proven effective in enhancing patient self-management in other chronic conditions, particularly diabetes. Accelerated integration of DHT and DT into the management of asthma patients is facilitated using digital inhalers that employ sensor technology (“smart” inhalers). These devices efficiently provide real-time feedback on controller adherence, SABA use, and inhaler technique that have the strong potential to optimize asthma control.

The usability of testing skin reaction applying skin prick tests with Comirnaty (Pfizer, USA) vaccine in detecting the risk of developing post-vaccination immediate hypersensitivity response (anaphylaxis) after administration of this vaccine
Gulas E, Bant A, Kruszewski J et al
Advances in Dermatology and Allergology/ Postępy Dermatologii i Alergologii 2023;40(5):655-660 (8 October)
https://doi.org/10.5114/ada.2023.131860

COVID-19 vaccines became a relevant element of prevention during COVID-19 pandemic. It is worth highlighting the importance of severe allergic post-vaccination reactions. In this study the authors evaluate the utility of skin reaction tests using skin prick tests with Comirnaty (Pfizer, USA) vaccine in risk detection of the post-vaccine immediate hypersensitivity reaction (anaphylaxis) after administration of this vaccine [PvIHR(A)]. They evaluated 102 people, 85 women and 17 men with a history of immediate hypersensitivity (anaphylaxis) [IHR(A)] performing a detailed medical history and skin prick tests among the participants. Overall, they found that COVIC-19 vaccination is associated with a low risk of anaphylaxis. with little utility in performing prick skin tests to the vaccine, due to their low sensitivity and low specificity.

WAO Reviews – Editors' Choice

Articles are selected for their importance to clinicians who care for patients with asthma and allergic and immunologic diseases by WAO Reviews Editors Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI.

Regulated on Activation, NormalT cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma
Li N, Mirzakhani H, Kiefer A et al
iScience 2021;24(10):103163 (24 September)
DOI: https://doi.org/10.1016/j.isci.2021.103163

Regulated on Activation, NormalT cell Expressed and Secreted (RANTES) has been implicated in allergic asthma and in T cell-dependent clearance of infection. The RANTES receptor family includes CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses result in the induction of RANTES production by epithelial cells. In this study, the authors explored the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma, extending this study by examining the airways of adults with and without asthma and finally translating these results to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Through these studies, they found an unpredicted therapeutic role of RANTES in the actual resolution of allergen-induced asthma, presumed through orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.

The majority of children sensitized before school age develop allergic disease before adulthood: A longitudinal population=based study
Bunne J, Hedman L, Perzanowski M et al
Journal of Allergy and Clinical Immunology: In Practice 2021; Published online ahead of print (22 October)
DOI: https://doi.org/10.1016/j.jaip.2021.10.023

While it is known that allergic sensitization increases the risk of and asthma and allergic rhinitis, the impact of age at onset of sensitization has been less studied. To understand this relationship better, the authors examined the cumulative incidence of asthma and rhinitis up to age 19 years in relation to age at onset of sensitization to airborne allergens. To do so, they invited all children in grades one and two (median age 8 years) in two municipalities in Northern Sweden to undergo skin prick tests and perform a questionnaire regarding allergic diseases (88% participated). At ages 12 and 19 years the protocol was repeated, with n=1510 individuals participating in all three examinations. Specific IgE was collected in a random sample at age 19, n=770. The authors stratified age of onset of sensitization to: ≤8 years, 8-12 years, 12-19 years, and never sensitized, finding that at age 19, those sensitized ≤8 year had the highest risk of asthma (RR 4.68 (95%CI 3.14- 66 6.97) and rhinitis (RR 22.3 (95%CI 13.3-37.6), with 84% had developing either asthma or rhinitis. They furthermore found that the combination of sensitization ≤8 year and family history of allergic diseases rendered high risks for asthma (RR 10.6 [6.71-16.7]) and rhinitis (RR 36.3 [18.9-69.7]). Individuals sensitized ≤8 year showed the significantly highest level of sensitization, as judged by number of positive skin tests and titers of specific IgE.

Psychological impacts of COVID-19 on people with asthma, allergic rhinitis and food allergy
Burrows AG, Ellis AK
Annals of Allergy Asthma and Immunology 2021; Published online ahead of print (28 December)
DOI: https://doi.org/10.1016/j.anai.2021.12.013

In this paper, Drs. Burrows and Ellis examine the psychological Impact of COVID-19 on people with allergic illness, finding that asthma patients perceived their risk of severe disease from COVID-19 as greater, which negatively impacted their psychological wellbeing. Presently, there are only limited data regarding the impact of COVID-19 in allergic rhinitis (AR) and food allergy (FA) patients; however, it has been found that some AR patients experienced high anxiety and depression compared to healthy controls. Parents and caregivers of children with asthma and FA were also affected with a higher psychological burden during COVID-19. The authors note that it is important that physicians be aware of the potential coincidence of mental illness and chronic allergic diseases, and refer these patients, and their caregivers, to appropriate resources, while also continuing to manage their allergic disease(s).

Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: Results from the REACT study, a retrospective cohort study
Fritzsching B, Contoli M, Porsbjerg C et al
Lancet Regional Health – Europe 2021;13:100275 (30 November)
DOI: https://doi.org/10.1016/j.lanepe.2021.100275

While a multitude of studies has demonstrated the efficacy of allergen immunotherapy (AIT), the long-term, real-life effectiveness of AIT has not been as well studied. To resolve this issue, the REACT (Real world effectiveness in allergy immunotherapy) was performed.  REACT was a retrospective cohort study using claims data between 2007 and 2017 in patients with a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analyzed both as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up. There were 46,024 AIT-treated subjects matched with control subjects, and 14,614 were included in the pre-existing asthma cohort. They found that compared to pre-index year, AIT was consistently associated with greater reductions compared to control subjects in both AR as well as asthma prescriptions (both asthma controller and reliever prescriptions). Additionally, the AIT group had a significantly greater likelihood of stepping down asthma treatment (P <0.0001) as well as a demonstrated reduction in severe asthma exacerbations (P<0.05).  They also found reductions in pneumonia with antibiotic prescriptions, hospitalizations, and duration of inpatient stays in the group on AIT. Overall, this study extends the existing RCT evidence for AIT, demonstrating long-term and sustained effectiveness of AIT in the real world, with an associated reduced likelihood of asthma exacerbation or pneumonia in patients with concurrent asthma.

Clinicopathological characteristics of IgG4-related lung disease
Liu J, Liu Y, Shen X et al
BMC Pulmonary Medicine 2021; 21(1):413 (15 December)DOI: https://doi.org/10.1186/s12890-021-01781-3

Immunoglobulin G4-related lung disease (IgG4-RLD) is a rare entity. To improve upon our ability to diagnose this illness, the authors retrospectively analyzed the clinical and histopathological characteristics of patients with pathologically confirmed IgG4-RLD. From a group of 4838 patients seen in their facility with pulmonary biopsy results, they found 65 patients with suspected IgG4-RLD, of whom analysis of these 10 patients revealed an average age of 59.7 years at diagnosis, and a male-to-female ratio was 9:1. The initial clinical manifestations were nonspecific, with cough being the most common symptom (4/10). More than one organ was involved in most patients (8/10), and mediastinal/hilar lymph node involvement was often observed (7/10). Serum IgG4 was analyzed in 6 patients and found to be elevated. Computed tomography (CT) of the chest and/or 18F-fuorodeoxyglucose positron emission tomography-computed tomography imaging revealed that 5 patients had a mixed type, 3 patients had the solid nodular type, and 2 patients had the bronchovascular type. All pulmonary masses and large nodules with solid patterns had spiculated margins and inhomogeneous enhancement with or without pleural indentation and a lobulated appearance. Abundant lymphoplasmacytic cell infiltration and fibrosis were observed in all patients. The expression of IgG4 and IgG was upregulated in the pulmonary sections. Seven patients were treated with glucocorticoids with or without additional immunosuppressants and responded well.

WAO Reviews – Editors' Choice

Articles are selected for their importance to clinicians who care for patients with asthma and allergic and immunologic diseases by WAO Reviews Editors Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI.

NSAID-exacerbated respiratory disease: a population study
Andersén H, Ilmarinen P, Honkamäki J et al
ERJ Open Research 2022; 8(1):00462-2021 (24 Jan)
https:/doi.org/10.1183/23120541.00462-2021

In this study, Andersén et al attempt to determine the prevalence of NSAID-exacerbated respiratory disease (N-ERD) as well as identify factors associated with N-ERD, by performing a cross-sectional questionnaire survey of a random adult population of 16 000 subjects aged 20–69 years in Helsinki and Western Finland. The response rate was 51.5 % and they found a prevalence of 1.4% for N-ERD, and 0.7% for aspirin-exacerbated respiratory disease (AERD).  Furthermore, the prevalence of N-ERD was 6.9% among subjects with asthma and 2.7% among subjects with rhinitis. Risk factors for N-ERD were older age, family history of asthma or allergic rhinitis, long-term smoking, and exposure to environmental pollutants. Subjects with N-ERD had a higher risk of respiratory symptoms, severe hypersensitivity reactions, and hospitalizations than asthmatic subjects without N-ERD.

