Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Management of obstructive sleep apnea syndrome type 1 in children and adolescents - A French consensus.

This document is the outcome of a group of experts brought together at the request of the French Society of Sleep Research and Medicine to provide recommendations for the management of obstructive sleep apnea syndrome type 1 (OSA1) in children. The recommendations are based on shared experience and published literature. OSA1 is suspected when several nighttime respiratory symptoms related to upper airway obstruction are identified on clinical history taking. A specialist otolaryngologist examination, including nasofibroscopy, is essential during diagnosis. A sleep study for OSA1 is not mandatory when at least two nighttime symptoms (including snoring) are noted. Therapeutic management must be individualized according to the location of the obstruction. Ear, nose, and throat (ENT) surgery is often required, as hypertrophy of the lymphoid tissues is the main cause of OSA1 in children. According to clinical findings, orthodontic treatment generally associated with specialized orofacial-myofunctional therapy might also be indicated. Whatever treatment is chosen, follow-up must be continuous and multidisciplinary, in a network of trained specialists.

[Obstructive sleep apnea and asthma: Clinical implications]. / Association entre l'asthme et le syndrome d'apnées hypopnées obstructives du sommeil : quelles conséquences en pratique clinique ?

Obstructive sleep apnea (OSA) and asthma are common respiratory diseases that can coexist in the same patient. Epidemiological and pathophysiological data suggest an independent link between these two diseases. Specially, OSA is frequently associated with non-eosinophilic and with poorly-controlled asthma. Common comorbidities including obesity, gastroesophageal reflux and rhinitis may promote this association. The impact of OSA treatment on the clinical and functional control of asthma has been extensively investigated. Numerous non-randomized studies suggest that continuous positive pressure treatment is likely to improve asthma symptoms, the control of the disease and quality of life in asthmatics with OSA. However, this impact has not been confirmed in the limited randomized trial available. To date, the optimal treatment approach in asthmatics with OSA is the best treatment of each disease separately and the recognition and treatment of comorbidities. When indicated, obesity surgery has a major impact on both diseases.

The association between sleep-related breathing disorders and pre-capillary pulmonary hypertension: A chicken and egg question.

The level of knowledge about a direct link between sleep-related breathing disorders and pre-capillary pulmonary hypertension (PH) is low and there is a chicken and egg question to know which disease causes the other. On one hand, sleep-related breathing disorders are considered as a cause of group 3 PH, in the subgroup of patients with hypoxemia without lung disease. Indeed, isolated sleep-related breathing disorders can lead to mild pre-capillary PH on their own, although this is rare for obstructive sleep apnea and difficult to establish for obesity-hypoventilation syndrome, the evolution towards PH being observed especially in the presence of respiratory comorbidities. The hemodynamic improvement under treatment with continuous positive airway pressure or non-invasive ventilation also argues for a causal link between pre-capillary PH and sleep-related breathing disorders. On the other hand, patients followed for pre-capillary PH, particularly pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, develop more sleep-related breathing disorders than the general population, especially sleep hypoxemia, central sleep apnea in patients with severe PH and obstructive sleep apnea in older patients with higher body mass index. The main objective of this article is therefore to answer two main questions, which will then lead us to discuss the bilateral link between these diseases: are sleep-related breathing disorders independent risk factors for pre-capillary PH and does pre-capillary PH induce sleep-related breathing disorders? In other words, who is the chicken and who is the egg?

[Characteristics of patients with connective tissue disease-associated pulmonary arterial hypertension treated with prostanoids: A multicenter retrospective study]. / Caractéristiques des patients traités par prostanoïdes pour une hypertension artérielle pulmonaire associée à une connectivite : étude multicentrique rétrospective.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD). Data on use of prostanoids in this particular subset of patients are lacking. We aimed to describe the characteristics of patients with PAH-CTD treated with prostanoids and the outcomes under treatment. METHODS: In this multicenter retrospective study, all patients treated with prostanoids since 2006 were included. Data on PAH and CTD were collected at the time of prostanoid introduction and under treatment. RESULTS: Twenty-one patients were included, of whom 20 (95%) had limited cutaneous systemic sclerosis. Nineteen patients were treated with oral monotherapy or combination before addition of prostanoid. Treprostinil was the most used molecule (57% of patients). At the time of prostanoid introduction, 90% of patients were considered at high risk for death. Among patients who had right heart catheterization during follow-up, there was no significant difference in haemodynamics. No extrarespiratory worsening of the CTD was reported. The 1-year survival under prostanoid was 62%. In univariate analysis, NYHA functional class was associated with survival under treatment. CONCLUSION: This study provides original data on use of prostanoids in a cohort consisting mainly of systemic sclerosis. It underlines the difficulty to achieve a standardized assessment in this subset of patients. Safety profile was comparable with data reported in idiopathic PAH.

