The 6 minute walk in idiopathic pulmonary fibrosis: longitudinal changes and minimum important difference

The response characteristics of the 6 minute walk test (6MWT) in studies of idiopathic pulmonary fibrosis (IPF) are only poorly understood, and the change in walk distance that constitutes the minimum important difference (MID) over time is unknown

Tumour necrosis factor-α production in fibrosing alveolitis is macrophage subset specific

BACKGROUND: Previous studies have revealed that tumour necrosis factor (TNF)-α is upregulated in fibrosing alveolitis (FA) in humans. The aim of this study was to compare the TNF-α secretory profile of alveolar macrophages (AMs) and peripheral blood monocytes (Mos) of patients with cryptogenic FA and systemic sclerosis (SSc), a rheumatological disorder in which lung fibrosis can occur. In particular, we wished to assess whether TNF-α levels differ between SSc patients with FA (FASSc) and a nonfibrotic group. METHODS: The reverse haemolytic plaque assay was used to evaluate the secretion of cytokine at a single cell level while immunostaining allowed subtyping of AMs and Mos. RESULTS: This study demonstrated a difference in total TNF-α levels produced by AMs when the levels in subjects with FA (cryptogenic FA and FASSc) were compared to levels in either SSc patients without FA (P = 0.0002) or normal healthy controls (P < 0.001). In addition, AMs from patients with FASSc secreted more TNF-α than those of patients with no FA (P = 0.003). In contrast, there were no significant differences in Mo TNF-α secretion between the groups. A positive correlation was found between total TNF-α level and number of neutrophils obtained by bronchoalveolar lavage from patients with FA (r = 0.49, P < 0.04). Finally, it was demonstrated that there was significant heterogeneity of TNF-α secretion and that a numerically significant subset of mononuclear phagocytes, RFD7, was responsible for more than 80% of TNF-α production. CONCLUSION: By demonstrating the primary cell source of TNF-α in FASSc, more accurately targeted, possibly localized, anti-TNF strategies might be employed with success in the future

In vitro pharmacoregulation of CC chemokine ligand 5 and its receptor CCR5 in diffuse lung diseases.

BACKGROUND: CC chemokine ligand (CCL)5 and its receptor CCR5 contribute to leukocyte migration into lungs of patients with diffuse lung diseases (DLD). Pharmacological regulation of CCL5 and CCR5 expression was therefore explored in bronchoalveolar cells obtained from patients with DLD. METHODS: Cells from 21 patients were co-cultivated in vitro with tumour necrosis factor-alpha and dexamethasone, cyclosporin A (CyA) or pentoxifylline. Chemokine mRNA expression and protein production was assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Dexamethasone altered CCL5 mRNA expression and suppressed its protein levels. CyA inhibited chemokine mRNA expression but not protein production. Pentoxifylline did not affected chemokine expression. Both dexamethasone and CyA suppressed CCR5 mRNA transcripts. CONCLUSION: In conclusion, while dexamethasone downregulates the CCL5 functional form, CyA and pentoxifylline have no effects on CCL5 protein. These data provide in vitro correlation for clinical applications of immunomodulators in therapy of DLD

PSMB2 and RPL32 are suitable denominators to normalize gene expression profiles in bronchoalveolar cells

