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Newsworthy Articles

Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis

Authors: Shona Cameron, Ali Donnelly, Conor Broderick, Tomoki Arichi, Ullrich Bartsch, Paola Dazzan, Jesper Elbeling, Emma Godfrey, Paul Gringras, Lauren C. Heathcote, Desaline Joseph, Tobias C. Wood, Carmine Pariante, Katya Rubia, Carsten Flohr

Abstract: Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD.

Standardization of clinical outcomes used in allergen immunotherapy in allergic asthma: An EAACI position paper

Authors: Jasper Kappen, Zuzana Diamant, Ioana Agache, Matteo Bonini, Jean Bousquet, G. Walter Canonica, Stephen R. Durham, George V. Guibas, Eckard Hamelmann, Marek Jutel, Nikolaos G. Papadopoulos, Graham Roberts, Mohamed H. Shamji, Petra Zieglmayer, Roy Gerth van Wijk, Oliver Pfaar

Introduction: In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma.
Methods: The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers.
Results: Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP.
Conclusion: This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT.

Decoding the genetic and epigenetic basis of asthma

Authors: Bernard S. Stikker, Rudi W. Hendriks, Ralph Stadhouders

Abstract: Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility is strongly influenced by genetics. Given its high prevalence and our incomplete understanding of the mechanisms underlying disease susceptibility, asthma is frequently studied in genome-wide association studies (GWAS), which have identified thousands of genetic variants associated with asthma development. Virtually all these genetic variants reside in non-coding genomic regions, which has obscured the functional impact of asthma-associated variants and their translation into disease-relevant mechanisms. Recent advances in genomics technology and epigenetics now offer methods to link genetic variants to gene regulatory elements embedded within non-coding regions, which have started to unravel the molecular mechanisms underlying the complex (epi)genetics of asthma. Here, we provide an integrated overview of (epi)genetic variants associated with asthma, focusing on efforts to link these disease associations to biological insight into asthma pathophysiology using state-of-the-art genomics methodology. Finally, we provide a perspective as to how decoding the genetic and epigenetic basis of asthma has the potential to transform clinical management of asthma and to predict the risk of asthma development.

A concept for integrated care pathways for atopic dermatitis—A GA2LEN ADCARE initiative

Authors: Torsten Zuberbier, Amir Abdul Latiff, Xenofon Aggelidis, Matthias Augustin, Radu-Gheorghe Balan, Christine Bangert, Lisa Beck, Thomas Bieber, Jonathan A. Bernstein1, Marta Bertolin Colilla, Alejandro Berardi1, Anna Bedbrook1, Carsten Bindslev-Jensen, Jean Bousquet, Marjolein de Bruin-Weller, Dayanne Bruscky, Betul Buyuktiryaki, Giorgio Walter Canonica, Carla Castro, Natia Chanturidze, Herberto Jose Chong-Neto, Chia-Yu Chu, Leena Chularojanamontri, Michael Cork, Roberta F. J. Criado, Laia Curto Barredo, Adnan Custovic, Ulf Darsow, Arben Emurlai, Ana de Pablo, Stefano Del Giacco, Giampiero Girolomoni, Tanja Deleva Jovanova, Mette Deleuran, Nikolaos Douladiris, Bruno Duarte, Ruta Dubakiene, Esben Eller, Batya Engel-Yeger, Luis Felipe Ensina, Nelson Rosario Filho, Carsten Flohr, Daria Fomina, Wojciech Francuzik, Maria Laura Galimberti, Ana M. Giménez-Arnau, Kiran Godse, Charlotte Gotthard Mortz, Maia Gotua, Michihiro Hide, Wolfram Hoetzenecker, Nicolas Hunzelmann, Alan Irvine Carolyn Jack, Ioanna Kanavarou, Norito Katoh, Tamar Kinaciyan, Emek Kocatürk, Kanokvalai Kulthanan, Hilde Lapeere, Susanne Lau, Mariana Machado Forti Nastri, Michael Makris, Eli Mansour, Alexander Marsland, Mara Morelo Rocha Felix Ana Paula Moschione Castro, Eustachio Nettis J. F. Nicolas Audrey Nosbaum, Mikaela Odemyr, Niki Papapostolou, Claudio A. S. Parisi, Sushil Paude, Jonny Peter, Prakash Pokharel, Luis Puig, Tamara Quint, German Dario Ramon Frederico Regateiro Giampaolo Ricci, Cristine Rosario Cansin Sackesen Peter Schmid-Grendelmeier, Esther Serra-Baldrich, Kristina Siemens, Cathrine Smith, Petra Staubach, Katarina Stevanovic, Özlem Su-Kücük, Gordon Sussman, Simona Tavecchio Natasa Teovska Mitrevska, Diamant Thaci, Elias Toubi,Claudia Traidl-Hoffmann, Regina Treudler, Zahava Vadasz, Ingrid van Hofman, Maria Teresa Ventura, Zhao Wang, Thomas Werfe, Andreas Wollenberg, Ariana Yang, Yik Weng Yew, Zuotao Zhao, Ricardo Zwiener, Margitta Worm

