Genetic susceptibility to severe childhood asthma and rhinovirus-C maintained by balancing selection in humans for 150 000 years.

Selective pressures imposed by pathogens have varied among human populations throughout their evolution, leading to marked inter-population differences at some genes mediating susceptibility to infectious and immune-related diseases. Here, we investigated the evolutionary history of a common polymorphism resulting in a Y529 versus C529 change in the cadherin related family member 3 (CDHR3) receptor which underlies variable susceptibility to rhinovirus-C infection and is associated with severe childhood asthma. The protective variant is the derived allele and is found at high frequency worldwide (69-95%). We detected genome-wide significant signatures of natural selection consistent with a rapid increase of the haplotypes carrying the allele, suggesting that non-neutral processes have acted on this locus across all human populations. However, the allele has not fixed in any population despite multiple lines of evidence suggesting that the mutation predates human migrations out of Africa. Using an approximate Bayesian computation method, we estimate the age of the mutation while explicitly accounting for past demography and positive or frequency-dependent balancing selection. Our analyses indicate a single emergence of the mutation in anatomically modern humans ~150 000 years ago and indicate that balancing selection has maintained the beneficial allele at high equilibrium frequencies worldwide. Apart from the well-known cases of the MHC and ABO genes, this study provides the first evidence that negative frequency-dependent selection plausibly acted on a human disease susceptibility locus, a form of balancing selection compatible with typical transmission dynamics of communicable respiratory viruses that might exploit CDHR3.

The cysteinyl leukotrienes: where do they come from? What are they? Where are they going?

Cysteinyl leukotrienes are established mediators of bronchial asthma and have agonist roles analogous to those of histamine in allergic rhinitis. We now know that the substance originally termed slow-reacting substance of anaphylaxis was composed of three cysteinyl leukotrienes that act in the inflammatory response via receptors on smooth muscle and on bone marrow-derived inflammatory cells. K. Frank Austen describes the work culminating in the identification, biosynthesis and functional characterization of these moieties.

Want to Work on Asthma Genetics?

Twins, data and emails. Some of the words that first come to mind when I think of Nick. Lots of twins. With lots of data. And short single-finger-typed emails. And great wine. Well, it works, there is no doubt. That's how I ended up in Australia, working on asthma genetics.

Changes in the prevalence of asthma and respiratory symptoms in western Sweden between 2008 and 2016.

BACKGROUND: Asthma is a common chronic inflammatory disease of the airways, with a noticeable increase in prevalence during the second half of the 20th century. Recent studies assessing the prevalence trends among adults have been inconsistent. We investigated the changes in the prevalence of asthma, respiratory symptoms, and risk factors between 2008 and 2016 in western Sweden. METHODS: The West Sweden Asthma Study (WSAS) is a population-based study which started in 2008 (WSAS I) and then repeated in 2016 (WSAS II) in western Sweden. Randomly selected individuals aged 16-75 years (N = 18 087 in 2008 and N = 24 534 in 2016) completed a questionnaire regarding obstructive lung diseases, respiratory symptoms, potential risk factors, and also questions from the GA2 LEN survey. RESULTS: The prevalence of reported ever asthma, physician-diagnosed asthma, use of asthma medication, and current asthma increased significantly from 9.6% to 11%, 8.3% to 10%, 8.6% to 9.8%, and 8.1% to 9.1%, respectively, between 2008 and 2016. There were also increases in the prevalence of respiratory symptoms during the same period. The greatest increase occurred in young adults aged 16-25 years. Female gender, allergic rhinitis, obesity, and family history of asthma remained the strongest risk factors for asthma in 2016 as it was in 2008. CONCLUSION: There were moderate increases in asthma and respiratory symptoms in adults in western Sweden between 2008 and 2016, the greatest increase occurring in younger adults. The potential risk factors for asthma remained the same during the study period.

Simultaneously elevated FeNO and blood eosinophils relate to asthma morbidity in asthmatics from NHANES 2007-12.

