Interstitial Lung Disease Subgroup Research Articles

Development, Progression, and Mortality of Suspected Interstitial Lung Disease in COPDGene.

Some with interstitial lung abnormalities (ILA) have suspected interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown. To determine rates of development and progression of suspected ILD and assess effects of individual ILD and progression criteria on mortality. Participants from COPDGene were included. ILD was defined as ILA and fibrosis and/or FVC <80% predicted. Prevalent ILD was assessed at enrollment, incident ILD and progression at 5-year follow-up. CT progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and ILD groups. Of 9,588 participants at enrollment, 267 (2.8%) had prevalent ILD. Those with prevalent ILD had 52% mortality after median 10.6 years, which was higher than ILA (33%; HR=2.0; p<0.001). The subgroup of prevalent ILD with fibrosis only had worse mortality (59%) than ILA (HR=2.2; p<0.001). 97 participants with prevalent ILD completed 5-year follow-up: 32% had stable CT and relative FVC decline <10%, 6% FVC decline ≥10% only, 39% CT progression only, and 22% both CT progression and FVC decline ≥10%. Mortality rates were 32%, 50%, 45%, and 46% respectively; those with CT progression only had worse mortality than ILA (HR=2.6; p=0.005). At 5-year follow-up, incident ILD occurred in 168/4,843 participants without prevalent ILD and had worse mortality than ILA (HR=2.5; p<0.001). Rates of mortality and progression are high among those with suspected ILD in COPDGene; fibrosis and radiologic progression are important predictors of mortality.

Comparison of race-specific and race-neutral spirometry equations on the classification of restrictive lung physiology, interstitial lung disease, and lung transplant referral eligibility

BackgroundRace-specific reference equations for spirometry including forced vital capacity (FVC) are under scrutiny in interstitial lung disease (ILD). Their influence on ILD and transplant decision-making warrants study. MethodsWe performed a retrospective cohort study of adults with FVC measurements at Duke University Medical Center between 1 October 2014 and 1 February 2023. Using Global Lung Initiative 2012 reference equations, we compared how race-specific and race-neutral equations classified FVC with potential restrictive physiology (z-score < -2). In the subgroup of patients diagnosed with ILD, we compared how race-specific and race-neutral equations classified FVC as warranting transplant referral (percent-predicted <80%). We compared overall rates, odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, and differences in timing. ResultsWe identified 45,587 patients including 550 with ILD. Race-specific equations classified potential restricted physiology 5.2% more White patients (23.8% versus 18.6%, OR 1.28, 95% CI 1.24-1.32), 14.3% fewer Black patients (24.1% versus 38.4%, OR 0.63, 95% CI 0.60-0.66), and 7.7% fewer Asian patients (14.8% versus 22.5%, OR 0.66, 95% CI 0.53-0.82) compared with race-neutral equations. In the ILD subgroup, race-specific equations classified 13.0% more White patients as warranting transplant referral consideration compared to race-neutral equations (57.8% versus 44.8%, OR 1.29, 95% CI 1.07-1.56). ConclusionRace-specific equations increased classification of potential restrictive physiology and transplant candidacy for White patients but decreased classification of potential restrictive physiology for Black and Asian patients. Race-specific equations in ILD and transplant decision-making warrant greater consideration given their potential to contribute to racial disparities.

Protein profiling in systemic sclerosis patients with different pulmonary complications using proteomic antibody microarray

BackgroundPulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are leading causes of systemic sclerosis (SSc)-related death. In this study, we aimed to identify biomarkers for detecting SSc pulmonary complications that are mild and in the early stages to improve the prognosis.MethodsWe screened for serum biomarkers using a proteomic antibody microarray that simultaneously assessed 1000 proteins. Differentially expressed proteins were further verified using ELISA. Finally, we performed a correlation analysis using clinical data.ResultsWe identified 125 differentially expressed proteins, of which calcitonin, sclerostin (SOST), CD40, and fibronectin were selected for further verification. Serum calcitonin and SOST levels were significantly elevated in all SSc pulmonary complication subgroups, whereas serum calcitonin levels were higher in the SSc with PAH subgroup than in the SSc without PAH and ILD subgroup. Serum SOST levels were possibly associated with the presence of ILD and positively related to the presence of cardiac and gastrointestinal involvement. Serum CD40 and calcitonin levels appeared to be positively related to the presence of renal involvement, and serum calcitonin was also positively related to the presence of gastrointestinal involvement.ConclusionsThis study indicated that serum calcitonin and SOST levels may be promising biomarkers for SSc-related PAH and ILD, respectively. Further research is needed to verify this result and understand the underlying mechanisms.

