T-box protein 4 mutation causing pulmonary arterial hypertension and lung diseaseTo the Editor:Pulmonary arterial hypertension (PAH) is a progressive disease mainly characterised by a widespread obstruction of distal pulmonary arteries [1]. Untreated, this disease rapidly leads to right heart failure, then to death [2]. Heritable PAH (hPAH) represents about 30% of PAH cases, and this category includes familial forms with or without identified mutations, and sporadic forms carrying a mutation. The first genetic abnormalities discovered in hPAH were bone morphogenetic protein receptor-2 (BMPR2) mutations. Loss of function of this receptor results in proliferation of vascular smooth muscle cells and selection of endothelial cell clones resistant to apoptosis [3]. Since, several other mutations have been implicated in PAH. Mutation in the T-box protein 4 (TBX4) gene lead to an autosomal-dominant disorder called "small patella syndrome" or "coxopodopatellar syndrome", characterised by patellar aplasia and abnormalities of the feet and pelvis [4]. Recently, TBX4 mutation has been reported in childhood-onset PAH [5] and, more rarely, in adults [6,7].We report a case of a TBX4 mutation carrier presenting PAH but also bronchial and pulmonary parenchymal abnormalities potentially related to this mutation.A 34-year-old woman presented in a tertiary care hospital with a potential diagnosis of severe PAH. She was a former smoker (5 pack-years) and had no medical history. The patient had progressive dyspnoea in New York Heart Association (NYHA) functional class III and she experienced right heart failure 2 months before admission.

Objective pulmonary arterial hypertension (PAH) is a leading cause of death in mixed connective tissue disease (MCTD). We aimed to describe PAH in well-characterized MCTD patients. Methods MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, systemic lupus erythematous (SLE) patients with PAH, and systemic sclerosis (SSc) patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. Results thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD), and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1 year, 5 years, and 10 years, following PAH diagnosis were 83%, 67%, and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. Conclusion PAH is a rare and severe complication of MCTD, associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia, and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as predictor of mortality in MCTD-PAH.

Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF.PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR dependent manner in control ones.PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease.Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using precision-cut lung slices.Our results identified PRRX1 as a mesenchymal transcription factor driving lung fibrogenesis.Brief SummaryInhibition of a single fibroblast-associated transcription factor, namely paired-related homeobox protein 1, is sufficient to dampen lung fibrogenesis.

Rationale Viral respiratory infections, including SARS-CoV-2 infection, can trigger respiratory symptoms among patients suffering from chronic respiratory diseases, leading to exacerbations and hospitalizations. Despite the tropism of SARS-CoV-2 into the respiratory tract, chronic respiratory diseases do not seem to be risk factors for severe forms of COVID-19. Objectives To assess whether hospitalized patients for COVID-19 with chronic respiratory diseases were at lower risk of developing a severe form than other patients. Methods This French study included patients admitted to hospital in COVID-19 ward, suffering from a SARS-CoV-2 infection, diagnosed on RT-PCR or chest computed tomography associated with clinical symptoms, from March 15 to June 30, 2020. Ambulatory patients who were tested in the emergency department and patients with severe hypoxaemia requiring intensive care were not included. All data were collected from electronic medical records up to discharge of the patient. Main Results 617 patients were included: 125 with a chronic respiratory disease, mainly chronic obstructive pulmonary disease (45%) and asthma (30%). The percentage of patients scoring 6 or higher on the WHO Clinical Progression Scale during hospital stay was lower in patients with chronic respiratory disease compared to those without chronic respiratory disease (21.6% versus 31.3%, respectively, p = 0.03). Among patients with chronic respiratory disease, temperature above 38 °C on admission (OR 16.88 (95% CI 4.01–71.00)), lymphopenia (OR 5.08 (1.25–20.72)), CPAP therapy (OR 4.46 (1.04–19.17)) and age (OR 1.09 (1.02–1.16)) were associated with an increased risk to reach a score of 6 or above. Conclusions Hospital admissions in COVID-19 ward of patients suffering from chronic respiratory diseases are at lower risk of developing a severe form of COVID- 19, especially in patients with chronic obstructive pulmonary disease or asthma. Prospective studies would confirm our results and allow to better organize the follow-up of these patients in a pandemic period.

No abstract

No abstract

RationaleDrugs approved for the treatment of pulmonary arterial hypertension (PAH) improve long-term outcomes. These drugs have pulmonary vasodilator properties which may potentially cause a decrease in arterial oxyhaemoglobin saturation (SaO2) in some patients.ObjectivesThe present retrospective study of the French PAH Registry aimed to describe clinical characteristics and outcomes of patients showing a ≥3% decrease in SaO2 while treated with PAH drugs.MethodsWe reviewed 719 PAH patients. The exclusion criteria were PAH associated with congenital heart disease and PAH with overt features of venous/capillaries involvement.Main ResultsOne hundred and seventy-three (24%) patients had a ≥3% decrease in SaO2. At diagnosis, they were older, with a lower diffusion capacity for carbon monoxide and a shorter 6-minute walk distance, when compared to those who did not display a ≥3% decrease in SaO2. The percentage of patients meeting the ESC/ERS low risk criteria at re-evaluation was significantly lower in those with a ≥3% decrease in SaO2 and more patients started long-term oxygen therapy in this group (16% versus 5%, p<0.001). A≥3% decrease in SaO2 was associated with a poorer survival (Hazard Ratio 1.81:95% confidence interval 1.43–2.34; p<0.0001). In a multivariate Cox analysis, a ≥3% decrease in SaO2 was a prognostic factor independent of age at diagnosis and ESC/ERS risk stratification at follow-up.ConclusionsWhen treated with PAH drugs, a large subset of patients experience a≥3% decrease in SaO2, which is associated with worst long-term outcomes and reduced survival.

General lymphatic anomaly (GLA) is a very rare disorder, characterised by multifocal lymphatic malformations into various tissues that is due to congenital abnormalities of lymphatic development. No treatment has ever proved its efficiency.We report a 22-year-old man with recurrent bronchial casts due to thoracic involvement of GLA. After a 6-month treatment with sildenafil (20 mg three times a day), a phosphodiesterase 5 inhibitor, chest CT scan showed a complete regression of ground-glass opacities and lung function test results improved substantially and remained stable for 1 year. The treatment was well tolerated.This observation suggests that sildenafil may be a therapeutic approach to be tested in thoracic involvement of GLA.