Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10, play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored.
We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch PH registry. A literature review explored the phenotypic spectrum of these patients.
Twenty-six PAH patients were identified: 20 harbouring heterozygous GDF2 variants, 1 homozygous GDF2 variant, 4 heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female-to-male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in NYHA functional class III or IV with severe haemodynamic compromise (median pulmonary vascular resistance 9.0 WU, range 3.3–40.6) WU. Haemoptysis was reported in four patients, none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT and identified cardiomyopathy and developmental disorders in BMP10 carriers.
GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to literature. BMP10 full phenotypic ramifications warrant further investigation.
Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of IFN-stimulated genes (ISGs). How asthma genetic susceptible genes modulate cellular response upon viral infection through fine-tuning ISGs induction and subsequent airway inflammation in genetically susceptible asthmatics remains largely unknown.
To decipher the functions of GSDMB in respiratory virus-induced lung inflammation.
In two independent cohorts, we analyzed expression correlation between GSDMB and ISGs. In human bronchial epithelial cell line or primary cells, we generated GSDMB-overexpressing and -deficient cells. A series of qPCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISGs induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and applied respiratory syncytial virus (RSV) infection to determine the role of GSDMB on RSV-induced lung inflammation in vivo.
Gasdermin B encoded by GSDMB, one of the most significant asthma-susceptible genes at 17q21, acts as a novel RNA sensor, promoting MAVS-TBK1 signaling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB gene in mouse airway epithelium leads to enhanced ISGs induction, increased airway inflammation with mucus hyper-secretion upon RSV infection.
GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.
Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. However, the involvement of T cell subsets remains unclear.
We enrolled ABPA patients, asthma patients and healthy controls. Th1, Th2, Th17, Treg and IL-21+CD4+T cells in total or sorted subsets of peripheral blood mononuclear cells (PBMCs) and ABPA Bronchoalveolar Lavage fluid (BALF) were analyzed by flow cytometry. RNA sequencing of subsets of CD4+T cells were done in exacerbated ABPA patients and healthy controls. Antibodies of T-B cell co-cultures in vitro were measured.
ABPA patients had increased Th2 cells, similar Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T cells was rarely detected in healthy controls but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T cells were mainly peripheral T helper (Tph) cells (PD-1+CXCR5–), which also presented in the BALF of ABPA patients. The proportions of circulating Tph were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T helper (Tfh) cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B cells into plasmablasts and significantly enhanced the production of IgE.
We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.
: In cystic fibrosis (CF), gastrointestinal dysfunction and lower airway infection occur early and are independently associated with poorer outcomes in childhood. This study aimed to define the relationship between the microbiota at each niche during the first 2-years of life, its association with growth and airway inflammation, and explanatory features in the metabolome.
Sixty-seven bronchoalveolar lavage (BAL), 62 plasma and 105 stool samples were collected from 39 infants with CF between 0–24-months who were treated with prophylactic antibiotics. 16S rRNA amplicon and shotgun metagenomic sequencing were performed on BAL and stool respectively; metabolomic analyses were performed on all sample types. Sequencing data from healthy age-matched infants were used as controls.
Bacterial diversity increased over the first 2-years in both BAL and stool, and microbial maturation was delayed in comparison to healthy controls from the RESONANCE cohort. Correlations between their respective abundances in both sites suggest stool may serve as a non-invasive alternative for detecting BAL Pseudomonas and Veillonella. Multi-site metabolomic analyses revealed age- and growth-related changes, associations with neutrophilic airway inflammation, and a set of core systemic metabolites. BAL Pseudomonas abundance was correlated with altered stool microbiome composition and systemic metabolite alterations, highlighting a complex gut-plasma-lung interplay and new targets with therapeutic potential.
Exploration of the gut-lung microbiome and metabolome reveals diverse multi-site interactions in CF that emerge in early life. Gut-lung metabolomic links with airway inflammation and Pseudomonas abundance warrant further investigation for clinical utility, particularly in non-expectorating patients.
FEV1Q is a simple approach to spirometry interpretation that compares measured lung function to a lower boundary. This study evaluated how well FEV1Q predicts survival compared to current interpretation methods and whether race impacts FEV1Q.