Genome-wide DNA methylation and transcriptome expression profiles of peripheral blood mononuclear cells in patients with systemic sclerosis with interstitial lung disease.

This study aims to investigate the genome-wide DNA methylation and transcriptome expression profiles of peripheral blood mononuclear cells (PBMCs) in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD), and to analyze the effects of DNA methylation on Wnt/β-catenin and chemokine signaling pathways. PBMCs were collected from 19 patients with SSc (SSc group) and 18 healthy persons (control group). Among SSc patients, there were 10 patients with ILD (SSc with ILD subgroup) and 9 patients without ILD (SSc without ILD subgroup). The genome-wide DNA methylation and gene expression level were analyzed by using Illumina 450K methylation chip and Illumina HT-12 v4.0 gene expression profiling chip. The effect of DNA methylation on Wnt/β-catenin and chemokine signal pathways was investigated. Genome-wide DNA methylation analysis identified 71 hypermethylated CpG sites and 98 hypomethylated CpG sites in the SSc with ILD subgroup compared with the SSc without ILD subgroup. Transcriptome analysis distinguished 164 upregulated genes and 191 downregulated genes in the SSc with ILD subgroup as compared with the SSc without ILD subgroup. In PBMCs of the SSc group, 35 genes in Wnt/β-catenin signaling pathway were hypomethylated, while frizzled-1 (FZD1), mitogen-activated protein kinase 9 (MAPK9), mothers against DPP homolog 2 (SMAD2), transcription factor 7-like 2 (TCF7L2), and wingless-type MMTV integration site family, member 5B (WNT5B) mRNA expressions were upregulated as compared with the control group (all P<0.05). Compared with the SSc without ILD subgroup, the mRNA expressions of dickkopf homolog 2 (DKK2), FZD1, MAPK9 were upregulated in the SSc with ILD subgroup, but the differences were not statistically significant (all P>0.05). In PBMCs of the SSc group, 38 genes in chemokine signaling pathway were hypomethylated, while β-arrestin 1 (ARRB1), C-X-C motif chemokine ligand 10 (CXCL10), C-X-C motif chemokine ligand 16 (CXCL16), FGR, and neutrophil cytosolic factor 1C (NCF1C) mRNA expressions were upregulated as compared with the control group (all P<0.05). Compared with the SSc without ILD subgroup, the mRNA expressions of ARRB1, CXCL10, CXCL16 were upregulated in the SSc with ILD subgroup, but the differences were not statistically significant (all P>0.05). There are differences in DNA methylation and transcriptome profiles between SSc with ILD and SSc without ILD. The expression levels of multiple genes in Wnt/β- catenin and chemokine signaling pathways are upregulated, which might be associatea with the pathogenesis of SSc.

A meta-analysis of the clinical significance of neutrophil-to-lymphocyte ratios in interstitial lung disease.

Interstitial lung disease (ILD) is a group of diffuse parenchymal infiltrating diseases of different etiologies. The neutrophil-to-lymphocyte ratio (NLR) can reflect ILD's existence, progression, and prognosis and is currently regarded as a promising biological marker. This meta-analysis assessed elevated NLR levels in ILD for their predictive value. From inception to July 27, 2022, the Scopus, Cochrane Library, Web of Science, Embase, and PubMed databases were checked thoroughly. We used the weighted mean difference (WMD) and 95% confidence interval (CI) to compare blood NLR values between groups. We examined the relationship between poor prognoses and elevated NLR concentrations in ILD patients using odds ratios (ORs) and 95% CI. After initially including 443 studies, 24 were ultimately analyzed. Fifteen studies(ILD:n = 2,912, Non-ILD: n = 2,868) revealed that the NLR values in the ILD group were relatively high (WMD = 0.61, 95% CI 0.43-0.79, p = 0.001). Eight articles (with poor prognoses: n = 407, without poor prognoses: n = 340) indicated that ILD patients with poor prognoses had higher NLR values (WMD = 1.33, 95% CI 0.32-2.33, p = 0.01). This distinction was especially noticeable in patients with the connective tissue disease (CTD)associated with ILD subgroup (WMD = 3.53, 95% CI 1.54-5.51, p = 0.0005). The pooled OR for increased NLR levels forecasting poor prognoses of ILD was 1.09 (95% CI 1.03-1.15, p = 0.0008). Increasing blood NLR values have clinical significance and application value for detecting ILD and predicting its poor prognosis, especially in CTD patients.

