Insights on chronic hypersensitivity pneumonitis' treatment: Factors associated with a favourable response to azathioprine.

BACKGROUND: The use of immunosuppressive and antifibrotic agents for the treatment of chronic hypersensitivity pneumonitis (CHP) appears promising, but there is still no evidence supporting the clinical decision regarding the implementation of each specific pharmacological strategy. METHODS: Patients diagnosed with CHP and treated with azathioprine (AZA) were retrospectively selected from a single centre for Interstitial Lung Diseases. Baseline clinical data, as well as functional, imaging, bronchoalveolar lavage (BAL) and histology features were assessed. Longitudinal data on functional parameters were collected and comparatively analysed with patients' characteristics. RESULTS: In this cohort of 80 patients, of those who reached 12 months of treatment, 78.3% presented a preserved forced vital capacity, with 59 being eligible to be classified as AZA responders (n = 36) or non-responders (n = 23). BAL lymphocytosis was associated with a favourable response to AZA treatment (OR 1.051; 95% CI 1.015-1.089), although it didn't identify all responders. CONCLUSIONS: AZA revealed to be effective in disease stabilisation in most patients, while ineffective for a subset. BAL lymphocytosis appears as a potentially valuable strategy to identify AZA responders, although with limited accuracy. Further studies are needed to clarify other response markers to immunosuppressive agents, in order to optimize the therapeutic options for this condition.

What is the effect of a Mediterranean compared with a Fast Food meal on the exercise induced adipokine changes? A randomized cross-over clinical trial.

BACKGROUND: Adipose tissue-derived adipokines are pro-inflammatory cytokines involved in metabolic-related diseases and can be influenced by diet and exercise. We aimed to compare the effect of a Mediterranean (MdM) compared with Fast Food (FFM) meal on the exercise induced adipokines changes. METHODS: In a double blinded cross over trial, 46 participants were randomly assigned to one of two standardized iso-energy pre-exercise meals: FFM or MdM-type. Three hours after each meal, participants completed a treadmill exercise test (EC). Serum adiponectin, resistin, PAI-1, lipocalin-2/NGAL and adipsin were determined by Luminex magnetic bead immunoassay. Wilcoxon signed rank test compared changes before/after meal and before/after EC and a linear mixed model evaluated the effect of meals on the adipokine response to exercise, adjusted for confounders. RESULTS: Thirty-nine participants (mean age of 25, with a standard deviation of 5 years) completed the trial (56% females). For both interventions, a significant reduction of adipsin after each meal and a significant increase of lipocalin, PAI-1, adipsin and resistin, after exercise was observed. When exercise was preceded by a MdM meal a higher increase in adipsin levels was seen. CONCLUSION: Acute exercise induced an increase of circulatory levels of adipsin, resistin, lipocalin and PAI-1, but not adiponectin. A pre-exercise Mediterranean meal potentiated the increase of adipsin after the exercise test, which possibly relates to the immune regulatory role of adipsin. These changes suggest a cross-talk between the immune and metabolic immediate response to exercise and its modulation by the pre-exercise diet composition.

NK and NKT cells in the diagnosis of diffuse lung diseases presenting with a lymphocytic alveolitis.

BACKGROUND: Diffuse lung diseases (DLD) are characterized by different immunophenotypes in the bronchoalveolar lavage fluid (BALF). We aimed to evaluate the diagnostic value of BALF NK and NKT cell counts of patients with DLD and lymphocytic alveolitis. METHODS: We assessed 202 patients with DLD, who underwent BALF immunophenotyping. Samples were routinely processed by flow cytometry and lymphocyte subsets were compared between patients with sarcoidosis (n = 106), hypersensitivity pneumonitis (HP; n = 53), and other DLDs (n = 43). We compared absolute counts and percentages of NK and NKT cells between patients with HP versus the remaining DLD patients. To assess the accuracy of BALF lymphocyte subsets in the diagnosis of HP, we calculated the respective areas under the receiver operating characteristic curves (AUC-ROC). RESULTS: Patients with HP had significantly higher numbers of BALF NK cells, and its percentage was significantly associated with a higher odds of HP, even after adjustment for the NKT and CD8+ cells. For the absolute number of BALF NK cells, we found an AUC-ROC of 0.76 (95%CI = 0.68-0.84) when comparing patients with HP versus the remaining DLD. The cut-offs of 2000 NK cells/mL and of 2.4% NK cells in the BALF had a specificity and a negative predictive value over 80% for the diagnosis of HP. BALF NK cells absolute counts were significantly higher in HP patients with a restrictive pattern. No such differences were observed for NKT cells. CONCLUSIONS: BALF NK immunophenotyping may be a helpful adjunct to the diagnostic work-up of DLD, particularly in the differential diagnosis of HP.