BACKGROUND: Fraction of exhaled nitric oxide (FeNO) and blood eosinophil (B-Eos) count are biomarkers for type 2 inflammation. However, they signal different inflammatory pathways. Simultaneously elevated, they are related to more asthma events in a general population and among younger asthmatics. OBJECTIVE: To investigate if simultaneously elevated FeNO and B-Eos relate to asthma outcomes and lung function among subjects with asthma at a wide age span, and how different cut-offs for the markers affect these relations. METHOD: FeNO, B-Eos and forced expiratory volume in 1 second (FEV1 ) were assessed in 1419 subjects with asthma, aged 6-79 years old, from the National Health and Nutrition Examination Survey (NHANES) 2007-12. Elevated levels were defined as FeNO ≥20 p.p.b. for children <12 years and ≥25 p.p.b. for subjects ≥12 years and B-Eos count ≥300 cells/µL. Additional analyses were performed for the cut-offs FeNO >35/30 and >50/35 p.p.b., and for B-Eos ≥400 and ≥ 500 cells/µL, as well as for different age subgroups (6-17, 18-44, >44 years old). Asthma events during the past year were self-reported. RESULTS: Subjects with simultaneously elevated FeNO and B-Eos compared with normal levels of both markers had a higher adjusted odds ratio (aOR (95%CI)) for having FEV1 <80% of predicted (2.15 (1.28-3.59), wheeze disturbing sleep (1.88 (1.27, 2.78)) but did not differ regarding asthma attacks past year. Elevated B-Eos, but not FeNO, was related to higher aOR for asthma attack (1.57 (1.14, 2.18) or emergency room (ER) visit due to asthma (1.88 (1.33, 2.64) when elevated FeNO and elevated B-Eos were studied as independent predictors. CONCLUSION: Simultaneously elevated FeNO and B-Eos related to reduced lung function in asthmatics, wheezing symptoms, but not to a history of asthma attacks. Asthma attacks and ER-visit due to asthma were related to increased B-Eos levels.

Allergic sensitization and clinical outcomes in urban children with asthma, 2013-2016.

BACKGROUND: The aim of this study was to examine if food and/or aeroallergen sensitization was associated with worse asthma, pulmonary function tests (PFT), and laboratory markers. METHODS: At our institution, 386 children with asthma were divided into allergic and nonallergic groups based on allergen-specific immunoglobulin E (IgE) testing classes 1-6 versus 0. Asthma severity and/or control, IgE level, eosinophil counts and/or percentages, forced vital capacity (FVC), forced expiratory volume in the first second of expiration (FEV1), and FEV1/FVC, were compared by using bivariate, regression, and subgroup analyses for children who were highly allergic (≥4 allergens). RESULTS: A total of 291 subjects with asthma were allergic, significantly older, and had higher mean IgE levels and eosinophil counts and percentages (all p < 0.001). A total of 203 subjects who were highly allergic had worse obstruction on PFTs. Increasing age predicted allergen sensitization after confounder adjustment, odds ratio (OR) 1.54 (95% confidence interval [CI], 1.18-2.02). Similarly, PFT obstruction was associated with multiple allergen sensitization (OR 0.97 [95% CI, 0.93-1.02]). CONCLUSION: Increasing age predicted allergic sensitization and multiple allergen sensitization. Worse obstruction on PFT also predicted multiple allergen sensitization. Continued surveillance of aeroallergen sensitization and PFT results may be beneficial in asthma management, particularly in older urban children.

Increased prevalence of allergic asthma from 1996 to 2006 and further to 2016-results from three population surveys.