<p>Abstract</p> <p>Background</p> <p>For accuracy of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), normalisation with suitable reference genes is required. To date, no reference genes have been validated for expression studies of bronchoalveolar (BAL) cells. The aims of this study were to identify gene(s) with stable mRNA expression in BAL cells irrespective of gender, smoking, BAL cellular composition, lung pathology, treatment; and to assess the influence of reference genes on target gene expression data.</p> <p>Results</p> <p>The mRNA expression of ten housekeeping genes (ACTB, ARF1, CANX, G6PD, GAPDH, GPS1, GNB2L1, PSMB2, PSMD2, RPL32) was investigated by qRT-PCR in BAL cells from 71 subjects across a spectrum of lung diseases. The analyses were validated in an independent BAL cohort from 63 sarcoidosis patients and 17 control subjects. A second derivative method was used to calculate expression values (CTt); an equivalence test, applets BestKeeper, geNorm and NormFinder were applied to investigate gene expression stability. Of the investigated genes, PSMB2 (CTt ± SD, 23.66 ± 0.86) and RPL32 (18.65 ± 0.92) were the most stable; both were constantly expressed in BAL samples from parallel investigated cohorts irrespective of evaluated variables. Finally, to demonstrate effect of traditional (ACTB/GAPDH) and novel (PSMB2/RPL32) reference genes as denominators, expression of two cytokines known associated with sarcoidosis was investigated in sarcoid BAL cells. While normalization with PSMB2/RPL32 resulted in elevated IFNG mRNA expression (<it>p </it>= 0.004); no change was observed using GAPDH/ACTB (<it>p </it>> 0.05). CCL2 mRNA up-regulation was observed only when PSMB2/RPL32 were used as denominators (<it>p </it>< 0.03).</p> <p>Conclusion</p> <p>PSMB2 and RPL32 are, therefore, suitable reference genes to normalize qRT-PCR in BAL cells in sarcoidosis, and other interstitial lung disease.</p

Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS® trials

AbstractBackground and purposeThe Phase II TOMORROW trial and two Phase III INPULSIS® trials investigated the efficacy and safety of nintedanib versus placebo in patients with idiopathic pulmonary fibrosis (IPF). To obtain an overall estimate of the treatment effect of nintedanib 150 mg twice daily (bid), pooled and meta-analyses of data from these three trials were conducted.MethodsPooled and meta-analyses were conducted for annual rate of decline in forced vital capacity (FVC), time to first acute exacerbation, change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and mortality over 52 weeks.Results1231 patients (nintedanib n = 723, placebo n = 508) were included in the pooled analysis. Adjusted annual rate of decline in FVC was −112.4 mL/year with nintedanib and −223.3 mL/year with placebo (difference: 110.9 mL/year [95% CI: 78.5, 143.3]; p < 0.0001). The hazard ratio for time to first acute exacerbation was 0.53 (95% CI: 0.34, 0.83; p = 0.0047). Adjusted mean change from baseline in SGRQ score at week 52 was 2.92 with nintedanib and 4.97 with placebo (difference: −2.05 [95% CI: −3.59, −0.50]; p = 0.0095). Hazard ratios for time to all-cause and on-treatment mortality were 0.70 (95% CI: 0.46, 1.08; p = 0.0954) and 0.57 (95% CI: 0.34, 0.97; p = 0.0274), respectively, in favour of nintedanib. The meta-analysis was generally consistent with the pooled analysis. Diarrhoea was the most frequent adverse event in the nintedanib group (61.5% of patients treated with nintedanib versus 17.9% of patients treated with placebo).ConclusionNintedanib has a beneficial effect on slowing disease progression in patients with IPF

Validation of test performance characteristics and minimal clinically important difference of the 6-minute walk test in patients with idiopathic pulmonary fibrosis

SummaryBackgroundThe 6-minute walk test distance (6MWD) has been shown to be a valid and responsive outcome measure in patients with idiopathic pulmonary fibrosis (IPF). The analyses were based, however, on a single phase 3 trial and require validation in an independent cohort.ObjectiveTo confirm the performance characteristics and estimates of minimal clinically important difference (MCID) of 6MWD in an independent cohort of patients with IPF.MethodsPatients randomized to placebo in the phase 3 CAPACITY trials who had a baseline 6MWD measurement were included in these analyses. The 6MWD and other functional parameters (lung function, dyspnea, and health-related quality of life) were measured at baseline and 24-week intervals. Validity and responsiveness were examined using Spearman correlation coefficients. The MCID was estimated using distribution- and anchor-based methods.ResultsThe analysis comprised 338 patients. Baseline 6MWD was significantly correlated with lung function measures, patient-reported outcomes, and quality-of-life measures (validity). Compared with baseline 6MWD, change in 6MWD (responsiveness) showed stronger correlations with change in lung function parameters and quality-of-life measures. Dyspnea measured by the University of California San Diego Shortness of Breath Questionnaire showed the strongest correlations with 6MWD (baseline: coefficient −0.35; 48-week change: coefficient −0.37; both p < 0.001). The distribution-based analyses of MCID using standard error of measurement yielded an MCID of 37 m, and distribution-based analyses by effect size resulted in 29.2 m. The MCID by anchor-based analysis using criterion referencing (health events of hospitalization or death) was 21.7 m.ConclusionsThe 6MWD is a valid and responsive clinical endpoint, which provides objective and clinically meaningful information regarding functional status and near-term prognosis. These results confirm previous findings in an independent cohort of patients with IPF

Idiopathic interstitial pneumonia: Do community and academic physicians agree on diagnosis?

