Should pulmonary embolism be suspected in exacerbation of chronic obstructive pulmonary disease?

BACKGROUND: The cause of acute exacerbation of chronic obstructive pulmonary disease (COPD) is often difficult to determine. Pulmonary embolism may be a trigger of acute dyspnoea in patients with COPD. AIM: To determine the prevalence of pulmonary embolism in patients with acute exacerbation of COPD. METHODS: 123 consecutive patients admitted to the emergency departments of two academic teaching hospitals for acute exacerbation of moderate to very severe COPD were included. Pulmonary embolism was investigated in all patients (whether or not clinically suspected) following a standardised algorithm based on d-dimer testing, lower-limb venous ultrasonography and multidetector helical computed tomography scan. RESULTS: Pulmonary embolism was ruled out by a d-dimer value <500 microg/l in 28 (23%) patients and a by negative chest computed tomography scan in 91 (74%). Computed tomography scan showed pulmonary embolism in four patients (3.3%, 95% confidence interval (CI), 1.2% to 8%), including three lobar and one sub-segmental embolisms. The prevalence of pulmonary embolism was 6.2% (n = 3; 95% CI, 2.3% to 16.9%) in the 48 patients who had a clinical suspicion of pulmonary embolism and 1.3% (n = 1; 95% CI, 0.3% to 7.1%) in those not suspected. In two cases with positive computed tomography scan, the venous ultrasonography also showed a proximal deep-vein thrombosis. No other patient was diagnosed with venous thrombosis. CONCLUSIONS: The prevalence of unsuspected pulmonary embolism is very low in patients admitted in the emergency department for an acute exacerbation of their COPD. These results argue against a systematic examination for pulmonary embolism in this population.

Chronic obstructive pulmonary disease in never-smoking animal farmers working inside confinement buildings

BACKGROUND: In animal farming, respiratory disease has been associated with indoor air contaminants and an excess in FEV1 decline. Our aim was to determine the characteristics and risk factors for chronic obstructive pulmonary disease (COPD) in never-smoking European farmers working inside animal confinement buildings. METHODS: A sample of participants in the European Farmers' Study was selected for a cross-sectional study assessing lung function and air contaminants. Dose-response relationships were assessed using logistic regression models. RESULTS: COPD was found in 18 of 105 farmers (45.1 SD 11.7 years) (17.1%); 8 cases (7.6%) with moderate and 3 cases (2.9%) with severe disease. Dust and endotoxin showed a dose-response relationship with COPD, with the highest prevalence of COPD in subjects with high dust (low=7.9%/high=31.6%) and endotoxin exposure (low=10.5%/high=20.0%). This association was statistically significant for dust in the multivariate analysis (OR 6.60, 95% CI 1.10-39.54). CONCLUSION: COPD in never-smoking animal farmers working inside confinement buildings is related to indoor dust exposure and may become severe. [Authors]

The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice.

OBJECTIVE: The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. METHODS: The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. RESULTS: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. CONCLUSIONS: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

TBS (Trabecular Bone Score) is More Sensitive Than BMD to Diabetes-Related Fracture Risk

