[COPD exacerbations]. / Exacerbations de BPCO.

COPD EXACERBATIONS. COPD exacerbations, characterized by an acute worsening of dyspnea and/or cough and sputum volume beyond daily variations, are a public health issue because of their frequency, the number of hospitalizations and the high rate of recurrence. Because of non-specific symptoms, differential diagnoses must be ruled out. Additional tests are rarely necessary, and treatment is outpatient, except in severe cases (respiratory distress, severity of COPD, socio-economic conditions). Increased bronchodilator treatment, and sometimes antibiotic and/or systemic corticosteroid therapy, are the main measures to be introduced and should be systematically reassessed. After an exacerbation, the aim is to optimize follow-up and treatment, to prevent recurrences.

EXACERBATIONS DE BPCO. Les exacerbations de bronchopneumopathie chronique obstructive (EBPCO), caractérisées par une aggravation aiguë de la dyspnée et/ou de la toux et du volume de l'expectoration au-delà des variations quotidiennes, constituent un enjeu de santé publique du fait de leur fréquence, du nombre d'hospitalisations et du taux élevé de récidives. L'absence de spécificité des symptômes impose d'éliminer les diagnostics différentiels. Les examens complémentaires sont rarement nécessaires, et le traitement est ambulatoire hormis en cas de signes de gravité (détresse respiratoire, sévérité de la BPCO, conditions socio-économiques). La majoration du traitement bronchodilatateur, parfois une antibiothérapie et/ou une corticothérapie systémique sont les principales mesures à instaurer et doivent faire l'objet d'une réévaluation systématique. Après une exacerbation, l'optimisation du suivi et du traitement a pour objectif la prévention d'une récidive.

Case report: Extracorporeal life support as a successful bridge to recovery in an incident case of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance (PVR) due to vascular remodeling of the small pulmonary arteries. In advanced RV failure or severe hypoxemia, extra corporeal life support (ECLS) is now to be considered, with the objective to bridge patients back to their baseline clinical state while waiting or right after lung transplantation, or bridge to pharmacological optimization of PAH (i.e., bridge to recovery). We describe herein a case of a 30-year-old woman (gravida 6, para 6) with an incident case of heritable PAH revealed by refractory hypoxemia. Despite the use of mechanical ventilation and fluid optimization, the patient remained profoundly hypoxemic. ECLS was then initiated to avoid tissue hypoxia. The mechanical option chosen was peripheral femoro-femoral venoarterial extracorporeal membrane oxygen (VA-ECMO), percutaneously implanted. Due to the absence of evidence of chronic respiratory disease or chronic thromboembolic pulmonary hypertension, this severe pre-capillary pulmonary hypertension was attributed to PAH. Therefore, epoprostenol infusion and an association of oral treatments (bosentan and tadalafil) were administered. A dramatic improvement was observed, allowing decannulation 7 days after the initiation of pharmacological treatment. After 29 days, the patient was discharged from the hospital with epoprostenol, bosentan, and tadalafil. The assessment has been completed by positive research on mutations (c.741C > G, p.Tyr247) corresponding to a loss of function of the bone morphogenetic protein receptor 2 (BMPR2) gene. The final diagnosis was heritable PAH. The use of ECLS has been well demonstrated in patients with PAH complicated by acute RV failure or refractory hypoxemia in the "bridge-to-transplantation" strategy. Only a few reports have described the use of ECLS as a "bridge-to-recovery" with PAH drugs in untreated or undertreated PAH patients, but none has described such a rapid improvement with resolution of refractory hypoxemia. More studies are needed to assess the benefits and limitations of the "bridge-to-recovery" strategy and to identify the patients most likely to benefit from it.

[Natural history of COPD: evolution of concepts]. / Histoire naturelle de la BPCO : évolution des concepts.

NATURAL HISTORY OF COPD: EVOLUTION OF CONCEPTS. Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease responsible for significant morbidity and mortality. The natural history of this disease is complex. The first cause is tobacco smoke exposure, followed by exposure to biomass smoke and occupational exposure to inhaled toxic substances. Genetic predisposing factors are known as the alpha-1-antitrypsin deficiency. The involvement of respiratory events in childhood in the genesis of the disease is also increasingly described. The decline of the different respiratory trajectories can be accelerated in COPD. The phenotypes of this disease also have a role in the evolution of respiratory function over time and their descriptions can modulate the therapeutic management in this disease.