[Telemonitoring in continuous positive airway pressure-treated patients with obstructive sleep apnoea syndrome: An algorithm proposal]. / Télésuivi des patients traités par pression positive continue pour un syndrome d'apnées/hypopnées obstructives du sommeil : proposition d'un arbre décisionnel.

Most of the continuous positive airway pressure (CPAP) devices currently in use allow telemonitoring of observance, leaks and the apnoea-hypopnoea index (AHI). La Société française de recherche et de médecine du sommeil (SFRMS) and La Société de pneumologie de langue française (SPLF) workgroup offer to CPAP prescribers and to home care providers a scientific document which has the following purposes: to underline the relevance of the telemonitoring of leaks and the AHI, to define alert thresholds, to describe the principal mechanisms generating excessive leaks and high AHI, and to propose a diagnostic algorithm.

Titrated mandibular advancement versus positive airway pressure for sleep apnoea.

The aim of this study was to compare mandibular advancement device (MAd) therapy and continuous positive airway pressure (CPAP) for obstructive sleep apnoea/hypopnoea syndrome (OSAHS) after one-night polysomnographic (PSG) titration of both treatments. 59 OSAHS patients (apnoea/hypopnoea index (AHI): 34+/-13 events x h(-1); Epworth scale: 10.6+/-4.5) were included in a crossover trial of 8 weeks of MAd and 8 weeks of CPAP after effective titration. Outcome measurements included home sleep study, sleepiness, health-related quality of life (HRQoL), cognitive tests, side-effects, compliance and preference. The median (interquartile range) AHI was 2 (1-8) events x h(-1) with CPAP and 6 (3-14) events x h(-1) with MAd (p<0.001). Positive and negative predictive values of MAd titration PSG for treatment success were 85% and 45%, respectively. Both treatments significantly improved subjective and objective sleepiness, cognitive tests and HRQoL. The reported compliance was higher for MAd (p<0.001) with >70% of patients preferring this treatment. These results support titrated MAd as an effective therapy in moderately sleepy and overweight OSAHS patients. Although less effective than CPAP, successfully titrated MAd was very effective at reducing the AHI and was associated with a higher reported compliance. Both treatments improved functional outcomes to a similar degree. One-night titration of MAd had a low negative predictive value for treatment success.

[Practical aspects of the management of patients treated by continuous positive airway pressure]. / Le suivi pratique des patients sous pression positive continue.

The therapeutic follow-up is a decisive factor of the success of a long course treatment by continuous positive airway pressure (CPAP). The effectiveness of this treatment on both symptoms and complications must be regularly verified. Polysomnography with CPAP could be necessary in order to check out the efficacy of this treatment and/or to find an associated diagnosis when symptoms persist, particularly a diurnal drowsiness, which is the main therapeutic target in obstructive sleep apnea syndrome (OSAS). The secondary effects that are likely to compromise the compliance of CPAP treatment must be resolved, particularly the nasal intolerance, which are enhanced by mask leakages and often corrected by using heated humidity with CPAP delivery systems. The efficacy of CPAP on both diurnal drowsiness and hypertension is related to the compliance of this treatment which must be regularly verified, at the same time that the clinical evaluation. The data obtained from the device's memory give information concerning the number of hours day to day, in which the CPAP device was running at the prescribed pressure. The first months with CPAP are decisive to avoid a failure of the treatment at long term. This period must be closely monitored by both the physician and the home care provider. Patients should use the CPAP at least 3-4 h by night and all possible means should be used to obtain a maximal compliance. Therapeutic educational programs could help to reach this goal.