Background:Type 2 diabetes (T2D) is associated with increased fracture risk but paradoxically greater BMD. TBS (trabecular bone score), a novel grey-level texture measurement extracted from DXA images, correlates with 3D parameters of bone micro-architecture. We evaluated the ability of lumbar spine (LS) TBS to account for the increased fracture risk in diabetes. Methods:29,407 women ≥50 years at the time of baseline hip and spine DXA were identified from a database containing all clinical BMD results for the Province of Manitoba, Canada. 2,356 of the women satisfied a well-validated definition for diabetes, the vast majority of whom (>90%) would have T2D. LS L14 TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident non-traumatic major osteoporotic fracture codes (mean follow-up 4.7 years). Results:In linear regression adjusted for FRAX risk factors (age,BMI, glucocorticoids, prior major fracture, rheumatoid arthritis, COPD as a smoking proxy, alcohol abuse) and osteoporosis therapy, diabetes was associated with higher BMD for LS, femoral neck and total hip but lower LS TBS (all p<0.001). Similar results were seen after excluding obese subjects withBMI>30. In logistic regression (Figure), the adjusted odds ratio (OR) for a skeletal measurement in the lowest vs highest tertile was less than 1 for all BMD measurements but increased for LS TBS (adjusted OR 2.61, 95%CI 2.30-2.97). Major osteoporotic fractures were identified in 175 (7.4%) with and 1,493 (5.5%) without diabetes (p < 0.001). LS TBS predicted fractures in those with diabetes (adjusted HR 1.27, 95%CI 1.10-1.46) and without diabetes (HR 1.31, 95%CI 1.24-1.38). LS TBS was an independent predictor of fracture (p<0.05) when further adjusted for BMD (LS, femoral neck or total hip). The explanatory effect of diabetes in the fracture prediction model was greatly reduced when LS TBS was added to the model (indicating that TBS captured a large portion of the diabetes-associated risk), but was paradoxically increased from adding any of the BMD measurements. Conclusions:Lumbar spine TBS is sensitive to skeletal deterioration in postmenopausal women with diabetes, whereas BMD is paradoxically greater. LS TBS predicts osteoporotic fractures in those with diabetes, and captures a large portion of the diabetes-associated fracture risk. Combining LS TBS with BMD incrementally improves fracture prediction.

