Combined immunosuppressive therapy provides favorable prognosis and increased risk of cytomegalovirus reactivation in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) is myositis-specific autoantibody associated with rapidly progressive interstitial lung disease (ILD) and poor prognosis. In this retrospective observational study, we aimed to verify the efficacy and safety of introducing combined immunosuppressive therapy for anti-MDA5 Ab-positive dermatomyositis (DM) from their early stage. We recruited all Japanese patients diagnosed with DM in our clinic between January 2011 and October 2018, who had anti-MDA5 Ab, anti-aminoacyl transfer RNA synthetase Ab or anti-transcriptional intermediary factor 1-γ Ab. Combined immunosuppressive therapy was defined as combination of systemic corticosteroids, i.v. cyclophosphamide and tacrolimus. The difference of clinical features among the three groups was analyzed by multiple comparison analysis. The longitudinal change of the measurements from baseline was examined by Wilcoxon signed-rank test. Association between therapeutic regimens and adverse events was examined by logistic regression analysis. As a result, combined immunosuppressive therapy was most frequently used in the anti-MDA5 Ab-positive group, which significantly improved their forced vital capacity of the lung. Interval time since initial visit until starting treatment was the shortest in the anti-MDA5 Ab-positive group. There was no significant difference in the incidence of death and recurrence among the three groups. Cytomegalovirus reactivation was most common in the anti-MDA5 Ab-positive group, associated with combined immunosuppressive therapy. Collectively, early introduction of combined immunosuppressive therapy was effective for DM patients with anti-MDA5 Ab. At the same time, clinicians should be aware of the risk of cytomegalovirus reactivation during the treatment.

Autoantibody status is not associated with change in lung function or survival in patients with idiopathic pulmonary fibrosis.

INTRODUCTION: A proportion of patients with idiopathic pulmonary fibrosis (IPF) have autoantibodies directed against intracellular targets. This study aimed to determine the relationship between serologic status, lung function decline and survival. METHODS: IPF patients assessed for antinuclear antibody (ANA) and related antigen-specific serology detected by addressable laser bead immunoassay (ALBIA) were included. Demographics, serial pulmonary function tests and survival were compared between patients with and without autoantibodies. Linear mixed models were used to estimate changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time. Cox-proportional hazards models were used to compare survival, adjusted for a composite score including age, sex and baseline lung function. RESULTS: Of 61 included patients, the mean baseline age was 70 years (SD = 9), 77% were male, and 87% were Caucasian. Either ANA or antigen-specific serology by ALBIA was positive in 25 (41%) during follow-up. ANA was detected in 23 (38%), and specific autoantibodies by ALBIA in 6 (10%). There was no difference in age, sex, race, smoking status, anti-fibrotic use or baseline FVC or DLCO in patients with and without autoantibodies. There was no association between autoantibody status and survival (HR = 1.18, 95% CI 0.61, 2.29), rate of decline in FVC or DLCO (difference in FVC = 4.2 mL/year, p = 0.82; difference in DLCO = 4.6*10-4 mL/min/mmHg/year, p = 0.20). CONCLUSION: These data suggest that autoantibodies are common in IPF and that patients with a subset of autoantibodies, but without features of autoimmunity, demonstrate similar disease behaviour to those without autoantibodies.

Development of a tool predicting severity of allergic reaction during peanut challenge.

BACKGROUND: Reliable prognostic markers for predicting severity of allergic reactions during oral food challenges (OFCs) have not been established. OBJECTIVE: To develop a predictive algorithm of a food challenge severity score (CSS) to identify those at higher risk for severe reactions to a standardized peanut OFC. METHODS: Medical history and allergy test results were obtained for 120 peanut allergic participants who underwent double-blind, placebo-controlled food challenges. Reactions were assigned a CSS between 1 and 6 based on cumulative tolerated dose and a severity clinical indicator. Demographic characteristics, clinical features, peanut component IgE values, and a basophil activation marker were considered in a multistep analysis to derive a flexible decision rule to understand risk during peanut of OFC. RESULTS: A total of 18.3% participants had a severe reaction (CSS >4). The decision rule identified the following 3 variables (in order of importance) as predictors of reaction severity: ratio of percentage of CD63hi stimulation with peanut to percentage of CD63hi anti-IgE (CD63 ratio), history of exercise-induced asthma, and ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio. The CD63 ratio alone was a strong predictor of CSS (P < .001). CONCLUSION: The CSS is a novel tool that combines dose thresholds and allergic reactions to understand risks associated with peanut OFCs. Laboratory values (CD63 ratio), along with clinical variables (exercise-induced asthma and FEV1/FVC ratio) contribute to the predictive ability of the severity of reaction to peanut OFCs. Further testing of this decision rule is needed in a larger external data source before it can be considered outside research settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02103270.