Obstructive sleep apnoea syndrome in patients living with diabetes: Which patients should be screened?

AIM: Because type 2 diabetes (T2D) is related to obesity, it is often associated with obstructive sleep apnoea syndrome (OSAS), although OSAS is also frequently diagnosed in patients with type 1 diabetes (T1D) and may promote gestational diabetes. Thus, this systematic review of the scientific evidence aimed to evaluate the epidemiological association between OSAS and all forms of diabetes, the current understanding of the pathophysiological mechanisms behind these associations, the expected benefits and limitations of OSAS treatment in patients with diabetes and, finally, to propose which patients require screening for OSAS. METHODS: A panel comprising French expert endocrinologists and pneumologists was convened. Two of these experts made a search of the relevant literature for each subpart of the present report; all panel experts then critically reviewed the entire report separately as well as collectively. RESULTS: There is little evidence to support the notion that OSAS treatment improves glycated haemoglobin, although it may improve nighttime blood glucose control and insulin sensitivity. However, there is robust evidence that OSAS treatment lowers 24-h blood pressure. CONCLUSION: The high prevalence of OSAS in patients with T1D and T2D justifies screening for the syndrome, which should be based on clinical symptoms, as the benefits of OSAS treatment are mainly improvement of symptoms related to sleep apnoea. There are also several clinical situations wherein screening for OSAS seems justified in patients with diabetes even when they have no symptoms, particularly to optimalize control of blood pressure in cases of resistant hypertension and microvascular complications.

[Drug-induced pneumonitis in a patient treated with venlafaxine and propanolol]. / Pneumopathie médicamenteuse sous traitement par venlafaxine et propranolol.

INTRODUCTION: Venlafaxine and propranolol have rarely been identified as causes of pulmonary pathology. We describe a case of drug-induced pneumonitis occurring in a patient treated with these two medications. CASE REPORT: A 55 years old woman with liver cirrhosis treated with venlafaxine for 1 year and propranolol for 1 month was admitted to the intensive care unit because of acute respiratory failure. A Mycoplasma pneumoniae pneumonitis was diagnosed. After initial improvement under antibiotics, a new deterioration of respiratory status was observed 4 days after the reintroduction of venlafaxine and propranolol. Spontaneous recovery occurred after these treatments were withheld. Co administration of venlafaxine and propranolol, 2 drugs with affinity for the same cytochrome P450 isoenzyme (CYP2D6), may have contributed to drug accumulation and pulmonary toxicity. The liver cirrhosis of our patient may also have contributed to decreased cytochrome P450 enzymatic activity. CONCLUSIONS: Venlafaxine and propranolol share the same metabolic pathway and their co-administration may be complicated by drug induced pneumonitis.

[Prevalence of symptoms of sleep apnea syndrome. Study of a French middle-aged population]. / Prévalence des symptômes du syndrome d'apnées du sommeil. Etude dans une population française d'âge moyen.

OBJECTIVE: To study the prevalence of symptoms of sleep apnoea syndrome (SAS) in a large French middle-aged population and to establish what proportion have symptoms that justify further investigation with a sleep study. METHODS: We performed a cross-sectional study of 2,195 men and 2,247 women, 33 to 69 year old (DESIR. cohort) recording responses to a self-administered "sleep" questionnaire and a general questionnaire including socio-economic characteristics and lifestyle factors. RESULTS: The prevalence of symptoms in men and women were respectively: snoring frequently (28%, 14%), frequent daytime sleepiness (14%, 18%) and frequent apnoeas (5%, 2%). Overall, 8.5% of men and 6.3% of women reported a pattern of symptoms suggestive of OSA, as they snored and had daytime sleepiness and/or apnoeas. This pattern was associated, for both sexes, with age, body mass index and after adjustment on these two factors, to a mediocre self-reported health status and treatment with benzodiazepines or other sedatives. For men only, the OSA pattern of symptoms was also associated with, hypertension, alcohol consumption and smoking. CONCLUSION: Snoring, daytime hypersomnolence and witnessed apnoeas are symptoms frequently observed in the general population. Subjects with a combination of these abnormalities suggesting a high probability of sleep apnoea syndrome and in whom a sleep study is warranted represent 7.5% of the adult population.

