Radiomultiomics: quantitative CT clusters of severe asthma associated with multi-omics.

RATIONALE: Lung quantitative computed tomographic (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways. METHODS: We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterize radiomultiomic-associated clusters (RACs). RESULTS: qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated BMI, mild airflow limitation, normal qCT parameters and upregulation of the complement pathway. RAC2 (n=34) subjects had a lower degree of airflow limitation, airway wall thickness and dilatation, with upregulation of proliferative pathways, including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B (NTRK2/TRKB), and down-regulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signaling and signaling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. CONCLUSIONS: U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent anovel strategy to identify new molecular pathways in asthma pathobiology.

Imagining the severe asthma decision trees of the future.

INTRODUCTION: There are no validated decision-making algorithms concerning severe asthma (SA) management. Future risks are crucial factors and can be derived from SA trajectories. AREAS COVERED: The future severe asthma-decision trees should revisit current knowledge and gaps. A focused literature search has been conducted. EXPERT OPINION: Asthma severity is currently defined a priori, thereby precluding a role for early interventions aiming to prevent outcomes such as exacerbations (systemic corticosteroids exposure) and lung function decline. Asthma 'at-risk' might represent the ultimate paradigm but merits longitudinal studies considering modern interventions. Real exacerbations, severe airway hyperresponsiveness, excessive T2-related biomarkers, noxious environments and patient behaviors, harms of OCS and high-doses inhaled corticosteroids (ICS), and low adherence-to-effectiveness ratios of ICS-containing inhalers are predictors of future risks. New tools such as imaging, genetic, and epigenetic signatures should be used. Logical and numerical artificial intelligence may be used to generate a consistent risk score. A pragmatic definition of response to treatments will allow development of a validated and applicable algorithm. Biologics have the best potential to minimize the risks, but cost remains an issue. We propose a simplified six-step algorithm for decision-making that is ultimately aiming to achieve asthma remission.

Post viral bronchiolitis obliterans in children: A rare and potentially devastating disease.

Post infectious bronchiolitis obliterans (PIBO) is a rare but severe disease in children. Several respiratory pathogens are incriminated but adenovirus is still the most represented. Risk factors are well described: the male gender, hypoxemia at diagnosis and required mechanical ventilation. No risk factor is linked to the newborn period. The clinical spectrum of PIBO is broad, ranging from asymptomatic patients with fixed airflow obstruction to severe respiratory insufficiency requiring continuous oxygen supplementation. Diagnosis includes a combination of a clinical history, absence of reversible airflow obstructions and ground glass and gas trapping on high resolution computed tomography. PIBO is primarily a neutrophilic pathology of small bronchioles characterized by high levels of pro-inflammatory cytokines leading to tissue remodeling and fibrosis of the small airways. The difficulty is to discriminate between the host's normal response, an exaggerated inflammatory response and the potential iatrogenic consequences of the initial infection treatment, particularly prolonged mechanical ventilation. Damage to the respiratory epithelium with a possible link to viral infections are considered as potential mechanisms of PIBO. No specific management exists. Much remains to be done in this field to clarify the underlying mechanisms, identify biomarkers, and develop clear monitoring pathways and treatment protocols.

Cell Culture Differentiation and Proliferation Conditions Influence the In Vitro Regeneration of the Human Airway Epithelium.