Type 2 inflammation in eosinophilic esophagitis: From pathophysiology to therapeutic targets
Racca F, Pellegatta G, Cataldo G et al
Frontiers in Physiology 2022; 12:815842 (12 January)
https://doi.org/10.3389/fphys.2021.815842

While there is broad consensus regarding first-line therapy for eosinophilic esophagitis (EoE), a subset of patients are non-responders to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This comprehensive review explores the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections, and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins, and transcription factors) that could represent present and future therapeutic targets.

The adverse reactions to vaccines practice parameter 10 years on – What have learned?
Kelso J
Annals of Allergy Asthma and Immunology 2022; In press (28 January)
https://doi.org/10.1016/j.anai.2022.01.026

This is a wonderful review that examines the evaluation and management of adverse reactions to vaccines. The author stresses that the risk of reactions to vaccination should be weighed against the risk of suffering a vaccine preventable disease if the vaccine is withheld. The literature demonstrates that there is no need to ask about egg allergy prior to the administration of influenza vaccines, including on screening forms. In most cases, an allergy to a vaccine constituent is not a contraindication to the vaccine containing it. Patients who have had possible anaphylactic reactions to vaccines should be evaluated by an allergist rather than simply being labeled allergic, because most can go on to receive subsequent doses. It is important to note that most immediate reactions to COVID-19 vaccines are not allergic, and care should be taken to not label such reactions as anaphylactic. Finally the role, if any, of polyethylene glycol (PEG) in these reactions has yet to be demonstrated.

Hypersensitivity to non-β-lactam antibiotics
Merk HF, Bickers DR
Allergologie select 2022; 6(1):11-17
https://doi.org/10.5414/ALX02311E

This review is focused on recent findings regarding the pathogenesis of allergic reactions to non-β-lactam antibiotics. While most allergic reactions to antibiotics are caused by β-lactam antibiotics, non-β-lactam antibiotics are also capable of causing both immediate allergic reactions as well as late-type reactions to these drugs. This is especially true for fluoroquinolones and sulfonamides. Of these, the combination of sulfamethoxazole with trimethoprim (Cotrimoxazol, eg, Bactrim) is most important. However, there are certain types of reactions to non-β-lactam antibiotics that are not associated with β-lactam antibiotics. These include photosensitivity to sulfonamides, tetracyclines, and fluoroquinolones as well as different patterns of drug metabolism and associations with human leukocyte antigen (HLA) alleles that may influence their prevalence.

Good’s Syndrome: Time to move on from reviewing the past
Kabir A, Alizadehfar R, Tsoukas CM
Frontiers in Immunology 2022; 12:815710 (12 January)
https://doi.org/10.3389/fimmu.2021.815710

In this review, the authors examine the current literature and identify research gaps regarding Good’s syndrome (GS). In order to resolve controversies and fill knowledge gaps, they propose a coordinated paradigm shift from incidence reporting to robust investigative studies, addressing mechanisms of disease, hoping this novel approach sets a clear direction to solve the current controversies. For seven decades, the pathophysiology of GS has remained a mystery, with few attempts to solve it. While initially described as an association between hypogammaglobulinemia and thymoma, controversy exists whether this is a subgroup of Common Variable Immune Deficiency (CVID) or a unique disease. Recently, some distinguishing aspects of both syndromes have come to light reflecting fundamental differences in their underlying pathophysiology. GS and CVID differ in demographic features and immune phenotype. GS is found almost exclusively in adults and is characterized by a significantly reduced or absence of peripheral B cells. In CVID, which also occurs in children, most patients have normal or slightly reduced peripheral B cells, with a distinguishing feature of low memory B cells. Similarly, differences in T cell dysregulation and manifestations of hematologic cytopenias may further distinguish GS from CVID. Knowledge of the clinical phenotype of this rare adult immune deficiency stems from individual case reports, retrospective, and cross-sectional data on a few cohorts with a limited number of well characterized patients. The authors note that understanding of pathophysiology in GS is hampered by the incomplete and inconsistent reporting of clinical and laboratory data, with a limited knowledge of its natural history.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study
Greuter T, Straumann A, Fernandez-Marrero Y et al
Allergy 2022; Published online ahead of print (29 January)
https://doi.org/10.1111/all.15233

In this study by Greuter et al, the authors attempt to characterize and classify an eosinophilic esophagitis (EoE) variant group who have symptoms of esophageal dysfunction, but peak eosinophil counts of <60/mm2 (<15/hpf) in esophageal biopsies and absence of gastro-esophageal reflux disease (GERD). Clinical, endoscopic, (immuno)-histological, and molecular features were determined and compared with EoE, gastroesophageal reflux disease (GERD), and healthy controls. In a group of 69 such patients, in which endoscopic abnormalities were found in 53.6%, they found EoE-like esophagitis (36/69, 52.2%), lymphocytic esophagitis (14/69, 20.3%), and non-specific esophagitis (19/69, 27.5%). Immunohistochemistry revealed—in contrast to EoE—no significant increase in inflammatory cell infiltrates compared with GERD and healthy controls, except for lymphocytes in lymphocytic esophagitis. EoE-typical Th2-response was absent in all EoE variants. However, considerable structural changes were detected based on histology and protein expression. Using next generation mRNA sequencing, they found the three EoE variants to have distinct molecular fingerprints partially sharing pronounced traits of EoE. Hierarchical sample clustering of RNA sequencing data confirmed the presence of an EoE-like (characterized by eotaxin-3 expression), non-specific, and lymphocytic variant cluster (characterized by CD3 cells and TSLP expression). Overall, all of these EoE variants were clinically and histologically active conditions, despite the absence of esophageal eosinophilia. EoE variants appear to be part of a disease spectrum, where classical EoE represents the most common and apparent phenotype.

Evaluation of budesonide-formoterol for maintenance and reliever therapy among patients with poorly controlled asthma: A systematic review and meta-analysis
Beasley R, Harrison T, Peterson S et al
JAMA Network Open 2022;5(3):e220615 (1 March)
https://doi.org/10.1001/jamanetworkopen.2022.0615

The Global Initiative for Asthma (GINA) recommends two alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid (ICS)-formoterol as both maintenance and reliever (SMART) or ICS-long-acting β2-agonist (ICS-LABA) as maintenance plus short-acting β2-agonist (SABA) as reliever. In order to understand optimal intervention better, the authors performed a systematic review and meta-analysis that compared budesonide-formoterol by SMART with maintenance ICS-LABA plus SABA reliever with the primary outcome being the first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression. They examined whether switching to SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance ICS-LABA plus SABA reliever among patients with poorly controlled asthma. Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). The authors found that switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation – with a 29% reduced risk compared with stepping up to step 4 ICS-LABA maintenance plus SABA reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85). These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance ICS-LABA plus SABA reliever therapy.

Delayed allergic skin reactions to vaccines
Aquino MR, Bingemann TA, Nanada A, Maples KM
Allergy & Asthma Proceedings 2022;43(1):20-29 (1 January)
https://doi.org/10.2500/aap.2022.43.210105

In this literature review, the authors focused on delayed reactions to vaccines, examining possible causative agents and providing practical information on how to diagnose, evaluate with patch testing, and manage subsequent dose administration. They note that most delayed hypersensitivity reactions to vaccines include cutaneous manifestations, which vary from local persistent pruritic nodules to systemic rashes. The onset is usually within a few days but there can be a delay of weeks. Several excipients have been identified that have been implicated in delayed vaccine reactions, including thimerosal, formaldehyde, aluminum, antibiotics, and gelatin. Treatment with antihistamines, topical corticosteroids, or systemic corticosteroids alleviates symptoms in most patients. It is important to note that these reactions are generally not contraindications to future vaccination. However, for more severe reactions, patch testing for causative agents can be used to aid in diagnosis and approach further vaccination.

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
Sparreman Mikus M, Kolmer J, Andersson LI et al
European Respiratory Journal 2022; 59(2):2100142 (17 February)
https://doi.org/10.1183/13993003.00142-2021

In this study, the authors identified plasma biomarkers associated with asthma phenotypes by applying a new proteomic panel to samples from two well-characterized cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, chronic obstructive pulmonary disorder (COPD) subjects, and healthy controls (HCs). The applied antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. They found in U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. Ten proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β, and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained, following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.

