PROLONG: a cluster controlled trial to examine identification of patients with COPD with poor prognosis and implementation of proactive palliative care.

BACKGROUND: Proactive palliative care is not yet common practice for patients with COPD. Important barriers are the identification of patients with a poor prognosis and the organization of proactive palliative care dedicated to the COPD patient. Recently a set of indicators has been developed to identify those patients with COPD hospitalized for an acute exacerbation who are at risk for post-discharge mortality. Only after identification of these patients with poor prognosis a multi disciplinary approach to proactive palliative care with support of a specialized palliative care team can be initiated. METHODS/DESIGN: The PROLONG study is a prospective cluster controlled trial in which 6 hospitals will participate. Three hospitals are selected for the intervention condition based on the presence of a specialized palliative care team. The study population consists of patients with COPD and their main informal caregivers. Patients will be included during hospitalization for an acute exacerbation. All patients in the study receive standard care (usual care). Besides, patients in the intervention condition who meet two or more criteria of the set of indicators for proactive palliative care will have additionally regular consultations with a specialized palliative care team. The objectives of the PROLONG study are: 1) to assess the discriminating power of the proposed set of indicators (indicator study) and 2) to assess the effects of proactive palliative care for qualifying patients with COPD on the wellbeing of these patients and their informal caregivers (intervention study). The primary outcome measure of the indicator study is time to death for any cause. The primary outcome measure of the intervention study is the change in quality of life measured by the St George Respiratory Questionnaire (SGRQ) three months after inclusion. DISCUSSION: The PROLONG study may lead to better understanding of the conditions to start and the effectiveness of proactive palliative care for patients with COPD. Innovative aspects of the PROLONG study are the use of a set of indicators for proactive palliative care, the active involvement of a specialized palliative care team and the use of a patient-tailored proactive palliative care plan. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR4037.

Effectiveness of the Assessment of Burden of Chronic Obstructive Pulmonary Disease (ABC) tool: study protocol of a cluster randomised trial in primary and secondary care.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a growing worldwide problem that imposes a great burden on the daily life of patients. Since there is no cure, the goal of treating COPD is to maintain or improve quality of life. We have developed a new tool, the Assessment of Burden of COPD (ABC) tool, to assess and visualize the integrated health status of patients with COPD, and to provide patients and healthcare providers with a treatment algorithm. This tool may be used during consultations to monitor the burden of COPD and to adjust treatment if necessary. The aim of the current study is to analyse the effectiveness of the ABC tool compared with usual care on health related quality of life among COPD patients over a period of 18 months. METHODS/DESIGN: A cluster randomised controlled trial will be conducted in COPD patients in both primary and secondary care throughout the Netherlands. An intervention group, receiving care based on the ABC tool, will be compared with a control group receiving usual care. The primary outcome will be the change in score on a disease-specific-quality-of-life questionnaire, the Saint George Respiratory Questionnaire. Secondary outcomes will be a different questionnaire (the COPD Assessment Test), lung function and number of exacerbations. During the 18 months follow-up, seven measurements will be conducted, including a baseline and final measurement. Patients will receive questionnaires to be completed at home. Additional data, such as number of exacerbations, will be recorded by the patients' healthcare providers. A total of 360 patients will be recruited by 40 general practitioners and 20 pulmonologists. Additionally, a process evaluation will be performed among patients and healthcare providers. DISCUSSION: The new ABC tool complies with the 2014 Global Initiative for Chronic Obstructive Lung Disease guidelines, which describe the necessity to classify patients on both their airway obstruction and a comprehensive symptom assessment. It has been developed to classify patients, but also to provide visual insight into the burden of COPD and to provide treatment advice. TRIAL REGISTRATION: Netherlands Trial Register, NTR3788.

Bortezomib partially protects the rat diaphragm from ventilator-induced diaphragm dysfunction.