HISTOIRE NATURELLE DE LA BPCO: ÉVOLUTION DES CONCEPTS. La bronchopneumopathie chronique obstructive (BPCO) est une maladie respiratoire chronique fréquente et responsable d'une morbi-mortalité importante. La compréhension de l'histoire naturelle de cette pathologie a évolué ces dernières années. La première cause de BPCO est le tabagisme, suivi de l'exposition à la fumée de biomasse et de l'exposition professionnelle à des toxiques inhalés. Des facteurs de prédisposition génétique sont connus, comme le déficit en alpha-1-antitrypsine. L'implication d'événements respiratoires au cours de l'enfance dans la genèse de la maladie est également de plus en plus décrite. Le déclin des différentes trajectoires de la fonction respiratoire peut être accéléré en cas de BPCO. Les phénotypes de cette maladie jouent aussi un rôle dans l'évolution de la fonction respiratoire au cours du temps et leur description peut moduler la prise en charge thérapeutique de cette maladie.

Development and external validation of a prediction model for the transition from mild to moderate or severe form of COVID-19.

OBJECTIVES: COVID-19 pandemic seems to be under control. However, despite the vaccines, 5 to 10% of the patients with mild disease develop moderate to critical forms with potential lethal evolution. In addition to assess lung infection spread, chest CT helps to detect complications. Developing a prediction model to identify at-risk patients of worsening from mild COVID-19 combining simple clinical and biological parameters with qualitative or quantitative data using CT would be relevant to organizing optimal patient management. METHODS: Four French hospitals were used for model training and internal validation. External validation was conducted in two independent hospitals. We used easy-to-obtain clinical (age, gender, smoking, symptoms' onset, cardiovascular comorbidities, diabetes, chronic respiratory diseases, immunosuppression) and biological parameters (lymphocytes, CRP) with qualitative or quantitative data (including radiomics) from the initial CT in mild COVID-19 patients. RESULTS: Qualitative CT scan with clinical and biological parameters can predict which patients with an initial mild presentation would develop a moderate to critical form of COVID-19, with a c-index of 0.70 (95% CI 0.63; 0.77). CT scan quantification improved the performance of the prediction up to 0.73 (95% CI 0.67; 0.79) and radiomics up to 0.77 (95% CI 0.71; 0.83). Results were similar in both validation cohorts, considering CT scans with or without injection. CONCLUSION: Adding CT scan quantification or radiomics to simple clinical and biological parameters can better predict which patients with an initial mild COVID-19 would worsen than qualitative analyses alone. This tool could help to the fair use of healthcare resources and to screen patients for potential new drugs to prevent a pejorative evolution of COVID-19. CLINICAL TRIAL REGISTRATION: NCT04481620. CLINICAL RELEVANCE STATEMENT: CT scan quantification or radiomics analysis is superior to qualitative analysis, when used with simple clinical and biological parameters, to determine which patients with an initial mild presentation of COVID-19 would worsen to a moderate to critical form. KEY POINTS: • Qualitative CT scan analyses with simple clinical and biological parameters can predict which patients with an initial mild COVID-19 and respiratory symptoms would worsen with a c-index of 0.70. • Adding CT scan quantification improves the performance of the clinical prediction model to an AUC of 0.73. • Radiomics analyses slightly improve the performance of the model to a c-index of 0.77.

Hemodynamic characteristics in patients with pulmonary hypertension and chronic obstructive pulmonary disease: A retrospective monocentric cohort study.