The human airway mucociliary epithelium can be recapitulated in vitro using primary cells cultured in an air-liquid interface (ALI), a reliable surrogate to perform pathophysiological studies. As tremendous variations exist among media used for ALI-cultured human airway epithelial cells, the aim of our study was to evaluate the impact of several media (BEGM, PneumaCult, Half & Half, and Clancy) on cell type distribution using single-cell RNA sequencing and imaging. Our work revealed the impact of these media on cell composition, gene expression profile, cell signaling, and epithelial morphology. We found higher proportions of multiciliated cells in PneumaCult-ALI and Half & Half, stronger EGF signaling from basal cells in BEGM-ALI, differential expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry factor ACE2, and distinct secretome transcripts depending on the media used. We also established that proliferation in PneumaCult-Ex Plus favored secretory cell fate, showing the key influence of proliferation media on late differentiation epithelial characteristics. Altogether, our data offer a comprehensive repertoire for evaluating the effects of culture conditions on airway epithelial differentiation and will aid in choosing the most relevant medium according to the processes to be investigated, such as cilia, mucus biology, or viral infection. We detail useful parameters that should be explored to document airway epithelial cell fate and morphology.

Airway remodelling in asthma and the epithelium: on the edge of a new era.

Asthma is a chronic, heterogeneous disease of the airways, often characterised by structural changes known collectively as airway remodelling. In response to environmental insults, including pathogens, allergens and pollutants, the epithelium can initiate remodelling via an inflammatory cascade involving a variety of mediators that have downstream effects on both structural and immune cells. These mediators include the epithelial cytokines thymic stromal lymphopoietin, interleukin (IL)-33 and IL-25, which facilitate airway remodelling through cross-talk between epithelial cells and fibroblasts, and between mast cells and airway smooth muscle cells, as well as through signalling with immune cells such as macrophages. The epithelium can also initiate airway remodelling independently of inflammation in response to the mechanical stress present during bronchoconstriction. Furthermore, genetic and epigenetic alterations to epithelial components are believed to influence remodelling. Here, we review recent advances in our understanding of the roles of the epithelium and epithelial cytokines in driving airway remodelling, facilitated by developments in genetic sequencing and imaging techniques. We also explore how new and existing therapeutics that target the epithelium and epithelial cytokines could modify airway remodelling.

Severe asthma care trajectories: the French RAMSES cohort.

Background: The French RAMSES study is an observational prospective multicentre real-life cohort including severe asthmatic subjects. The objective of the study was to compare the characteristics of patients, in terms of phenotype and asthma care trajectories, between those managed by tertiary referral centres (TRCs) or secondary care centres (SCCs). Methods: Patients were prospectively recruited and enrolled for a 5-year follow-up. Patients' characteristics were analysed at inclusion and compared between TRCs and SCCs. Results: 52 centres (24 TRCs and 28 SCCs) included 2046 patients: 1502 (73.4%) were included by a TRC and 544 (26.6%) by a SCC. Patients were mainly women (62%), 53±15 years old, 67% with Asthma Control Test <20; at inclusion, 14% received oral corticosteroids (OCS) and 66% biologics. Compared with the SCC group, the TRC group had more frequent comorbidities and lower blood eosinophil counts (262 versus 340 mm-3; p=0.0036). OCS and biologics use did not differ between groups, but patients in the TRC group benefited more frequently from an educational programme (26% versus 18%; p=0.0008) and received more frequently two or more sequential lines of biologics (33% versus 24%; p=0.0105). In-depth investigations were more frequently performed in the TRC group (allergy tests: 74% versus 62%; p<0.0001; exhaled nitric oxide fraction: 56% versus 21%; p<0.0001; induced sputum: 6% versus 3%; p=0.0390). Conclusions: Phenotypes and care trajectories differed in the RAMSES cohort between SCCs and TRCs, probably related to different levels of asthma severity and differences in medical resources and practices among centres. This highlights the need for standardisation of severe asthma care.

Pulmonary adverse events of breast silicone implants and silicone injection.

