New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome.

Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES.

Outcomes and risk factors with COVID-19 or influenza in hospitalized asthma patients.

BACKGROUND: At the time of the SARS-CoV-2 emergence, asthma patients were initially considered vulnerable because respiratory viruses, especially influenza, are associated with asthma exacerbations, increased risk of hospitalization and more severe disease course. We aimed to compare the asthma prevalence in patients hospitalized for COVID-19 or influenza and risk factors associated with poor prognosis with the diseases. METHODS: This retrospective cohort study used the Paris university hospitals clinical data warehouse to identify adults hospitalized for COVID-19 (January to June 2020) or influenza (November 2017 to March 2018 for the 2017-2018 influenza period and November 2018 to March 2019 for the 2018-2019 period). Asthma patients were identified with J45 and J46 ICD-10 codes. Poor outcomes were defined as admission in intensive care or death. RESULTS: Asthma prevalence was significantly higher among influenza than COVID-19 patients (n = 283/3 119, 9.1%, 95% CI [8.1-10.1] in 2017-2018 and n = 309/3 266, 9.5%, 95% CI [8.5-10.5] in 2018-2019 versus n = 402/9 009, 4.5%, 95% CI [4.0-4.9]). For asthma patients, 31% with COVID-19 were admitted to an intensive care unit versus 23% and 21% with influenza. Obesity was a risk factor for the 2017-2018 influenza period, smoking and heart failure for the 2018-2019 period. Among COVID-19 patients with asthma, smoking and obesity were risk factors for the severe form. CONCLUSIONS: In this study, patients with an asthma ICD-10 code were less represented among COVID-19 patients than among influenza-infected ones. However, outcomes were poorer for COVID-19 than influenza patients, both with asthma. These data highlight the importance of protective shields and vaccination against influenza and COVID-19 in this population.

Articular manifestations related to anti-interleukin-5 therapies in severe asthma: a case series.

Articular manifestations should be screened before and during anti-IL-5/5R biologic treatment in severe asthma. Rigorous multidisciplinary team discussion should be carried out to assess the risk-benefit balance of withholding effective treatment. https://bit.ly/3vfPn4k.

[New developments in the diagnosis and management of adult asthma]. / Actualités dans le diagnostic et la prise en charge de l'asthme de l'adulte.

NEW DEVELOPMENTS IN THE DIAGNOSIS AND MANAGEMENT OF ADULT ASTHMA Asthma management must be comprehensive, focusing on control¬ling symptoms with inhaled corticosteroids adapted to the stage of severity, but also on limiting the occurrence of exacerbations by correcting poor control factors and educating the patient. The diagnosis of asthma is not only clinical, but it must also include a measurement of respiratory function. Research is active in the field of asthma, with the development of new strategies for prescribing inhaled corticosteroids, which are simpler for patients, but which prescribers must take on board in order to control them. Biotherapies have revolutionized the management of severe asthma. It is important to identify severe patients so that they can benefit from these treat¬ments. It can be considered that any patient who has had two exa¬cerbations in the year should be referred to pulmonology.

ACTUALITÉS DANS LE DIAGNOSTIC ET LA PRISE EN CHARGE DE L'ASTHME DE L'ADULTE La prise en charge de l'asthme doit être globale, s'attachant à la fois à contrôler les symptômes avec un traitement par corticoïdes inhalés adapté au stade de sévérité, et à limiter la survenue des exacerbations en corrigeant les facteurs de mauvais contrôle et en éduquant le patient. Le diagnostic d'asthme n'est pas seulement clinique, il doit intégrer une mesure de la fonction respiratoire. La recherche est active dans le domaine de l'asthme, avec le dévelop-pement de nouvelles stratégies de prescription des corticoïdes inha¬lés, plus simples pour les patients, mais que les prescripteurs doivent s'approprier pour les maîtriser. Les biothérapies ont quant à elles révolutionné la prise en charge des asthmatiques sévères. Dépister les patients atteints de formes sévères est important pour pouvoir les faire bénéficier de ces traitements. On peut considérer que tout patient ayant fait deux exacerbations dans l'année devrait être adressé en pneumologie.

[Asthma exacerbations in adults: Preventing and treat]. / Les exacerbations d'asthme chez l'adulte : prévenir et guérir.

Exacerbations of asthma are still responsible for 900 deaths per year in France, most of which are considered preventable. They have a major impact on the quality of life of patients and are responsible for a large part of the socio-economic cost of asthma in France. Exacerbations of asthma can be partly prevented by inhaled corticosteroid treatment as controller therapy, at a dose adapted to the level of control of symptoms and the management of aggravating factors. Every patient should benefit from a written action plan that allows them to start oral corticosteroid therapy as soon as possible during an exacerbation. The treatment combines short-acting bronchodilators with systemic corticosteroids. Systemic antibiotic therapy has no place in the treatment of exacerbations. The patient must be seen early in the course of an exacerbation of asthma to review all of his follow-up.