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Here we present pharmacological and clinical properties of a new fixed triple inhaled combination including an inhaled corticoid, a long acting ?2 agonist and a long acting anticholinergic for the treatment of severe chronic obstructive pulmonary disease (COPD). Trixeo Aerosphere® is the name of this triple combination which contains 160 µg budesonide, 4,8 µg formoterol and 9 µg glycopyrronium delivered by a pMDI. As compared to a budesonide/formoterol combination, Trixeo Aerosphere® improves forced expiratory volume in the first second (FEV1). As compared to glycopyrronium/formoterol combination, Trixeo Aerosphere® reduces exacerbation rate, improved quality of life and most importantly reduces mortality with a benefit increasing with blood eosinophil count. Trixeo Aerosphere® 320/18/9.6 is delivered twice daily 2 inhalations and is indicated in moderate to severe COPD insufficiently controlled by LABA/LAMA (long-acting ?2-adrenergic receptor agonist/ long-acting ?2-muscarinic receptor agonist) or ICS/LABA (inhaled corticosteroid/long-acting ?2-adrenergic receptor agonist).Nous présentons dans cet article les propriétés pharmacologiques et les effets cliniques d’une nouvelle triple combinaison fixe inhalée comprenant un corticoïde inhalé, un ?2 mimétique à longue durée d’action et un anticholinergique à longue durée d’action, destinée au traitement de la bronchopneumopathie chronique obstructive (BPCO) sévère. Cette combinaison qui porte le nom de Trixeo Aerosphere® regroupe, dans le même dispositif, 160 µg de budésonide, 4,8 µg de formotérol et 18 µg de glycopyrronium. Par rapport à une combinaison budésonide/formotérol, le Trixeo Aerosphere® améliore la valeur du volume expiratoire maximum par seconde (VEMS). Par rapport à une combinaison formotérol/glycopyrronium, le Trixeo Aerosphere® réduit la fréquence des exacerbations et réduit la mortalité avec un bénéfice qui augmente avec le taux des éosinophiles circulants. Le Trixeo Aerosphere®, à la dose de 2X2 bouffées/24h, est indiqué dans le traitement des patients BPCO modérés à sévères insuffisamment contrôlés par une bithérapie LABA/LAMA (long-acting ?2-adrenergic receptor agonist/ long-acting ?2-muscarinic receptor agonist) ou ICS/LABA (inhaled corticosteroid/long-acting ?2-adrenergic receptor agonist).

Introduction : le syndrome de détresse respiratoire (SDR) est une des principales complications de la prématurité, évoluant dans la majorité des cas vers la dysplasie broncho-pulmonaire (DBP). La corticothérapie systémique post-natale précoce diminue la sévérité du SDR et prévient la DBP mais n’est pas recommandée au vu de ses effets généraux adverses. L’addition de budésonide (glucocorticoïde local) au surfactant dans la prise en charge du SDR est proposée pour diminuer la DBP en évitant les effets indésirables. La posologie de budésonide généralement utilisée (0,250 mg/kg/dose) pourrait entrainer des effets systémiques chez des enfants extrêmes prématurés. La posologie optimale pour un meilleur rapport tolérance/efficacité reste donc à déterminer chez ces enfants vulnérables.Objectif : évaluer la tolérance et l’impact respiratoire précoce d’une administration intra-trachéale de faibles doses de budésonide (0,150 mg/kg) associées au surfactant chez les enfants nés extrêmes prématurés et présentant un SDR. Méthode : étude observationnelle, rétrospective, d’une population d’enfants d’âge gestationnel (AG) < 28 SA et recevant du surfactant pour un SDR. Les enfants nés du 1er janvier 2019 au 31 juillet 2020 ayant reçu du budésonide associé au surfactant (« Surfactant + Bud »), ont été comparés à une cohorte historique (nés du 1er août 2017 au 31 décembre 2018) ayant reçu du surfactant seul.Résultats : 102 enfants ont été inclus. L’AG et le poids de naissance (PN) moyen étaient de 25,3 (+/- 1,1) SA, et 739 (+/- 143) grammes. Les caractéristiques périnatales, notamment l’AG, le PN, le sexe, la corticothérapie anténatale et le mode d’administration du surfactant étaient comparables entre les deux groupes. Les taux de ventilation mécanique (VM) à J3 (35,3 % vs. 69,7 %, p = 0,01) et J7 (26% vs. 46,9 %, p < 0,05) et la durée de VM au cours de la 1ère semaine de vie (2,4 vs. 3,8 jours, p = 0,02) étaient significativement plus bas dans le groupe d’enfants « Surfactant + Bud ». Il n’y avait pas d’effets sur la DBP à 36SA d’AC. Les valeurs de pression artérielle, le recours à une insulinothérapie pour hyperglycémie et les complications néonatales étaient comparables entre les deux groupes d’enfants. Conclusion : dans cette étude, l’addition de faibles doses de budésonide au surfactant chez des enfants extrêmes prématurés présentant un SDR a été bien tolérée et s’est associée à une réduction de la morbidité respiratoire précoce. Afin de confirmer ces résultats préliminaires, une étude randomisée en double aveugle contre placebo est nécessaire.

