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What is already known about this topic? Patients with asthma are rare in epidemiological studies of severe acute respiratory syndrome coronavirus 2 pneumonia.What does this article add to our knowledge? Being asthmatic is not a risk factor for severe acute respiratory syndrome coronavirus 2.How does this study impact current management guidelines? Severe acute respiratory syndrome coronavirus 2 pneumonia may not induce severe asthma exacerbation.BACKGROUND: Viral infections are known to exacerbate asthma in adults. Previous studies have found few patients with asthma among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia cases. However, the relationship between SARS-CoV-2 infection and severe asthma exacerbation is not known. OBJECTIVE: To assess the frequency of asthma exacerbation in patients with asthma hospitalized for SARS-CoV-2 pneumonia and compare symptoms and laboratory and radiological findings in patients with and without asthma with SARS-CoV-2 pneumonia.METHODS: We included 106 patients between March 4 and April 6, 2020, who were hospitalized in the Chest Diseases Department of Strasbourg University Hospital; 23 had asthma. To assess the patients' asthma status, 3 periods were defined: the last month before the onset of COVID-19 symptoms (p1), prehospitalization (p2), and during hospitalization (p3). Severe asthma exacerbations were defined according to Global INitiative for Asthma guidelines during p1 and p2. During p3, we defined severe asthma deterioration as the onset of breathlessness and wheezing requiring systemic corticosteroids and inhaled b2 agonist. RESULTS: We found no significant difference between patients with and without asthma in terms of severity (length of stay, maximal oxygen flow needed, noninvasive ventilation requirement, and intensive care unit transfer); 52.2% of the patients with asthma had Global INitiative for Asthma step 1 asthma. One patient had a severe exacerbation during p1, 2 patients during p2, and 5 patients were treated with systemic corticosteroids and inhaled b2 agonist during p3. CONCLUSIONS: Our results demonstrate that patients with asthma appeared not to be at risk for severe SARS-CoV-2 pneumonia. Moreover, SARS-CoV-2 pneumonia did not induce severe asthma exacerbation.

BACKGROUND: Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 (Bmpr2) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmpr2 mutation were susceptible to developing more severe PAH. METHODS: The zinc finger nuclease method was used to establish rat lines with mutations in the Bmpr2 gene. These rats were then characterized at the hemodynamic, histological, electrophysiological, and molecular levels. RESULTS: Rats with a monoallelic deletion of 71 bp in exon 1 (Δ71 rats) showed decreased BMPRII expression and phosphorylated SMAD1/5/9 levels. Δ71 Rats develop age-dependent spontaneous PAH with a low penetrance (16%-27%), similar to that in humans. Δ71 Rats were more susceptible to hypoxia-induced pulmonary hypertension than wild-type rats. Δ71 Rats exhibited progressive pulmonary vascular remodeling associated with a proproliferative phenotype and showed lower pulmonary microvascular density than wild-type rats. Organ bath studies revealed severe alteration of pulmonary artery contraction and relaxation associated with potassium channel subfamily K member 3 (KCNK3) dysfunction. High levels of perivascular fibrillar collagen and pulmonary interleukin-6 overexpression discriminated rats that developed spontaneous PAH and rats that did not develop spontaneous PAH. Finally, detailed assessments of cardiomyocytes demonstrated alterations in morphology, calcium (Ca 2+), and cell contractility specific to the right ventricle; these changes could explain the lower cardiac output of Δ71 rats. Indeed, adult right ventricular cardiomyocytes from Δ71 rats exhibited a smaller diameter, decreased sensitivity of sarcomeres to Ca 2+ , decreased [Ca 2+ ] transient amplitude, reduced sarcoplasmic reticulum Ca 2+ content, and short action potential duration compared with right ventricular cardiomyocytes from wild-type rats. CONCLUSIONS: We characterized the first Bmpr2 mutant rats and showed some of the critical cellular and molecular dysfunctions described in human PAH. We also identified the heart as an unexpected but potential target organ of Bmpr2 mutations. Thus, this new genetic rat model represents a promising tool to study the pathogenesis of PAH.