Epithelial and sensory mechanisms of nasal hyperreactivity
Velasco E, Delicado-Miralles M, Hellings PW et al
Allergy 2022; Published online ahead of print (17 February)
https://doi.org/10.1111/all.15259

In this review by Velasco and colleagues, the authors explore how nasal hyperreactivity may be the result of three different mechanisms: (1) impaired barrier function, (2) hypersensitivity to external and endogenous stimuli, and (3) potentiation of efferent systems. They describe the known molecular basis of hyperreactivity related to the functional impairment of epithelial cells and somatosensory innervation, and suggest that there remains a need to identify thermal, chemical, and mechanical sensors determining hyperreactivity in humans. They discuss research directions that may provide new insights into nasal hyperreactivity associated with rhinitis/rhinosinusitis pathophysiology and therapeutics, stressing that understanding of the molecular mechanisms underlying nasal hyperreactivity is essential for the treatment of rhinitis in precision medicine.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Treatment patterns and frequency of key outcomes in acute severe asthma in children: A Paediatric Research in Emergency Departments International Collaborative (PREDICT) multicentre cohort study
Craig S, Powell CVE, Nixon GM, Oakley E, Hort J et al
BMJ Open Respiratory Research 2022;9(1):e001137 (17 March)
http://dx.doi.org/10.1136/bmjresp-2021-001137

In this large retrospective cohort study of over 14,000 children with an emergency department diagnosis of asthma or wheeze in Australian and New Zealand hospitals, the authors examined the use and type of escalation of treatment. They found in those with escalation of treatment required a longer LOS (44.2 hours, IQR 27.3–63.2 hours) than children without escalation 6.7 hours, IQR 3.5–16.3 hours; p<0.001). The most common treatment escalations were respiratory support alone (400; 2.9%, 95% CI 2.6% to 3.1%), parenteral bronchodilator treatment alone (380; 2.7%, 95% CI 2.5% to 3.0%), and both respiratory support and parenteral bronchodilator treatment (209; 1.5%, 95% CI 1.3% to 1.7%). Respiratory support was predominantly nasal high-flow therapy (99.0%). The most common intravenous medication regimens were: magnesium alone (50.4%), magnesium and aminophylline (24.6%), and magnesium and salbutamol (10.0%). Overall, they found a wide variation in both the frequency and nature of escalation of treatment for children with emergency department presentations for acute severe asthma.

Strategies for using topical corticosteroids in children and adults with eczema
Lax SJ, Harvey J, Axon E, Howells L, Santer M et al
Cochrane Database of Systematic Reviews 2022; 11:3:CD013356 (11 March)
https://doi.org/10.1002/14651858.CD013356.pub2

While topical corticosteroids have been a first-line treatment for eczema for decades, there are uncertainties over their optimal use. Thus, the objective of this Cochrane analysis was to establish the effectiveness and safety of different ways of using topical corticosteroids for treating eczema. Through this analysis the authors found that potent and moderate topical corticosteroids are probably more effective than mild topical corticosteroids, primarily in moderate or severe eczema; however, it should be noted that there is uncertain evidence to support any advantage of very potent over potent topical corticosteroids. Furthermore, effectiveness is similar between once daily and twice daily (or more) frequent use of potent topical corticosteroids to treat eczema flare-ups, and topical corticosteroids weekend (proactive) therapy is probably better than no topical corticosteroids/reactive use to prevent eczema relapse (flare-ups). The authors found that adverse events were not well reported and came largely from low- or very low-certainty, short-term trials. In trials that reported abnormal skin thinning, frequency was low overall and increased with increasing potency. The authors found no trials on the optimum duration of treatment of a flare, branded versus generic topical corticosteroids, and time to leave between application of topical corticosteroids and emollient. They conclude by noting that there is a need for longer-term trials in people with mild eczema.

Bradykinin-induced angioedema in the emergency department
Hébert J, Boursiquot JN, Chapdelaine H, Laramée B, Desjardins M et al
International Journal of Emergency Medicine 2022;15:15 (26 March)
https://doi.org/10.1186/s12245-022-00408-6

It is well known that poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of several treatment options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. In this article the authors present a systematic literature review exploring the effectiveness of the available therapies for managing such cases and explore differences in bradykinin versus histamine-induced angioedema. In contrast to bradykinin-induced angioedema, histamine-induced angioedema is faster in onset and often presents with urticaria. The authors highlight that acute airway angioedema in the ED should initially be treated with anaphylactic protocols (if physiology of angioedema is unknown), focusing on airway management and treatment with epinephrine, antihistamine, and systemic steroids. Bradykinin-induced angioedema should be considered if this standard treatment is not effective, despite proper dosing and regard of beta-adrenergic blockade.

Predicting the course of asthma from childhood until early adulthood
Koefoed HJL, Vonk JM, Koppelman GH
Current Opinion in Allergy and Clinical Immunology 2022;22(2):115-112 (1 April)
https://doi.org/10.1097/ACI.0000000000000810

This review highlights recent insights regarding the natural history of childhood asthma, with a focus on prediction of persistence and remission of childhood asthma, up to early adulthood. Studies demonstrate that lung function around the age of 8–9 years is the strongest predictor: obstructive lung function predicts asthma persistence up to early adulthood, whereas normal lung function predicts remission. Furthermore, the ability to predict asthma remission improves when lung function is combined with blood eosinophil levels and degree of bronchial hyperresponsiveness. Interventions, such as inhaled corticosteroids and immunotherapy do not appear to alter the course of asthma. Epigenetic studies have revealed potential novel biomarkers of asthma remission, such as micro-RNA patterns in blood. Specifically, lower serum levels of mi-R221-5p, which is associated with lower IL-6 release and eosinophilic inflammation, predict remission, while levels of blood DNA-methylation of a CpG site in Peroxisomal Biogenesis Factor 11 Beta appear to be associated with asthma remission.

SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13
Morrison CB, Edwards CE, Shaffer KM, Ehre C
Proceedings of the National Academy of Sciences 2022;119(16):e2119680119 (19 April)
https://doi.org/10.1073/pnas.2119680119

Muco-obstructive lung diseases are typically associated with high risks of COVID-19 severity; except in the case of allergic asthma, where there appears to be reduced susceptibility. To investigate viral spread, primary human airway epithelial (HAE) cell cultures were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Host–virus interactions were examined via electron microscopy, immunohistochemistry, RNA in situ hybridization, and gene expression analyses. In HAE cell cultures, angiotensin-converting enzyme 2 (ACE2) expression governed cell tropism and viral load and was up-regulated by infection. Electron microscopy identified intense viral egress from infected ciliated cells and severe cytopathogenesis, culminating in the shedding of ciliated cells packed with virions, providing a large viral reservoir for spread and transmission. Intracellular stores of MUC5AC, a major airway mucin involved in asthma, were rapidly depleted, likely to trap viruses. To mimic asthmatic airways, HAE cells were treated with interleukin-13 (IL-13), which resulted in reduction in titers, viral messenger RNA, and cell shedding, and significantly diminished the number of infected cells. Although mucus hyper-production played a shielding role, IL-13–treated cells maintained a degree of protection despite the removal of mucus. Using Gene Expression Omnibus databases, bulk RNA-sequencing analyses revealed that IL-13 up-regulated genes controlling glycoprotein synthesis, ion transport, and antiviral processes (albeit not the typical interferon-induced genes) and down-regulated genes involved in cilial function and ribosomal processing. More precisely, we showed that IL-13 reduced ACE2 expression, intracellular viral load, and cell-to-cell transmission while increasing the cilial keratan sulfate coating. In conclusion, intense viral and cell shedding caused by SARS-CoV-2 infection was attenuated by IL-13, which affected viral entry, replication, and spread.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Asthma remission – What is it and how can it be achieved?
Thomas D, McDonald VM, Pavord ID, Gibson PG
European Respiratory Journal 2022; Published online ahead of print (31 March)
https://doi.org/10.1183/13993003.02583-2021

Currently, asthma treatment goals focus on symptom and exacerbation control rather than remission. This review explores the current definitions of remission in asthma, the prevalence and predictors, pathophysiology of remission, possibility of achieving remission via using the available treatment options, and future research directions. Asthma remission is described as a high level of disease control (including the absence of symptoms and exacerbations), with normalization or optimization of lung function with or without ongoing treatment. The authors point out that even in patients who achieve a symptomatic remission of their asthma, persistent pathological abnormalities are common, leading to a risk of subsequent relapse at any time. Therefore, complete remission requires normalization or stabilization of any underlying pathology beyond symptomatic remission. It should be noted that remission can occur as part of the natural history of asthma, with the reported prevalence of remission in the adult asthma population varying between 2% and 52%. Factors associated with remission include: mild asthma, better lung function, better asthma control, younger age, early-onset asthma, shorter duration of asthma, milder bronchial hyper-responsiveness, fewer comorbidities, and smoking cessation or never smoking. Although previous studies have not targeted treatment-induced remission, there is some evidence to show that the current long-term add on therapies such as biologics and azithromycin can achieve some criteria for asthma remission on treatment, at least in a subgroup of patients. Certainly, more research is needed, as remission is our ultimate goal.