The most commonly reported pattern of anti-PD-1 induced colitis is an active colitis characterized by neutrophilic inflammation and prominent apoptosis. On the other hand, reports of collagenous colitis (which is a microscopic colitis) are exceptional. In this report, we describe an unusual case of anti-PD1-associated collagenous colitis in a 76-year-old man, treated with pembrolizumab for a stage IV cutaneous melanoma. Fourteen months after the start of pembrolizumab, the patient developed a grade 3 diarrhea (up to 9 stools per day) associated with profound hypokalemia. No bacterial, viral or parasitological infectious agents were found from stool analysis. The rectosigmoidoscopy showed colonic diffuse congestion with no ulceration. Systematic biopsies were performed during endoscopy. Histologically, the fragments analyzed revealed a moderately thickened subepithelial collagen layer (20-30μm thick) associated with a mild mixed inflammatory infiltrate within the lamina propria. There were no granuloma lesions, ulcerations or viral inclusion bodies. The patient was initially successfully treated with corticosteroids (prednisone) and temporary interruption of pembrolizumab. However, during corticosteroids tapering, a relapse was observed. The treatment was switched to budesonide, leading to a complete and definitive resolution of diarrhea. To date, budesonide has been stopped and pembrolizumab has not been restarted. Currently, there is a bone progression treated by radiotherapy alone. In case of a more important progression, a systemic treatment will be secondarily discussed.

[Analyse de : Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA 2018;319:1485-96. DOI: 10.1001/jama.2018.2769] Cette synthèse méthodique avec méta-analyse de bonne qualité méthodologique montre que l’utilisation de la méthode SMART chez les patients souffrant d’asthme persistant comparativement à l’utilisation de CSI (combinés ou non à des LABA) a été associée à une diminution des exacerbations. Son efficacité est principalement basée sur un résultat composite incluant des exacerbations de l’asthme nécessitant des corticostéroïdes systémiques, des hospitalisations ou des visites aux urgences. Les preuves actuelles concernant les enfants âgés de 4 à 11 ans sont limitées, mais elles suggèrent également une efficacité similaire associée à SMART. Cette étude ne montre pas d’association entre SMART et des changements de qualité de vie. Il serait intéressant que de futures études analysent ces critères.

Analyse de "Kalish L, Snidvongs K, Sivasubramaniam R, et al. Topical steroids for nasal polyps. Cochrane Database Syst Rev 2012, Issue 12." Question clinique : Cette méta-analyse méthodologiquement correcte, conclut qu’une corticothérapie topique est efficace versus placebo chez les patients souffrant de rhinosinusite chronique avec des polypes, améliorant la symptomatologie (obstruction nasale), diminuant la taille des polypes et prévenant leur réapparition après chirurgie. Cette méta-analyse ne permet pas de définir ni les dosages les plus adéquats, ni les modes de pulvérisation les plus efficaces, au vu d’un nombre insuffisant d’études. Conclusion Minerva : Quelle est l’efficacité de l’utilisation de corticostéroïdes topiques dans le traitement de la rhinosinusite chronique chez des patients adultes avec des polypes nasaux ?

Several long-term studies designed to assess pharmacological treatments for Chronic Obstructive Pulmonary Disease (COPD) have been published recently. Only such long-term studies allow an accurate analysis of the effect of treatments on criteria of effectiveness such as survival or decline in pulmonary function. A review of these studies is opportune.The high drop out rate, which is not a random event, leads to serious methodological problems that are of importance in the interpretation of these studies. Post hoc analysis of both the TORCH and UPLIFT trials suggest a positive effect of long-acting bronchodilators on survival. Up to now, no treatment has convincingly demonstrated an effect on the rate of decline of FEV(1). The treatments evaluated lead to a decrease in exacerbation rates and an improvement in quality of life although the effects of inhaled corticosteroids are subject to methodological concerns. The treatments are all well tolerated.The design of future studies should avoid the withdrawal of treatments at enrolment into a study in order to limit the number of drop outs.Long-term studies have made important progress in the knowledge, not only of the effects of the treatments assessed but also of the methodological issues which need to be addressed.

