Spyridon Papiris

Static and dynamic mechanics of the murine lung after intratracheal bleomycin

BackgroundDespite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure.MethodsSingle intratracheal injections of saline (50 μL) or bleomycin (2 mg/Kg in 50 μL saline) were administered to C57BL/6 (n = 40) and Balb/c (n = 32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (RN ), tissue damping (G) and elastance coefficient (H), hysteresivity (η), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD post hoc tests.ResultsBoth C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and G and H non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. G and H, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, H and G was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls.ConclusionsLung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.

Serum uric acid as a predictor of mortality and future exacerbations of COPD

Serum uric acid is increased in respiratory disease, especially in the presence of hypoxia and systemic inflammation. We evaluated serum uric acid as a biomarker for prediction of mortality and future acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Serum uric acid was measured in 314 eligible consecutive patients on admission for AECOPD. Patients were evaluated monthly for 1 year. Uric acid levels were higher in patients with more severe airflow limitation and in those experiencing frequent exacerbations. High uric acid levels (≥6.9 mg·dL−1) were an independent predictor of 30-day mortality in multivariate Cox regression analysis (HR 1.317, 95% CI 1.011–1.736; p=0.044), but not of 1-year mortality. Patients with high serum uric acid required more prolonged hospitalisation, and more often needed noninvasive ventilation and admission to the intensive care unit within 30 days. In addition, high uric acid levels were associated with increased risk and hospitalisation for AECOPD in 1 year in multivariate Poisson regression analysis (incidence rate ratio 1.184 (95% CI 1.125–1.246) and 1.190 (95% CI 1.105–1.282), respectively; both p<0.001). Serum uric acid is associated with increased 30-day mortality and risk for AECOPD and hospitalisations in 1-year follow-up. This low-cost biomarker may be useful in the identification of high-risk chronic obstructive pulmonary disease patients that could benefit from intensive management. Serum uric acid was linked with airflow limitation in COPD and predicted mortality and future exacerbations http://ow.ly/qflaZ

Associations between BODE Index and Systemic Inflammatory Biomarkers in COPD

Background: COPD is a multicomponent disease and systemic inflammation represents one of the possible mechanisms responsible for its systemic manifestations, including skeletal muscle weakness and cachexia. Fat-free mass index (FFMI) that reflects the skeletal muscle mass, has been shown to be associated with both dyspnoea and exercise capacity. We hypothesized that the multidimensional BODE index, that reflects the multicomponent nature of COPD, might be related to biomarkers of systemic inflammation. We further evaluated associations between FFMI and systemic inflammation. Methods: BODE index and FFMI were calculated in 222 stable COPD patients and 132 smokers or ex-smokers with normal lung function. Systemic inflammation was evaluated with the measurement of leptin, adiponectin, CRP, IL-6, and TNF-α in serum samples of COPD patients. Results: In patients with COPD, both BODE index and FFMI presented significant positive and negative associations respectively with leptin levels (R2 0.61 and 0.65, respectively), whereas FFMI presented an additional negative association with the levels of TNF-α (R2 0.38). No significant associations were observed in smokers or ex-smokers with normal lung function. Conclusions: Both BODE index and FFMI, are related to the circulating levels of leptin in patients with COPD, suggesting a possible role for leptin in the systemic component of COPD. The additional association of FFMI with TNF-α may further support a role of systemic inflammation in muscle wasting in COPD.

Diagnostic value of triggering receptor expressed on myeloid cells-1 and C-reactive protein for patients with lung infiltrates: an observational study

BackgroundDifferential diagnosis of patients with lung infiltrates remains a challenge. Triggering receptor expressed on myeloid cells (TREM)-1 is a neutrophil and monocyte receptor up-regulated during infection. The aim of this study was to evaluate the diagnostic accuracy of TREM-1 and of C-reactive protein (CRP) from patients with lung infiltrates to discern community acquired lung infections.Methods68 patients admitted to a medical ward with acute respiratory illness were enrolled in the study. Neutrophil and monocyte TREM-1 expression were measured by flow cytometry, sTREM-1 by an enzyme immunoassay and C-reactive protein by nephelometry. Clinical pulmonary infection score was recorded.Results34 patients were diagnosed with bacterial community acquired pneumonia (group A) and 34 with non-bacterial pulmonary disease (group B). Median serum TREM-1 concentration was 102.09 pg/ml in group A and lower than 15.10 pg/ml (p < 0.0001) in group B. Mean±SE neutrophil TREM-1 expression was 4.67 ± 0.53 MFI in group A and 2.64 ± 0.25 MFI (p = 0.001) in group B. Monocyte TREM-1 expression was 4.2 ± 0.42 MFI in group A and 2.64 ± 0.35 MFI (p = 0.007) in group B and mean±SE CRP was 18.03 ± 2 mg/ml in group A and 7.1 ± 1.54 mg/ml (p < 0.001) in group B. A cut-off of 19.53 pg/ml of sTREM-1 with sensitivity 82.6% and specificity 63% to discriminate between infectious and non-infectious pulmonary infiltrates was found. sTREM-1 at admission greater than 180 pg/ml was accompanied with unfavourable outcome.ConclusionTREM-1 myeloid expression and sTREM-1 are reliable markers of bacterial infection among patients with pulmonary infiltrates; sTREM-1 is a predictor of final outcome.