Characterization of asthma by age of onset, a multi-database cohort study
Baan EJ, de Roos EW, Engelkes M et al
Journal of Allergy and Clinical Immunology: In Practice 2022; Preproof
https://doi.org/10.1016/j.jaip.2022.03.019

While the onset of asthma can occur at any age, the differences in patient characteristics between childhood-, adult-, and late-onset asthma are not well understood. Thus, in this study Baan and colleagues investigated patient characteristics by age at asthma onset, through mining European electronic data. They categorized patients based on their age at asthma onset: childhood-onset (age at onset < 18 years), adult-onset (age at onset 18-40 years) and late-onset asthma (age at onset >=40 years). Comorbidities were assessed at study entry. For each characteristic and comorbidity, odds ratios (OR) and age- and sex-adjusted OR(ORadj) comparing asthma onset categories were estimated per database and combined in a meta-analysis using a random effect model. They found that patients with adult onset compared to childhood-asthma had higher risk of being overweight/obese (ORadj 1.4, 95%CI 1.1- 1.8) and lower risk of having atopic disorders (ORadj 0.8, 95% CI 0.7-0.95). Patients with late-onset compared to adult-onset asthma had higher risk of nasal polyposis (ORadj 1.8, 95%CI 1.2-2.6), overweight/obesity (ORadj 1.3, 95%CI 1.2-1.4), gastro-oesophageal reflux disease (ORadj 1.4, 95%CI 1.2-1.7) and diabetes (ORadj 2.3, 95%CI 1.8-2.9). They also found a significant association between late-onset asthma and uncontrolled asthma (ORadj 2.8, 95%CI 1.7-4.5)). Overall, this study demonstrates clear differences in comorbidities between childhood-, adult-, and late-onset asthma phenotypes in adults.\

Short-acting β₂-agonist exposure and severe asthma exacerbations: SABINA findings from Europe and North America
Quint JK, Arnetorp S, Kocks JWH et al
Journal of Allergy and Clinical Immunology: In Practice 2022; Preproof
https://doi.org/10.1016/j.jaip.2022.02.047

Expert national/global asthma management recommendations raise the issue of whether a safe threshold exists of short-acting β2-agonist (SABA) use without concomitant inhaled corticosteroids (ICS). To answer this question, Quint and colleagues examined SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe via observational analyses of 10 SABa use IN Asthma (SABINA) datasets which included 1,033,564 patients (≥12 years) from around the world. They found that across severities, 40.2% of patients were prescribed/possessed ≥3 SABA canisters/year. Per GINA-2018 definitions, step 3‒5-treated patients prescribed/possessing ≥3 vs. 1‒2 SABA experienced more severe exacerbations (between 1.08 [1.04‒1.13], US-Medicare; 2.11 [1.96‒2.27], Poland). This association was not observed in all step 1‒2-treated patients (the Netherlands 1.25 [0.91‒1.71]; US-commercial 0.92 [0.91‒0.93]; US-Medicare 0.74 [0.71‒0.76]). The authors suggest that this inverse association between SABA and severe exacerbations in the US datasets was the large patient population possessing <3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face healthcare provider encounters. In US SABA monotherapy-treated patients, ≥3 SABA was associated with more emergency/outpatient visits and hospitalizations (1.31 [1.29‒1.34]). Most GINA 2‒5-treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of ≥3 SABA and severe exacerbations persisted (1.32 [1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when the UK SABA data was analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications. This study demonstrates that increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy and reinforces the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.

Characteristics of exogenous allergen in breast milk and their impact on oral tolerance induction
Kosmeri C, Rallis D, Kostara M et al
Frontiers in Pediatrics 2022; 830718 (4 March)
https://doi.org/10.3389/fped.2022.830718

In light of the rising prevalence of food allergies, many have focused on ways to diminish this trend – including the consideration of breast feeding as a modality to induce oral tolerance. This review summarized the evidence from experimental and human studies regarding allergen characterization of human breast milk that may influence oral tolerance induction. Studies demonstrate that the dose of antigen in human milk is in the range of nanograms/ml. The authors point out that the presence of antigen-specific immunoglobulins, forming immune complexes with antigens, has been reported to be more tolerogenic compared with free allergens. This articles also provides a great discussion regarding gaps in our present knowledge.

Food protein-induced enterocolitis syndrome: A large French multicentric experience
Lemoine A, Colas AS, Le S et al
Clinical and Translational Allergy 2022;12(2):312112 (17 February)
https://doi.org/10.1002/clt2.12112

There is concern that variability may exist regarding culprit foods, and age of tolerance in food protein-induced enterocolitis syndrome (FPIES) depending on the country of origin. In this study, the authors explore the characteristics of a French population of children with FPIES and define risk factors for failure during challenge through retrospective evaluation of children from two French pediatric tertiary centers with a diagnosis of FPIES (based on international consensus guidelines). In the 192 described FPIES patients, the age at first symptoms was 5.8 months old with the main offending foods being cow's milk (60.3%), hen's egg (16.2%), and fish (11.7%). Single FPIES was observed in 94.4% and multiple FPIES in 5.6% of cases. The age at resolution of FPIES was 2.2 years old, and resolution occurred later for fish than for milk (2.9 years vs. 2.0, p = 0.01). Severe acute FPIES was a risk factor for delayed resolution (RR: 3.3 [1.2–9.2]), but not IgE sensitization.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Systemic immunomodulatory treatments for atopic dermatitis: Update of a living systematic review and network meta-analysis
Drucker AM, Morra DE, Prieto-Merino D et al.
JAMA Dermatology 2022;158(5):532-532 (16 March)
https://doi.org/10.1001/jamadermatol.2022.0455

The purpose of the manuscript was to evaluate the comparative efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis through use of a network meta-analysis. The authors found that overall, abrocitinib (200 mg) and upadacitinib (30 mg daily) were associated with slightly better scores than dupilumab; and upadacitinib (15 mg daily) was associated with similar scores to dupilumab. Abrocitinib (100 mg daily), baricitinib (4 mg and 2 mg daily), and tralokinumab (300 mg) every 2 weeks were associated with slightly worse scores.

Personalized treatment of asthma: The importance of sex and gender differences
Jenkins CR, Boulet LP, Lavoie K et al
JACI: In Practice 2022;10(4):963-971.e3 (8 February)
https://doi.org/10.1016/j.jaip.2022.02.002

In this commentary, the authors explore the impact of an individual’s sex and gender influence on the clinical course of asthma in several ways. It is well known that more boys than girls have asthma, but after puberty, more women than men have asthma. The authors point out that despite the widely reported sex- and gender-based differences in asthma and asthma management, these issues are rarely considered by health care professionals. This review details the impact an individual’s sex and gender can have on the pathogenesis, clinical course, diagnosis, treatment, and management of asthma.

Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD)
Hyodo K, Masuko H, Oshimo H et al
PLoS One 2022;17(3):e0264397 (21 March)
https://doi.org/10.1371/journal.pone.0264397

It is well known that chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, the authors attempted to clarify the exacerbation-prone phenotypes beyond disease labels. This included investigating the role of the IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes. To do so, they examined a study population comprised of patients with asthma (n = 117), asthma-COPD overlap (ACO; n = 37) or COPD (n = 48), and a history of exacerbation within the previous year utilizing analyses. Two-step cluster analyses identified five clusters. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total IgE levels. A significant association with rs8832 was observed for cluster 5 (odds ratio, 3.88 (1.34–11.26), p = 0.013) and also for the type 2 exacerbation-prone phenotypes (clusters 1 and 5: odds ratio, 2.73 (1.45–5.15), p = 1.9 × 10−3. Overall, these data indicate that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the treatment of exacerbations of chronic inflammatory airway diseases.

Development of the cold urticaria activity score
Ahsan DM, Altrichter S, Gutsche A et al
Allergy 2022; Published online ahead of print (11 April)
https://doi.org/10.1111/all.15310

In this study, the authors share the development of the  ColdUAS , which is the first disease-specific PROM to assess ColdU disease activity. The ColdUAS, a self-administered questionnaire for the prospective assessment of disease activity in patients with ColdU, consists of 4 items: 1. the frequency and severity of the signs (wheals and/or angioedema), 2. the frequency and severity of the symptoms (e.g., itch and burn), 3. the exposure to specific triggers, and 4. the avoidance of these triggers. The recall period for each item is the last 24 h. The authors hope that through the use of this tool we can better assess patients' disease status in routine clinical practice as well as in clinical trials.

Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis:
A systematic review and network meta-analysis
Journal of Allergy and Clinical Immunology 2022;149(4):1286-1295 (17 September 2021)
https://doi.org/10.1016/j.jaci.2021.09.009

In this very interesting report by Oykhman and colleagues, the authors compared the relative efficacy of mAbs and aspirin desensitization (ASA-D) for treatment of CRSwNP through use of a network meta-analysis of sinusitis symptoms, heath-related quality of life, rescue oral corticosteroids and surgery, endoscopic and radiologic scores, and adverse events, utilizing the GRADE approach. They identified 29 randomized controlled trials evaluating 8 treatments (n =3461) which were included in their analysis, finding a moderate-to-high certainty evidence that health-related quality of life (SNOT-22) improved with dupilumab (mean difference [MD] -19.91 [95% confidence interval (CI) -22.50, -17.32]), omalizumab (MD -16.09 [95% CI -19.88, -12.30]), mepolizumab (MD -12.89 [95% CI -16.58, -9.19], ASA-D (MD -10.61 [95% CI -14.51, -6.71]), and benralizumab (MD -7.68 [95% CI -12.09, -3.27]). The risk of rescue nasal polyp surgery decreased with dupilumab (risk difference [RD] -16.35% [95% CI -18.13, -13.48]), omalizumab (RD -7.40% [95% CI -11.04, -2.43]), mepolizumab (RD -12.33% [95% CI -15.56, 27.22]), and ASA-D (RD -16.00% [95% CI -19.79, 0.21]; all moderate certainty). Overall, they found with moderate to high certainty that dupilumab ranks among the most beneficial for 7 of 7 outcomes, omalizumab for 2 of 7, mepolizumab for 1 of 7, and ASA-D for 1 of 7.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Cluster analysis of nasal cytokines during rhinovirus infection identifies different immunophenotypes in both children and adults with allergic asthma
Muehling LM, Heymann PW, Carper H et al.
Clinical & Experimental Allergy 2022; Published online ahead of print (16 May)
https://doi.org/10.1111/cea.14176