Immunological mechanisms underlying infectious and chronic lung diseases

Le système respiratoire permet l'échange de gaz entre un organisme et son environnement. Pour fonctionner efficacement, il doit lutter contre les infections tout en maintenant une tolérance aux particules inoffensives. Les cytokines sont des petites protéines qui permettent la communication entre les différentes cellules et jouent un rôle important dans la régulation de l'homéostasie et de l'immunité des surfaces pulmonaires. Une production altérée des cytokines sous-tend beaucoup de maladies du système pulmonaire. Ainsi, la compréhension de la biologie fondamentale des cytokines pourrait contribuer à la mise au point de nouveaux traitements. Dans le cadre de cette thèse, nous avons étudié le rôle de deux cytokines, le TSLP (Thymic stromal lymphopoietin) et l'IL-17 (Interleukin 17) dans les réponses immunitaires bénéfiques et nuisibles en utilisant des modèles précliniques de souris des maladies pulmonaires. L'asthme est une maladie qui est caractérisée par la bronchoconstriction réversible, l'inflammation des voies respiratoires inférieures, l'hyperréactivité bronchique et le remodelage tissulaire. Le type d'inflammation affectant les voies respiratoires et la présence ou non d'allergie permettent d'établir les différents types d'asthme. La TSLP est une cytokine qui est principalement exprimée à des niveaux élevés dans les poumons de patients souffrant d'asthme allergique. En conséquence, la majeure partie de la recherche sur la TSLP a mis l'accent sur le rôle joué par celle- ci dans les réponses négatives conduisant au développement de l'asthme allergique. Dans cette thèse, nous montrons que la TSLP joue aussi un rôle bénéfique dans les réponses immunitaires pulmonaires. Nous avons découvert que la TSLP atténue la grippe en augmentant les réponses des lymphocytes T cytotoxiques contre le virus. Nous avons également étudié la fonction de la TSLP dans l'asthme non allergique. Contrairement à l'asthme allergique, nous avons constaté que la TSLP diminue les réponses inflammatoires dans l'asthme non allergique en réglant la production de l'IL-17, une cytokine qui favorise la maladie. Ainsi, nous démontrons les fonctions pleiotropes de la TSLP dans des contextes spécifiques de la maladie. Nos résultats ont des implications importantes pour le développement de thérapies ciblant la TSLP dans l'asthme. Dans la deuxième partie de la thèse, nous avons étudié les mécanismes pathogéniques qui sous-tendent le développement de la broncho-pneumopathie chronique obstructive (BPCO). La BPCO est une maladie chronique le plus largement associée aux fumeurs. Elle est caractérisée par une limitation progressive et irréversible du débit d'air et la destruction de la structure des poumons. L'augmentation globale de l'incidence de la maladie encourage grandement la compréhension des mécanismes pathogéniques et l'identification de nouvelles cibles thérapeutiques. Nous avons découvert que les micro-organismes trouvés dans les voies respiratoires aggravent la maladie en augmentant la production de l'IL-17. L'IL-17 est une cytokine inflammatoire qui est impliquée dans plusieurs maladies pulmonaires chroniques, dont la BPCO. Dans notre modèle animal de la maladie, nous avons neutralisé 1ÌL-17A en utilisant un anticorps spécifique et observé une reprise de la fonction pulmonaire. Dans cette étude, nous avons identifié 2 axes potentiels pour l'intervention thérapeutique contre la BPCO. Cibler les bactéries dans les voies respiratoires soit par l'utilisation d'antibiotiques ou l'utilisation de thérapies à base immunitaire qui antagonisent l'activité spécifiques de l'IL-17. Dans l'avenir, notre laboratoire va collaborer avec des cliniciens pour acquérir des échantillons humains et tester la pertinence de nos résultats dans la maladie humaine. -- L'interaction avec l'environnement extérieur est vitale pour le fonctionnement du système respiratoire. Par conséquent, ce dernier a adopté une multitude de réseaux effecteurs et régulateurs qui permettent de distinguer les particules inhalées comme «dangereuses» ou «inoffensives» et de réagir en conséquence. L'équilibre entre ces réseaux est essentielle pour lutter contre le «danger» déclenché par une infection ou des dommages, et finalement pour le retour à l'homéostasie. Le milieu de cytokine local contribue de manière significative à la mise au point de ces réponses. Ainsi, la caractérisation du rôle des cytokines dans l'état d'équilibre et la maladie a des implications claires pour les interventions thérapeutiques dans les maladies respiratoires aiguës et chroniques. Cette thèse a porté sur le rôle des cytokines, la lymphopoïétine stromale thymique (TSLP) et TIL-17A dans l'élaboration de réponses immunitaires pulmonaires. La TSLP est principalement produite par les cellules épithéliales et peut cibler une myriade de cellules immunitaires. Bien qu'elle ait été montrée être un puissant inducteur des réponses de type Th2, son rôle dans d'autres contextes inflammatoires est relativement inexploré. Dans le premier projet de cette thèse, nous avons découvert une nouvelle fonction de la TSLP dans l'immunité antivirale contre la grippe, une infection virale. Nous avons constaté que la TSLP a réglementé la réponse neutrophile au début de l'infection, en amplifiant l'immunité adaptative spécifique du virus. Mécaniquement, la TSLP a augmenté l'expression de l'IL-15 et du CD70 sur les cellules dendritiques recrutées dans les poumons suite à l'infection et a renforcé leur capacité de stimuler localement les lymphocytes T CD8+ spécifiques du virus. En outre, nous avons étudié la TSLP dans le cadre de divers phénotypes de l'asthme et également démontré l'impact pléiotropique qu'elle a sur les réponses immunitaires pulmonaires. En accord avec les rapports précédents, nous avons constaté que la TSLP a exacerbé l'inflammation atopique médiée par le Th2. En revanche la TSLP a réduit les réponses de l'IL-17A et l'inflammation neutrophile subséquente dans le modèle non atopique, ainsi que l'exacerbation du modèle atopique provoqué par une infection virale. Nos résultats démontrent une dichotomie dans le