Objectives To retrospectively investigate the incidence of acute adrenal infarction (AAI) in patients who underwent chest CT for severe SARS-CoV-2 infection and to correlate findings with prognosis. Methods The local ethics committee approved this retrospective study and waived the need of informed consent. From March 9 to April 10, 2020, all patients referred to our institution for a clinical suspicion of COVID-19 with moderate to severe symptoms underwent a chest CT for triage. Patients with a/parenchymal lesion characteristics of COVID-19 involving at least 50% of lung parenchyma and b/positive RT-PCR for SARS-CoV-2 were retrospectively included. Adrenal glands were reviewed by two independent readers to look for AAI. Additional demographics and potential biological markers of adrenal insufficiency were obtained. Correlations with ICU stay and mortality were sought. Results Out of the 219 patients with critical (n = 52) and severe lung (n = 167) parenchyma lesions, 51 (23%) had CT scan signs of AAI, which was bilateral in 45 patients (88%). Four patients had an acute biological adrenal gland insufficiency (8%). Univariate analysis in AAI+ patients demonstrated a higher rate of ICU stay (67% vs. 45%, p < 0.05) and a longer stay (more than 15 days for 31% for AAI+ vs. 19%, p < 0.05) compared with AAI− patients. Mortality rate was similar (27%, p = 0.92). Conclusions Acute adrenal infarction on initial chest evaluation of severe COVID-19 is frequent (51/219, 23%) and might be a sign of poorer prognosis. Key Points • Acute adrenal infarction on initial chest CT evaluation of severe COVID-19 is frequent (51/219). • AAI might be a factor of poorer prognosis, with increased rate of ICU hospitalization and length of stay.

Beyond the major gene BMPR2, several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the KDR gene was found in a large genetic association study.We prospectively analysed the KDR gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.Two index cases with severe PAH from two different families were found to carry a loss-of-function mutation in the KDR gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for haemoglobin (DLCOc) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low DLCOc, or have only decreased DLCOc, whereas non-carrier relatives have normal DLCOc. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal DLCOc.We provided genetic evidence for considering KDR as a newly identified PAH-causing gene by describing the segregation of KDR mutations with PAH in two families. In our study, KDR mutations are associated with a particular form of PAH characterised by low DLCOc and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema.

Tyrosine kinase inhibitors (TKIs) targeting BCR/ABL such as imatinib, nilotinib, dasatinib, bosutinib and ponatinib have revolutionised the management of patients with chronic myeloid leukaemia (CML) [1]. Pleural effusions and pulmonary arterial hypertension (PAH) have been reported in patients treated with these agents [2][3][4]. These side-effects are more frequently observed with dasatinib use, with partial or complete reversibility after drug withdrawal [3]. Bosutinib is a second-generation TKI prescribed in case of intolerance or resistance to imatinib, nilotinib or dasatinib. In the present report, we describe two cases of worsening of dasatinib-induced PAH and two cases of severe pleural effusions, suggesting overlapping pulmonary toxicity of bosutinib and dasatinib.Patient 1, a 44-year-old Caucasian woman with CML, was successively treated with hydroxycarbamide, imatinib, nilotinib and dasatinib. After 3 years on dasatinib, she complained of exertional dyspnoea, New York Heart Association functional class (NYHA FC) II. Echocardiography showed a dilated right ventricle and an estimated systolic pulmonary artery pressure (PAP) of 80 mmHg. Right heart catheterisation demonstrated pre-capillary pulmonary hypertension (mean PAP 34 mmHg, pulmonary capillary wedge pressure (PCWP) 9 mmHg, cardiac index (CI) 3.8 L·min

Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation.DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analyzed using bioinformatics tools.Unsupervised hierarchical clustering allowed the identification of two clusters of probes that discriminates controls and PAH patients. Among 147 differential methylated promoters, 46 promoters coding for proteins or miRNAs were related to lipid metabolism. Top 10 up and down-regulated genes were involved in lipid transport including ABCA1, ABCB4, ADIPOQ, miR-26A, BCL2L11. NextBio meta-analysis suggested a contribution of ABCA1 in PAH. We confirmed ABCA1 mRNA and protein downregulation specifically in PAH PEC by qPCR and immunohistochemistry and made the proof-of-concept in an experimental model of the disease that its targeting may offer novel therapeutic options.In conclusion, DNA methylation analysis identifies a set of genes mainly involved in lipid transport pathway which could be relevant to PAH pathophysiology.