As is well known, infection with rhinovirus (RV) is a major risk factor for disease exacerbations in patients with allergic asthma. Thus, to better understand the pathophysiology occurring during exacerbation, the authors examined cytokines in the noses of children who were experimentally infected with RV in order to identify immunophenotypes that may link to virus-induced episodes. Through analysis of a core set of 7 cytokines (IL-6, CXCL8/IL-8, IL-15, EGF, G-CSF, CXCL10/IP-10 and CCL22/MDC) they found higher levels in children with acute wheeze versus those with stable asthma or controls. Multivariate analysis identified two clusters that were enriched for acutely wheezing children; one displaying high viral load (“RV high”) with robust secretion of CXCL10, and the other displaying high IgE with elevated EGF, CXCL8 and both eosinophil- and neutrophil-derived mediators. Broader assessment of 39 cytokines confirmed that children with acute wheeze were not deficient in type 1 anti-viral responses. Analysis of 18 nasal cytokines in adults with asthma who received RV challenge identified two clusters; one that was “RV-high” and linked to robust induction of anti-viral cytokines and anti-IgE; and the other associated with more severe symptoms and a higher inflammatory state featuring eosinophil and neutrophil factors. The authors note that these disparities in cytokine profiles may reflect the ability to regulate anti-viral responses.

Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes
Olaguibel JM, Sastre J, Rodríguez JM, Del Pozo V
Journal of Investigational Allergology and Clinical Immunology 2022;32(3):165-180
https://doi.org/10.18176/jiaci.0823

Hypereosinophilia has been observed in 4%-25% of patients treated with the IL-4/IL-13 pathway blocker dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. It should be noted that cases of EGPA have been reported with all biologics, including anti–IL-5 agents, and with leukotriene receptor antagonist. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti–IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti–IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. The authors note that blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/µL), in which case an anti–IL-5/IL-5R agent is preferable. The authors recommend that when switching from an anti–IL-5/5R to an anti–IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. The authors suggest that dual therapy with anti–IL-5/5R and anti–IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation.

Genetic Associations and Architecture of Asthma-COPD Overlap
John C, Guyatt AL, Shrine N, Packer R et al
Chest 2022;161(5):1155-1166 (28 January)
https://doi.org/10.1016/j.chest.2021.12.674

In trying to better understand asthma-COPD overlap, the authors examined the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma by performing a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank. They found eight novel signals (P < 5 x 10–8 ) for asthma-COPD overlap. The authors note that these signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. The authors suggest that these signals may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

The Multidimensional Burden of Atopic Dermatitis Among Adults: Results From a Large National Survey
Elsawi R, Dainty K, Smith Begolka W et al
JAMA Dermatology 2022; Published online (29 June)
https://doi.org/10.1001/jamadermatol.2022.1906

In this study, Elsawi and colleagues utilized multivariable ordinal regression analysis to assess associations between demographic and clinical variables and patient-reported overall atopic dermatitis (AD) impact through a survey of 1065 subjects of diverse age. Of the group, 489 (46%) participants reported low-moderate AD impact scores (2-3), 544 (51%) reported high-significant impact scores (4-5), whereas 32 (3%) reported no association of AD with disease. The authors found that variables strongly associated with overall impact scores were current AD severity (moderate: OR, 4.13; 95% CI, 2.94-5.79; severe: OR, 13.63; 95% CI, 8.65-21.50 vs mild), and time spent managing AD (11-20 hours: OR, 2.67; 95% CI, 1.77-4.03, >21 hours: OR, 5.34; 95% CI, 3.22-8.85, vs <5 hours).

Long-Term Natural History of Severe Asthma Exacerbations and Their Impact on the Disease Course
Lee TY, Petkau J, Sadatsafavi M
Annals of the American Thoracic Society 2022;19(6):907-915
https://doi.org/10.1513/AnnalsATS.202012-1562OC

To investigate the long-term natural history of asthma among patients who are hospitalized for asthma for the first time in terms of the risk of future severe exacerbations and heterogeneity in this risk across patients. Lee and colleagues mined the administrative health databases of British Columbia, Canada (January 1, 1997 to March 31, 2016), to create an incident cohort of patients with at least one asthma exacerbation that required inpatient care. Through this they estimated the 5-year cumulative incidence of severe exacerbations after successive numbers of previous events and employed a joint frailty model to investigate the extent of between-individual variability in exacerbation risk and the associations of each exacerbation with the rate of subsequent events. Analyses were conducted separately for pediatric (<14 years old) and adult (>14 years old) patients. This analysis included 3,039 pediatric (mean age at baseline, 6.4; 35% female) and 5,442 (mean age at baseline, 50.8; 68% female) adult patients. The 5-year rates of severe exacerbations after the first three events were 0.16, 0.29, and 0.35 for the pediatric group, and 0.14, 0.33, and 0.49 for the adult group. Both groups exhibited substantial variability in patient-specific risks of exacerbation: the mid-95% interval of 5-year risk of experiencing a severe exacerbation ranged from 11% to 24% in pediatric patients and from 8% to 40% in adult patients. After controlling for potential confounders, the first follow-up exacerbation was associated with an increase of 79% (95% confidence interval [CI], 11–189%) in the rate of subsequent events in the pediatric group, whereas this increase was 188% (95% CI, 35–515%) for the adult group. The authors conclude that after the first severe exacerbation, the risk of subsequent events is substantially different among patients and the number of previous severe exacerbations carries nuanced prognostic information about future risk.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Current and future strategies for the diagnosis and treatment of the Alpha-Gal Syndrome (AGS)
Vaz-Rodrigues R, Mazuecos L, de la Fuente J
Journal of Asthma and Allergy 2022;15:957-970 (18 July)
https://doi.org/10.2147/JAA.S265660

The α-Gal syndrome (AGS) is an immunoglobulin E (IgE)-mediated delayed anaphylaxis in foods containing the oligosaccharide galactose-α-1,3-galactose (α-Gal), including mammalian meat and dairy products. Clinical presentation of AGS can also comprise immediate hypersensitivity due to anticancer therapy, gelatin-containing vaccines, or mammalian serum-based antivenom. The initial IgE sensitization is caused by hard-bodied tick bites and symptomatic individuals typically develop delayed pruritus, urticaria, angioedema, anaphylaxis, malaise, or gut-related symptoms. As a consequence of the delayed reactions and a wide variety in patients’ clinical history, the AGS diagnosis and treatment remain challenging. This review covers not only current diagnostic methods in making the diagnosis, but also explores potentially relevant next-generation diagnostic tools, such as the mast cell activation test (MAT), the histamine- release (HR) assay, omics technologies, and model-based reasoning (MBR).

Long-term efficacy of the sublingual and subcutaneous routes in allergen immunotherapy
Penagos M, Durham SR
Allergy and Asthma Proceedings 2022;43(4):292-298 (1 July)
ttps://doi.org/10.2500/aap.2022.43.220026

Allergen immunotherapy is highly effective in selected patients with allergic rhinitis, allergic asthma, and Hymenoptera venom allergy. Unlike anti-allergic drugs, both subcutaneous and sublingual immunotherapies have been shown to modify the underlying cause of the disease, with proved long-term clinical benefits after treatment cessation. In this review, the authors examined 10 randomized, double-blind, placebo controlled clinical trials of allergen immunotherapy that included blinded follow-up for at least 1 year after treatment withdrawal. Three studies of pollen subcutaneous immunotherapy provided evidence that a sustained, tolerogenic effect of subcutaneous immunotherapy can be achieved after 3 years of treatment. Six trials of sublingual immunotherapy provided robust evidence for long-term clinical benefit and persistent immunologic changes after grass pollen, house-dust mite, or Japanese cedar immunotherapy; whereas, a clinical trial of both sublingual and subcutaneous grass pollen immunotherapies showed that 2 years of immunotherapy were efficacious, but insufficient to induce long-term tolerance. Overall, these studies strongly supported international guidelines that recommend at least 3 years of allergen immunotherapy to achieve disease modification and sustained clinical and immunologic tolerance.

Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
Reinke SN, Naz S, Chaleckis R, Gallart-Ayala H, Kolmert J et al
European Respiratory Journal 2022;59(6):2101733 (30 June)
https://doi.org/10.1183/13993003.01733-2021

Asthma is a heterogeneous disease with multiple, poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment such as OCS, may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. In this study, the authors aimed to identify dysregulated metabolic processes in relation to asthma severity and medication via measuring baseline urine prospectively from healthy participants (n=100), patients with mild to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analyzed using univariate and multivariate methods.