Introduction: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems.
Methods: The GA2LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2EN ADCARE centres.
Results: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD.
Conclusion: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.

Atopic outcomes at 2 years in the CORAL cohort, born in COVID-19 lockdown

Authors: Sadhbh Hurley, Ruth Franklin, Naomi McCallion, Aideen M. Byrne, John Fitzsimons, Martin White, Liam O'Mahony, Jonathan O'B. Hourihane

Introduction: The CORAL study is a cohort of infants born during the first weeks of the first SARS-CoV-2 (COVID-19) lockdown. This cohort has had lower antibiotic exposure, higher breastfeeding rates and lower infection rates, especially in the first year of life. We hypothesized that the altered early-life environment of infants born during lockdown would change the incidence of allergic conditions.
Methods: This longitudinal, observational study followed 365 infants born between March and May 2020 from enrolment to the age of 2 years. Infants attended three research appointments at 6-, 12-, and 24-months and completed detailed questionnaires. At research appointments, children had skin prick testing, and atopic dermatitis (AD) assessment. Statistical analysis focused on changes within the group at different time points, the influence of specific environmental factors on allergic risk and compared the incidence of atopic conditions with a pre-pandemic Irish infant cohort, BASELINE.
Results: AD was more common in CORAL group at both 12 (26.5% vs. 15.5%; p < .001) and 24 months (21.3% vs. 15.9%; p = .02) compared with pre-pandemic BASELINE cohort. Within the CORAL group, those with AD at both 12-and 24-month appointments had a more severe AD phenotype associated with a higher risk of allergic sensitization. There was less milk (0% vs. 1%; p = .09), peanut (0.6% vs. 1.8%; p = .3), and egg allergy (0% vs. 2.9%; p < .001) in the CORAL group at 24 months compared with the BASELINE cohort. Aeroallergen sensitization increased between 12 and 24 months in the CORAL cohort (1.5% vs. 8.9%; p < .001), as did parent-reported wheezing episodes (9% vs. 24%; p < .001).
Conclusions: Despite higher AD incidence in the CORAL cohort, the incidence of food sensitization and allergy are lower than expected pre-pandemic rates possibly reflecting the early introduction and maintenance of dietary allergens enhanced by changes in infant infections, antibiotic use, and breastfeeding in the first 2 years of life in the group. These beneficial effects of the lockdown could be outweighing the expected risk of less early-life microbial encounters outlined by the hygiene hypothesis.

Autoreactive IgE: Pathogenic role and therapeutic target in autoimmune diseases

Authors: Nicolas Charles, Inge Kortekaas-Krohn, Emek Kocaturk, Jörg Scheffel, Sabine Altrichter, Carolin Steinert, Yi-Kui Xiang, Jan Gutermuth, Laurent L. Reber, Marcus Maurer

Abstract: Autoimmunity is the break of tolerance to self-antigens that leads to organ-specific or systemic diseases often characterized by the presence of pathogenic autoreactive antibodies (AAb) produced by plasmablast and/or plasma cells. AAb are prevalent in the general population and not systematically associated with clinical symptoms. In contrast, in some individuals, these AAb are pathogenic and drive the development of signs and symptoms of antibody-mediated autoimmune diseases (AbAID). AAb production, isotype profiles, and glycosylations are promoted by pro-inflammatory triggers linked to genetic, environmental, and hormonal parameters. Recent evidence supports a role for pathogenic AAb of the IgE isotype in a number of AbAID. Autoreactive IgE can drive the activation of mast cells, basophils, and other types of FcεRI-bearing cells and may play a role in promoting autoantibody production and other pro-inflammatory pathways. In this review, we discuss the current knowledge on the pathogenicity of autoreactive IgE in AbAID and their status as therapeutic targets. We also highlight unresolved issues including the need for assays that reproducibly quantify IgE AAbs, to validate their diagnostic and prognostic value, and to further study their pathophysiological contributions to AbAID.

