Spyros Papiris

Lung involvement in primary Sjögren’s syndrome is mainly related to the small airway disease

OBJECTIVE To evaluate lung involvement in patients with primary Sjögren’s syndrome. METHODS Sixty one consecutive, non-smoking patients, 58 women and three men, were evaluated clinically, physiologically, and radiologically. A bronchial and/or transbronchial biopsy was performed on 13 of the patients. Physiological data were compared with that of a control group of 53 healthy non-smoking subjects matched for age and sex. RESULTS In 41% of the patients the main symptom was dry cough. Physiological studies revealed that the patients presented significantly lower expiratory flow values (% pred) when compared with those of the control group: the forced expiratory volume in one second (FEV1) (mean (SD)) was 96% (16) v 111% (13) (p<0.0001), the maximal expiratory flow at the 50% of the vital capacity (MEF50) was 72% (24) v103% (17) (p<0.0001), and the maximal expiratory flow at the 25% of the vital capacity (MEF25) was 49% (25)v 98 % (20) (p<0.0001). No significant difference was noted for the carbon monoxide diffusion value (% pred), between patients and controls. Blood gases were evaluated in 44 patients: mild hypoxemia was observed, and the alveolo-arterial oxygen difference (P(A-a)o 2) correlated significantly with MEF50 (r=0.35, p<0.01) and MEF25 (r=0.33, p<0.01) values. Chest radiography showed mild, interstitial-like changes in 27 patients while slightly increased markings were present in 21. High resolution computed tomography of the lungs was performed in 32 patients (four with a normal chest radiograph, six with suspected interstitial pattern, 19 with apparent interstitial pattern, and three with hyperinflation) and revealed predominantly wall thickening at the segmental bronchi. All positive findings by computed tomography derived from the patients with abnormal chest radiographs. Transbronchial and/or endobronchial biopsy specimens in 10 of the 11 sufficient tissue samples revealed peribronchial and/or peribronchiolar mononuclear inflammation, while interstitial inflammation coexisted in two patients. CONCLUSION The airway epithelia seem to be the main target of the inflammatory lesion of the lung in patients with primary Sjögren’s syndrome. It seems to be common, subclinically leading to obstructive small airway physiological abnormalities.

Sjögren's Syndrome

Sjögrens syndrome is a rather common autoimmune disease primarily characterized by the dysfunction and destruction of exocrine glands associated with lymphocytic infiltrations. The disorder has a quite broad clinical presentation, ranging from glandular disease to systemic involvement and to the development of lymphoid malignancy. This article reviews the current aspects in clinical diagnosis and management and the immunopathogenesis of the disorder.

Exhaled breath condensate in patients with asthma: implications for application in clinical practice

Exhaled breath condensate (EBC) analysis, a rather appealing and promising method, can be used to evaluate conveniently and non‐invasively a wide range of molecules from the respiratory tract, and to understand better the pathways propagating airway inflammation. A large number of mediators of inflammation, including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, prostanoids, nitrogen oxides, peptides and cytokines, have been studied in EBC. Concentrations of such mediators have been shown to be related to the underlying asthma and its severity and to be modulated by therapeutic interventions. Despite the encouraging positive results to date, the introduction of EBC in everyday clinical practice requires the resolution of some methodological pitfalls, the standardization of EBC collection and finally the identification of a reliable biomarker that is reproducible has normal values and provides information regarding the underlying inflammatory process and the response to treatment. So far, none of the parameters studied in EBC fulfils the aforementioned requirements with one possible exception: pH. EBC pH is reproducible, has normal values, reflects a significant part of asthma pathophysiology and is measurable on‐site with standardized methodology although some methodological aspects of measurement of pH in EBC (e.g. the effect of ambient CO2, sample de‐aeration, time for pH measurement) require further research. However, EBC pH has not been evaluated prospectively as a guide for treatment, in a manner similar to exhaled NO and sputum eosinophils. EBC represents a simple and totally non‐invasive procedure that may contribute towards our understanding of asthma pathophysiology. Besides the evaluation of new biomarkers, the standardization of the already existing procedures is warranted for the introduction of EBC in clinical practice.

Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Tumor necrosis factor (TNF)-α is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-α in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-α were assessed using combined experimentation with TNF-α gene–deficient mice and in vivo TNF-α neutralization. To expand the scope of preclinical data, TNF-α and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-α of host and tumor origin was present. TNF-α neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-α and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-α gene–sufficient and TNF-α gene–deficient mice. In mouse cancer cells, TNF-α functioned via nuclear factor-κB– and neutral sphingomyelinase–dependent pathways to induce TNF-α and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-α and VEGF content of human MPE. We conclude that tumor-derived TNF-α is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-α blockade against malignant pleural disease. [Cancer Res 2007;67(20):9825–34]

Exhaled Nitric Oxide and Exhaled Breath Condensate pH in Severe Refractory Asthma

BACKGROUND Distinct inflammatory cellular phenotypes of severe refractory asthma (SRA) have been reported. Fractional exhaled nitric oxide (FeNO) primarily is related to eosinophilic inflammation. Exhaled breath condensate (EBC) pH has been suggested as a noninvasive tool in the assessment of patients with asthma. We sought to determine whether FeNO and EBC pH could identify the presence and type of the underlying cellular inflammation in patients with SRA. METHODS Twenty-nine patients with SRA, 27 patients with moderate asthma, and 17 healthy subjects underwent FeNO measurement, EBC collection for pH measurement, and sputum induction for cell count identification. RESULTS FeNO was significantly higher and pH significantly lower in patients with SRA than in the other groups. In SRA, FeNO levels of > 19 parts per billion were associated with a sensitivity of 0.78 and a specificity of 0.73 for sputum eosinophilia, whereas FeNO levels of < 19 parts per billion were associated with a sensitivity of 0.63 and a specificity of 0.9 for sputum neutrophilia irrespective of the presence of eosinophils. The pH failed to predict the cellular profile in SRA, but a cutoff value of < 7.37 could predict sputum eosinophilia in moderate asthma. CONCLUSIONS In patients with SRA, different FeNO threshold values can identify those with predominant eosinophilia as well as those with neutrophilia. FeNO levels were reduced in patients with predominant neutrophilia regardless of the concomitant presence of eosinophilia. Although pH could not identify the cellular profile in SRA, it seemed to be a better index for predicting eosinophilia in moderate asthma.

The impact of depressive symptoms on recovery and outcome of hospitalised COPD exacerbations.

The impact of depressive symptoms on outcomes of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been thoroughly evaluated in prospective studies. We prospectively enrolled 230 consecutive patients hospitalised for AECOPD, without previous diagnosis of depression. Depressive symptoms were evaluated with Becks depression inventory. Pulmonary function tests, arterial blood gases, COPD assessment test (CAT) and Borg dyspnoea scale were recorded on admission and on days 3, 10 and 40. Patients were evaluated monthly for 1 year. Patients with depressive symptoms required longer hospitalisation (mean±sd 11.6±3.7 versus 5.6±4.1 days, p<0.001). Clinical variables improved during the course of AECOPD, but depressive symptoms on admission had a significant impact on dyspnoea (p<0.001) and CAT score (p=0.012) improvement. Patients with depressive symptoms presented more AECOPD (p<0.001) and more hospitalisations for AECOPD (p<0.001) in 1 year. In multivariate analysis, depressive symptoms were an independent predictor of mortality (hazard ratio 3.568, 95% CI 1.302–9.780) and risk for AECOPD (incidence rate ratio (IRR) 2.221, 95% CI 1.573–3.135) and AECOPD hospitalisations (IRR 3.589, 95% CI 2.319–5.556) in 1 year. The presence of depressive symptoms in patients admitted for AECOPD has a significant impact on recovery and is related to worse survival and increased risk for subsequent COPD exacerbations and hospitalisations in 1 year.

Body mass index is associated with leukotriene inflammation in asthmatics.

