Speaker: Nikos Papadopoulos

There has been a lot of discussion around targeting interventions and understanding how and when asthma develops. Despite asthma being a prevalent issue worldwide, notable variability exists between and within countries, which poses a challenge in explaining solely based on environmental factors. The latest Global Asthma Network (GAN) study reveals varying trends in asthma prevalence over the years across different nations, with some countries experiencing decreases, others increasing, and some remaining stable. Interestingly, while childhood asthma prevalence appears to remain relatively stable, there is a notable drop in asthma cases among preschool children, with more than 200,000 individuals affected. This decline was particularly pronounced between 2010 and 2015, raising questions about causality, especially in the COVID-19 pandemic years 2020 and 2021, where reduced exposures might correlate with decreased symptomatic cases.

The rapid transmission of information and the evolving definitions of conditions like preschool asthma change more swiftly than environmental factors. Observations from a UK database reveal fluctuations in asthma incidence across different age groups, notably a decrease in preschool-aged children alongside a slight increase in exacerbations. These fluctuations underscore the importance of considering environmental shifts and evolving medical definitions when discussing asthma. When examining the onset of asthma, research suggests that a significant portion of individuals experience their first asthma-like symptoms during infancy, often misidentified as bronchiolitis. Many infants who experience severe bronchiolitis may continue to exhibit wheezing, termed Preschool Wheeze, with cases associated with rhinovirus showing a higher likelihood of persistence at age three.

A systematic review was conducted to evaluate the occurrence of either recurrent wheezing or asthma following bronchiolitis. The findings suggest that the condition that ensues after a rhinovirus infection tends to persist and evolve into what could be termed asthma. Despite previous epidemiological descriptions distinguishing asthma from non-atopic or transient wheezes, a closer examination of the Tucson cohort reveals a continuity in the condition, with approximately 15% of new cases emerging over time. These new cases often exhibit frequent wheezing episodes, while a significant proportion of early transient wheezers experience relapses. Additionally, there are two distinct groups: late-onset wheezers and persistent wheezers. Interestingly, half of the persistent wheezers experience remission by age 16. This highlights the variability in the clinical presentation of asthma, which undergoes significant changes over time.

The approach involved examining the definition of asthma, encompassing inflammation and bronchoconstriction. The study focused on young children displaying symptoms akin to asthma or preschool wheezing. Findings indicated that these children exhibited inflammation, evidenced by elevated exhaled nitric oxide levels, and increased resistance using impulse oscillometry during symptomatic episodes. These cardinal characteristics of asthma and symptoms were consistently observed across multiple studies, suggesting a longitudinal association between inflammation, airway obstruction, and symptoms. Although a cross-sectional association wasn't evident, longitudinal data revealed this correlation. Replication across different child cohorts validated these findings. Notably, asthma characteristics were present even before school age, emphasizing the onset of asthma in preschoolers. However, the definition of asthma influenced the interpretation, as asthma is defined by symptoms starting at age five, which differs from earlier onset asthma.

The differences in asthma among children, especially in preschool-aged children, stem from the maturation of various systems associated with the condition. Factors such as immunity, airway development, and the microbiome influence asthma's clinical presentation at different ages. Each element of the immune system evolves at its own pace, impacting the characterization of asthma and related allergic diseases. Research has investigated these maturation trajectories in cohorts of allergic and non-allergic individuals with asthma and rhinitis, analyzing peripheral blood mononuclear cells (PBMCs) stimulated with Toll-like Receptor (TLR) ligands. Cytokine responses, particularly interferon alpha, TNF alpha, and interleukin 10, vary significantly with age and allergic status, especially when cells are exposed to TLR ligands mimicking viral or pathogenic infections. These findings highlight the importance of considering maturation trajectories in understanding and characterizing asthma, particularly eosinophilic asthma, where a threshold of 150 eosinophils has been traditionally associated with the condition. 

The discussion focused on a cohort comprising over a thousand German individuals, including asthma patients and healthy controls. Specifically, the analysis centered on the distribution of eosinophils in adults among the healthy control group. The median eosinophil count for healthy adults was found to be approximately 160, with the majority exceeding 150. Additionally, the 90th percentile was observed to be 360. In contrast, among children, specifically encompassing infancy through preschool age, the 90th percentile rose to 470. These findings delineate various phenotypic shifts across different age groups, particularly noticeable transitions between infancy and preschool age and from preschool to school age. Subsequently, the pattern stabilizes until around 30 or 35, after which another shift is observed.

Interferons play a crucial role in combating viruses, especially in individuals with atopic asthma, where studies indicate reduced interferon responses. The ratio of interferon-gamma to IL-4 differs significantly between healthy individuals and those with atopic asthma, affecting how epithelial cells respond to viruses. Research suggests that atopic individuals may experience longer durations of hyperresponsiveness following viral infections, potentially leading to more frequent infections and asthma episodes. While non-atopic individuals typically return to baseline hyperresponsiveness after around a hundred days, some atopic individuals remain hyperresponsive even after nine months. The "predictor hypothesis" explains this phenomenon, suggesting that genetic susceptibility and repeated infections could perpetuate a hyperreactive immune state, leading to persistent asthma symptoms.

The session delved into the microbiological aspect, particularly focusing on the virome, which encompasses the collective community of viruses within us, especially in the respiratory system. These viruses, including eukaryotic (like influenza and rhinovirus) and prokaryotic viruses (bacteriophages), play a significant role in influencing the immune system and the bacterial microbiome. A recent study examining the micro-virome of preschool-age children revealed a notable disparity in the number and diversity of bacteriophages in asthmatic individuals compared to healthy ones. Further analysis identified three distinct clusters of virome dominance: anelloviruses, eukaryotic viruses (predominantly rhinovirus), and bacteriophages. The dominance of bacteriophages distinguished the healthy group, while asthmatic individuals exhibited expanded clusters of anelloviruses and eukaryotic viruses, correlating with disease severity and control. The session emphasized that while early viral infections like rhinovirus may not directly lead to asthma, the risk of developing or persisting asthma significantly increases when coupled with a pathological microbiome and specific immune responses. This underscores the dynamic interplay between immune response, respiratory system maturation, and microbiology in childhood asthma. To better understand and intervene in the natural history of asthma, intensive monitoring is proposed, focusing on symptoms, control, adherence, and comorbidities. Despite varying priorities among stakeholders, there's a consensus on the importance of standardized tools for evaluating and enhancing adherence and control. A recent collaborative effort resulted in recommendations for pediatric asthma monitoring, providing a simple yet comprehensive framework for effective management, published in Pediatric Allergy and Immunology.

The overall session emphasized the importance of systematic monitoring in children to comprehend the natural progression of asthma. It is crucial not only for understanding its natural history but also for effectively managing the condition. The key takeaway is that asthma's early onset may not solely be due to environmental factors but also influenced by definitions. Asthma can manifest as early as preschool age or even earlier, depending on its definition. The complexity of this issue is evident, as it involves the maturation of not only the immune system but also the microbiome and respiratory structure. Systematic monitoring remains paramount for gaining insights into asthma's natural course and effectively managing the disease.

European Academy of Allergy and Clinical Immunology (EAACI) 2024, 31st May-3rd June, Valencia