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Pneumopathies interstitielles diffuses médicamenteuses au cours des maladies systémiques

Les immunosuppresseurs et les immunomodulateurs sont destinés à réguler une réponse immunitaire excessive responsable de lésions inflammatoires et sont de prescription de plus en plus répandue en médecine interne.

Ces médicaments sont reconnus pour leur efficacité mais sont dotés d’une toxicité parfois importante notamment au niveau pulmonaire, à l’origine de pneumopathies interstitielles diffuses (PID). Certains facteurs exposent à la toxicité pulmonaire notamment l’âge avancé, le polymorphisme génétique et l’existence au préalable d’une pathologie pulmonaire. La cytotoxicité et l’hypersensibilité sont les principaux mécanismes de toxicité pulmonaire. Il n’existe aucune classification universelle des PID médicamenteuses. Théoriquement, les médicaments peuvent être responsables de tous les aspects histologiques de la pneumopathie interstitielle.

Le méthotrexate est le médicament le plus connu comme pourvoyeur de PID avec une prévalence de 0,3 à 11,6 %. Des cas de PID ont été décrits également avec les nouvelles biothérapies utilisées au cours des maladies systémiques. La démarche diagnostique devant la suspicion d’une PID médicamenteuse consiste à éliminer les causes non médicamenteuses notamment infectieuses et tumorales avant d’explorer la sémiologie clinique et les résultats de l’imagerie et de la cytologie du lavage broncho-alvéolaire. L’analyse de la sémiologie clinique vérifie la compatibilité de la chronologie des signes cliniques et/ou radiologiques de la pneumopathie avec la prise du médicament suspecté. Par la suite, les données du cas clinique sont confrontées à celles de la littérature.

Le traitement consiste en l’arrêt du médicament incriminé. Le recours à une corticothérapie est parfois nécessaire en cas de signes de gravité ou d’évolution traînante.

Immunosuppressants and immunomodulators are designed to regulate excessive immune response responsible for inflammatory lesions and are prescribed more and more in internal medicine. These drugs are known for their efficiency but with a significant toxicity including interstitial lung disease (ILD). Some factors liable to pulmonary toxicity include advanced age, genetic polymorphism and the existence of prior pulmonary disease.

Cytotoxicity and hypersensitivity are the main mechanisms of pulmonary toxicity. There is no universal classification of drug induced-lung disease. Theoretically, drugs may be responsible for all histological aspects of ILD. Methotrexate is the most well-known drug as a provider of ILD with a prevalence of 0.3 to 11.6%. Some cases of ILD have also been reported with the new biologics used in systemic diseases. The diagnostic approach to the suspicion of drug ILD is to eliminate non-medicinal causes of pneumonia including infections and tumors before exploring the clinical symptomatology and the results of imaging and bronchoalveolar lavage cell profile. The analysis of the clinical symptomatology check the compatibility of the chronology of clinical and/or radiological pneumonia with the medication suspected. Subsequently, data from the clinical case are compared with those of the literature.

Treatment involves stopping the suspected drug. The use of corticosteroids may be required in case of signs of severity or a lingering evolution.

Actualités dans la mucoviscidose

Les progrès constants sur les deux dernières décennies dans la prise en charge de la mucoviscidose ont permis une progression régulière de l’espérance de vie qui approche 40ans à la naissance. De manière corollaire, la population de patients adultes n’a cessé d’augmenter et représente actuellement 50 % des patients suivis en France. Ces progrès thérapeutiques ont justifié la mise en place en 2003 d’un dépistage néonatal généralisé de la mucoviscidose.