Mediastinal lymph node enlargement predicts progressive pulmonary fibrosis

OBJECTIVE: To determine whether mediastinal lymph node enlargement (MLNE) predicts progressive pulmonary fibrosis (PPF).METHODS: A total of 800 patients hospitalised for interstitial lung diseases (ILDs) were included in our study. The clinical presentations, radiographic features and laboratory findings of the patients were reviewed.RESULTS: MLNE was present in 313 (39.1%) ILD patients and were associated with higher total fibrosis score and risk of death than ILD patients without MLNE. The risk factors for PPF were age (OR 1.044, 95% CI 1.020-1.069; P < 0.001), the total extent of fibrosis (OR 1.396, 95% CI 1.116-1.746; P = 0.003) and MLNE (OR 2.130, 95% CI 1.362-3.332; P = 0.001) compared to non-PPF. Multivariable analysis showed that age, the lactate dehydrogenase level, MLNE, the total fibrosis score and pulmonary arterial systolic pressure were risk/prognostic factors for ILD patients. The model was robust in patients with idiopathic pulmonary fibrosis. However, the only risk/prognostic factor common to other ILD subgroups was the total fibrosis score.CONCLUSIONS: MLNE is associated with higher total fibrosis score and worse prognosis in ILD patients and could predict the occurrence of PPF. The only risk/prognostic factor applicable to all subgroups of ILDs is the total pulmonary fibrosis score.

Prevalence of airway reversibility in connective tissue disease-interstitial lung disease (CTD-ILD)

Background: Spirometry is the most reproducible and objective measurement of airflow limitation. Improvement in FEV1 and/or FVC by 12% or 200ml after using bronchodilator is definitive of reversible airway disease.[1] Several conditions like sarcoidosis predominantly involve the interstitium have nevertheless been associated with reversible airways obstruction. Connective tissue diseases (CTDs) form another important subgroup of interstitial lung disease(ILD). CTDs usually produce a restrictive pattern of lung involvement on spirometry, but might have unrecognized additional reversible airway obstruction. Seeking out and treating the latter components of disease may be crucial in optimizing lung function and alleviating the breathlessness that is common to the problem. Aim: The aim of this study is therefore to determine the post bronchodilator response in patients with connective tissue disease related interstitial lung disease (CTD-ILD) and thus potentially help improve quality of life by addressing the latter component by inhaled bronchodilator-steroid therapy. Methods: Consecutive patients with a confirmed diagnosis of CTD-ILD were identified in the out-patient clinics of our institute. CTD was diagnosed by a combination of clinical and serological parameters. ILD was confirmed by high resolution computed tomography (HRCT) images. &#x0D;

Predictive Features and Clinical Presentation of Interstitial Lung Disease in Inflammatory Myositis