The incidence of breast implants and silicone injections has continuously increased since their FDA approval for use in the 1960's. The prevalence of overall adverse events is approximately 20%. The actual incidence of pulmonary adverse events is unknown. This review focuses on the pulmonary adverse events of breast implants and silicone injections. Vascular complications are represented by acute and chronic embolisation syndromes with a clinico-radiological presentation of alveolar hemorrhage. Inflammatory complications are numerous, including siliconoma, which is a granulomatous reaction mimicking a mesothelioma. On the other hand, there are some reports arguing a link between the development of auto-immune diseases and breast implants, such as scleroderma, rheumatoid arthritis, Sjögren's syndrome, and dermatomyositis. Finally, for patients with asthma, breast implants may contribute to poor disease control. Cases of eosinophilic granulomatosis with polyangeitis have been described. Thus, it is of interest to decipherate mechanisms and incidence of these effects in prospective studies to better manage pulmonary diseases in patients wearing breast implants in order to understand their role as culprits or bystanders. In addition, characterization of subpopulations with increased risk of adverse events is needed as we highlighted that some subpopulations seem to be at greater risk of developing them, notably asthmatics.

Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids.

Rationale: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure. Methods: Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study. Measurements and main results: The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12-18 months. Conclusion: The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.

Natural killer cells in the lung: potential role in asthma and virus-induced exacerbation?

Asthma is a chronic inflammatory airway disorder whose pathophysiological and immunological mechanisms are not completely understood. Asthma exacerbations are mostly driven by respiratory viral infections and characterised by worsening of symptoms. Despite current therapies, asthma exacerbations can still be life-threatening. Natural killer (NK) cells are innate lymphoid cells well known for their antiviral activity and are present in the lung as circulating and resident cells. However, their functions in asthma and its exacerbations are still unclear. In this review, we will address NK cell activation and functions, which are particularly relevant for asthma and virus-induced asthma exacerbations. Then, the role of NK cells in the lungs at homeostasis in healthy individuals will be described, as well as their functions during pulmonary viral infections, with an emphasis on those associated with asthma exacerbations. Finally, we will discuss the involvement of NK cells in asthma and virus-induced exacerbations and examine the effect of asthma treatments on NK cells.

Implication of allergy and atopy in IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic multi-organic immune fibrosing disease. It affects preferentially men around middle age and almost any organs can be involved; however, lymph nodes, submandibular and lacrimal glands, pancreas, and retroperitoneum are the most affected. The mainstay treatment is corticosteroids, sometimes adjuncts with DMARDs or rituximab as steroid sparing agents. Th2 inflammation is implicated in the pathophysiology of the disease. Several reports indicate that allergy and/or atopy often affect patients with IgG4-RD. The frequency varies greatly between studies with allergies/allergic diseases reported in 18-76% while atopy is reported in 14-46%. In studies including both, they affect 42 and 62% of patients. Rhinitis and asthma are the most frequent allergic diseases. IgE and blood eosinophiles are often elevated and few studies report that basophils and mast cells could participate in the disease pathogenesis; however, the implication of allergy and atopy remain unclear. No common allergen has been identified and IgG4 production seems to be polyclonal. Although a direct causal effect is unlikely, they could potentially shape the clinical phenotype. Allergies/allergic diseases and/or atopy are reported to be more frequent in IgG4-RD patients presenting head, neck, and thoracic involvement, with higher IgE and eosinophils and less frequent in retroperitoneal fibrosis; however, studies regarding allergy and atopy in IgG4-RD are highly heterogenous. The aim of this article is to review what is currently known about the allergy and atopy in the context of Ig4-RD.

A Charter to Fundamentally Change the Role of Oral Corticosteroids in the Management of Asthma.

Asthma affects 339 million people worldwide, with an estimated 5-10% experiencing severe asthma. In emergency settings, oral corticosteroids (OCS) can be lifesaving, but acute and long-term treatment can produce clinically important adverse outcomes and increase the risk of mortality. Therefore, global guidelines recommend limiting the use of OCS. Despite the risks, research indicates that 40-60% of people with severe asthma are receiving or have received long-term OCS treatment. Although often perceived as a low-cost option, long-term OCS use can result in significant health impairments and costs owing to adverse outcomes and increased utilization of healthcare resources. Alternative treatment methods, such as biologics, may produce cost-saving benefits with a better safety profile. A comprehensive and concerted effort is necessary to tackle the continued reliance on OCS. Accordingly, a threshold for OCS use should be established to help identify patients at risk of OCS-related adverse outcomes. Receiving a total dose of more than 500 mg per year should trigger a review and specialist referral. Changes to national and local policies, following examples from other chronic diseases, will be crucial to achieving this goal. Globally, multiple barriers to change still exist, but specific steps have been identified to help clinicians reduce reliance on OCS. Implementing these changes will result in positive health outcomes for patients and social and economic benefits for societies.