Perinatal exposure to foodborne inorganic nanoparticles: A role in the susceptibility to food allergy?

Authors: Mohammad Issa, Gilles Rivière, Eric Houdeau and Karine Adel-Patient

Abstract: Food allergy (FA) is an inappropriate immune response against dietary antigens. Various environmental factors during perinatal life may alter the establishment of intestinal homeostasis, thereby predisposing individuals to the development of such immune-related diseases. Among these factors, recent studies have emphasized the chronic dietary exposure of the mother to foodborne inorganic nanoparticles (NP) such as nano-sized silicon dioxide (SiO2), titanium dioxide (TiO2) or silver (Ag). Indeed, there is growing evidence that these inorganic agents, used as food additives in various products, as processing aids during food manufacturing or in food contact materials, can cross the placental barrier and reach the developing fetus. Excretion in milk is also suggested, hence continuing to expose the neonate during a critical window of susceptibility. Due to their immunotoxical and biocidal properties, such exposure may disrupt the host-intestinal microbiota’s beneficial exchanges and may interfere with intestinal barrier and gut-associated immune system development in fetuses then the neonates. The resulting dysregulated intestinal homeostasis in the infant may significantly impede the induction of oral tolerance, a crucial process of immune unresponsiveness to food antigens. The current review focuses on the possible impacts of perinatal exposure to foodborne NP during pregnancy and early life on the susceptibility to developing FA.

On failure, trust and our common humanity.

Authors: Professor Elmi Muller

Abstract: A few weeks ago, a patient came to see me. He had received a transplant from his sister in 2017 and the kidney failed in 2022. I had done the transplant. He told me that his graft never really functioned properly. According to him, this was most likely the result of how I did his surgery in 2017. Now he was coming for a second transplant – a kidney donated by his wife. He was meeting me to tell me that he didn’t want me to be involved in his transplant, although he was worked up for this procedure by people in my practice and in my team.

A few months ago, I transplanted a patient with a donor kidney from a friend. The day after the transplant the patient developed a very low blood pressure and a few hours later the patient died. We were not sure what had happened – if he had a myocardial infarction, had sepsis or was bleeding. Whatever it was that happened – the outcome was dismal.

Why am I telling you these stories of failure and difficulty on an evening where you want to celebrate your new qualification and success?

The answer is that failure explicates. In other words, failure makes us analyse our life events in more detail.

The increasing burden of asthma in South African children: A call to action

Authors: R Masekela, C L Gray, R J Green, A I Manjra, M Clin Pharm; F E Kritzinger, M Levin, H Zar, on behalf of the South African Childhood Asthma Working Group

Background: Asthma is a heterogeneous condition characterised by chronic inflammation and variable expiratory airflow limitation, as well as airway reversibility. The burden of asthma in children is increasing in low- and middle-income countries and remains underrecognised and poorly managed.
Objectives: To quantify the burden of asthma in the South African (SA) population and identify the risk factors associated with disease severity in the local context.
Methods: The SA Childhood Asthma Working Group (SACAWG) convened in January 2017 with task groups, each headed by a section leader, constituting the editorial committee on assessment of asthma epidemiology, diagnosis, control, treatments, novel treatments and self-management plans. The epidemiology task group reviewed the available scientific literature and assigned evidence according to the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system.
Conclusions: Asthma in children remains a common condition, which has shown an increasing prevalence in urban and rural populations of SA. Of concern is that almost half of children in urban communities experience severe asthma symptoms, and many asthmatics lack a formal diagnosis and thus access to treatment. Exposure to tobacco smoke and living in highly polluted areas increase the severity of wheezing in young children.

Looking beyond the magic bullet: Novel asthma drugs or education, which works better?