Eur J Clin Invest 2010; 41 (1): 30–38

Bench-to-bedside review: Pulmonary–renal syndromes – an update for the intensivist

The term Pulmonary–renal syndrome refers to the combination of diffuse alveolar haemorrhage and rapidly progressive glomerulonephritis. A variety of mechanisms such as those involving antiglomerular basement membrane antibodies, antineutrophil cytoplasm antibodies or immunocomplexes and thrombotic microangiopathy are implicated in the pathogenesis of this syndrome. The underlying pulmonary pathology is small-vessel vasculitis involving arterioles, venules and, frequently, alveolar capillaries. The underlying renal pathology is a form of focal proliferative glomerulonephritis. Immunofluorescence helps to distinguish between antiglomerular basement membrane disease (linear deposition of IgG), lupus and postinfectious glomerulonephritis (granular deposition of immunoglobulin and complement) and necrotizing vasculitis (pauci-immune glomerulonephritis). Patients may present with severe respiratory and/or renal failure and require admission to the intensive care unit. Since the syndrome is characterized by a fulminant course if left untreated, early diagnosis, exclusion of infection, close monitoring of the patient and timely initiation of treatment are crucial for the patients outcome. Treatment consists of corticosteroids in high doses, and cytotoxic agents coupled with plasma exchange in certain cases. Renal transplantation is the only alternative in end-stage renal disease. Newer immunomodulatory agents such as those causing TNF blockade, B-cell depletion and mycophenolate mofetil could be used in patients with refractory disease.

Sleep oxygen desaturation predicts survival in idiopathic pulmonary fibrosis.

BACKGROUND Recent studies suggest poor sleep quality in patients with idiopathic pulmonary fibrosis (IPF). However, so far, the impact of IPF-related sleep breathing disorders (SBDs) on survival has not been extensively studied. METHODS In a cohort of 31 (24 males) treatment-naïve, newly diagnosed consecutive IPF patients, we prospectively investigated the relationship of SBD parameters such as apnea-hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO2), and lowest sleep oxygen saturation (lowest SpO2) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal (6-min walk test [6MWT]) and maximal exercise variables (cardiopulmonary exercise test [CPET]), and right ventricular systolic pressure (RVSP). RESULTS Sleep oxygen desaturation exceeded significantly that of maximal exercise (p < 0.001). Maxdiff SpO2 was inversely related to survival, DLCO%, and SpO2 after 6MWT, and directly with dyspnea, AHI, and RVSP. The lowest SpO2 was directly related to survival and to functional (TLC%, DLCO%) as well as submaximal and maximal exercise variables (6MWT distance, SpO2 after 6MWT, peak oxygen consumption/kg, SpO2 at peak exercise), while an inverse association with dyspnea score, AHI, and RVSP was observed. CONCLUSIONS Our findings provide evidence that intermittent sleep oxygen desaturation significantly exceeds that of maximal exercise and is associated with survival in IPF patients. Furthermore, they imply the existence of a link between lung damage and apnea events resulting to the induction and severity of intermittent sleep oxygen desaturation that aggravate pulmonary arterial hypertension and influence IPF survival.

Zoledronic Acid Is Effective against Experimental Malignant Pleural Effusion

RATIONALE Aminobiphosphonates, such as zoledronic acid (ZA), exert potent indirect antitumor effects and are currently being tested against human solid tumors. The antitumor actions of aminobiphosphonates, including angiostasis, are relevant to the pathogenesis of malignant pleural effusion (MPE), but no study has addressed the efficacy of these compounds against malignant pleural disease. OBJECTIVES Here we hypothesized that treatment of immunocompetent mice with ZA would halt tumor progression in a mouse model of adenocarcinoma-induced MPE. METHODS To induce MPE in mice, Lewis lung carcinoma cells were delivered directly into the pleural space. Subsequently, animals were treated with ZA in both a prevention and a regression protocol. MEASUREMENTS AND MAIN RESULTS ZA treatment resulted in significant reductions in pleural fluid accumulation and tumor dissemination, while it significantly prolonged survival. These effects of ZA were linked to enhanced apoptosis of pleural tumor cells, decreased formation of new vessels in pleural tumors, and reduced pleural vascular permeability. In addition, ZA was able to inhibit the recruitment of mononuclear cells to pleural tumors, with concomitant reductions in matrix metalloproteinase-9 release into the pleural space. Finally, ZA limited the expression of proinflammatory and angiogenic mediators, as well as the activity of small GTP proteins Ras and RhoA, in tumor cells in vivo and in vitro. CONCLUSIONS ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.