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy.

BACKGROUND: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. OBJECTIVE: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. METHODS: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. RESULTS: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. CONCLUSIONS: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction.

Stratification of asthma by lipidomic profiling of induced sputum supernatant.

BACKGROUND: Asthma is a chronic respiratory disease with significant heterogeneity in its clinical presentation and pathobiology. There is need for improved understanding of respiratory lipid metabolism in asthma patients and its relation to observable clinical features. OBJECTIVE: We performed a comprehensive, prospective, cross-sectional analysis of the lipid composition of induced sputum supernatant obtained from asthma patients with a range of disease severities, as well as from healthy controls. METHODS: Induced sputum supernatant was collected from 211 adults with asthma and 41 healthy individuals enrolled onto the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study. Sputum lipidomes were characterized by semiquantitative shotgun mass spectrometry and clustered using topologic data analysis to identify lipid phenotypes. RESULTS: Shotgun lipidomics of induced sputum supernatant revealed a spectrum of 9 molecular phenotypes, highlighting not just significant differences between the sputum lipidomes of asthma patients and healthy controls, but also within the asthma patient population. Matching clinical, pathobiologic, proteomic, and transcriptomic data helped inform the underlying disease processes. Sputum lipid phenotypes with higher levels of nonendogenous, cell-derived lipids were associated with significantly worse asthma severity, worse lung function, and elevated granulocyte counts. CONCLUSION: We propose a novel mechanism of increased lipid loading in the epithelial lining fluid of asthma patients resulting from the secretion of extracellular vesicles by granulocytic inflammatory cells, which could reduce the ability of pulmonary surfactant to lower surface tension in asthmatic small airways, as well as compromise its role as an immune regulator.

Airway epithelial type-2 alarmin profiles: Blood eosinophil counts remain in memory.

Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air-liquid interface (ALI) epithelial cultures and whether this local orientation can be related to systemic patterns (e.g., blood eosinophil counts [BECs]). We investigated alarmin release related to high versus low T2 phenotypes associated with chronic airway diseases. ALIs were reconstituted from 32 control, 40 chronic obstructive pulmonary disease, and 20 asthmatic patients. Interleukin-8 (IL-8; a T1-cytokine), IL-25, IL-33, and thymic stromal lymphopoietin (T2-alarmins) concentrations were assessed in subnatants at steady state and used to explain blood neutrophil and eosinophil counts. IL-25 and IL-8 levels were highest in asthma ALI-subnatants, whereas IL-33 was sparsely detected. Thymic stromal lymphopoietin levels were similar among groups. All asthma cell cultures were T1-high/T2-high, while chronic obstructive pulmonary disease and controls tended to be mixed. BECs were independently explained by both disease and in-culture T2-alarmin levels, irrespective of the T2-alarmin considered. The epithelial ALI-T2 signature was more frequently high in patients with a BEC > 300/mm3 . Despite removal from an in vivo environment for ≥2 months, ALIs release disease-specific cytokine "cocktails" into their subnatants, suggesting continued persistence of alarmin orientation in differentiated cell line environments.