BACKGROUND: Pulmonary hypertension (PH) is a hemodynamic condition characterized by an abnormal elevation in pulmonary arterial pressures. Several pathophysiological pre-capillary and post-capillary mechanisms have been described. PH is a common complication of chronic obstructive pulmonary disease (COPD), however, the prevalence of each mechanism in the development of PH in patients with COPD has been hardly studied. METHODS: We reported the clinical, functional, hemodynamic characteristics and outcomes of patients diagnosed with COPD and PH among the expert PH center of Nancy between January 1st, 2015 and March 31st, 2021. RESULTS: 123 patients with COPD and PH were included. Most patients (n=122, 99%) had a pre-capillary mechanism, 9% (n=11) a post-capillary mechanism, and 1% (n=1) an unclassified mechanism. 111 (90%) patients had pure pre-capillary PH and 11 (9%) patients had combined pre- and post-capillary PH. Combined pre- and post-capillary PH group was characterized by higher prevalence of cardiovascular comorbidities and of sleep apnea-hypopnea syndrome, a higher body mass index, lower lung volumes, higher mean pulmonary arterial pressure, pulmonary arterial wedge pressure and right atrial pressure. At follow-up (median 30 months), 52 patients had died, and 11 had undergone lung transplantation. One-year, three-year and five-year transplant-free survival rates were 71%, 29% and 11% respectively. There was no difference on outcomes between groups. CONCLUSION: PH in COPD patients is mostly due to pre-capillary mechanism. However, the existence of various and numerous comorbidities in COPD, especially cardiovascular, can lead to the participation of post-capillary mechanisms in the development of PH. Further studies are needed to confirm these findings and to assess the impact on outcomes and management strategies in these different patients.

Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study.

BACKGROUND: Survivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life. METHODS: Adults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study. RESULTS: Among 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (D LCO) and significant radiological sequelae, respectively. During extended follow-up, both D LCO and forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated with D LCO at 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images. CONCLUSIONS: Although pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Prevalence of and Factors Associated with Respiratory Symptoms Among Patients with Inflammatory Bowel Disease: A Prospective Study.

BACKGROUND: No large, prospective study has investigated respiratory symptoms in patients with inflammatory bowel diseases. We aimed to describe the prevalence of and factors associated with respiratory symptoms in patients with inflammatory bowel disease. METHODS: In an observational, prospective, cross-sectional study, we evaluated the frequency of respiratory symptoms using a validated self-reporting questionnaire from February 2019 to February 2021 during routine follow-up outpatient visits of patients with inflammatory bowel disease followed in the Gastroenterology Department of the Nancy University Hospital. In case of a positive questionnaire, patients were systematically offered a consultation with a pulmonologist in order to investigate a potential underlying respiratory disease. RESULTS: There were 325 patients included, and 180 patients had a positive questionnaire (144 with Crohn's disease). Of the included patients, 165 (50.8%) presented with respiratory symptoms, with dyspnea being the most frequent symptom (102 patients). There were 102 patients (56.7%) who benefited from a consultation in the pulmonology department: 43 (42.2%) were diagnosed with a respiratory disease, mainly asthma (n = 13) or chronic obstructive pulmonary disease (n = 10). Fourteen patients (13.7%) had obstructive sleep apnea. A body mass index increase, being a smoker or ex-smoker, and having articular extra-intestinal manifestations were independently associated with a higher prevalence of respiratory symptoms. CONCLUSIONS: Half of patients with inflammatory bowel disease reported respiratory symptoms in our study. Patients with inflammatory bowel disease should be systematically screened, as pulmonary disease is frequently present in this population, with specific attention being given to smokers or ex-smokers and patients with extra-articular intestinal manifestations.

We conducted a large-scale, prospective study, finding a high prevalence of respiratory symptoms in patients with inflammatory bowel disease, which led to a variety of respiratory diseases, including asthma and obstructive pulmonary disease. Patients should therefore be systematically screened for pulmonary manifestations.

Relationship between ectopic calcifications and bone fragility depicted on computed tomography scan in 70 patients with systemic sclerosis.