Collagenous colitis belongs to the group of microscopic colitis. The aetiology and pathogenesis are unknown but different pathogenic hypothesis, autoimmune, infectious, alimentary and medicinal being are advanced, the last one being the most frequent aetiology. The collagenous gastritis is a rare entity and its association with collagenous colitis was exceptionally reported, only six cases being published. We report the seventh case of collagenous gastritis, ileitis and colitis in a 75-year-old woman with chronic diarrhea and important weight loss. This thickened subepithelial collagen band was appeared in an autoimmune injury context with antecedent of Hashimoto's thyroiditis and probably chronic atrophic Biermer's gastritis. The clinical and histological evolution was favourable with budesonide.

In 1999, 80% of French neonatal centers used corticosteroids, mainly betamethasone (BMT), to prevent or treat bronchopulmonary dysplasia (BPD) [Lee SK, McMillan DD, Ohlson A, et al. Variations in practice and outcomes in the canadian NICU Network 1996-1997. Pediatrics 2000;106:1070-9]. As many data suggested a low risk-benefit ratio, an updated assessment of this use was necessary [Desnoulez L, Empana J, Anceschi M, et al. Prise en charge de l'immaturité pulmonaire en néonatologie : enquête sur les pratiques européennes. Arch Pediatr 2005;12:4-9; Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (less than 96h) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003:CD001146; Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-13; Lin YJ, LKin CH, Wu JM, et al. The effects of early postnatal dexamethasone therapy on pulmonary outcome in premature infants with respiratory distress syndrome: a 2-year follow-up study. Acta Paediatr 2005;94:310-16].Questionnaires addressing the use of and indications for corticosteroids were sent to all French neonatal centers.The study was conducted over 5 months (July to November 2006). Of 202 questionnaires sent out, 186 (92%) were completed. Of these 186 centers, 147 (79%) had a standard protocol for corticosteroid use, covering systemic and inhaled steroids (76 units), only systemic steroid therapy (30 units) and only inhaled steroids (41 units). Systemic corticosteroids were used in 106 centers for hemodynamic purposes in 42 cases (40%), prevention of BPD in 1 case (1%), early treatment of BPD (day 4 to day 21) in 23 cases (22%) and late treatment of BPD (after day 21) in 74 cases (70%). Hemisuccinate hydrocortisone (HSHC) was the only corticoid used for hemodynamic failure. The steroid used for early treatment of BPD was BMT (21 out of 23). The duration of treatment was less than 4 days in 10 centers (43%). The steroid most often used for late treatment was BMT (67 out of 74). The duration of treatment was less than 4 days in 29 centers, between 4 and 8 days in 22 centers, and longer than 8 days in 26 centers. Among 117 centers administering corticosteroids by inhalation, 74% used budesonide. Use of corticosteroids was higher in teaching hospitals (86%) than in others (49%), likely due to the immaturity of the neonates hospitalized in these centers.We showed a still frequent use of corticosteroids in preterm infants in France but only after the fourth day of life to treat BPD and not as a prevention therapy. We also found a marginal use of DXM in accordance with both short-term and long-term adverse side effects, suggesting an unbalanced risk-benefit ratio even though it has a beneficial effect on respiratory status. Our findings indicate the need for national recommendations and trials to assess oral BMT treatment in premature neonates with BPD.

The neurological manifestations of Crohn's disease are rare, dominated by multiple mononeuropathies and the abnormalities of the white matter. Polyradiculoneurities remain exceptional.We report the case of a 33-year-old patient admitted for an ascending weakness of all four limbs. Eight years earlier he had presented a similar episode which had regressed spontaneously. The neurological examination revealed a tetraparesis with areflexia and hypotonia. These manifestations were concomitant with chronic diarrhea which had been neglected to date. The electrophysiological aspect was compatible with an acute polyradiculoneuritis. The analysis of the cerebrospinal fluid showed an albumino-cytological dissociation. The existence of the diarrhea directed the investigations towards an inflammatory enteropathy, which was attested later on by the endoscopic, radiologic and histological data leading to the diagnosis of active Crohn's disease. The diagnosis of a relapsing polyradiculoneuritis associated with Crohn's disease was retained. The patient was treated by salazopyrine-budesonide with improvement in the digestive and neurological manifestations after 3 years.The frequency of neurological features in Crohn's disease is not well documented. The incriminated mechanisms are either directly related to the disease (deficit in B12 vitamin or folic acid and/or by the means of an auto-immune vascularitis) or secondary to long-term treatment with metronidazole. The course of neurological manifestations is largely dependent on the course of the inflammatory disease.