Serologic evaluation in idiopathic interstitial pneumonias.

Purpose of reviewDiagnosis of idiopathic interstitial pneumonias (IIPs) requires the exclusion of, among others, concomitant connective tissue diseases (CTDs), which may present as interstitial lung disease (ILD). This review focuses on the evaluation required to separate these entities through serology, although not exclusively. Recent findingsSeveral recent data suggest that patients diagnosed with IIPs can show evidence of CTDs on follow-up. This is especially true for nonspecific interstitial pneumonia but may also be seen with other forms of ILD. SummaryILDs may occur alone, IIPs, or in association with, among others, CTDs. In the latter case, they may present before, during or even several months or years after the fulfillment of undisputed criteria for CTDs. If present before, their presentation presupposes their occurrence in early undiagnosed, undefined or undifferentiated CTD, which occasionally indefinitely maintains this status of diagnostic uncertainty, especially if ILD is empirically treated by immunosuppressants. Serologic evaluation for autoantibodies assisted by serum inflammatory biomarkers, detailed search for clinical clues of CTDs and suggestive histopathologic features on lung specimens may provide a framework to build the correct diagnosis. Obtaining a diagnosis of ILD associated with CTD exceeds semantics as this subset of patients may present different natural history, pathobiology, treatment and prognosis.

Predictors of response to therapy with omalizumab in patients with severe allergic asthma - a real life study.

ABSTRACT Objectives: Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody, used for the treatment of severe refractory allergic asthma. However, not all patients with IgE levels within the limits of administration, respond to treatment. The aim of the present study, was to determine clinical and inflammatory characteristics that could predict response to omalizumab. Methods: We studied retrospectively patients treated with omalizumab as per GINA guidelines in one asthma tertiary referral center. Demographic and functional characteristics, level of asthma control, fractional exhaled nitric oxide, blood and eosinophils and IgE level, induced sputum cell count, eosinophil cationic protein and Interleukin-13 in sputum supernatant were recorded. All measurements were performed before starting treatment with omalizumab. Response to treatment was evaluated according to the physician’s global evaluation of treatment effectiveness. Patients were characterized as early responders when improvement was achieved within 16 weeks and as late responders when improvement was achieved between 16 and 32 weeks. Patients who did not show any improvement after 32 weeks of therapy were considered as non-responders. Results: Forty-one patients treated with omalizumab were included in the study. 28 (68.3%) patients were characterized as responders while 13 patients (31.7%) were considered as non-responders. Among responders, 25 (89%) were early responders and 3 (n = 11%) were late responders. Responders were characterized by lower baseline FEV1 and FEV1/FVC and higher IL-13 levels in induced sputum supernatant compared to non-responders. Late responders had higher serum IgE levels, shorter disease duration and higher number of blood eosinophils. Finally, using ROC curve analysis, the best predictors of response to omalizumab were FEV1 (AUC = 0.718) and IL-13 in sputum supernatant (AUC = 0.709). Conclusion: Lower baseline FEV1 and higher IL-13 levels in induced sputum supernatant were predictors of response to omalizumab. Patients with higher baseline serum IgE levels, shorter disease duration and higher blood eosinophils may experience a late response and might benefit from a more prolonged treatment before being characterized as non-responders.

Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract

Combined pulmonary fibrosis and emphysema (CPFE) is a clinical entity characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. Patients with this condition experience severe dyspnea and impaired gas exchange with preserved lung volumes. The diagnosis of the CPFE syndrome is based on HRCT imaging, showing the coexistence of emphysema and pulmonary fibrosis both in varying extent and locations within the lung parenchyma. Individual genetic background seem to predispose to the development of the disease. The risk of the development of pulmonary hypertension in patients with CPFE is high and related to poor prognosis. CPFE patients also present a high risk of lung cancer. Mortality is significant in patients with CPFE and median survival is reported between 2.1 and 8.5 years. Currently, no specific recommendations are available regarding the management of patients with CPFE. In this review we provide information on the existing knowledge on CPFE regarding the pathophysiology, clinical manifestations, imaging, complications, possible therapeutic interventions and prognosis of the disease.