Background: A higher risk of osteoporotic fracture was described in systemic sclerosis patients than in healthy patients. Objective: To evaluate the relation between osteoporotic fracture risk measured by the scanographic bone attenuation coefficient of the first lumbar vertebra (SBAC-L1) on computed tomography (CT) scan and the presence of ectopic calcifications: vascular, valvular and spinal. Methods: This monocentric retrospective study was performed on patients followed between 2000 and 2014 at Nancy University Hospital. Systemic sclerosis patients, according to ACR/EULAR 2013 criteria, followed from 2000 to 2014 and who underwent, during their follow-up, a CT including the first lumbar vertebra were included. The SBAC-L1 was measured with a threshold set at 145 Hounsfield units (HU). Vascular and spinal calcifications were studied on CT. For vascular calcifications, the Agatston score was used. Valvular calcifications were studied on echocardiography. Results: A total of 70 patients were included (mean age: 62.3 (±15.6) years, women 88.5%). The mean SBAC-L1 was 157.26 (±52.1) HU, and 35 patients (50%) presented an SBAC-L1 ⩽ 145 HU. The reproducibility of the calcification evaluation was good, with kappa coefficients varying between 0.63 and 1. In univariate analysis, spinal and vascular calcifications were associated with an SBAC-L1 ⩽ 145 HU, with ORs of 13.6 (1.6-113.3) and 8 (95%CI: 2.5-25.5), respectively. In multivariate analysis, the SBAC-L1 was not associated with the presence of any ectopic calcifications. The SBAC-L1 decreased with age (p = 0.0001). Conclusion: Patients with systemic sclerosis with an SBAC-L1 ⩽ 145 HU were older, but they did not have more ectopic calcification. Trial registration: The ethics committee of Nancy Hospital agreed with this study (referral file number 166). This study was designed in accordance with the general ethical principles outlined in the Declaration of Helsinki.

Growth of home respiratory equipment from 2006 to 2019 and cost control by health policies.

BACKGROUND: Home respiratory equipment (HRE) designed for the management of chronic respiratory failure includes oxygen therapy (O2), noninvasive ventilation (NIV) and mechanical insufflation-exsufflation (MI-E). The growth of the number of patients treated by HRE, the prevalence and the associated costs in France have not been determined. METHODS: The French open access national health insurance aggregated data was used to estimate the evolution of theses parameters from 2006 to 2019. RESULTS: The number of patients treated by HRE increased by 117% between 2006 and 2019, reaching a total of 245,896 patients (367/100,000). Prescriptions for O2, NIV, and MI-E increased by 88%, 189% and 162%, respectively. In 2019, 139,323 patients received long-term home O2 alone (208/100,000) with a 13% decrease for liquid O2 compared to a 44% increase for O2 concentrator. The number of patients treated by portable oxygen concentrator increased by 509% over the last 5 years. In 2019, 96,126 patients received NIV (144/100,000) and 97% of these patients were treated by NIV for less than 12 h/day. A total of 9,158 patients were treated by MI-E in 2019 (13.6/100,000). Despite the global increase in the number of patients, health costs decreased from 9% to 8% of total medical device spending in 2019 due to adjustment of health policies, such as a reduction of reimbursement rates. CONCLUSION: Our results highlighted the high rate of HRE prescription, but with cost control as a result of adapted health policies.

Progression to a severe form of COVID-19 among patients with chronic respiratory diseases.

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.

Interstitial pneumonia with autoimmune features: Evaluation of connective tissue disease incidence during follow-up.

OBJECTIVES: Among interstitial pneumonia with autoimmune features (IPAF) patients, identifying those at risk to develop a connective tissue disease (CTD) during the disease course is a key issue. The aim of this study was to evaluate the incidence of definite CTD diagnosis in IPAF patients during follow-up. METHODS: We performed a multicentric cohort study of interstitial lung disease (ILD) from 2010 to 2017 in pneumology and immunology departments of tertiary care centers. Patients with a known cause of ILD (including established CTD) at diagnosis were excluded. Among patients with idiopathic ILD and at least three years of follow-up, two groups (IPAF and non-IPAF) were retrospectively analyzed at time of diagnosis. RESULTS: A total of 249 patients with ILD were enrolled, including 70 IPAF and 179 non-IPAF patients. After a mean follow-up time of 77 ± 44 months, 18/70 IPAF patients (26%) had a CTD diagnosis - 9 antisynthetase syndrome, 8 systemic sclerosis and 1 overlap myositis - compared with 4/179 non-IPAF patients (2%). IPAF patients were at higher risk of CTD occurrence at 3 years of follow-up compared to non-IPAF patients (HR 10.1, 95% CI 3.1-33.1, p < 0. 01). IPAF patients progressing to CTD tended to be younger, more often female and have more frequently puffy fingers, capillaroscopy abnormalities and antisynthetase antibodies at diagnosis. CONCLUSIONS: We found that a significant proportion of IPAF patients had associated CTD diagnosis during follow-up. Prospective studies are needed to confirm baseline predictive factors of CTD occurrence in IPAF patients.