BACKGROUND: During the latter half of the 20th century, the prevalence of asthma and many other allergic diseases has increased. Information on asthma prevalence trends among adults after 2010, especially regarding studies separating allergic asthma from non-allergic asthma, is lacking. OBJECTIVE: The aim was to estimate prevalence trends of current asthma among adults, both allergic and non-allergic, from 1996 to 2016. METHODS: Three cross-sectional samples from the same area of Sweden, 20-69 years, participated in surveys with the same questionnaire in 1996 (n=7104 participants, 85% response rate), 2006 (n=6165, 77%) and 2016 (n=5466, 53%), respectively. Allergic rhino-conjunctivitis (ARC) was used as a marker for allergic sensitization to define allergic asthma. RESULTS: The prevalence of current asthma increased from 8.4% (95% CI: 7.8-9.0) in 1996 to 9.9% (95% CI: 9.2-10.6) in 2006 and 10.9% (95% CI: 10.1-11.7) in 2016 (P<.001). Allergic asthma increased from 5.0% (95% CI: 4.5-5.5) in 1996 to 6.0% (95% CI: 5.4-6.6) in 2006 and further to 7.3% (95% CI: 6.6-8.0) in 2016 (P<.001), while the prevalence of non-allergic asthma remained stable around 3.4%-3.8%. The increase in current asthma was most pronounced among women and among the middle-aged. Physician-diagnosed asthma, asthma medication use and ARC also increased significantly, while the prevalence of symptoms common in asthma such as wheeze and attacks of shortness of breath decreased slightly or was stable. The prevalence of current smoking decreased from 27.4% in 1996 to 12.3% in 2016. CONCLUSIONS AND CLINICAL RELEVANCE: The prevalence of allergic asthma increased from 1996 to 2006 and further to 2016, while the prevalence of non-allergic asthma remained on a stable prevalence level. The prevalence of symptoms common in asthma decreased slightly or was stable despite a substantial decrease in the prevalence of current smoking. Clinicians should be aware that the previously observed increase in prevalence of allergic asthma is still ongoing.

[IgE and Anti-IgE in Asthma: A Chequered History]. / IgE und Anti-IgE bei Asthma: eine wechselvolle Geschichte.

A long and winding road led to the discovery of immunoglobulin E (IgE) in 1966 and 1967. We are currently on a long and winding road to understand the immunologic basis of the clinical effects of the anti-IgE antibody omalizumab in asthma. It is possible that patients with asthma (as patients with chronic spontaneous urticaria) benefit in different immunologic ways from omalizumab treatment. This article reviews the history of IgE discovery and current concepts of anti-IgE therapy in asthma.

The effects of air pollution on asthma hospital admissions in Adelaide, South Australia, 2003-2013: time-series and case-crossover analyses.

BACKGROUND: Air pollution can have adverse health effects on asthma sufferers, but the effects vary with geographic, environmental and population characteristics. There has been no long time-series study in Australia to quantify the effects of environmental factors including pollen on asthma hospitalizations. OBJECTIVES: This study aimed to assess the seasonal impact of air pollutants and aeroallergens on the risk of asthma hospital admissions for adults and children in Adelaide, South Australia. METHODS: Data on hospital admissions, meteorological conditions, air quality and pollen counts for the period 2003-2013 were sourced. Time-series analysis and case-crossover analysis were used to assess the short-term effects of air pollution on asthma hospitalizations. For the time-series analysis, generalized log-linear quasi-Poisson and negative binomial regressions were used to assess the relationships, controlling for seasonality and long-term trends using flexible spline functions. For the case-crossover analysis, conditional logistic regression was used to compute the effect estimates with time-stratified referent selection strategies. RESULTS: A total of 36,024 asthma admissions were considered. Findings indicated that the largest effects on asthma admissions related to PM2.5 , NO2 , PM10 and pollen were found in the cool season for children (0-17 years), with the 5-day cumulative effects of 30.2% (95% CI: 13.4-49.6%), 12.5% (95% CI: 6.6-18.7%), 8.3% (95% CI: 2.5-14.4%) and 4.2% (95% CI: 2.2-6.1%) increases in risk of asthma hospital admissions per 10 unit increments, respectively. The largest effect for ozone was found in the warm season for children with the 5-day cumulative effect of an 11.7% (95% CI: 5.8-17.9%) increase in risk of asthma hospital admissions per 10 ppb increment in ozone level. CONCLUSION: Findings suggest that children are more vulnerable and the associations between exposure to air pollutants and asthma hospitalizations tended to be stronger in the cool season compared to the warm season, with the exception of ozone. This study has important public health implications and provides valuable evidence for the development of policies for asthma management.