OBJECTIVE: Controlled mechanical ventilation leads to diaphragmatic contractile dysfunction and atrophy. Since proteolysis is enhanced in the diaphragm during controlled mechanical ventilation, we examined whether the administration of a proteasome inhibitor, bortezomib, would have a protective effect against ventilator-induced diaphragm dysfunction. DESIGN: Randomized, controlled experiment. SETTINGS: Basic science animal laboratory. INTERVENTIONS: Anesthetized rats were submitted for 24 hrs to controlled mechanical ventilation while receiving 0.05 mg/kg bortezomib or saline. Control rats were acutely anesthetized. MEASUREMENTS AND MAIN RESULTS: After 24 hrs, diaphragm force production was significantly lower in mechanically ventilated animals receiving an injection of saline compared to control animals (-36%, p<.001). Importantly, administration of bortezomib improved the diaphragmatic force compared to mechanically ventilated animals receiving an injection of saline (+15%, p<.01), but force did not return to control levels. Compared to control animals, diaphragm cross-sectional area of the type IIx/b fibers was significantly decreased by 28% in mechanically ventilated animals receiving an injection of saline (p<.01) and by 16% in mechanically ventilated animals receiving an injection of bortezomib (p<.05). Diaphragmatic calpain activity was significantly increased in mechanically ventilated animals receiving an injection of saline (+52%, p<.05) and in mechanically ventilated animals receiving an injection of bortezomib (+36%, p<.05). Caspase-3 activity was increased after controlled mechanical ventilation with saline by 55% (p<.05), while it remained similar to control animals in mechanically ventilated animals receiving an injection of bortezomib. Diaphragm 20S proteasome activity was slightly increased in both ventilated groups, and the amount of ubiquitinated proteins was significantly and similarly enhanced in mechanically ventilated animals receiving an injection of saline and mechanically ventilated animals receiving an injection of bortezomib. CONCLUSIONS: These data show that the administration of bortezomib partially protects the diaphragm from controlled mechanical ventilation-induced diaphragm contractile dysfunction without preventing atrophy. The fact that calpain activity was still increased after bortezomib treatment may explain the persistence of atrophy. Part of bortezomib effects might have been due to its ability to inhibit caspase-3 in this model.

Fibrillin-1 staining anomalies are associated with increased staining for TGF-beta and elastic fibre degradation; new clues to the pathogenesis of emphysema.

We recently demonstrated aberrant staining of fibrillin-1 in lung tissue specimens with emphysematous lesions. In this study, we have extended this observation by an elaborate analysis of the elastic fibre. Using domain-specific antibodies to fibrillin-1, and to other elastin fibre-associated molecules, lung tissue derived from patients without obvious clinical emphysema, but harbouring various degrees of microscopical emphysematous lesions, was analysed. In addition, the fibrillin-regulated growth factor TGF-beta was studied. Electron microscopy and biochemical analysis of desmosine (a marker for elastin) were also performed. Results were compared with lung tissue derived from patients with clinical emphysema. Domain-specific antibodies recognizing the C-terminal, N-terminal, and middle part of fibrillin-1 showed aberrant staining patterns associated with increasing degrees of microscopical emphysema. Staining for elastin, emilin-1, and fibulin-2 was, however, not aberrant. TGF-beta staining was markedly increased. On the electron microscopic, but not light microscopical, level, initial elastic fibre degradation was noticed in specimens with microscopical emphysema. Lung specimens from patients with clinical emphysema also displayed fragmented fibrillin-1 staining and, in addition, displayed extensive degradation of the elastic fibre. The results suggest that fibrillin-1 anomalies and TGF-beta overexpression are associated with initial events occurring during the emphysematous process. Based on these and other data, a mechanism for emphysematogenesis is proposed.

Spacers and Valved Holding Chambers-The Risk of Switching to Different Chambers.

Spacers are pressurized metered-dose inhaler (pMDI) accessory devices developed to reduce problems of poor inhaler technique with pMDIs. Spacers that feature a 1-way inspiratory valve are termed valved holding chambers (VHCs); they act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a 2-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. Both spacers and VHCs have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce corticosteroid-related side effects such as throat irritation, dysphonia, and oral candidiasis commonly seen with the use of pMDIs alone. Spacers and VHCs are not all the same, and also are not interchangeable: the performance may vary according to their size, shape, material of manufacture and propensity to become electrostatically charged, their mode of interface with the patient, and the presence or otherwise of valves and feedback devices. Thus, pairing of a pMDI plus a spacer or a VHC should be considered as a unique delivery system. In this Rostrum we discuss the risk potential for a patient getting switched to a spacer or VHC that delivers a reduced dose medication.

Lung function in idiopathic pulmonary fibrosis--extended analyses of the IFIGENIA trial.

BACKGROUND: The randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set. METHODS: We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients. RESULTS: In trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower. CONCLUSION: This descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.

Diaphragm adaptations in patients with COPD.

Inspiratory muscle weakness in patients with COPD is of major clinical relevance. For instance, maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered pathologic of nature. Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single fiber level is associated with loss of myosin content in these fibers. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. This review postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities. Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings indicate the ubiquitin-proteasome pathway as a prime target to attenuate diaphragm wasting in COPD.

Clinical relevance of Mycobacterium chelonae-abscessus group isolation in 95 patients.