Predictors of future exacerbation risk in patients with asthma

ABSTRACT Objectives: Although modern treatment of asthma improves asthma control, some patients still experience exacerbations. The aim of the present study was to detect predictors of asthmatic exacerbations Methods: We included patients with asthma followed up in asthma clinics of 2 tertiary University hospitals. Demographic and functional characteristics, levels of exhaled NO, and inflammatory biomarkers (IL-13, ΕCP και IL-8) and cell counts in induced sputum were recorded at baseline. Measurements were performed with the patients in stability and were considered as their personal best. Patients received optimal treatment with good compliance and were followed up for 1 year for asthma exacerbations occurrence. Evaluation of the effect of recorded parameters on asthma exacerbations was performed with univariate and multivariate Poisson regression analysis. Results: 171 patients (118 female) with bronchial asthma (mean age 51.6 ± 13.2 years) were included in the study. The mean number of exacerbations in 1 year of follow up was 0.4 ± 0.8 while the majority of patients (71.9%) did not experience any exacerbation. In multivariate Poisson Regression analysis only 3 characteristics were predictors of future exacerbations: FEV1 [IRR(95% CI)], [0.970(0.954–0.987)], p = 0.001, high BMI [1.078(1.030–1.129)], p = 0.001, and the need for permanent treatment with oral corticosteroids for asthma control maintenance [2.542(1.083–5.964)], p = 0.032 Conclusion: Optimal guideline-based asthma management results in minimal occurrence of exacerbations in the majority of patients. Predictors of exacerbations are low FEV1 levels in stability, high BMI and the need for permanent treatment with oral corticosteroids.

Venlafaxine-induced acute eosinophilic pneumonia

INTRODUCTION Acute Eosinophilic Pneumonia (AEP) is a severe syndrome which can be potentially induced by many reasons, including drugs. It is characterized by pulmonary infiltrates, peripheral blood eosinophilia and respiratory failure. AEP has rarely been associated with antidepressant treatment. CASE REPORT We report a case of an 80-year-old woman who presented with fever, lung infiltrates, peripheral blood eosinophilia and acute respiratory failure. All evidence charge venlafaxine as the only possible causal factor. The syndrome rapidly resolved after discontinuation of the drug and upon reception of corticosteroids in low doses. The patient had a past medical history of AEP induced by sertraline and a recent medical history of Acute Lung Injury on the context of acute pancreatitis during treatment with venlafaxine. DISCUSSION Pathophysiological mechanisms implicated in the development of AEP in our patient seems to be associated with eotaxin and serotonin eosinophilic-specific chemoattracting action. CONCLUSION This is a case report with clinical adverse reaction of AEP in two antidepressant agents (venlafaxine and sertraline) with a similar neurochemical mechanism of action via the serotoninergic system.

Idiopathic Pulmonary Fibrosis and Emphysema: Between Scylla and Charybdis.

cific interstitial pneumonia, which has a better prognosis compared to IPF. In this issue of Respiration, Kohashi et al. [14] add further information on the impact of emphysema on IPF prognosis. The novelty of their study lies in the fact that they strictly included patients with biopsy-proven IPF. A total of 47 patients with biopsy-proven IPF were analyzed. For the assessment of emphysema and fibrosis, high-resolution computed tomography scans were evaluated semiquantitatively by visual scoring. The lungs were divided into six zones (upper, middle, and lower zones bilaterally) and each zone was evaluated separately according to the following: score 0 = none; score 0.5 = <5%; score 1 = 5–24%; score 2 = 25–49%; score 3 = 50–74%, and score 4 = ≤ 75%. IPF-emphysema was defined as IPF cases with a total emphysema score greater than 3.0, with mean scores of all 6 zones greater than 0.50. Eight patients fulfilled the previous criteria forming the group of IPF-emphysema. Patients with IPF-emphysema had a statistically significantly worst survival compared to IPF alone patients by Kaplan-Meier analysis (median survival 1,734 vs. 2,229 days, respectively, p = 0.007). As expected, emphysema had upper lobe predominance. Regarding other prognostic parameters on univariate analysis, Krebs von Idiopathic pulmonary fibrosis (IPF) is the commonest of the idiopathic interstitial pneumonias and carries the most ominous prognosis with a median survival of 3 years [1] . IPF often coexists with emphysema. The coexistence of IPF and emphysema is intriguing as they share common pathogenetic mechanisms [2] and alongside lung cancer they have been considered as different manifestations of smoking on a susceptible genetic background [3] . But also from a clinical view the coexistence of IPF and emphysema is very interesting [4] . Firstly, it represents a characteristic case in which the presence of slightly subnormal or even normal forced vital capacity does not exclude the possibility of underlying fibrosis. Secondly, it has opened the question of whether combined pulmonary fibrosis and emphysema (CPFE) patients exhibit worse survival in comparison to sole IPF patients. Literature so far has exhibited contradicting results regarding the survival of CPFE versus sole IPF patients with some of the studies showing worsened survival [5, 6] and other studies showing no difference [7, 8] or even improved survival [9, 10] . Several reasons could be implicated for the discrepant results of the studies so far [11–13] . One of these reasons could be the inclusion in the pulmonary fibrosis group of patients with nonspePublished online: September 8, 2016