Serum levels of adiponectin and leptin in asthmatic patients and its relation with asthma severity, lung function and BMI

INTRODUCTION: Asthma is one of the diseases which has a high prevalence in developed and developing countries. The relationship between asthma and obesity has always been focused by researchers. In this field, adipokines, especially adiponectin and leptin have highly attended by the scientist. The aim of this study was to determine the serum level of adiponectin, leptin and the leptin/adiponectin ratio in asthmatic patients and its relationship with disease severity, lung function and BMI (body mass index). METHODS: In this cross-sectional study, 90 asthmatic women admitted to the tertiary referral hospital in Kurdistan province - Iran, were examined. First, BMI was measured and then pulmonary function tests were performed in all asthmatics patient. Forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and FEV1/FVC, were measured. At the end, blood samples were collected and serum level of adiponectin and leptin were measured by ELISA method. RESULT: Serum leptin and leptin/adiponectin levels correlated positively with asthma severity and BMI (p = 0.0001), but there was no correlation between adiponectin level with asthma severity and BMI (p > 0.05), also serum leptin and leptin/adiponectin levels inversely correlated with FEV1 and FVC in patient (p = 0.0001). CONCLUSION: Asthma is linked with obesity, and there is an association between asthma severity and BMI with serum leptin and leptin/adiponectin levels, but our results do not support a significant role of adiponectin in obesity or asthma

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Antinuclear autoantibodies are more prevalent in COPD in association with low body mass index but not with smoking history.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a higher prevalence of antinuclear autoantibodies (ANAs). However, a significant subgroup of patients is ANA negative. It remains to be determined which patient groups carry autoantibodies. METHODS: The association of smoking behaviour, disease status, gender, age and body mass index (BMI) with the presence of autoantibodies in the serum was determined in 124 patients with COPD and 108 non-COPD control subjects. In addition, the role of B cells in autoantibody generation in COPD was investigated by sequencing the antibody repertoire of B cells in the lungs of patients with COPD and of ex-smoking and never-smoking control subjects. RESULTS: Patients with COPD had a significantly higher risk of being serum positive for ANAs (OR 3.12, 95% CI 1.68 to 5.76, p<0.001). ANAs were not significantly associated with age, smoking status, gender or pack-years of smoking. Within the COPD population, subjects with BMI <22 kg/m2 had a significantly higher risk of ANAs (OR 4.93, 95% CI 1.50 to 16.50, p=0.009) than those with normal or high BMI. The antibody repertoire of B cells in the lungs of patients with COPD had a high frequency of positively charged CDR3 residues, a feature which is associated with self-reactive antibodies. CONCLUSION: The results show that COPD is a heterogeneous disease with respect to the prevalence of ANAs. ANAs are primarily associated with the presence of COPD and with low BMI, but not with smoking and forced expiratory volume in 1 s.

[The relationship between the lung function and the level of TNF-α in serum in COPD department of respiratory].

AIM: To explore the relationship between the lung function and the level of TNF-α in serum in COPD. METHODS: 60 patients with COPD and 35 normal subjects were involved in the study. The serum TNF-α level was measured by ELISA and the lung function were determined. RESULTS: The level of TNF-α were significantly different in acute and stable COPD group, control group (P < 0.01). The levels of FEVI, FVC, FEVI/FVC and MMEF in acute and stable COPD group were significantly lower than those control group (P < 0.01). The levels of TNF-α was negatively correlated with FEVI, FVC, FEVI/FVC and MMEF (r = -0.586, -0.714, -0.527, -0.639, P < 0.05). CONCLUSION: The TNF-α are involved in airway inflammation and the pathogenetic process of COPD, and may influence the lung function.

Cardiorespiratory and immune response to physical activity following exposure to a typical smoking environment.

OBJECTIVE: Millions of non-smokers suffer daily passive smoking (PS) at home or at work, many of whom then have to walk fast for several minutes or climb a few sets of stairs. We conducted a randomised single-blind crossover experiment to assess the cardiorespiratory and immune response to physical activity following PS. DESIGN: Data were obtained from 17 (eight women) non-smoking adults during and following 30 minutes of moderate cycling administered at baseline and at 0 hour, 1 hour and 3 hours following a 1-hour PS exposure set at bar/restaurant PS levels. RESULTS: We found that PS was associated with a 36% and 38.7% decrease in mean power output in men and women, respectively, and that this effect persisted up to 3 hours (p<0.05). Moreover, at 0 hour almost all cardiorespiratory and immune variables measured were markedly reduced (p<0.05). For instance, FEV(1) values at 0 hour dropped by 10.2% in men and 10.8% in women, while IL-5 increased by 59.2% in men and 44% in women, respectively (p<0.05). At 3-hour mean values of respiratory quotient, mean power, perceived exertion, cotinine, FEV(1), IL-5, IL-6 and INFgamma in both sexes, recovery diastolic and mean arterial pressure, IL-4 and TNFalpha in men, as well as percentage predicted FEV(1) in women remained different compared to baseline (p<0.05). Also, some of the PS effects were exacerbated in less fit individuals. CONCLUSION: It is concluded that 1 hour of PS at bar/restaurant levels adversely affects the response to moderate physical activity in healthy non-smokers for at least 3 hours following PS.