rôle de la TSLP dans la pathogenèse de l'asthme et soulignent la nécessité d'envisager plusieurs phénotypes d'asthme pour une évaluation approfondie de son potentiel thérapeutique dans cette maladie. Dans la seconde partie de cette thèse, nous avons caractérisé les mécanismes pathogènes qui sous-tendent la broncho-pneumopathie chronique obstructive (BPCO). La BPCO est une maladie hétérogène définie par une diminution progressive de la fonction pulmonaire. Bien que des déclencheurs environnementaux puissent aggraver la maladie, chez les personnes sensibles une maladie établie peut progresser à travers un cercle inflammatoire auto-entretenu. Nous avons cherché à définir les mécanismes sous-jacents à l'aide d'un modèle murin d'inflammation chronique, qui reproduit les caractéristiques pathologiques de la maladie humaine. Puisqu'ont été associés à la BPCO sévère des changements dans le microbiome des voies respiratoires, nous avons supposé que les signaux dérivés de certains microbes pourraient favoriser des voies inflammatoires chroniques de progression de la maladie. Nous avons observé que, en l'absence d un microbiome, la maladie s'est améliorée tel que démontré par une réduction de l'inflammation des voies respiratoires et une amélioration de la fonction pulmonaire. Cela a été lié spécifiquement à une production réduite d'IL-17A, une cytokine qui a été impliquée dans la maladie humaine. De plus la cinétique de production de 1IL- 17A dépendant du microbiote est corrélé à la sévérité de la maladie. Sur la base de ces données, la neutralisation de l'IL-17A a également eu un effet bénéfique sur l'évolution de la maladie. Le rôle significatif de 1TL-17A dans l'aggravation de la maladie a été couplé à sa capacité à engager un dialogue entre les voies inflammatoires innées et adaptatives. Il a influencé le recrutement et le phénotype des neutrophiles et des macrophages, ce qui a eu un impact direct et indirect sur la formation et la fonction des tissus lymphoïdes tertiaires associée à des stades sévères de la maladie. -- The interaction with the external environment is vital for the functioning of the respiratory system. Consequently, it has adopted a multitude of effector and regulatory networks that enable it to distinguish inhaled particles as 'dangerous' or 'innocuous' and respond accordingly. The balance between these networks is crucial to counteract the 'danger' triggered by infection or damage, and ultimately return to homeostasis. The local cytokine milieu contributes significantly to the fine- tuning of these responses. Thus, characterizing the role of cytokines in steady state and disease has clear implications for therapeutic interventions in acute and chronic respiratory disorders. This thesis focused on the role of the cytokines, thymic stromal lymphopoietin (TSLP) and IL-17A in shaping pulmonary immune responses. TSLP is primarily produced by barrier epithelial cells and can target a myriad of immune cells. Although it has been shown to be potent inducer of Th2 type responses, its role in other inflammatory settings is relatively unexplored. In the first project of this thesis, we discovered a novel function of TSLP in antiviral immunity to Influenza A infection. We found that while TSLP regulated the early neutrophilic response to infection, it amplified virus specific adaptive immunity. Mechanistically, TSLP enhanced the expression of IL-15 and CD70 on the lung recruited inflammatory dendritic cells and strengthened their ability to stimulate virus specific CD8+ T cell responses locally. In addition we investigated TSLP in the context of diverse asthma phenotypes and further demonstrated the pleiotropic impact it has on pulmonary immune responses. In concurrence with previous reports we found that TSLP exacerbated Th2 mediated atopic inflammation. In contrast TSLP curtailed IL-17A responses and subsequent neutrophilic inflammation in the non-atopic model as well as virus induced exacerbation of the atopic model. Our findings demonstrate a dichotomy in the role of TSLP in asthma pathogenesis and emphasize the need to consider multiple asthma phenotypes for a thorough evaluation of its therapeutic potential in this disease. In the next part of this thesis we characterized the pathogenic mechanisms underlying chronic obstructive pulmonary disease. COPD is a heterogeneous disease defined by a progressive decline in lung function. Although environmental triggers exacerbate the disease, in susceptible individuals the established disease can progress through a self-sustained inflammatory circle. We sought to delineate the underlying mechanisms by using a murine model of chronic inflammation, which reproduced key pathological features of the human disease. As changes in the airway microbiome have been linked to severe COPD, we speculated that microbial derived signals could facilitate the establishment of chronic inflammatory pathways that favour disease progression. We found that the absence of a microbiota ameliorated disease, exhibited by a reduction in airway inflammation and an improvement in lung function. This was linked specifically to an impaired production of IL-17A, a cytokine that has been implicated in human disease. Moreover the kinetics of microbiota-dependent IL-17A production correlated with the disease severity. Based on these data targeted neutralization of IL-17A also had a beneficiai effect on the disease outcome. The prominent role played by IL-I7A in driving the disease was coupled to its ability in engaging and mediating cross talk between pathogenic innate and adaptive immune pathways. It influenced the recruitment and phenotype of neutrophils and macrophages, as well as impacted upon the formation and function of tertiary lymphoid tissue associated with severe disease. Thus, temporal and spatial changes in cytokine production, their cellular targets and interaction with the local milieu determine the balance between immunity and pathology in the lung. Collectively our findings provide novel mechanistic insights in the complex role played by cytokines in orchestrating pulmonary immune responses and have clear implications for human disease.