Authors: R Masekela, M Levin, P M Jeena, M Annamalai, V Naidoo, A van Niekerk, D Hawarden, S Emanuel, H Zar, R J Green, F E Kritzinger, A I Manjra on behalf of the South African Childhood Asthma Working Group (SACAWG)

Abstract: Although ˂5% of children with asthma suffer from severe asthma, they account for the highest use of health resources. The field of asthma therapy is changing rapidly, with a number of new drugs and biologics being added to the treatment armamentarium, particularly for adults. This, though, is not the case for paediatric patients, in whom a number of these novel molecules and drugs have not been investigated. Even though adults have shown responses to medication in some studies, this does not necessarily imply that there will be similar results in children. In the management of severe asthma, use of specific interventions to ensure treatment adherence and goal-setting for selfmanagement is critical to ensure the best treatment outcomes. The objective of this article is to review and grade the current evidence base for use of novel asthma drugs and to make evidence-based recommendations for their administration in children with severe asthma in the South Africa context. We also review the evidence for medication-adherence strategies and self-management plans.

Asthma management and control in children, adolescents, and adults in 25 countries: a Global Asthma Network Phase I cross-sectional study

Authors: Luis García-Marcos*, Chen-Yuan Chiang*, M Innes Asher, Guy B Marks, Asma El Sony, Refiloe Masekela, Karen Bissell, Eamon Ellwood, Philippa Ellwood, Neil Pearce, David P Strachan, Kevin Mortimer†, Eva Morales†, and the Global Asthma Network Phase I Study Group‡

Background: Asthma is one of the most common non-communicable diseases globally. This study aimed to assess asthma medicine use, management plan availability, and disease control in childhood, adolescence, and adulthood across different country settings.

Methods: We used data from the Global Asthma Network Phase I cross-sectional epidemiological study (2015–20). A validated, written questionnaire was distributed via schools to three age groups (children, 6–7 years; adolescents, 13–14 years; and adults, ≥19 years). Eligible adults were the parents or guardians of children and adolescents included in the surveys. In individuals with asthma diagnosed by a doctor, we collated responses on past-year asthma medicines use (type of inhaled or oral medicine, and frequency of use). Questions on asthma symptoms and health visits were used to define past-year symptom severity and extent of asthma control. Income categories for countries based on gross national income per capita followed the 2020 World Bank classification. Proportions (and 95% CI clustered by centre) were used to describe results. Generalised structural equation multilevel models were used to assess factors associated with receiving medicines and having poorly controlled asthma in each age group.

Findings: Overall, 453 473 individuals from 63 centres in 25 countries were included, comprising 101 777 children (6445 [6·3%] with asthma diagnosed by a doctor), 157 784 adolescents (12 532 [7·9%]), and 193 912 adults (6677 [3·4%]). Use of asthma medicines varied by symptom severity and country income category. The most used medicines in the previous year were inhaled short-acting β2 agonists (SABA; range across age groups, 29·3–85·3% participants) and inhaled corticosteroids (12·6–51·9%). The proportion of individuals with severe asthma symptoms not taking inhaled corticosteroids (inhaled corticosteroids alone or with long-acting β2 agonists) was high in all age groups (934 [44·8%] of 2085 children, 2011 [60·1%] of 3345 adolescents, and 1142 [55·5%] of 2058 adults), and was significantly higher in middle-to-low-income countries. Oral SABA and theophylline were used across age groups and country income categories, contrary to current guidelines. Asthma management plans were used by 4049 (62·8%) children, 6694 (53·4%) adolescents, and 3168 (47·4%) adults; and 2840 (44·1%) children, 6942 (55·4%) adolescents, and 4081 (61·1%) adults had well controlled asthma. Independently of country income and asthma severity, having an asthma management plan was significantly associated with the use of any type of inhaled medicine (adjusted odds ratio [OR] 2·75 [95% CI 2·40–3·15] for children; 2·45 [2·25–2·67] for adolescents; and 2·75 [2·38–3·16] for adults) or any type of oral medicine (1·86 [1·63–2·12] for children; 1·53 [1·40–1·68] for adolescents; and 1·78 [1·55–2·04] for adults). Poor asthma control was associated with low country income (lower-middle-income and low-income countries vs high-income countries, adjusted OR 2·33 [95% CI 1·32–4·14] for children; 3·46 [1·83–6·54] for adolescents; and 4·86 [2·55–9·26] for adults).

Interpretation: Asthma management and control is frequently inadequate, particularly in low-resource settings. Strategies should be implemented to improve adherence to asthma treatment guidelines worldwide, with emphasis on access to affordable and quality-assured essential asthma medicines especially in low-income and middle-income countries.

Funding: International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca, UK National Institute for Health Research, UK Medical Research Council, European Research Council, the Spanish Instituto de Salud Carlos III.

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