A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.

BACKGROUND: The specific genetic contributions to childhood asthma have been difficult to elucidate. A recent whole-genome association study suggested that single nucleotide polymorphisms at loci controlling the expression of the ORMDL3 gene and others in the neighborhood of the NRG1 and ERO1LB genes might be important. OBJECTIVE: We sought to replicate the associations of these genetic markers with asthma in a large population of asthmatic patients from Scotland and to assess the effect of these variants on asthma outcomes. METHODS: Using mouthwash-derived DNA and clinical interviews and measurements, we investigated the association of 3 single nucleotide polymorphisms in the candidate genes with susceptibility to asthma in a case-control study and also exacerbations in a group of 1054 patients aged 3 to 22 years. RESULTS: A common C/T polymorphism at a locus controlling ORMDL3 gene expression (rs7216389) was significantly associated with the risk of childhood asthma (P = 1.73 x 10(-12)), with a single copy of the T allele conferring an odds ratio of 1.50 (95% CI, 1.24-1.81) and 2 copies of the T allele conferring an odds ratio of 2.11 (95% CI, 1.71-2.61), respectively. In asthmatic patients the T allele was associated with exacerbations of the condition (P = .008). Polymorphisms at the loci of nearby genes for NRG1 (rs4512342) and ERO1LB (rs10924993) were associated with neither the occurrence of nor exacerbations of asthma. CONCLUSION: A common genetic variation at a locus controlling the expression of the ORMDL3 locus increases the susceptibility to asthma and is associated with poor control of the condition in children and young adults.

Repeated sputum inductions induce a transient neutrophilic and eosinophilic response.

INTRODUCTION: Sputum induction is a tool to monitor airway inflammation, yet it may induce by itself a neutrophilic response when repeated within 24 to 48 h. This limits its repeated use in clinical trials. OBJECTIVE: We aimed to investigate the induction and resolution of inflammation generated by repeated sputum inductions. SUBJECTS AND DESIGN: Sixteen healthy intermittent smokers participated in a study on the short-term effects of smoking. The nonsmoking arm consisted of seven successive sputum inductions with increasing time intervals (3, 6, 12, 24, 48, and 96 h). Inflammatory cellular characteristics and different soluble mediators were investigated. MEASUREMENTS AND RESULTS: The median percentage of sputum neutrophils increased significantly from baseline to 6 h (58.9% [range, 31.8 to 94.2%] to 83.2% [range, 26.7 to 98.3%], respectively). Surprisingly, the percentage of eosinophils also increased significantly from baseline to 6, 12, 24, and 48 h, as follows: 0.3% (range, 0.0 to 1.2%) to 1.7% (range, 0.0 to 15.5%), 2.2% (range, 0.5 to 12.5%), 1.2% (range, 0.0 to 4.8%), and 0.8% (range, 0.0 to 2.8%), respectively. Interleukin-8 increased significantly from baseline to 24 h (1,553 pg/mL [range, 462 to 8,192 pg/mL] to 2,178 pg/mL [range, 666 to 128,544 pg/mL]). CONCLUSIONS: Repeated sputum inductions should preferably be avoided within 48 h. It induces not only a short-lived neutrophilic response but also a prolonged eosinophilic inflammatory response in healthy subjects, possibly by local changes in osmolarity, and subsequent epithelial and/or mast cell activation.

Specific sensitization to common allergens and pulmonary function in the European Community Respiratory Health Survey.

BACKGROUND: The role of atopy in the evolution to chronic obstructive disease remains controversial. AIM: We aimed to assess the association between individual sensitization to common allergens and lung function. METHOD: We analysed data from 12,687 subjects aged 20 to 44 years, from 34 centres in 15 countries participating in the European Community Respiratory Health Survey (ECRHS). Participants performed a blood test, lung function test, methacholine challenge, and answered an administered questionnaire. The relationships between specific IgE, FEV1 and FEV1/FVC ratio were assessed for each study centre stratified by sex, followed by random effects meta-analysis. RESULTS: Asthmatics sensitized to house dust mite had a lower FEV1 (-119 mL in women and -112 mL in men) and FEV1/FVC ratio (-1.95%, and -2.48%) than asthmatics without sensitization. Asthmatics sensitized to cat had a lower FEV1 (statistically significant for women only) and a lower FEV1/FVC ratio. Asthmatic women sensitized to grass had a lower FEV1 and a lower ratio, and those sensitized to Cladosporium had a lower FEV1. A weak association was found with sensitization to cat and to Cladosporium among non-asthmatic women, which disappeared after adjusting for BHR. CONCLUSION: We conclude that atopy was related to a lower lung function, which was only apparent among asthmatics. This relationship was explained by specific sensitization to cat and to house dust mite, the latter being homogeneous across areas.