White and Black adults with complete spirometry and mortality data from the National Health and Nutrition Examination Survey (NHANES) III and United Network for Organ Sharing (UNOS) database for lung transplant referrals were included. FEV1Q was calculated as forced expiratory volume in one second (FEV1) divided by 0·4 L for females or 0·5 L for males. Cumulative distributions of FEV1 were compared across races. Cox proportional hazard models tested mortality risk from FEV1Q adjusting for age, sex, height, smoking, income, and among UNOS individuals, referral diagnosis. Harrell's C-statistics were compared between absolute FEV1, FEV1Q, FEV1/height2, FEV1 z-scores and FEV1% predicted. Analyses were stratified by race.
Among 7182 individuals from NHANES and 7149 from UNOS, 1907 (27%) and 991 (14%) were Black respectively. The lower boundary FEV1 values did not differ between Black and White individuals in either population (FEV1 1st percentile difference: ≤0·01 L; p-value>0·05). Decreasing FEV1Q was associated with increasing hazard ratio (HR) for mortality (NHANES HR 1·33, 95% CI 1·28–1·39; UNOS HR 1·18, 95% CI 1·12–1·23). The associations were not confounded nor modified by race. Discriminative power was highest for FEV1Q compared to alternative FEV1 approaches in both Black and White individuals.
FEV1Q is an intuitive and simple race-neutral approach to interpreting FEV1 that predicts survival better than current alternative methods.
People with CF (PwCF) carrying at least one copy of the F508del allele can benefit from a small molecule therapy referred to as CFTR modulators (CFTRm). Triple CFTRm combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) resulted in marked improvement in clinical outcomes such as the percentage of predicted forced expiratory volume in 1 s (ppFEV1) and body mass index (BMI) [1]; however, granular data from the clinical trial also showed that the treatment response to CFTRm varied among PwCF, even among PwCF carrying the same CFTR genotype. To date, only short-circuit-current measurements on human nasal epithelial cells have been validated as a predictive biomarker of CFTRm treatment response [2]. The forskolin-induced swelling assay (FIS) performed on patient-derived intestinal organoids (IOs) has been tested as another candidate tool for predicting the CFTRm response [3–5]. To date, no studies have compared the extent of FIS (i.e., numeric values of the area under the curve, AUC) and the magnitude of clinical response to ELX/TEZ/IVA in real life. Thus, we investigated this correlation to assess whether the FIS can predict clinical outcomes in F508del homozygous PwCF treated with ELX/TEZ/IVA.
]]>Chronic Obstructive Pulmonary Disease (COPD) is a significant global health burden due to its rising prevalence and the complexity of its management [1]. The development of personalized medicine approaches tailored to individual patient needs and disease characteristics is seen as a promising direction, but it faces challenges in implementation and accessibility [2]. One of the main limitations in the treatment of COPD patients is the heterogeneous nature of its pathogenesis, as it involves the activation of multiple inflammatory cells, such as lymphocytes, neutrophils, macrophages, and eosinophils, which contribute to the inflammatory response [3]. Of all the culprits involved in COPD pathogenesis, type 2 inflammation represents a distinct pathway, primarily involving type 2 helper T cells (Th2 cells) and associated cytokines [3]. The emergence of type 2 monoclonal antibodies such as anti-IL5, anti-IL33, anti-TSLP and anti-IL4R, initially developed for the treatment of severe uncontrolled asthma, offers new hope for a subset of COPD patients, who have type 2 airway inflammation as the main driver of their disease. In this review, we will discuss the role of type 2 inflammation and the potential therapeutic approaches targeting it in COPD.
]]>Long COVID (also known as "post-acute sequelae of COVID-19") is a multi-system disorder that follows an acute bout of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [1]. Although its exact prevalence is unknown, it is estimated to affect approximately 10% of SARS-CoV-2 infected individuals, though in reality the percentage is likely much higher owing to under-reporting of cases [1]. The prevalence is elevated in patients who have had acute SARS-CoV-2 pneumonia requiring hospitalization and lower in those who have been previously vaccinated or were infected with the Omicron variant [1]. In approximately 6% of the cases of long COVID, pulmonary symptoms such as dyspnea, cough and wheeziness are prominent, leading to considerable disability and morbidity [2, 3]. While it is attractive to view long COVID as one disease, it is likely a very complex, heterogeneous disorder, with multiple different phenotypes, each driven by a unique set of molecules and pathways [1].