Outcomes of patients with decreased arterial oxyhaemoglobin saturation on pulmonary arterial hypertension drugs.

BACKGROUND: Drugs 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 (S aO2 ) in some patients. The present retrospective study of the French Pulmonary Hypertension Registry aimed to describe the clinical characteristics and outcomes of patients showing a ≥3% decrease in S aO2 while treated with PAH drugs. METHODS: We reviewed 719 PAH patients. The exclusion criteria were PAH associated with congenital heart disease and PAH with overt features of venous/capillaries involvement. RESULTS: 173 (24%) patients had a ≥3% decrease in S aO2 . At diagnosis, they were older with a lower diffusing capacity of the lung for carbon monoxide and a shorter 6-min walk distance compared with those who did not display a ≥3% decrease in S aO2 . The percentage of patients meeting the European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria at re-evaluation was significantly lower in those with a ≥3% decrease in S aO2 and more patients started long-term oxygen therapy in this group (16% versus 5%; p<0.001). A ≥3% decrease in S aO2 was associated with a poorer survival (hazard ratio 1.81, 95% CI 1.43-2.34; p<0.0001). In a multivariate Cox analysis, a ≥3% decrease in S aO2 was a prognostic factor independent of age at diagnosis and ESC/ERS risk stratification at follow-up. CONCLUSIONS: When treated with PAH drugs, a large subset of patients experience a ≥3% decrease in S aO2 , which is associated with worse long-term outcomes and reduced survival.

Relationship between calcifications and structural lesions on hand radiography and axial calcifications on CT-scan: A retrospective study in systemic sclerosis.

The objectives of this study were to describe the prevalence and characteristics of radiographic lesions of the hands, and calcifications of the spine on computer tomography scans (CT-scans), and to investigate the relationships between radiographic and CT-scan abnormalities and clinical features in a population of patients with systemic sclerosis (SSc).Subjects underwent X-ray examination of the hands, and thoracic or thoraco-abdominal and pelvic CT scan or lumbar CT scan in the year. Structural lesions on hand X ray was scored and spinal calcifications were evaluated in the anterior, intracanal and posterior segments. Intra and inter-reliability was tested for radiography and CT- scan. Prognostic factors considered were interstitial pulmonary lesions on the CT scan, pulmonary arterial hypertension (PAH) and death.This study involved 77 SSc patients, 58 (75%) with limited cutaneous SSc (lcSSc) and 19 (25%) with diffuse SSc (dSSc). The prevalences of radiographic lesions of the hand were 28.6% for periarticular calcifications and 26% for calcinosis. On CT scan, 64 (83%) patients exhibited at least 1 calcification. Spine calcifications were depicted in 80.5%, 27.3%, and 35.1% at the anterior, intracanal and posterior segments respectively. Calcifications were mainly localized on thoracic spine. Inter reader reliabilities were good for hands and moderate for spine respectively. Spine calcifications and periarticular calcifications in the hands were associated (P = .012). Calcinosis in the hands was related to PAH (P = .02). Posterior calcification segment and foraminal calcifications were associated with interstitial lung disease (ILD) (P = .029) and death (P = .001).More than 80% of systemic sclerosis patients presented spine calcifications. A significant association between hands and spinal calcifications were confirmed and some localization in the posterior segment considered as a bad prognostic factor.

Exercise Hemodynamics in the Prognosis of Patients with Pulmonary Arterial Hypertension.

BACKGROUND: Assessment of prognosis is of major importance when deciding on a therapeutic strategy in patients with pulmonary arterial hypertension (PAH). OBJECTIVES: The aim of this study was to investigate the prognostic value of pulmonary hemodynamics during exercise and changes during treatment in patients with PAH. METHODS: Consecutive incident patients (n = 49) with PAH undergoing right heart catheterization at rest and during a constant workload cycle exercise in supine position were included. Predictors of survival were identified at baseline using Cox proportional hazard regression models in a univariate analysis unadjusted and adjusted for age and gender. RESULTS: During a median follow-up period of 42 months, 13 (27%) of the 49 patients studied died. Two predictors of death were found: rest-to-exercise changes in heart rate and systolic pulmonary artery pressure. Adjusted hazard ratios were 0.92 (95% CI 0.86-0.99) and 0.93 (95% CI 0.88-0.99), respectively. These 2 variables were correlated with each other (r = 0.55, p < 0.001). CONCLUSIONS: Rest-to-exercise changes in heart rate and systolic pulmonary artery pressure measured at diagnosis are predictors of survival in patients with PAH. These measurements taken from an exercise test reflect right ventricular function.