This case report describes a rare situation in which a superinfected cyst of the urachus complicated initially unknown and inactive Crohn's disease.A 21-year-old man presented a chronic fever finally attributed to a superinfected urachal cyst. Six months after ablation of the cyst, progressive Crohn's disease was diagnosed.The association of Crohn's disease and a superinfected urachal cyst is extremely rare. The case reported here is original in two aspects: the slowly progressive Crohn's disease was diagnosed after its complication; the superinfection developed through local bacterial translocation (ileal loop adjacent to the urachal cyst).

Inhaled corticosteroids are widely used in allergic asthma and rhinitis. They are most often used alone or sometimes in association. Allergic side-effects of inhaled corticosteroids are less frequent than those of topical corticosteroids. We report a case of a connubial dermatitis to a budesonide spray.A 3-year old boy was treated for asthma by budesonide (Pulmicort) and terbutaline (Bricanyl) aerosols with an inhalation chamber (Babyhaler). From the fourth day of treatment onwards, his mother had swollen and itchy lesions on the face with conjunctivitis several hours after the administration of the corticosteroids using the inhalation chamber. The last eruptions were marked by extensive lesions. The patient reported a worsening of her eruption when she was treated with a desonide cream (Tridesonit). Prick-tests conducted later on confirmed the contact allergy to budesonide and Pulmicort spray. They were also positive for Tridesonit cream and triamcinolone acetonide. Repeated open application tests with a 17-butyrate hydrocortisone cream (Locoid) for three weeks remainded negative.Our observation is original: allergic contact dermatitis to inhaled corticosteroids is rare, the clinical presentation mimicked angioedema although it was a delayed-type hypersensitivity, hypersensitivity was limited to group B corticosteroids and it was in fact a connubial contact dermatitis.

The combination of budesonide 160 micrograms/formoterol 4.5 micrograms (Symbicort TH) in the same dry powder inhaler (turbohaler) results in a drug that possesses powerful bronchial anti-inflammatory, bronchoprotective and bronchodilating activities. Symbicort TH is registered as a maintenance treatment for asthma from the age of 12 years. This drug is indicated in the treatment of moderate and severe persistent asthma as well as in asthma which remains mild persistent despite the regular use of low doses of inhaled corticoids alone. Symbicort TH rapidly improves asthma control by reducing symptoms, relief medication consumption and by improving lung function. Importantly, when taken regularly over a prolonged period, the drug reduces the number of mild and severe exacerbations. The dose of Symbicort TH is adjustable according to the disease severity and generally fluctuates between 2 x 1/24 h and 4 x 2/24 h. Symbicort TH is a simple and a efficient treatment likely to improve the compliance of asthmatics to their treatment in real life.

Inflammation plays a major role in the pathogenesis of bronchopulmonary dysplasia of preterm infants. Having a strong anti-inflammatory effect, corticosteroids have been proposed in the management of this disease. Antenatal steroids protect the newborn against its development. Postnatal systemic administration of steroids reduces the duration of mechanical ventilation and oxygen therapy, but is associated with short term and long term adverse effects. Early administration of dexamethasone (before 7 days of life) reduces the incidence and the severity of chronic lung disease at 28 days of life and 36 weeks of post-conceptional age. Inhaled steroids are associated with less adverse effects than dexamethasone administration, but they are also less effective.

Inhaled corticosteroids are the treatment of choice for asthma. However, poor compliance by patients is one of the principal difficulties forced by clinicians. Thus, it seems important to propose the minimal daily number of doses. This study has compared the various modes of administration of inhaler corticosteroids and was carried out in patients with mild to moderate persistent asthma. Thus, comparing two to four doses per day shows an identical efficacy if the dose is less than 800 micrograms per day. At higher doses only two studies have been carried out and there are discordant results. The studies compare two doses versus one single dose per day and equally disagree with numerous works in favor of a single daily dose. In the single study carried out for at least twelve months the twice daily dose was the most effective. Thus it seems reasonable to suggest a single dose for mild persistent asthmatics. For moderate persistent asthmatics the choice between a single or twice daily dose would depend on the therapeutic compliance of the patient.