[Update on the respiratory management of patients with chronic neuromuscular disease]. / Mise au point dans la prise en charge respiratoire des maladies neuromusculaires chroniques.

BACKGROUND: Neuromuscular diseases include a wide range of conditions that may involve potentially life-threatening respiratory complications (infection, respiratory failure). SURVEILLANCE AND PULMONARY FUNCTION TESTS: For patients with neuromuscular diseases, clinical assessment of respiratory function and regular pulmonary function tests are needed to screen for nocturnal respiratory disorders, weakness of the diaphragm and potential restrictive disorders and/or chronic hypercapnic respiratory insufficiency, possibly with couch deficiency. MANAGEMENT OF NOCTURNAL RESPIRATORY DISORDERS AND CHRONIC RESPIRATORY FAILURE: Nocturnal respiratory assistance is an important phase of care for nocturnal respiratory disorders and chronic respiratory failure. This may involve continuous positive airway pressure, adaptative servo-ventilation or non-invasive ventilation with a facial or nasal mask. As needed, diurnal assistance may be proposed by mouthpiece ventilation. Should non-invasive ventilation prove insufficient, or if significant swallowing disorders or recurrent bronchial obstruction develop, or in case of prolonged intubation, tracheotomy may be required. LOWER AIRWAY OBSTRUCTION: In case of lower airway infection with ineffective cough, physical therapy, associated with air stacking, intermittent positive pressure breathing or mechanical in-exsufflation may be proposed. PATIENT-CENTERED MANAGEMENT: Care for swallowing disorders, nutritional counseling (cachexia, obesity), vaccinations and therapeutic education are integral elements of patient-centered management aiming to prevent the negative impact of infection and to manage respiratory failure of chronic neuromuscular disease.

[Sleep apneas, metabolic syndrome and cardiovascular risk: Data from the Pays de la Loire sleep cohort]. / Apnées du sommeil, syndrome métabolique et risque cardiovasculaire : données de la cohorte sommeil des Pays de la Loire.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a prevalent disease characterized by recurrent episodes of partial or complete obstruction of upper airway during sleep. Untreated moderate to severe OSAHS is recognized as a cardiovascular (CV) risk factor. Data from the Pays de la Loire sleep cohort and other clinic- or population-based cohorts demonstrate a strong association between OSAHS and the different components of the metabolic syndrome including systemic hypertension, diabetes and impaired lipid metabolism. Beside sleep-disordered breathing severity, these factors contribute to increase the risk of CV events in OSAHS patients. Continuous positive airway pressure (CPAP) therapy of OSAHS is associated with a modest but clinically significant blood pressure reduction. Conversely, there is no clear evidence in support of a metabolic impact of CPAP in OSAHS patients. Considering the multifactorial pathophysiology of CV risk in OSAHS patients and the beneficial impact of various lifestyle and pharmacologic interventions on blood pressure and metabolic dysfunction, combined modality therapy is a promising strategy to improve CV outcomes in individuals with OSAHS.

[Vascular dysfunction in obstructive sleep apnoea: Implication of microparticules]. / Atteinte vasculaire associée au syndrome d'apnées hypopnées obstructives du sommeil : rôle des microparticules.

Obstructive sleep apnea (OSA) is associated with increased cardiovascular diseases, including myocardial infarction and stroke and promotes cardiovascular risk factors including diabetes and hypertension. OSA has also been proposed to have a direct proatherogenic effects. Recent studies have investigated the role of microparticles (MPs) in the atherogenic process. MPs are small plasma membrane vesicles that can be released by a variety of vascular or blood cells and that contain membrane and cytosolic elements. Case-control studies have suggested that OSA is associated with an increase in circulating platelet-, endothelial- and leukocyte-derived MPs. MPs from OSA patients injected to mice have also been shown to induce vascular inflammation and endothelial dysfunction. In this article, we provide an overview of the main characteristics of MPs expressed in OSA and their potential role in the atherogenic process.

[Central apnea developing during treatment with a mandibular advancement device]. / Apnées centrales induites sous traitement par orthèse d'avancée mandibulaire.