Targeting p16INK4a Promotes Lipofibroblasts and Alveolar Regeneration after Early-Life Injury.

Rationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether the cell-cycle inhibitor p16INK4a limits lung regeneration after newborn bronchopulmonary dysplasia (BPD), a condition characterized by the arrest of alveolar development, leading to adult sequelae.Methods: We exposed p16INK4a-/- and p16INK4aATTAC (apoptosis through targeted activation of caspase 8) transgenic mice to postnatal hyperoxia, followed by pneumonectomy of the p16INK4a-/- mice. We measured p16INK4a in blood mononuclear cells of preterm newborns, 7- to 15-year-old survivors of BPD, and the lungs of patients with BPD.Measurements and Main Results: p16INK4a concentrations increased in lung fibroblasts after hyperoxia-induced BPD in mice and persisted into adulthood. p16INK4a deficiency did not protect against hyperoxic lesions in newborn pups but promoted restoration of the lung architecture by adulthood. Curative clearance of p16INK4a-positive cells once hyperoxic lung lesions were established restored normal lungs by adulthood. p16INK4a deficiency increased neutral lipid synthesis and promoted lipofibroblast and alveolar type 2 (AT2) cell development within the stem-cell niche. Besides, lipofibroblasts support self-renewal of AT2 cells into alveolospheres. Induction with a PPARγ (peroxisome proliferator-activated receptor γ) agonist after hyperoxia also increased lipofibroblast and AT2 cell numbers and restored alveolar architecture in hyperoxia-exposed mice. After pneumonectomy, p16INK4a deficiency again led to an increase in lipofibroblast and AT2 cell numbers in the contralateral lung. Finally, we observed p16INK4a mRNA overexpression in the blood and lungs of preterm newborns, which persisted in the blood of older survivors of BPD.Conclusions: These data demonstrate the potential of targeting p16INK4a and promoting lipofibroblast development to stimulate alveolar regeneration from childhood to adulthood.

Evolution and Predictive Factors of Improvement of Obstructive Sleep Apnea in an Obese Population After Bariatric Surgery.

STUDY OBJECTIVES: Our objectives were to determine in an obese population (body mass index > 35 kg/m²) the number of patients, after gastric bypass (GBP), who no longer met French Ministry of Health criteria for utilizing positive airway pressure (PAP), and the predictive factors of obstructive sleep apnea (OSA) improvement. METHODS: Between June 2012 and August 2014 we diagnosed OSA in 129 incident patients requiring PAP therapy before GBP. A postoperative sleep recording was undertaken for 44 of these patients after a weight loss of at least 10%. RESULTS: Most of the patients showed severe OSA with a mean [standard deviation] apnea-hypopnea index (AHI) of 52.8 [23.8] events/h. The body mass index was 46.1 [5.1] kg/m². All the patients were treated via PAP and most of them via auto-titrating PAP with a range of 4-16 cmH2O. Following the GBP, in 31 patients (70.5%) OSA was improved, allowing PAP to be stopped (AHI < 15 events/h). The Epworth Sleepiness Scale score, the modified Medical Research Council dyspnea scale, the loudness of snoring, and sleep structure were improved. AHI was decreased by a mean of 40.9 [22.4] events/h (P < .001). In a multivariate logistic regression model, age (P = .018) and sleep oxygen desaturation index (P = .049) appeared to predict improvement of OSA. CONCLUSIONS: After GBP, 70.5% of the patients no longer met French Ministry of Health criteria for utilizing PAP, allowing discontinuation of this treatment. At diagnosis, a younger age and a less severe sleep oxygen desaturation were predictive factors of this improvement.

Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.