35 asthmatic patients, aged from 23 to 73 years, participated in an open study aimed to compare the efficacy and tolerance of terbutaline and budesonide administered in similar amounts with a metered-dose inhaler fitted with a spacer (Nebuhaler) or by a powder inhaler (Turbuhaler). The patients used each device for seven weeks after a running-in phase of two weeks and gave at the end their preference for one or the other mode of administration. Among lung function values, the forced expiratory volume in the first second (FEV1) was significantly higher during the Turbuhaler period than during the period with metered-dose inhaler whereas the forced vital capacity, mid-expiratory flow rate and peak-flow morning and evening were not significantly different. The use of beta 2-bronchodilators and clinical scores were similar with a non-significant trend in favor of the Turbuhaler period. 25 patients on 35 expressed a preference for the Turbuhaler. The administration of terbutaline and budesonide by Turbuhaler is similarly or more efficient then the inhalation from a metered-dose inhaler with a Nebuhaler spacer and is preferred by a majority of patients.

Although steroids have been prescribed as antiinflammatory preparation for the treatment of asthma for many years, fear of side effects has limited their wider use. The development of new steroid derivatives administered by inhalation has reduced these risks. Oral and inhaled steroids can be used in a separate way, oral steroids being reserved for the control of acute exacerbations and inhaled steroids for the baseline treatment of chronic asthma. Inhaled and oral steroids can also be used concurrently in the same patient. Studies have shown a reduction in the dose of oral steroids in patients taking inhaled steroids. Works carried out by the Canadian research worker Toogood have addressed the question of the equivalent clinical dosing potency of inhaled and oral steroids. Finally, the reversibility of airway obstruction in subjects affected by non-specific chronic obstructive diseases might worth be assessed by using an inhaled steroid preparation.

Although inflammation plays a crucial role in asthma, asthma is not equivalent to inflammation. On the one hand, the relationship between the degree of airway inflammation and the level of bronchial responsiveness to pharmacological agents is not well established. On the other hand, even if late asthmatic reactions has many inflammatory characteristics, the response to the inhalation of a beta-2 adrenergic agent is generally good, which suggests some muscular contraction as well in the reduction of airway caliber. The chronic use of antiinflammatory preparations improves the level of bronchial hyperresponsiveness but this effect is not constant, does not generally result in-normal values and may be short-lived after ending the administration of the drug. It is unknown as to whether the chronic use of these preparations: 1) will reduce the mortality and morbidity of asthma; 2) will be devoted of long-term side effects; 3) will be accompanied by a satisfactory compliance. A greater awareness of these potential problems should therefore be kept in mind before prescribing low-dose inhaled steroids.

The effect of inhaled steroids on adrenal glands of asthmatic subjects are often difficult to assess because subjects may have received oral steroids before. Moreover, even if the Synacthen test is abnormal, it does not necessarily mean that the adrenals are clinically inefficient. Adrenal insufficiency can certainly occur at high doses of inhaled steroids. Possible long term effects on bone are under study. Ecchymosis has been described. Oropharyngeal candidiasis is frequent but rarely symptomatic and responds well to treatment. Hoarseness is rare but troublesome. In children, inhaled steroids, even taken at low dose, can induce growth impairment. After cessation of inhaled steroids, adrenal insufficiency is only theoretical. Asthmatic flare-ups are more of a threat. Although inhaled steroids are of remarkable efficacy and tolerance, one should not exclude the possibility of long-term negative effects, especially in children.

Corticosteroids restore the bronchial responsiveness to beta-adrenergic stimulants in man. This has been shown both in severe asthmatic patients and in normal subjects, rendered insensitive by artificial means. On the contrary, in patients with bronchial asthma who have airways reactive to beta-adrenergic stimulants, the combination of corticosteroids and sympathicomimetics results in an additive effect of their bronchodilating capacity. Animal models, both in vivo and in vitro, show the same type of interaction between corticosteroids and beta-adrenergic stimulants. The mechanism by which corticosteroids restore the bronchial sensitivity to beta-adrenergic stimulation is not completely understood. Several mechanisms may be involved such as increased agonist binding, decreased receptor turn-over, increased uncoupling between receptor and adenylcyclase, decreased extraneuronal uptake, decreased COMT-activity. The relevance of the influence of corticosteroids on the metabolism of membrane phospholipids remains highly speculative.