INTRODUCTION: Mandibular advancement (MA) has emerged over the last decade as an alternative solution to nasal continuous airway pressure (nCPAP) for the treatment of obstructive sleep apnea syndrome (OSAS). OBSERVATION: We report the case of a patient with history of chronic atrial fibrillation and moderate supine-dependent OSAS in whom central sleep apneas developed during treatment by a bi-bloc MA device. Central apneas increased with the level of MA and preferentially occurred in the supine position. We hypothesized that mouth opening under excessive mandibular advancement in supine position may have led to pharyngeal narrowing at the base of the tongue and potentially unstable ventilation. Sleep fragmentation that enhanced during progressive MA may also have compromised ventilatory control stability in our patient. Finally, chronic atrial fibrillation may have predisposed to central sleep apneas. CONCLUSION: Our case report highlights the importance of follow-up nocturnal recordings during progressive MA.

[Pleurisy induced by atorvastatin]. / Pleurésie induite par l'atorvastatine.

INTRODUCTION: Whereas numerous case reports have described statin-induced lung injuries, statin-induced pleural effusions are uncommon. CASE REPORT: An 84-year-old man presented with bilateral pleural effusions two years after starting treatment with atorvastatin. No other cause of pleural effusion was found and all symptoms and radiological signs resolved rapidly after discontinuation of the drug. Furthermore, an accidental reintroduction of the treatment resulted in recurrence of the same clinical picture, reinforcing the hypothesis that atorvastatin was responsible for this pleural effusion. CONCLUSION: Pleuropulmonary manifestations in a patient treated with atorvastatin should rapidly evoke an iatrogenic origin and the discontinuation of the drug should be discussed.

Osteoprotegerin levels are associated with liver fat and liver markers in dysmetabolic adults.

AIM: This study aimed to determine the association between visceral adipose tissue (VAT), liver fat (LF) content, and other markers of the metabolic syndrome (MetS) and osteoprotegerin (OPG) in dysmetabolic adults. METHODS: Subjects from the NUMEVOX cohort were included if they fulfilled at least one MetS criterion. They then underwent a thorough metabolic and cardiovascular evaluation, including arterial stiffness, atherosclerotic plaques, homoeostasis model assessment for insulin resistance (HOMA-IR) indices and OPG. VAT and LF content were measured by magnetic resonance imaging (MRI). Ultrasound examination of arteries and arterial stiffness were recorded, and age- and gender-adjusted paired correlations calculated. RESULTS: Body mass index, waist circumference and MRI-derived VAT correlated with OPG, whereas abdominal subcutaneous fat did not. OPG levels were strongly correlated with LF content (r=0.25, P=0.003), liver markers such as alanine aminotransferase (r=0.39, P<0.001) and HOMA-IR index (r=0.39, P<0.0001). Plasma OPG also correlated with arterial stiffness and the number of atherosclerotic sites. CONCLUSION: Plasma OPG levels are positively associated with both liver markers and increased LF content, but not with subcutaneous fat in dysmetabolic men. These findings suggest that elevated OPG levels may play a role in the link between fatty liver disease and enhanced cardiovascular risk.

[Invasive pulmonary aspergillosis complicating septic shock]. / Aspergillose pulmonaire invasive compliquant un choc septique.

INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is an opportunistic infection with a poor prognosis, occurring primarily in patients who are severely immunocompromised. CASE REPORT: We report a case of IPA that occurred in a 37-year-old woman with no history of previous immunosuppression or significant co-morbidity. She was admitted to our intensive care unit (ICU) with septic shock and multi-organ failure complicating a bacterial pneumonia. After an initial improvement, her condition deteriorated on the 10th day after admission with fever and lesions consistent with IPA seen on high-resolution computed tomography (HRCT). IPA was confirmed by isolating Aspergillus fumigatus from bronchoalveolar lavage and by a positive circulating galactomannan test (sandwich ELISA). First line therapy with voriconazole had to be stopped after 12 days due to hepatic toxicity. The patient was successfully treated with caspofungine for 2 months then itraconazole for 4 months with progressive improvement of HRCT abnormalities. Her galactomannan test became negative at 6 months. CONCLUSION: The diagnosis of IPA must be considered in critically ill patients even in the absence of underlying immunosupression where suggestive HRCT abnormalities occur in the context of septic shock and multiple organ failure.