[The Escouflaire Laboratories].

Escouflaire antiasthmatic cigarettes and powders knew certain success during almost one century. The medical use of solanaceae with bronchodilator properties helped relieve numerous asthmatics. The Belgian pharmacist Charles Adolphe Escouflaire (1857-1909), pharmacist from the university of Leuven, Belgium, awarded his diploma in 1879. He created his antiasthmatic products in his pharmacy of Ath and established in 1885 a pharmaceutical laboratory. He registered trademarks under the brand name Zematone for its antiasthmatic cigarettes. His products will be rapidly known and sold all over the world. The discovery of a complete box of medical cigarettes in the Czech Republic allows us to evoke his products, the distributor F. S chnöbling in this country, the modes of display and uses. This article redraws the history of the laboratory under the direction of three generations of the Escouflaire family. The laboratory will expand after WWII with production factories in Baisieux and Blandain before definitely close in 1974.

Changing roles of eosinophils in health and disease.

OBJECTIVE: To review and highlight the unappreciated roles of eosinophils suggested by recent studies. DATA SOURCES: The literature, unpublished observations, and insights by the authors. STUDY SELECTIONS: Basic studies of mouse models and patient-based clinical studies of disease. RESULTS: Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease. CONCLUSION: Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies.

President Calvin Coolidge's asthma and modern management of asthma patients in the dental setting.

Asthma affects millions of individuals worldwide. President Calvin Coolidge was one of these individuals. Coolidge suffered from asthma since childhood. It affected his outlook toward aggressive physical activity and was a strong factor in shaping his personality and, eventually, his politics. He was devoted to the status quo in American business enterprises and was known for his reserved personality and conservative political beliefs. One can speculate as to what role his passive personality, developed as a direct and conscious result of his desire for physical self-preservation in light of his asthma, played in leading the United States to the brink of the Great Depression. Dentists encounter individuals with asthma in their private practices daily. It is imperative that all dentists be aware of the symptoms of asthma, its many orofacial manifestations and possible modifications to dental treatment.

Asthma: a simple concept but in reality a complex disease.

BACKGROUND: Asthma is a disorder of the conducting airways that contract too easily and too much to cause variable airflow obstruction with symptoms of wheeze, cough, chest tightness and shortness of breath. Based on this knowledge, initial treatments were directed to dilating the contracted airways with anticholinergic and adrenergic drugs. The recognition that allergic-type inflammation underlay the hyperresponsive airways in asthma led to the introduction of anti-inflammatory drugs such as sodium cromoglicate and corticosteroids. Over the 2 decades that followed, these drugs have been progressively improved by increasing their therapeutic index and duration of action. METHODS: A review of the recent literature indicates that since the 1980s, the explosive increase in knowledge of the cell and mediator mechanisms of asthma has only led to modest improvements in therapy including the introduction of leukotriene modifiers and a blocking monoclonal antibody against IgE. Indeed, biologics targeting allergic cytokines and effector cells have on the whole proven disappointing despite initial promise being shown in animal models. RESULTS: Part of the difficulty lies in the oversimplified concept that asthma is only driven by allergic processes when in reality there are many environmental causes and triggers and the view that it is a homogeneous disorder only varying in severity. CONCLUSIONS: The more recent views that asthma is a complex disorder made up of different subtypes with differing causes, treatment responses and natural histories creates a new opportunity for stratified medicine in which therapies acting upstream selectively target specific disease subtypes identified by specific diagnostic biomarkers.