Les dernières données de ce dépistage font état d’une incidence de la mucoviscidose de 1/5359 naissances vivantes, largement inférieure à l’incidence de 1/2500 qui était communément admise il y a une vingtaine d’années. Les performances de ce dépistage actuellement basé sur le dosage de la trypsine immunoréactive, suivi en cas de dépassement du seuil d’une recherche des 30 mutations les plus fréquentes, permettent de dépister de l’ordre de 96 % des 150 à 200 cas annuels de mucoviscidose. L’hypothèse d’un faux négatif du dépistage ne peut donc être exclue devant un tableau évocateur de mucoviscidose même pour des enfants nés après 2003 et il faudra savoir dans ces situations demander un test de la sueur. Alors que les traitements jusqu’à présent disponibles ne s’attaquaient qu’aux conséquences de la mucoviscidose, une nouvelle classe thérapeutique visant à corriger le défaut fonctionnel de la protéine mutée, appelée modulateurs de CFTR, est en train d’apparaître.

L’ivacaftor, chef de file de cette nouvelle classe, appartenant à la catégorie des « potentiateurs de CFTR » a obtenu son autorisation de mise sur le marché en septembre 2012 pour les patients porteurs de la mutation G551D. D’autres molécules, qualifiées de « correcteurs de CFTR » qui pourraient s’associer de manière synergique à l’ivacaftor et concerner des patients porteurs de la mutation la plus fréquente – DF 508 – sont en cours de développement.

The improvement over the last two decades in the treatment of cystic fibrosis led to an increase in life expectancy approaching 40 years at birth. Logically, the population of adult patients has been increasing and is currently 50% of patients followed in France. These therapeutic advances have justified the establishment in 2003 of a generalized neonatal screening for cystic fibrosis.

The latest data of this screening show an incidence of CF of 1/5359 live births, far below the incidence of 1/2500 which was widely accepted twenty years ago. The performance of this screening is currently based on the dosage of trypsin immuno reactive, followed in case of exceeding the threshold of a search of the 30 most common mutations, can detect around 96% of 150 to 200 CF cases every year. Therefore, the possibility of a false negative of the screening cannot be excluded and evocative symptoms of cystic fibrosis, even for children born after 2003, will lead to prescribe a sweat test. While treatments available so far goal consequences of cystic fibrosis, a new therapeutic class to correct the functional defect of the mutated protein, called CFTR modulators, is emerging. Ivacaftor, leader of this new class, belonging to the category of “CFTR potentiator” got its access on the market in September 2012 for patients carrying the G551D mutation.

New other molecules, named “CFTR correctors” which can have synergistic effect with ivacaftor and concern patients carrying the most common mutation - DF 508 - are under development.

The safety of beta-blocker use in chronic obstructive pulmonary disease patients with respiratory failure in the intensive care unit.

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The safety of beta-blocker use in chronic obstructive pulmonary disease patients with respiratory failure in the intensive care unit.

Multidiscip Respir Med. 2014;9(1):8

Authors: Kargin F, Takir HB, Salturk C, Goksenoglu NC, Karabay CY, Mocin OY, Adiguzel N, Gungor G, Balci MK, Yalcinsoy M, Kargin R, Karakurt Z

Abstract
BACKGROUND: The safety of beta-blockers as a heart rate-limiting drug (HRLD) in patients with acute respiratory failure (ARF) due to chronic obstructive lung disease (COPD) has not been properly assessed in the intensive care unit (ICU) setting. This study aims to compare the use of beta-blocker drugs relative to non-beta-blocker ones in COPD patients with ARF due to heart rate-limiting with respect to length of ICU stay and mortality.
METHODS: We performed a retrospective (January 2011-December 2012) case-control study in a level III ICU in a teaching hospital. It was carried out in a closed ICU by the same intensivists. All COPD patients with ARF who were treated with beta-blockers (case group) and non-beta-blocker HRLDs (control group) were included. Their demographics, reason for HRLD, cause of ARF, comorbidities, ICU data including acute physiology and chronic health evaluation (APACHE II) score, type of ventilation, heart rate, and lengths of ICU and hospital stays were collected. The mortality rates in the ICU, the hospital, and over 30 days were also recorded.
RESULTS: We enrolled 188 patients (46 female, n = 74 and n = 114 for the case and control groups, respectively). Reasons for HRLD (case and control group, respectively) were atrial fibrillation (AF, 23% and 50%), and supraventricular tachycardia (SVT, 41.9% and 54.4%). Patients' characteristics, APACHE II score, heart rate, duration and type of ventilation, and median length of ICU-hospital stay were similar between the groups. The mortality outcomes in the ICU, hospital, and 30 days after discharge in the case and control groups were 17.6% versus 15.8% (p > 0.75); 18.9% versus 19.3% (p > 0.95) and 20% versus 11% (p > 0.47), respectively.
CONCLUSIONS: Our results suggest that beta-blocker use for heart rate control in COPD patients with ARF is associated with similar ICU stay length and mortality compared with COPD patients treated with other HRLDs.