Bronchial interleukin-5 and eotaxin expression in nasal polyposis. Relationship with (a)symptomatic bronchial hyperresponsiveness.

An eosinophilic bronchial inflammation was previously demonstrated in patients with nasal polyposis (NP) and asymptomatic bronchial hyperresponsiveness (BHR) similar to that observed in asthmatic patients with NP, whereas patients with NP without BHR did not. The aim of the study was to investigate the contribution of interleukin 5 (IL-5) and eotaxin to the pathogenesis of BHR associated with NP. Eleven patients with NP without BHR (Group A), 8 patients with NP and asymptomatic BHR (Group B), and 9 patients with NP and asthma (Group C) were included. Bronchial biopsies were studied for IL-5 and eotaxin immunoreactivity and IL-5 mRNA expression. IL-5 levels were determined in bronchial lavage (BL). Compared with Groups A and B, Group C patients exhibited higher numbers of IL-5 protein(+) cells, IL-5 mRNA(+) cells, and eotaxin(+) cells in bronchial submucosa. Compared with Group A, Group B patients showed an increased number of IL-5 protein(+) cells, whereas the number of IL-5 mRNA(+) cells and eotaxin(+) cells was similar. IL-5 levels in BL were increased only in Group C. Our study provides evidence of IL-5 involvement in bronchial eosinophilia and in the pathogenesis of asymptomatic BHR associated with NP, whereas both IL-5 and eotaxin are involved in asthma associated with NP.

Immunological findings and respiratory function in cotton textile workers.

Immunological parameters were studied in a group of 24 cotton textile workers. These were volunteers from a cohort of 106 (83 women and 23 men) previously studied textile workers. A group of 30 employees from a bottle packing plant served as a control for the immunologic studies. The subgroup of volunteers undergoing immunologic testing did not differ from the original cohort of textile workers in age, sex, smoking history, or prevalence of most chronic respiratory symptoms, nor were there any significant differences in baseline lung function or across-shift changes. The 24 cotton worker volunteers underwent skin testing with extracts of cotton dust and cotton seed. Eight of these 24 (33.3%) had positive tests, and 5 of the 8 had elevated serum immunoglobulin E (IgE) levels. Only one of the 8 skin-test-positive workers had symptoms of byssinosis. Only 1 of 30 control workers' skin tested with cotton extract reacted, and none had an increased serum IgE level (P less than 0.01). Both baseline lung function and across-shift changes did not differ between workers with positive and negative skin test reactions or between workers with normal and elevated IgE levels. Additionally, we studied the response in vitro of nonsensitized guinea pig trachea to cotton bract extract and demonstrated a dose-dependent contractile response. These data suggest that while immunological findings are frequent in textile workers, they correlate poorly with respiratory symptoms and function and may not be the basis for the airway obstruction seen in this disease.

Immunoglobulin G subclasses and spirometry in patients with chronic obstructive pulmonary disease.

Immunoglobulin G (IgG) subclass levels were measured in 58 patients with chronic obstructive pulmonary disease (COPD) and in 125 healthy controls. Total IgG values were significantly lower in the 27 COPD patients on steroid therapy compared with patients not taking steroids (8.31 (0.14) vs 9.80 (0.14), p less than 0.05), geometric mean (log SD). Total IgG (9.80 (0.14) vs 12.18 (0.16), p less than 0.005), IgG1 (5.87 (0.19) vs 6.68 (0.12), p less than 0.05) and IgG2 levels (2.75 (0.21) vs 3.70 (0.20), p less than 0.005) were significantly reduced in the COPD patients not taking steroids compared with the controls. IgG3 values were significantly elevated in smokers compared with nonsmokers in both the control and COPD groups. Fifteen COPD patients (25.9%) had a low level of one or more subclasses. IgG2 subclass deficiency was the most common, being present in 9 patients. A significant correlation was found between forced expiratory volume in one second (FEV1) and IgG2 subclass levels (r = 0.415; p less than 0.005). IgG subclass deficiencies may contribute to the development and progression of respiratory disease in COPD patients.