OBJECTIVES: To determine the clinical relevance of Mycobacterium chelonae-abscessus group isolation from clinical samples. METHODS: We retrospectively reviewed medical files of all patients from whom these mycobacteria were isolated between January 1999 and January 2005 and re-identified the isolates by rpoB sequencing. We applied the American Thoracic Society (ATS) diagnostic criteria to establish clinical relevance. RESULTS: Ninety-five patients were traced (56 M. chelonae, 25 Mycobacterium abscessus, 8 Mycobacterium massiliense, 6 Mycobacterium bolletii). Most isolates were cultured from pulmonary samples in patients with pre-existing pulmonary disease. Among patients with pulmonary isolates, 27% (20/74) meets ATS criteria; M. abscessus is most relevant (50%; 9/18), followed by M. massiliense (29%; 2/7), M. bolletii (20%; 1/5) and M. chelonae (18%; 8/44). Extrapulmonary disease presented as disseminated skin disease, eye disease specific for M. chelonae and otomastoiditis for M. abscessus. Treatment, especially for pulmonary M. abscessus disease, yielded limited results. CONCLUSIONS: One-fourth of the patients with pulmonary M. chelonae-abscessus group isolates met the ATS criteria; this percentage differs by species. Species distribution and clinical relevance differ from other regions. M. abscessus isolation in cystic fibrosis patients warrants special attention. Current ATS criteria might be too lenient to diagnose M. chelonae-abscessus group disease.

The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer.

The phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) pathway is associated with all three major radiation resistance mechanisms: intrinsic radiosensitivity, tumor cell proliferation, and hypoxia. In cell signaling cascades, the PI3-K/AKT signaling pathway is a key regulator of normal and cancerous growth and cell fate decisions by processes such as proliferation, invasion, apoptosis, and induction of hypoxia-related proteins. Activation of this pathway can be the result of stimulation of receptor tyrosine kinases such as epidermal growth factor receptor or vascular endothelial growth factor receptor or from mutations or amplification of PI3-K or AKT itself which are frequently found in non-small cell lung cancer (NSCLC). Furthermore, several treatment modalities such as radiotherapy can stimulate this survival pathway. Monitoring and manipulation of this signal transduction pathway may have important implications for the management of NSCLC. Strong and independent associations were found between expression of activated AKT (pAKT) and treatment outcome in clinical trials. Direct targeting and inhibition of this pathway may increase radiosensitivity by antagonizing the radiation induced cellular defense mechanisms especially in tumors that have activated the PI3-K/AKT cascade. To successfully implement these treatments in daily practice, there is a need for molecular predictors of sensitivity to inhibitors of PI3-K/AKT activation. In conclusion, the PI3-K/AKT pathway plays a crucial role in cellular defense mechanisms. Therefore, quantification of the activation status is a potential parameter for predicting treatment outcome. More importantly, specific targeting of this pathway in combination with radiotherapy or chemotherapy may enhance tumor control in NSCLC by antagonizing cellular defense in response to treatment.

Predictive value and utility of oral steroid testing for treatment of COPD in primary care: the COOPT study.

BACKGROUND: The oral prednisolone test is widely used to distinguish chronic obstructive pulmonary disease (COPD) patients who might benefit from inhaled steroid treatment. Previous studies used selected patient groups that did not represent the large COPD population in primary care. METHODS: The study included smokers and exsmokers with chronic bronchitis or COPD from primary care, who underwent prednisolone testing (30 mg for 14 days) before randomization in a three-year follow-up randomized controlled trial (COOPT Study). Spirometry was performed before and after the test. Responders and nonresponders were classified according to international criteria. Effectiveness of inhaled fluticasone relative to placebo was compared in terms of health status (Chronic Respiratory Disease Questionnaire), exacerbations, and postbronchodilator forced expiratory volume in one second (FEV(1)), using repeated measurement analysis. RESULTS: Two hundred eighty-six patients recruited from 44 primary care practices were randomized. Nine percent to 16% of the COPD population was classified as responder, depending on the international guideline criteria used. On average, responders did not reach the minimum clinically important difference in health status (0.29 points/year, P = 0.05), although a borderline significant effect of inhaled fluticasone was noted. Possible clinically relevant reductions in exacerbation rate (rate ratio 0.67) and FEV(1) decline (39 mL/year) occurred in responders, but did not reach statistical significance. CONCLUSIONS: Oral steroid testing identifies a limited proportion of COPD patients, but does not reveal any clinically relevant benefit from inhaled steroid treatment on health status. No significant effects on exacerbation rate and lung function decline occurred.