End-tidal carbon dioxide monitoring using a naso-buccal sensor is not appropriate to monitor capnia during non-invasive ventilation.

BACKGROUND: In acute respiratory failure, arterial blood gas analysis (ABG) is used to diagnose hypercapnia. Once non-invasive ventilation (NIV) is initiated, ABG should at least be repeated within 1 h to assess PaCO2 response to treatment in order to help detect NIV failure. The main aim of this study was to assess whether measuring end-tidal CO2 (EtCO2) with a dedicated naso-buccal sensor during NIV could predict PaCO2 variation and/or PaCO2 absolute values. The additional aim was to assess whether active or passive prolonged expiratory maneuvers could improve the agreement between expiratory CO2 and PaCO2. METHODS: This is a prospective study in adult patients suffering from acute hypercapnic respiratory failure (PaCO2 ≥ 45 mmHg) treated with NIV. EtCO2 and expiratory CO2 values during active and passive expiratory maneuvers were measured using a dedicated naso-buccal sensor and compared to concomitant PaCO2 values. The agreement between two consecutive values of EtCO2 (delta EtCO2) and two consecutive values of PaCO2 (delta PaCO2) and between PaCO2 and concomitant expiratory CO2 values was assessed using the Bland and Altman method adjusted for the effects of repeated measurements. RESULTS: Fifty-four datasets from a population of 11 patients (8 COPD and 3 non-COPD patients), were included in the analysis. PaCO2 values ranged from 39 to 80 mmHg, and EtCO2 from 12 to 68 mmHg. In the observed agreement between delta EtCO2 and deltaPaCO2, bias was -0.3 mmHg, and limits of agreement were -17.8 and 17.2 mmHg. In agreement between PaCO2 and EtCO2, bias was 14.7 mmHg, and limits of agreement were -6.6 and 36.1 mmHg. Adding active and passive expiration maneuvers did not improve PaCO2 prediction. CONCLUSIONS: During NIV delivered for acute hypercapnic respiratory failure, measuring EtCO2 using a dedicating naso-buccal sensor was inaccurate to predict both PaCO2 and PaCO2 variations over time. Active and passive expiration maneuvers did not improve PaCO2 prediction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01489150.

The ADO Index as a Predictor of Two-Year Mortality in General Practice-Based Chronic Obstructive Pulmonary Disease Cohorts.

BACKGROUND: Existing prediction models for mortality in chronic obstructive pulmonary disease (COPD) patients have not yet been validated in primary care, which is where the majority of patients receive care. OBJECTIVES: Our aim was to validate the ADO (age, dyspnoea, airflow obstruction) index as a predictor of 2-year mortality in 2 general practice-based COPD cohorts. METHODS: Six hundred and forty-six patients with COPD with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV were enrolled by their general practitioners and followed for 2 years. The ADO regression equation was used to predict a 2-year risk of all-cause mortality in each patient and this risk was compared with the observed 2-year mortality. Discrimination and calibration were assessed as well as the strength of association between the 15-point ADO score and the observed 2-year all-cause mortality. RESULTS: Fifty-two (8.1%) patients died during the 2-year follow-up period. Discrimination with the ADO index was excellent with an area under the curve of 0.78 [95% confidence interval (CI) 0.71-0.84]. Overall, the predicted and observed risks matched well and visual inspection revealed no important differences between them across 10 risk classes (p = 0.68). The odds ratio for death per point increase according to the ADO index was 1.50 (95% CI 1.31-1.71). CONCLUSIONS: The ADO index showed excellent prediction properties in an out-of-population validation carried out in COPD patients from primary care settings. © 2014 S. Karger AG, Basel.