Meal-exercise challenge and physical activity reduction impact on immunity and inflammation (MERIIT trial).

BACKGROUND: The effect of a pre-exercise meal as countermeasure to exercise induced immunodepression is poorly known. Also, sedentary behavior is associated with increased cardiometabolic risk but studies on immune changes are lacking. Therefore, we aimed to assess: 1) the impact of a pre-exercise Mediterranean meal (MdM) compared with a fast-food type meal (FFM) on exercise-induced immunological changes and 2) the impact of an induced acute period of sedentary behavior on neuro-immune-endocrine status. METHODS: /Design: This is a two steps clinical trial including: (a) randomized crossover clinical trial, comparing the effect a high-fat/low-nutrient dense meal, FFM, with an isoenergetic similar high-nutrient dense meal, MdM, in the immune response to an exercise challenge (EC) and (b) a pilot trial assessing the neuro-immune-endocrine change induced by acute decreasing by half the usual physical activity level. RESULTS: A total of 46 participants (26 females), median aged 25 years were included. Of those 39-completed protocol, including overweight, physical active and inactive and participants with asthma. There were no differences in the EC between interventions. Dietary factors and physical activity were closely monitored during interventions and kept similar. During physical inactivity induction, 31% reached the target of 50% reduction in mean step number and 77% reached a 30% reduction. CONCLUSION: The use of a pre-exercise meal to modulate immune response and the understanding of the immunological impact of physical inactivity might help to establish future recommendations on how to practice exercise in a safer way and to recognize the potential impact of inactivity.

Serum metalloproteinases 1 and 7 in the diagnosis of idiopathic pulmonary fibrosis and other interstitial pneumonias.

INTRODUCTION: Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) has important therapeutic and prognostic implications and would be greatly aided by reliable diagnostic biomarkers as IPF has sometimes overlapping features with other interstitial lung diseases (ILD). OBJECTIVES: To explore the value of serum metalloproteinases (MMP) 1 and 7 levels in the differential diagnosis of IPF with other ILD. METHODS: MMP-1/7 serum levels were measured using Luminex xMAP technology in 139 patients- 47 IPF, 36 non-IPF Usual Interstitial Pneumonia (UIP), 14 idiopathic Nonspecific Interstitial Pneumonia (iNSIP), 29 secondary NSIP (secNSIP), 13 stage IV sarcoidosis- and 20 healthy controls, and compared using the Mann-Whitney U test. RESULTS: MMP-1 was significantly higher in IPF than non-IPF UIP (P = .042) and sarcoidosis (P = .027). MMP-7 was significantly higher in IPF than controls (P < .001), non-IPF UIP (P = .003), secNSIP (P < .001), and sarcoidosis (P < .001). The Area Under the Curve for IPF versus other ILD was 0.63 (95%CI, 0.53-0.73) for MMP-1, 0.73 (95%CI, 0.65-0.81) for MMP-7, and 0.74 (95%CI, 0.66-0.82) for MMP-1/MMP-7 combined. Sensitivity and specificity for MMP-7 cutoff = 3.91 ng/mL was 72.3% and 66.3%, respectively, Positive Predictive Values = 52.3% and Negative Predictive Values = 82.4%. CONCLUSIONS: MMP-1 and particularly MMP-7 serum levels were significantly higher in IPF than in non-IPF UIP, the main entity in differential diagnosis. The value of these biomarkers as additional tools in a multidisciplinary approach to IPF diagnosis needs to be considered and further explored.