Thoracic manifestations of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a recently described rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 persons per year. The disease can affect virtually any organ and is characterized by unifying histopathological findings. Recently, four subgroups of patients have been characterized: hepatobiliary, head and neck, Mikulicz syndrome and retroperitoneal fibrosis, who illustrate the mainly abdominal and ENT tropism of the disease. Yet, thoracic involvement is not uncommon. It can be detected in up to 30% of patients with systemic IgG4-RD and is the exclusive manifestation of the disease in about 10% of cases. Clinical symptoms are nonspecific and may include dyspnoea, cough or chest pain. Chest CT findings are heterogeneous and primarily include peribronchovascular thickening, nodules, ground-glass opacities and lymphadenopathy. There is no specific diagnostic test for IgG4-RD thoracic involvement, which may mimic malignancy or vasculitis. Therefore, a cautious approach is needed to make an accurate diagnosis: a search for extra-thoracic manifestations, elevated serum IgG4 levels, circulating levels of plasmablasts and pathologic evidence of disease is warranted. Although very suggestive, neither the presence of a polyclonal IgG4 lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis are sufficient to confirm the histological diagnosis. Steroids are recommended as first-line therapy. Rituximab or disease-modifying antirheumatic drugs may be used in relapsed or rare cases of steroid-refractory disease. In this review, we summarize current knowledge regarding the pathophysiology, epidemiology, diagnostic modalities (clinical-biological-imaging-histopathology) and treatment of IgG4-RD thoracic involvement.

Eosinopenia as Predictor of Poor Outcome in Hospitalized COVID-19 Adult Patients from Waves 1 and 2 of 2020 Pandemic.

During SARS-CoV-2 infection, eosinopenia may reflect a hyperactive immune response. In this study of hospitalized COVID-19 patients, we aimed to better understand the prognostic value of severe eosinopenia (absolute eosinophil count = 0 G/L) and decipher its underlying mechanisms. We retrospectively analyzed the records of COVID-19 patients hospitalized from March to June 2020 in three university hospitals in Marseille, France. We assessed the association between severe eosinopenia and a composite poor outcome in these patients, including the need for oxygen supplementation at >6 L/min, ICU admission, and in-hospital death. Among the 551 COVID-19 patients included in this study, severe eosinopenia was found in 228 (51%) of them on admission to hospital and was associated with a composite poor outcome using multivariate analysis (OR = 2.58; CI95 [1.77−3.75]; p < 0.0001). We found a significant association between the presence of severe eosinopenia on admission and the elevation in C-reactive protein, ferritin, IP-10, and suPAR. The histological findings in a series of 37 autopsies from patients who died from severe COVID-19 and presented with severe eosinopenia showed no pulmonary eosinophil trapping. Severe eosinopenia can be a reliable biomarker associated with a composite poor outcome in hospitalized COVID-19 adult patients. It may reflect the magnitude of immune hyperactivation during severe-to-critical COVID-19.

Long-term effectiveness and safety of omalizumab in pediatric and adult patients with moderate-to-severe inadequately controlled allergic asthma.

Omalizumab is recommended as an add-on therapy in patients aged ≥6 years with inadequately controlled, moderate-to-severe persistent allergic asthma. The efficacy and safety of omalizumab treatment in allergic asthma clinical trials and its effectiveness in the real world have been reported in numerous studies. In this review, we examine clinical evidence in pediatric and adult patients with allergic asthma who received omalizumab treatment for at least 2 years, to assess its effectiveness, durability, and trajectory of response over time as well as safety. We performed a literature search from inception until March 2022 in PubMed using the keywords "omalizumab" and "allergic asthma" to retrieve articles examining the effects of omalizumab in patients with allergic asthma, aged ≥6 years. Only articles that evaluated the effectiveness of omalizumab for at least 2 years were included. Data from case reports were excluded. Our review confirmed the long-term effectiveness and safety of omalizumab, demonstrating reduced rate of exacerbations, improved lung function, asthma control, and quality of life, decreased health care resource utilization, and use of corticosteroids (oral/inhaled) with a favorable safety and tolerability profile for up to 9 years in adult patients with moderate-to-severe allergic asthma. Similar results were also observed in the pediatric population with up to 7.5 years of omalizumab treatment. This review highlights and confirms the sustained clinical benefits of omalizumab over long periods of treatment in pediatric and adult populations with allergic asthma.