Metabolomics data were acquired using high-resolution mass spectrometry and analyzed using univariate and multivariate methods. The investigators identified 90 metabolites of which 40 significantly altered (p <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. It should be noted that this is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. The authors suggest that altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

A meta-analysis on randomized controlled trials of treating eosinophilic esophagitis with budesonide
Liu X, Xiao X, Liu D, Tan C
Annals of Medicine 2022;54(1):2078-2088 (21 July)
https://doi.org/10.1080/07853890.2022.2101689

Eosinophilic esophagitis (EoE) is a chronic, local immune-mediated inflammatory esophageal disease. Although Budesonide is recommended as one of the first-line drugs for EoE treatment, studies have shown inconsistent outcomes. In the study, the authors performed and updated a meta-analysis in which they retrieved 958 articles, of which 10 articles met inclusion criteria, yielding a sample size of 712 cases. The main outcome indicators of the meta-analysis were as follows: (1) Histological remission: the budesonide group performed better than the placebo control group when it came to histological remission of injuries [RR = 23.82, 95%CI = (13.46, 42.21), p < .001]; (2) Eosinophil count: the budesonide group was superior to the control group in terms of reduced eosinophil count [SMD = -1.34, 95%CI = (-1.52, -1.15), p < .001]. The authors conclude that overall, high-quality randomised controlled trials show that oral budesonide in the treatment of eosinophils esophagitis was better than placebo. While mounting high-quality RCTs have confirmed the efficacy of oral budesonide in the treatment of eosinophilic esophagitis, it should be noted that the effects of this drug may not be so dose-dependent. Furthermore, they found that it is safe to take budesonide for a prolonged period of time

Prevalence of sensitization to molecular food allergens in Europe: A systematic review
Lisik D, Ioannidou A, Spolidoro G, Ali M, Sungkutu N et al
Clinical and Translational Allergy 2022;12(7):e12175 (6 July)
https://doi.org/10.1002/clt2.12175

This review explores the sensitization to molecular food allergens, finding that overall, it is low, especially for primary sensitizers from the food, such as peanut storage proteins. The highest sensitization rates were seen in cross-reactive PR-10 proteins, for which birch pollen is known to be the primary sensitizer.  The authors conclude by noting that more population-representative studies are needed to better understand sensitization patters to molecular food allergens in Europe.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Respiratory syncytial virus prevention within reach: The vaccine and monoclonal antibody landscape
Mazur NI, Terstappen J, Baral R et al
The Lancet Infectious Diseases 2022;S1473-3099(22):00291-2
https://doi.org/10.1016/S1473-3099(22)00291-2

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. The authors of this review note that 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralizing antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. The authors note that an extended half-life monoclonal antibody for all infants is likely to be within one year of regulatory approval. Live-attenuated vaccines are in development for older infants (aged >6 months), while subunit vaccines are in late-stage trials for pregnant women to protect infants, vector, subunit, and nucleic acid approaches are being developed for older adults.

Microbiome, metabolism, and immunoregulation of asthma: An American Thoracic Society and National Institute of Allergy and Infectious Diseases Workshop Report
Kozik AJ, Holguin F, Segal LN et al
American Journal of Respiratory Cell and Molecular Biology 2022;67(2):155-163
https://doi.org/10.1165/rcmb.2022-0216ST

This report presents the proceedings from a jointly sponsor workshop (American Thoracic Society and National Institute of Allergy and Infectious Disease), titled “Microbiome, Metabolism and Immunoregulation of Asthma” that was held virtually May 13 and 14, 2021. This was an interdisciplinary group of experts with backgrounds in asthma immunology, microbiome science, metabolomics, computational biology, and translational pulmonary research. The main purpose of this panel was to identify key scientific gaps and needs to further advance research on microbial and metabolic mechanisms that may contribute to variable immune responses and disease heterogeneity in asthma. Discussions focused on several topics, including: 1) immune and microbial mechanisms of asthma pathogenesis in murine models, 2) the role of microbes in pediatric asthma exacerbations, 3) dysregulated metabolic pathways in asthma associated with obesity, 4) metabolism effects on macrophage function in adipose tissue and the lungs, 5) computational approaches to dissect microbiome–metabolite links, and 6) potential confounders of microbiome–disease associations in human studies. This report explored identification of specific knowledge gaps, challenges, and suggested directions for future research. These include questions surrounding mechanisms by which microbiota and metabolites shape host health versus an allergic or asthmatic state; direct and indirect influences of other biological factors, exposures, and comorbidities on these interactions; and ongoing technical and analytical gaps for clinical translation.

European guideline (EuroGuiDerm) on atopic eczema: Part I – systemic therapy
Wollenberg A, Kinberger M, Arents B et al
Journal of The European Academy of Dermatology and Venereology 2022;36(9):1409-1431
https://doi.org/10.1111/jdv.18345

This evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual resulting from four consensus conferences held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users, and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment used in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab, and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib). The second part of this guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant, and breastfeeding patients.

BSACI guideline for the diagnosis and management of pollen food syndrome in the UK
Skypala IJ, Hunter H, Krishna MT et al
Clinical & Experimental Allergy 2022;52(9):1018-1034
https://doi.org/10.1111/cea.14208

Pollen food syndrome (PFS) is a very prevalent food allergy affecting pollen-sensitized children and adults. Sufferers experience allergic symptoms when consuming raw plant foods, due to the homology between the pollen allergens and unstable proteins in these foods. The triggers involved can vary depending on the pollen sensitization, which in turn is affected by geographical location. The British Society of Allergy and Clinical Immunology (BSACI) Standards of Care Committee (SOCC) identified a need to develop a guideline for the diagnosis and management of PFS in the United Kingdom (UK). Guidelines produced by the BSACI use either the GRADE or SIGN methodology; but, due to a lack of high-quality evidence these recommendations were formulated using the SIGN guidelines, which is acknowledged to be less robust than the GRADE approach.

The authors stress that the correct diagnosis of PFS ensures the avoidance of a misdiagnosis of a primary food allergy, such as peanut or tree nut allergy or confusion with another plant food allergy to non-specific lipid transfer proteins. The characteristic foods involved, and rapid-onset oropharyngeal symptoms, means that PFS can often be diagnosed from the clinical history alone. However, reactions involving tree nuts, peanuts and soya milk or severe/atypical reactions to fruits and vegetables may require additional diagnostic tests. Management of this illness involves avoidance of known trigger foods, which may appear to be simple, but can be highly problematic if coupled with a pre-existing food allergy or for individuals following a vegetarian/vegan diet. The authors note that immunotherapy to pollens is not an effective treatment for PFS, and although oral or sublingual immunotherapy to foods seems more promising, large, controlled studies are needed before these therapies can be recommended for this illness. While the typically mild symptoms of PFS can lead to an erroneous perception that this condition is always easily managed, it should be noted that severe reactions can occur, and anxiety about the onset of symptoms to new foods can have a profound effect on patients’ quality of life.

Allergic and eosinophilic asthma in the era of biomarkers and biologics: Similarities, differences and misconceptions
Oppenheimer J, Hoyte FCL, Phipatanakul W et al
Annals of Allergy Asthma & Immunology 2022;129(2):169-180
https://doi.org/10.1016/j.anai.2022.02.021

Severe asthma is associated with substantial personal and economic burden; maintaining disease control is the key management goal. Increased understanding of asthma heterogeneity and development of type 2 (T2)-targeting biologics has substantially advanced disease management and outcomes; however, despite both being driven by T2 inflammation, allergic and eosinophilic asthma have different treatment recommendations. In this review, the authors examine the literature regarding similarities and differences between allergic and eosinophilic asthma and highlight where misconceptions may arise. The authors note that severe allergic and eosinophilic asthma are both driven by T2 inflammation with eosinophils playing a cardinal role. Despite this overlap, treatment recommendations differ based on asthma classification. T2 cytokine gene expression is a reasonably well-established research tool, but not a well-established biomarker in clinical practice, unlike blood eosinophil counts, fractional exhaled nitric oxide, and IgE; the clinical relevance of IgE as a predictive biomarker remains unclear. Asthma classifications that can be easily characterized at the patient level to ensure accurate diagnosis, predict disease trajectory, and treatment response are required. The authors suggest that the current dichotomy of allergic and eosinophilic asthma classifications is likely too simplistic, given the similar eosinophil-mediated disease pathophysiology in both classifications and better understanding may aid in defining responders more precisely with personalized medicine approaches.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

T2-high asthma phenotypes across lifespan
Maison N, Omony J, Illi S et al
European Respiratory Journal 2022;60(3):2102288
https://doi.org/10.1183/13993003.02288-2021

While it is common practice in adults to personalise asthma treatment based upon T2 phenotypes, it is unclear whether such classification is achievable in children. The purpose of this study was to define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages by examining the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls). In this study extensive clinical characterisation (questionnaires, blood differential count, allergy testing, and lung function and sputum induction [in adults]) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28.

Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood.

Overall, the study demonstrates that through easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype and potentially these patients may benefit from therapy with biologicals even at a young age.

Association between aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months
Daley MF, Reifler LM, Glanz JM et al
Academic Pediatrics 2022;In press (28 September)
https://doi.org/10.1016/j.acap.2022.08.006

In this study by Daley and colleagues the authors examined the association between exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months via a retrospective cohort study conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The authors defined asthma as 1 inpatient or 2 outpatient asthma encounters, and ≥2 long-term asthma control medication dispenses.

