December 2019

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Hypersensitivity pneumonitis (HP) and telomeropathy

B.Ley et al  AJRCCM 2019 200 1154-1163

telomereRepeated exposure to environmental antigens, mainly organic such Farmer’s Lung, provokes an HP characterized by alveolitis, giant-cells granulomas, then Fibrosis (Chronic HP) indistinguishable from Idiopathic pulmonary Fibrosis. In France since 1970 and in many European countries, FL is recognized as occupational disease. However, not all individual exposed develop an immunopathologic response and there is a genetic susceptibility due to defects in telomere replication and extension such mutations leading to shorter lengths associated with bad clinical outcomes and significant reduced survival. This genetic predisposition is also found for many other disorders such IPF, characterized by Mucin 5 B (MUC5B) and telomere shortening : early graying of the hair , hepatic, pulmonary and bone marrow abnormalities and are referred to as “telomeropathy”.

The recent article from San-Francisco University researchers, on CHP, is the follow up of previously published observation showing dysfunction in the pathogenesis and prognosis of the diseases and in a minority of patients in rare protein-altering gene variants associated with short peripheral blood cell telomere and reduced transplant-free survival. Moreover blood cells counts appeared to be biomarkers of disease prognosis. Finally, this is the 1st study in the literature linking genetic anomalies in telomere homeostasis with the prognosis of CHP.



Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Robert Bissonnette & al JACI 2019 Nov 1274-1289

C. ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis.
The dermatologists from Quebec undertook a phase 2a, single-center, vehicle-controlled, intra patient study to further characterize the mechanism of action of C through evaluation of clinical efficacy and changes in skin biomarkers in 40 adults with mild-to-moderate AD. Two target lesions were randomized in an intra patient (1:1) manner to double-blind C/vehicle applied twice daily for 14 days. Patients then applied C (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.
• C. treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application.
• C.-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8.
• C. significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation.
In conclusion C reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD and allows avoidance of corticosteroids.



Food allergy to wheat following skin exposure by cosmetics
Noguchi et al JACI 2019 Nov 144 5 1354-1363

Food allergy is a growing health problem worldwide. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). In this research, the Japanese authors provide the 1st demonstration that allergy to wheat may be due not only to food but also to cosmetics. Key findings of this study include the following:

1. IgE reactivity to HWP sensitized through skin was not correlated with that to Ω-5 gliadin.
2. Genetic variation contribute to susceptibility to HWP allergy. A genome-wide association study of HWP allergy was conducted in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Strong associations with HLA-DQ variants were identified with the class II HLA region on 6p21 and confirmed in the replication data set.
3. Variants in the HLA-DQ region associated in the literature with increased risk of peanut allergy were associated with protection from HWP allergy through skin exposure.
These data provide the first demonstration of genetic risk for HWP allergy which is mainly represented by multiple combinations of HLA variants.


Misperception of asthma symptoms
P.J Barnes et   al JACI 2019 144 5 1180-1186         

It is well known:

- That both under perception and over perception assessed during induced bronchoconstriction or bronchodilation or during changes in airway resistance are common across all age group,
- and that aging disease severity, smoking, sex, ethnicity, psychologic factors, and medication are all associated with differences in perception.
Importantly, airway inflammation was associated with impaired perception and a history of severe or near-fatal asthma. The British authors reviewed evidence from a systemic literature search for misperception in asthmatic patients, OVID (Medline and Medline [R] in process [PubMed]), Embase, and Adisearch/Odyssey databases), restricting this search to human studies published in English from 1990–2018, with no restrictions particularly in relationship to incorrect use of reliever inhalers.
Notable findings included the following:
- Airway inflammation appears to blunt the perception of airway narrowing.
- However, there was knowledge gaps about how perception can vary over time and how it affects reliever use, indicating that more studies are needed on this important topic.
In conclusion misperception of airway obstruction is common in asthmatic patients of all ages and can expose the patients to the risk of undertreatment or overtreatment.                               



The projected economic and health burden of incontrolled asthma in USA
Yaghoubi et al. AJRCCM 2019.2000 9 1182-1211

It is a work of Britsh Columbia University, Vancouver – Canada. On average, 38% of children and 50% of adults with asthma, in the USA had uncontrolled asthma symptoms which reduces the quality of life of patients and those who care for them, results in missed school or work, and increases the risk and severity of asthma exacerbation. In 2017, more than 11 million people reported having at least one asthma exacerbation in the last 12 months, and there were 1.8 million emergency department visits, nearly 200,000 hospitalizations, and about 3,500 deaths.
In this context, this study provides important new information. By using a computer model that combined multiple sources of evidence, this study estimated and projected the economic and humanistic burden of asthma among U.S. adults. Asthma cost the U.S. economy an estimated $81.9 billion in 2013 alone. Across states in USA the average per capita ranged from 2,209 dollars in Arkansas to 6,132 in Connecticut and will continue to grow.
Uncontrolled asthma will cost the U.S. economy an estimated $300 billion (in 2018 dollar values) in the next 20 years in direct medical costs alone. This value increases to an estimated $963 billion if costs due to loss of work productivity are included. The impact on quality of life is projected to be equal to loss of 15.5 million years with full health.
The authors examined national and state-level projections of the economic burden; a fraction is preventable and better adherence to management strategies may reduce the cost. The answer to the question “What will uncontrolled asthma cost in the United States?” the response is clear: Too much. !! Anyway, this work is a good example for many countries in Europe.


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Last updated 29 November 2019
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