Integrin α E ß 7 (CD103) expression in bronchoalveolar lymphocytes of patients with hypersensitivity pneumonitis.

PURPOSE: CD4+/CD8+ ratio in bronchoalveolar lavage fluid (BALF) often retrieves contradictory findings when used for diagnosis of sarcoidosis and hypersensitivity pneumonitis (HP), so CD103+ has been investigated as a possible differential marker. We aimed to compare CD103+ expression in BALF T-lymphocytes between patients with HP, sarcoidosis and other interstitial lung diseases (ILD). METHODS: An observational study carried out over a 2-year period included consecutive patients with suspected ILD who underwent BALF as part of their initial diagnostic work-up; CD103+ expression on BALF T-lymphocytes was evaluated. After a final diagnosis established according to international criteria, three patient subgroups-HP, ILD (which included idiopathic interstitial pneumonia and connective tissue disease-associated lung disorders) and sarcoidosis-were considered for further analysis. RESULTS: A total of 77 subjects were enrolled, 20 with HP, 16 with other ILD and 41 with sarcoidosis. A significantly higher number of CD4+ CD103+ and CD8+ CD103+ lymphocytes were found in HP patients. Among patients with sarcoidosis, 12 (29.3 %) presented a BALF CD4+/CD8+ <3.5, all of them with histological confirmation. Compared to these patients, also statistically significant higher CD4+ CD103+ counts in HP patients were observed (p = 0.007). Among HP patients, although bird fanciers (n = 14) presented higher percentages of both CD4+ CD103+ and CD8+ CD103+ T-lymphocytes than those with work-related HP (n = 5), the differences did not reach statistical significance. CONCLUSIONS: Patients with HP present significantly higher counts of CD103+ T-lymphocytes in BALF, both in the CD4+ and CD8+ subsets, when compared to sarcoidosis, even with sarcoidosis subgroup presenting a BALF CD4+/CD8+ <3.5. The expression of CD103 may help in the interpretation of BALF data in these diffuse granulomatous lung disorders.

Neurogenic inflammation in allergen-challenged obese mice: A missing link in the obesity-asthma association?

AIM: A number of studies have shown an association between obesity and asthma. Controversy remains on the mechanisms supporting this association. In this study we aimed to assess neurogenic inflammation in a model of diet-induced obesity and allergen-challenged mice. METHODS: High fat diet-induced (HFD) obese Balb/c mice were sensitized and challenged with ovalbumin (OVA). Glucose, insulin, OVA-specific IgE and substance P (SP), and the main tachykinin involved in neurogenic inflammation, were quantified in sera. Cell counts were performed in bronchoalveolar lavage fluid (BALF). The extent of peribronchial infiltrates was estimated on lung tissue sections and inflammation was score based on inflammatory cell counts surrounding the bronchi. RESULTS: Obesity per se and allergen-sensitization per se increased serum SP (P = .027, P = .004, respectively). Further increased was observed in obese-sensitized mice (P = .007). Obese-sensitized mice also showed higher insulin (P = .0016), OVA-specific IgE (P = .016), peribronchial inflammatory score (P = .045), and tendency for higher glycemia. The interaction of obesity and asthma on SP levels was confirmed (P = .005, R(2) = 0.710). SP was positively correlated with metabolic (glycemia, r = 0.539, P = .007) and allergic inflammation parameters (BALF eosinophils, r = 0.445, P = 0.033; BALF mast cells, r = 0.574, P = .004; peribronchial inflammation score, r = 0.661, P < .001; and OVA-specific IgE, r = 0.714, P < .001). CONCLUSIONS: Our findings provide support to the neurogenic inflammation link between obesity and asthma in mice. These two conditions independently increased SP and the presence of both pathologies further increased this level. Neurogenic inflammation may be a previously unrecognized mechanism beyond the obese-asthma phenotype. Further studies are need to confirm this role of SP in human obesity-asthma association.

Diagnostic value of CD103 expression in bronchoalveolar lymphocytes in sarcoidosis.