The cohort examined included 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum exposure was 4.07 mg (SD 0.60) and 3.98 mg (SD 0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25).  Overall, they demonstrated that a positive association was found between vaccine-related aluminum exposure and persistent asthma. The authors note the small effect sizes identified and the potential for residual confounding require additional study for validation.

Are blood cytokines reliable biomarkers of allergic disease diagnosis and treatment responses?
Radonjic-Hoesli S, Pavolv N, Simon HU, Simon D
Journal of Allergy and Clinical Immunology 2022;150(2):251-258
https://doi.org/10.1016/j.jaci.2022.06.008

The development of targeted therapies for allergic diseases reinforces the need for biomarkers supporting disease diagnosis and management has increased. In this review article, the authors critically examine the literature regarding the use of cytokine measurements in association with disease diagnosis and management. The authors note that among the variety of potential cytokines, thymus and activation-regulated chemokine stands out and can indeed serve as a biomarker of atopic dermatitis. Unfortunately, both biologic characteristics and technical issues determine the reliability and limit the use of blood cytokines as biomarkers.

Reduced miR-146a-5p is a Biomarker of Infant Respiratory Diseases Contributing to Immune Dysregulation in Small Airway Epithelial Cells
Rodrigo-Muñoz JM, Gil-Martínez M, Lorente-Sorolla C et al
Cells 2022;11(17):2746 (2 September)
https://doi.org/10.3390/cells11172746

Respiratory diseases such as bronchiolitis, and wheezing episodes, are highly important during infancy due to their potential chronicity. Immune response dysregulation is critical in perpetuating lung damage. Epigenetic modifications including microRNA (miRNA) post-transcriptional regulation are among the factors involved in alleviating inflammation. In this study Rodrigo-Muñoz and colleagues evaluated the expression of miR-146a-5p in order to study epigenetic regulation of the immune response. miR-146a-5p has previously been described as a negative regulator of immunity, in infants with respiratory diseases. To do so, they examined nasopharyngeal aspirate (NPA) obtained from infants with bronchiolitis (ongoing and post-disease) or with wheezing episodes in addition to healthy controls. Virus presence was determined by nested PCR, while miRNA and gene expression were studied in cells from NPAs using qPCR. Healthy small airway epithelial cells (SAECs) were used as an in vitro model. We observe a reduction in miR-146a-5p expression in infants with either of the two diseases compared to controls, suggesting the potential of this miRNA as a disease biomarker. Post-bronchiolitis, miR-146a-5p expression was found to increase, though without reaching levels of healthy controls. MiR-146a-5p expression correlates inversely with the immune-related gene PTGS2, while its expression correlates directly with TSLP. In heathy donor when SAECs are stimulated by poly:IC, the authors found an increase in miR-146a-5p, with wounds having a synergistic effect.  Overall, this indicates that infants with respiratory diseases present reduced miR-146a-5p expression, which possibly affects immune dysregulation.

A clinician's guide for administration of high-concentration and facilitated subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency diseases
Epland K, Suez D, Paris K
Allergy Asthma & Clinical Immunology 2022/18(1):87 (30 September)
https://doi.org/10.1186/s13223-022-00726-7

Immunoglobulin replacement therapy is the standard-of-care treatment for patients with primary immunodeficiency diseases who have impaired antibody production and function. Clinicians and patients have the option of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG), with each route offering different potential benefits. The authors of this practical review note that IVIG requires fewer infusion sites and less frequent infusions than some formulations of SCIG. However, SCIG does not require venous access, is associated with fewer systemic adverse infusion reactions than IVIG, and can independently be self-administered at home. The authors stress the importance of tailoring treatment experiences to the needs of the individual may improve treatment adherence and quality of life for patients with primary immunodeficiency diseases.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Allergen immunotherapy: Past, present and future
Durham SR, Shamji MH
Nature Reviews Immunology 2022 (17 October)
https://doi.org/10.1038/s41577-022-00786-1

This is an excellent review on allergy immunotherapy by Drs Durham and Shamji. The authors begin from its origin reviewing subcutaneous immunotherapy and then explore sublingual immunotherapy for aeroallergy, noting its better safety profile, even discussing oral immunotherapy for peanut. They then explore recent research examining the mechanisms underlying immunotherapy-induced tolerance, which includes reduction of allergen-specific T helper 2 (TH2) cells, an induction of regulatory T and B cells, and production of IgG and IgA “blocking” antibodies. To better harness these mechanisms, novel strategies are being explored to achieve safer, effective, more convenient regimens and more durable long-term tolerance; these include: alternative routes for current immunotherapy approaches, novel adjuvants, use of recombinant allergens (including hypoallergenic variants) and combination of allergens with immune modifiers or monoclonal antibodies targeting the TH2 cell pathway.

Clinical indicators for asthma-COPD overlap: A systematic review and meta-analysis
Peng J, Wang M, Wu Y, Shen Y, Chen L
International Journal of Chronic Obstructive Pulmonary Disease 2022;17: 2567—2575
https://doi.org/10.2147/COPD.S374079

Some clinical indicators have been reported to be useful in differentiating asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) from pure asthma/COPD, but the results have been inconsistent. Thus, the aim of this study was to evaluate the diagnostic value of these indicators for ACO by performing a systematic review of the literature. The authors identified 48 eligible studies and the pooled results indicated that compared with pure asthma, ACO patients had lower levels of forced expiratory volume in the first second (FEV1)% predicted (pred) (SMD=−1.09, 95% CI −1.3 to −0.87), diffusion lung capacity for carbon monoxide (DLCO)% pred (SMD=−0.83, 95% CI −1.24 to −0.42), fractional exhaled nitric oxide (FeNO) (SMD=−0.23, 95% CI −0.36 to −0.11), and higher levels of induced sputum neutrophil (SMD = 0.51, 95% CI 0.21 to 0.81), circulating YKL-40 (SMD = 0.96, 95% CI 0.27 to 1.64). However, relative to COPD alone, ACO patients had higher levels of FEV1% pred (SMD = 0.15, 95% CI 0.05 to 0.26), DLCO% pred (SMD = 0.38, 95% CI 0.16 to 0.6), FeNO (SMD = 0.59, 95% CI 0.40 to 0.78), serum total immunoglobulin (Ig)E (SMD = 0.42, 95% CI 0.1 to 0.75), blood eosinophil (SMD = 0.44, 95% CI 0.29 to 0.59), induced sputum eosinophil (SMD = 0.62, 95% CI 0.42 to 0.83), and lower levels of induced sputum neutrophil (SMD=−0.48, 95% CI −0.7 to −0.27), circulating YKL-40 (SMD=−1.09, 95% CI −1.92 to −0.26). They concluded that via these indicators one could differentiate ACO from pure asthma/COPD.

Ever and cumulative occupational exposure and lung function decline in longitudinal population-based studies: A systematic review and meta-analysis
Rabbani G, Nimmi N, Benke GP et al
Occupational & Environmental Medicine 2022; Published online before print (24 October)
https://doi.org/10.1136/oemed-2022-108237

It is well known that adverse occupational exposures can accelerate age-related lung function decline. The aim of this study was to examine this association using findings reported by longitudinal population-based studies. The authors found that ever exposures to gases/fumes, vapors, gases, dusts, fumes (VGDF) and aromatic solvents were significantly associated with FEV1 decline in meta-analyses. Cumulative exposures for these three occupational agents observed a similar trend of FEV1 decline. Ever exposures to fungicides and cumulative exposures to biological dust, as well as fungicides and insecticides were associated with FEV1 decline in fixed-effect models only; while, no statistically significant association was observed between mineral dust, herbicides and metals and FEV1 decline in this meta-analyses. Overall, these pooled estimates from the longitudinal population-based studies have provided evidence that occupational exposures are associated with FEV1 decline. The authors conclude that specific exposure control and respiratory health surveillance are required to protect the lung health of the workers.

Dog ownership in infancy is protective for persistent wheeze in 17q21 asthma-risk carriers
Tutino M, Granell R, Curtin JA et al
Journal of Allergy & Clinical Immunology 2022; Published online ahead of print (20 October)
https://doi.org/10.1016/j.jaci.2022.10.012

As noted by the authors asthma-associated SNPs from large GWAS studies only explain a fraction of genetic heritability. Potential causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.

The aim of this study was to examine the association of GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze. Wheezing classes derived from five UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. 9149 children had both pet ownership and genotype data available. From this, the authors found that the rs2305480 G allele was associated with increased risk of Persistent Wheeze (additive model OR=1.37; CI=1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. Furthermore, they found significant evidence of a GxE interaction between rs2305480 and dog ownership (P=8.3e-4) on Persistent Wheeze; amongst dog owners the G allele was no longer associated with an increased risk of Persistent Wheeze (additive model OR=0.95; CI=0.73-1.24). For those without pets, G allele was associated with increased risk of Persistent Wheeze (OR=1.61; CI=1.40-1.86). Among cat owners no such dampening of the genetic effect was observed.