Rationale: Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult. Objectives: Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers. Methods: Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days. Measurements and Main Results: Each observer’s diagnosis was coded into one of eight categories. A statistic allowing formultiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (Kappa= 0.55–0.71) than within community centers (Kappa=0.32–0.44). Clinically significant disagreement was present between academic and communitybased physicians (Kappa=0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians. Conclusions: Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91941/1/2007 AJRCCM Idiopathic interstitial pneumonia - Do community and academic physicians agree on diagnosis.pd

Hypoxemia and Arrhythmia during Daily Activities and Six-minute Walk Test in Fibrotic Interstitial Lung Diseases

We performed 24-hr monitoring of pulse oximetric saturation (SpO2) with ECG and six-minute walk test (6MWT) in 19 patients with fibrotic interstitial lung diseases (ILD) to investigate; 1) The frequency and severity of hypoxemia and dysrhythmia during daily activities and 6MWT, 2) safety of 6MWT, and 3) the parameters of 6MWT which can replace 24-hr continuous monitoring of SpO2 to predict hypoxemia during daily activities. All patients experienced waking hour hypoxemia, and eight of nineteen patients spent > 10% of waking hours in hypoxemic state. Most patients experienced frequent arrhythmia, mostly atrial premature contractions (APCs) and ventricular premature contractions (VPCs). There were significant correlation between the variables of 6MWT and hypoxemia during daily activities. All of the patients who desaturated below 80% before 300 meters spent more than 10% of waking hour in hypoxemia (P = 0.018). In contrast to waking hour hypoxemia, SpO2 did not drop significantly during sleep except in the patients whose daytime resting SpO2 was already low. In conclusion, patients with fibrotic ILD showed significant period of hypoxemia during daily activities and frequent VPCs and APCs. Six-minute walk test is a useful surrogate marker of waking hour hypoxemia and seems to be safe without continuous monitoring of SpO2

Identifying nurses' rewards: a qualitative categorization study in Belgium

BACKGROUND: Rewards are important in attracting, motivating and retaining the most qualified employees, and nurses are no exception to this rule. This makes the establishment of an efficient reward system for nurses a true challenge for every hospital manager. A reward does not necessarily have a financial connotation: non-financial rewards may matter too, or may even be more important. Therefore, the present study examines nurses' reward perceptions, in order to identify potential reward options. METHODS: To answer the research question "What do nurses consider a reward and how can these rewards be categorized?", 20 in-depth semi-structured interviews with nurses were conducted and analysed using discourse and content analyses. In addition, the respondents received a list of 34 rewards (derived from the literature) and were asked to indicate the extent to which they perceived each of them to be rewarding. RESULTS: Discourse analysis revealed three major reward categories: financial, non-financial and psychological, each containing different subcategories. In general, nurses more often mentioned financial rewards spontaneously in the interview, compared to non-financial and psychological rewards. The questionnaire results did not, however, indicate a significant difference in the rewarding potential of these three categories. Both the qualitative and quantitative data revealed that a number of psychological and non-financial rewards were important for nurses in addition to their monthly pay and other remunerations. In particular, appreciation for their work by others, compliments from others, presents from others and contact with patients were highly valued. Moreover, some demographical variables influenced the reward perceptions. Younger and less experienced nurses considered promotion possibilities as more rewarding than the older and more senior ones. The latter valued job security and working for a hospital with a good reputation higher than their younger and more junior colleagues. CONCLUSION: When trying to establish an efficient reward system for nurses, hospital managers should not concentrate on the financial reward possibilities alone. They also ought to consider non-financial and psychological rewards (in combination with financial rewards), since nurses value these as well and they may lead to a more personalized reward system