BACKGROUND: Pulmonary sarcoidosis is frequently characterized by a CD4(+)/CD8(+) ratio ≥3.5 in bronchoalveolar lavage fluid (BALF), although up to 40% of the cases present a normal or even decreased ratio, pointing out its variability and limitation as a diagnostic marker for sarcoidosis. Lung lymphocytes within the bronchial epithelium, the alveolar walls, and BALF express the integrin CD103. Our aim was to compare the expression of CD103 in BALF T-lymphocytes between sarcoidosis and other interstitial lung diseases (ILD) and to evaluate its relevance as a BALF diagnostic marker for sarcoidosis. METHODS: A total of 86 patients with ILD (mean age ± standard deviation, 42.6 ± 16.6 years; 60.5% female), who underwent BALF as part of their initial diagnostic work-up, were enrolled into 2 groups: sarcoidosis (n = 41) and other ILD (n = 45). Area under the receiver operating characteristic (ROC) curve (AUC) was used to describe the performance of CD103 for sarcoidosis diagnosis. RESULTS: Sarcoidosis patients presented a significantly reduced CD103 expression in BALF T-lymphocytes, more pronounced in the CD4(+) subset. The BALF CD103(+)CD4(+)/CD4(+) ratio for a cutoff point of 0.45 was associated with a better diagnostic performance for sarcoidosis (AUC: 0.86 [95% confidence interval (95% CI): 0.78-0.94]; sensitivity: 81%; specificity: 78%), even for those with a CD4(+)/CD8(+) ratio <3.5 (AUC: 0.79 [95% CI: 0.64-0.93]; sensitivity: 75%; specificity: 78%). CONCLUSIONS: Assessment of CD103 expression in BALF CD4(+) T-lymphocytes may be a reliable tool for sarcoidosis diagnosis, independently of CD4(+)/CD8(+) ratio, pointing out the relevance of evaluating the CD103(+)CD4(+)/CD4(+) ratio in the ILD diagnostic work-up.

[Assessment of antibodies anti-saccharomyces cerevisiae (ASCA) and autoantibodies in patients with inflammatory bowel disease]. / Avaliação de anticorpos antisaccharomyces cerevisiae e auto-anticorpos em doentes com doença inflamatória intestinal.

The incidence of inflammatory bowel disease (IBD) has been increasing worldwide, and despite the advances regarding their pathogenesis and therapeutics, the differential diagnosis between Crohn's Disease (CD) and Ulcerative Colitis (UC) is mainly based on clinically invasive tests. Recent studies have identified new serological markers with a potential value for the diagnosis of these pathologies, in particular the anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA). Also of note are the anti-goblet cells antibodies (anti-CCI) and the anti-pancreatic exocrine autoantibodies that react with the pancreatic acinus (anti-AP). We assessed these new serological markers and compared the efficiency between immune enzymatic (ELISA) and indirect immunofluorescence tests in the identification of ASCA of IgG or IgA class. We studied a set of 81 serum samples (with an initial diagnosis of IBD) and 33 control samples from healthy blood donors. The laboratory tests were correlated with the diagnosis of each patient, established in the Gastroenterology outpatient unit based on conventional methods. The agreement between the two laboratory methods employed in the identification of the ASCA was excellent (k = 0.63) for the IgG antibodies and good (k = 0.56) for the IgA antibodies. We found a weak agreement (k = 0.137) between ELISA (MPO and PR3 purified antigens) and the IFA test for ANCA. Regarding the serologic markers ANCA, anti-AP and anti-CCI, only the later showed no differences in the distribution of positive results between the studied groups. Positive ASCA IgG and IgA were significantly associated with diagnosis of DC, with both laboratorial methods tested. The identification of ANCA with the available solidphase tests does not seem appropriate for the screening of the autoantibodies with the atypical p-ANCA pattern of IBD. The combination between anti-AP and ASCA antibodies seems a good option for the laboratorial diagnosis of CD. This study shows that these serologic markers in spite of being non invasive laboratory tests, also have a considerable overlapping in the different IBD. Nevertheless, further prospective studies based on larger populations are required to clarify the relationship between these antibodies, the diagnosis and clinical evolution of inflammatory bowel disease.