Targeting B cells and plasma cells in autoimmune diseases: From established treatments to novel therapeutic approaches
Merino-Vico A, Frazzei G, van Hamburg JP, Tas SW
European Journal of Immunology 2022; Published online ahead of print (31 October)
https://doi.org/10.1002/eji.202149675 or https://pubmed.ncbi.nlm.nih.gov/36314264/

In this review article the authors provide an overview of novel strategies to target B lineage cells in autoimmune diseases, with the focus on rheumatic diseases. Both advanced therapies, that have recently become available, and more experimental treatments that may reach the clinic in the near future, are discussed.

Autoimmune diseases are characterized by the recognition of self-antigens by the immune system, which leads to inflammation and tissue damage. B cells are directly and indirectly involved in the pathophysiology of autoimmunity, both via antigen-presentation to T cells and production of proinflammatory cytokines and/or autoantibodies. Consequently, B lineage cells have been identified as therapeutic targets in autoimmune diseases. B cell depleting strategies have proven beneficial in the treatment of rheumatoid arthritis (RA), systemic lupus erythematous (SLE), ANCA-associated vasculitis (AAV), multiple sclerosis (MS), and a wide range of other immune-mediated inflammatory diseases (IMIDs). However, not all patients respond to treatment or may not reach (drug-free) remission. Moreover, B cell depleting therapies do not always target all B cell subsets, such as short-lived and long-lived plasma cells. The authors stress that these cells play an active role in autoimmunity and in certain diseases their depletion would be beneficial to achieve disease remission.

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Improving antimicrobial stewardship with penicillin allergy testing: A review of current practices and unmet needs
Mabilat C, Gros MF, Van Belkum A et al
JAC – Antimicrobial Resistance 2022;4(6):dlac116 (19 November)
https://doi.org/10.1093/jacamr/dlac116

Penicillin allergy, the most frequently reported drug allergy, has been associated with suboptimal antibiotic therapy, resulting in increased antimicrobial resistance, increased rates of Clostridioides difficile colonization and infection, as well as extended hospital length of stay and overall increased cost. Although up to 10% of all patients may report penicillin allergy, most penicillin allergies are not confirmed. In essence, most patients with a penicillin allergy can still safely use penicillin and related drugs following a more precise assessment. In this review authors explore the current practices and unmet needs in penicillin allergy testing. The diagnostic algorithm is mostly based on a clinical history assessment followed by in vivo testing, i.e., skin test, and/or drug challenge. As these tests are labor/ resource intensive, there is increased interest in point-of care penicillin allergy de-labelling solutions incorporated into Antimicrobial Stewardship Programs including digital assessment tools. As noted by the authors, reducing residual risk remains essential and in vivo drug challenge and/or skin testing should be systematically encouraged. Gradual understanding and convergence of the risk stratification of the clinical presentation of penicillin allergy is enabling a wider implementation of this essential aspect of antimicrobial stewardship through digitalized decision tools and in vivo testing. As noted by the authors, further research is needed to deliver point of care in vitro diagnostic tools to democratize this de-labelling practice, which would be highly beneficial to patient care.

Monitoring of molecular profiling of allergen-antibody responses in HDM-immunotherapy patients
Nittner-Marszalaka M, Kopeć A, Foks-Ciekalska A, et al
Human Vaccines & Immunotherapeutics 2022; Published online ahead of print (29 November)
https://doi.org/10.1080/21645515.2022.2148815
https://www.tandfonline.com/doi/full/10.1080/21645515.2022.2148815

Among the potential hazards of house dust mite (HDM) immunotherapy (AIT) with HDM allergenic extracts is the possible initiation of de novo sensitizations caused by a lack of complementarity between a given HDM vaccine’s content and a patient’s molecular sensitization profile. The aim was to investigate whether immunotherapy with HDM extracts affects changes in the profile of sensitizations to allergens contained within the extract and whether neo sensitizations occur. Serum samples from patients with HDM allergies (N=63) who received 1 year of treatment with subcutaneous AIT were tested for allergen-specific IgE (sIgE) reactivity to 7 microarrayed HDM allergen molecules (Der p 1, 2,10,11,23; D far 1 and 2) with ImmunoCAP. The HDM non-AIT patients (N=22), who did not receive immunotherapy constituted the study’s control group with data analyzed at baseline and after 6 and 12 months. In the HDM-AIT group, no neo sensitizations after 6 and 12 months of immunotherapy were reported, while in the HDM non-AIT group, only neo sensitizations to Der p 10 were observed. In the study group, sIgE levels against the HDM extract of D. pteronyssinus, D. farinae, rDer p 1, rDer p 2, and Der f 2 decreased after 12 months of AIT (p< .05). SIgE levels against Der f 1, Der p 10, 11 and 23 remained unchanged in the course of 12 months of immunotherapy. Furthermore, in patients with allergic rhinitis with or without concomitant HDM-induced asthma treated with HDM AIT for 12 months, no neo sensitizations related to the examined HDM molecules were observed.

A confluence of advanced treatment options for atopic dermatitis, eosinophilic lung diseases and chronic urticarial brought about by the revolutionary discovery of biologics and Janus kinase inhibitors
Bellanti JA, Settipane RA
Allergy and Asthma Proceedings 2022;43(6):471-473
https://doi.org/10.2500/aap.2022.43.220081

In this editorial Drs. Bellanti and Settipane highlight the most recent issue of Allergy and Asthma Proceedings which explored the complexities of asthma, COVID-19, monkeypox, hereditary angioedema, pet allergies, food allergy, eosinophilic lung disease, chronic urticaria, anaphylaxis, contact dermatitis, and atopic dermatitis with practical information focused on aiding the practicing allergist.

Higher risk for influenza-associated pulmonary aspergillosis (IAPA) in asthmatic patients: A Swiss multicenter cohort study on IAPA in critically ill influenza patients
Waldeck F, Boroli F, Zingg S et al
Influenza and Other Respiratory Viruses 2022; Published online ahead of print (16 November)
https://doi.org/10.1111/irv.13059
https://onlinelibrary.wiley.com/doi/10.1111/irv.13059

Influenza-associated pulmonary aspergillosis (IAPA) is an important complication of severe influenza with associated high morbidity and mortality. To better understand this association, the authors performed a retrospective multicenter study in tertiary hospitals in Switzerland during 2017/2018 and 2019/2020 influenza seasons. All adults with PCR-confirmed influenza infection and treatment in the intensive-care unit (ICU) for >24 h were included. IAPA was diagnosed according to previously published clinical, radiological, and microbiological criteria. From this data, the authors explored risk factors for IAPA and predictors for poor outcome, which was a composite of in-hospital mortality, ICU length of stay ≥7 days, mechanical ventilation ≥7 days, or extracorporeal membrane oxygenation. They found that asthma was more common in IAPA patients (17% vs. 4% in non-IAPA, P = 0.05). Asthma (OR 12.0 [95% CI 2.1–67.2]) and days of mechanical ventilation (OR 1.1 [1.1–1.2]) were associated with IAPA. IAPA patients frequently required organ supportive therapies including mechanical ventilation (88% in IAPA vs. 53% in non-IAPA, P = 0.001) and vasoactive support (75% vs. 45%, P = 0.03) and had more complications including ARDS (53% vs. 26%, P = 0.04), respiratory bacterial infections (65% vs. 37%, P = 0.04), and higher ICU-mortality (35% vs. 16.4%, P = 0.05). IAPA (OR 28.8 [3.3–253.4]), influenza A (OR 3.3 [1.4–7.8]), and higher SAPS II score (OR 1.07 [1.05–1.10]) were independent predictors of poor outcome. Overall, this data suggest that high clinical suspicion, early diagnostics, and therapy are indicated in IAPA because of high morbidity and mortality and that asthma is likely an underappreciated risk factor for IAPA.

As-needed intranasal corticosteroid spray for allergic rhinitis: A systematic review and meta-analysis
Hoang MP, Chitsuthipakorn W, Seresirikachorn K, Snidvongs K
Rhinology 2022;60(4):242-251
https://doi.org/10.4193/Rhin21.355

As-needed intranasal corticosteroid spray (INCS) is commonly used by patients with allergic rhinitis (AR) who have suboptimal symptom control. Thus far, several small studies have demonstrated somewhat conflicting results, thus this systematic review aimed to assess the effectiveness of as-needed INCS for treating AR with primary outcomes being total nasal symptom score (TNSS) and disease-specific quality of life (DSQoL). Through analysis of the 8 studies (882 participants) that met the criteria the authors found that regular use of INCS showed greater improvements than as-needed INCS in TNSS, DSQoL, nasal peak inspiratory flow, sneezing, and nasal congestion scores with small effect sizes. There were, however, no differences between regular and as-needed INCS usage for ocular symptoms, symptom-free days, nasal itching, and rhinorrhea scores. As-needed INCS was superior to as-needed antihistamine and placebo with medium effect sizes. There were no differences in risk of adverse events between the groups in all three comparisons. Overall, the study demonstrated that regular use of INCS improved total nasal symptoms score and DSQoL better than as-needed INCS. However, as-needed INCS improved TNSS better than as-needed antihistamine and placebo, while the effects of as-needed INCS were closer to regular INCS usage than to placebo or as-needed AH use.