PMID: 24495706 [PubMed]

Influenza A (H1N1) vs non-H1N1 ARDS: Analysis of clinical course.

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Influenza A (H1N1) vs non-H1N1 ARDS: Analysis of clinical course.

J Crit Care. 2013 Dec 30;

Authors: Töpfer L, Menk M, Weber-Carstens S, Spies C, Wernecke KD, Uhrig A, Lojewski C, Jörres A, Deja M

Abstract
PURPOSE: The purpose of the study is to compare H1N1-induced acute respiratory distress syndrome (ARDS) with ARDS due to other causes of severe community-acquired pneumonia focusing on pulmonary function.
MATERIALS AND METHODS: This is a retrospective data analysis of adult ARDS patients between January 2009 and December 2010 in an ARDS referral center. Patient characteristics, severity of illness scores, modalities, and duration of extracorporeal lung support were evaluated as well as intensive care unit stay and survival. Parameters of mechanical ventilation and pulmonary function were analyzed on day of admission and over the consecutive 10 days using a nonparametric analysis of longitudinal data in a 2-factorial design. In a logistic regression analysis, risk factors for extracorporeal lung support were investigated.
RESULTS: Twenty-one patients with H1N1-ARDS and 41 with non-H1N1-ARDS were identified. Gas exchange was more severely impaired in patients with H1N1-ARDS over course of time. Extracorporeal membrane oxygenation was more frequently needed in H1N1-ARDS. Despite significantly prolonged weaning off extracorporeal lung support and intensive care unit stay in H1N1 patients, the proportion of survivors did not differ significantly. Only Sepsis-Related Organ Failure Assessment score could be identified as an independent predictor of extracorporeal lung support.
CONCLUSIONS: Clinical course of H1N1-ARDS is substantially different from non-H1N1-ARDS. Affected patients may require extensive therapy including extracorporeal lung support in ARDS referral centers.

PMID: 24508203 [PubMed - as supplied by publisher]

Mesenchymal Stem Cell Trials for Pulmonary Diseases.

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Mesenchymal Stem Cell Trials for Pulmonary Diseases.

J Cell Biochem. 2014 Feb 11;

Authors: Antunes MA, Laffey JG, Pelosi P, Rocco PR

Abstract
All adult tissues, including the lung, have some capacity to self-repair or regenerate through the replication and differentiation of stem cells resident within these organs. While lung resident stem cells are an obvious candidate cell therapy for lung diseases, limitations exist regarding our knowledge of the biology of these cells. In contrast, there is considerable interest in the therapeutic potential of exogenous cells, particularly mesenchymal stem/stromal cells (MSCs), for lung diseases. Bone marrow derived-MSCs are the most studied cell therapy for these diseases. Preclinical studies demonstrate promising results using MSCs for diverse lung disorders, including emphysema, bronchopulmonary dysplasia, fibrosis, and acute respiratory distress syndrome. This mini-review will summarize ongoing clinical trials using MSCs in lung diseases, critically examine the data supporting their use for this purpose, and discuss the next steps in the translational pathway for MSC therapy of lung diseases. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.

PMID: 24515922 [PubMed - as supplied by publisher]

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