Mobilisation of HLA-F on the surface of bronchial epithelial cells and platelets in asthmatic patients.

Uncontrolled inflammation of the airways in chronic obstructive lung diseases leads to exacerbation, accelerated lung dysfunction and respiratory insufficiency. Among these diseases, asthma affects 358 million people worldwide. Human bronchial epithelium cells (HBEC) express both anti-inflammatory and activating molecules, and their deregulated expression contribute to immune cell recruitment and activation, especially platelets (PLT) particularly involved in lung tissue inflammation in asthma context. Previous results supported that HLA-G dysregulation in lung tissue is associated with immune cell activation. We investigated here HLA-F expression, reported to be mobilised on immune cell surface upon activation and displaying its highest affinity for the KIR3DS1-activating NK receptor. We explored HLA-F transcriptional expression in HBEC; HLA-F total expression in PBMC and HBEC collected from healthy individuals at rest and upon chemical activation and HLA-F membrane expression in PBMC, HBEC and PLT collected from healthy individuals at rest and upon chemical activation. We compared HLA-F transcriptional expression in HBEC from healthy individuals and asthmatic patients and its surface expression in HBEC and PLT from healthy individuals and asthmatic patients. Our results support that HLA-F is expressed by HBEC and PLT under healthy physiological conditions and is retained in cytoplasm, barely expressed on the surface, as previously reported in immune cells. In both cell types, HLA-F reaches the surface in the inflammatory asthma context whereas no effect is observed at the transcriptional level. Our study suggests that HLA-F surface expression is a ubiquitous post-transcriptional process in activated cells. It may be of therapeutic interest in controlling lung inflammation.

Efficacy and Safety of Masitinib in Corticosteroid-Dependent Severe Asthma: A Randomized Placebo-Controlled Trial.

Background: Masitinib is an oral tyrosine kinase inhibitor that selectively targets mast cell activity and platelet-derived growth factor receptor (PDGFR) signaling, both of which are implicated in various mechanisms of asthma pathogenesis. Objective: Assessment of masitinib as an add-on to standard maintenance therapy as compared with placebo in the treatment of oral corticosteroid-dependent severe asthma. Methods: We conducted a randomized (2:1), placebo-controlled study of masitinib (6 mg/kg/d) in adults with severe asthma uncontrolled by high dose inhaled corticosteroids and long-acting beta-adrenoreceptor agonists plus oral corticosteroids (OCS) (≥7.5 mg/d). No minimum baseline blood eosinophil count was specified. Following a protocol amendment, the primary endpoint was reduction of annualized severe asthma exacerbation rate adjusted for the overall time on treatment (SAER). Subgroup analysis according to yearly cumulative OCS intake was also performed, a higher OCS dose indicating more severe asthma that is harder to control. Results: Following an average exposure of approximately 13 months, masitinib (n = 240) reduced the SAER by 35% relative to placebo (n = 115) (rate ratio (RR) 0.65 (95% CI [0.47-0.90]; P = 0.010)). For patients with eosinophil ≥150 cell/µL, masitinib (n = 181) reduced SAER by 38% relative to placebo (n = 87); RR 0.62 (95% CI [0.42-0.91]; P = 0.016). Benefit of masitinib was shown to increase in the most severely affected patients (OCS intake of >1000 mg/year), with a significant (P < 0.01) reduction in SAER of 50%-70%. Safety was consistent with the known masitinib profile. Conclusion: Orally administered masitinib reduces the risk of asthma exacerbations in severe asthma patients, with an acceptable safety profile. Masitinib may potentially provide a new treatment option for oral corticosteroid-dependent severe asthma.