]]>Interleukin-6 (IL-6) has been linked with the pathobiology of pulmonary arterial hypertension (PAH). IL-6 plasma levels are elevated in PAH patients and closely linked to survival (1). Both increased IL-6 activity and gene knockout influence the development of, and resistance to, pulmonary hypertension in animal models (2–4). IL-6 can repress expression of BMPR2, a gene key to PAH risk (5).
]]>Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. However, the association between individual exposure to air pollutants and lung cancer development in patients with IPF is unknown. This study aimed to assess the effect of individual exposure to nitrogen dioxide (NO2) on lung cancer development in patients with IPF.
We enrolled 1085 patients from the IPF cohort (mean age: 65.6 years, male: 80.6%). We estimated individual-level long-term exposures to NO2 at the patient's residential addresses using a national-scale exposure prediction model based on the data from air quality regulatory monitoring stations. To evaluate the association between NO2 levels and lung cancer development in IPF, we used an individual- and area-level covariates adjusted model as our primary model.
The estimated average annual NO2 concentration was 23.1 parts per billion (ppb). During a follow-up of 4.3 years (median), 86 patients (7.9%) developed lung cancer. NO2 concentration was associated with lung cancer development in an unadjusted model (hazard ratio [HR], 1.219; p=0.042), while a marginal association was found in the primary model (HR 1.280; p=0.084). When NO2 concentration was divided by the median value (21.0 ppb), exposure to high NO2 levels (≥ 21.0 ppb) was associated with a 2.0-fold increase in the risk of lung cancer development (HR, 2.023; p=0.047) in the primary model.
Individual exposure to high NO2 levels may increase the risk of lung cancer development in patients with IPF.
The ISHAM working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) nearly a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics.
An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM, fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%.
We recommend screening for A. fumigatus sensitization using fungus-specific IgE in all newly diagnosed adult asthmatics at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitization and serum total IgE ≥500 IU·mL–1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia, or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum.
We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response.
We have framed consensus guidelines for diagnosing, classifying, and treating ABPA(M) for patient care and research.
This study aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulations, and fibrotic-like changes) and pulmonary function, three years following coronavirus disease 2019(COVID-19).
This prospective, longitudinal cohort study enrolled COVID-19 survivors who exhibited residual lung abnormalities upon discharge from two hospitals. Follow-up assessments were conducted at 6 months, 12 months, 2 years, and 3 years post-discharge, and included pulmonary function tests, 6-minute walk distance (6MWD), chest CT scans, and symptom questionnaires. Non-COVID-19 controls were retrospectively recruited for comparative analysis.
728 COVID-19 survivors and 792 controls were included. From 6 months to 3 years, there was a gradual improvement in reduced diffusing capacity of the lungs for carbon monoxide (DLCO<80% predicted, 49% versus 38%, p=0.001), 6MWD (496 m versus 510 m, p=0.002) and residual lung abnormalities(46% versus 36%, p<0.001), regardless of the disease severity. Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32% versus 16%, p<0.001), lower 6MWD (494 m versus 510 m, p=0.003), and abnormal DLCO (57% versus 27%, p<0.001) compared to those with complete resolution. Compared to the controls, the proportion of DLCO impairment (38% versus 17%, p<0.001) and respiratory symptoms (23% versus 2.2%, p<0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up.
Most patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than one-third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.
Idiopathic pulmonary fibrosis (IPF) with co-existent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts.
Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE:non-CPFE: derivation cohort=317:183; replication cohort=358:152), who were subgrouped using 10%, or 15% visual emphysema thresholds, and an unsupervised machine learning model considering emphysema and ILD extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (DLco) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups.
In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline DLco compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year DLco decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations.
When assessing disease progression in IPF, DLco decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.