Interstitial lung disease (ILD) represents one of the most severe extra-muscular features of idiopathic inflammatory myositis (IIM). We aimed to identify any clinical and serological predictors of ILD in a monocentric cohort of 165 IIM patients.ILD+ patients were defined as having restrictive impairment in lung function tests and signs of ILD at chest high-resolution computed tomography (HRCT). Available HRCT images were centralized and classified in different ILD patterns: non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), usual interstitial pneumonia-like (UIP), indeterminate for UIP, and interstitial lung abnormalities (ILA). Lung function test data were recorded at onset, at 1 and 5 years after ILD diagnosis.ILD was found in 52 IIM patients (31.5%): 46.2% was affected by anti-synthetase syndrome (ARS), 21% by polymyositis (PM), 19% by dermatomyositis (DM), and 13.5% by overlap myositis. Most of ILD+ showed NSIP (31.9%), OP (19%), indeterminate for UIP (19%), and UIP (12.8%) patterns. At multivariate analysis, ILD was predicted by anti-Ro52 (p: 0.0026) and dyspnea (p: 0.015) at IIM onset. Most of ILD onset within is 12 months after IIM. In five cases, ILD occurs after 12 months since IIM diagnosis: these patients more frequently show dry cough and anti-Ku antibodies. Anti-Ro52 + ILD patients showed a significant increase of DLCO at 1 and 5 years of follow-up, compared with anti-Ro52 negative cases.ILD occurs in about one third of IIM and was predicted by dyspnea at onset and anti-Ro52 antibodies. Anti-Ro52 defines a subgroup of ILD showing a significant improvement of DLCO during follow-up. This retrospective study has been approved by local ethic committee (ASST-Spedali Civili of Brescia, Italy); protocol number: NP3511

Galactin-1, 3 and 9: Potential biomarkers in idiopathic pulmonary fibrosis and other interstitial lung diseases

IntroductionGalectins are proteins that bind β-galactosides such as N-acetylactosamine present in N-linked and O-linked glycoproteins and that seem to be implicated fibrotic mechanisms. Here we aimed to define the role of serum galectins in idiopathic pulmonary fibrosis and idiopathic non-specific interstitial pneumonia (NSIP) by comparison with other chronic interstitial lung diseases (ILDs) and healthy subjects. MethodsForty-one fibrotic ILD patients (median age (IQR), 65 years (20); 50 % male) were enrolled in the study. Peripheral blood concentrations of galectins-1, 3 and 9 were determined with commercial ELISA kits. ResultsGalectin-1 and 9 concentrations were higher in the ILD group than in healthy controls (p = 0.0318 and p < 0.0001, respectively). Galectin-3 was also higher in ILD patients (borderline significant p = 0.0617). In particular, significantly higher Gal-1 concentrations were found in sarcoidosis and NSIP patients (p = 0.0418 and p = 0.0015, respectively), while Gal-9 concentrations were significantly higher in all ILD subgroups. Specific cut-offs for all galectins were calculated by receiver operating curve (ROC) analysis. Several correlations with lung function parameters were found. DiscussionGalectins 1, 3 and 9 concentrations were found altered in serum of ILD patients suggesting their potential utility as clinical, diagnostic and prognostic biomarkers. Inhibition of galectins may be useful in the therapeutic management of pulmonary fibrosis. Further studies on larger case series would be worthwhile.

Exhaled breath analysis by use of eNose technology: a novel diagnostic tool for interstitial lung disease.

Early and accurate diagnosis of interstitial lung diseases (ILDs) remains a major challenge. Better noninvasive diagnostic tools are much needed. We aimed to assess the accuracy of exhaled breath analysis using eNose technology to discriminate between ILD patients and healthy controls, and to distinguish ILD subgroups. In this cross-sectional study, exhaled breath of consecutive ILD patients and healthy controls was analysed using eNose technology (SpiroNose). Statistical analyses were done using partial least square discriminant analysis and receiver operating characteristic analysis. Independent training and validation sets (2:1) were used in larger subgroups. A total of 322 ILD patients and 48 healthy controls were included: sarcoidosis (n=141), idiopathic pulmonary fibrosis (IPF) (n=85), connective tissue disease-associated ILD (n=33), chronic hypersensitivity pneumonitis (n=25), idiopathic nonspecific interstitial pneumonia (n=10), interstitial pneumonia with autoimmune features (n=11) and other ILDs (n=17). eNose sensors discriminated between ILD and healthy controls, with an area under the curve (AUC) of 1.00 in the training and validation sets. Comparison of patients with IPF and patients with other ILDs yielded an AUC of 0.91 (95% CI 0.85-0.96) in the training set and an AUC of 0.87 (95% CI 0.77-0.96) in the validation set. The eNose reliably distinguished between individual diseases, with AUC values ranging from 0.85 to 0.99. eNose technology can completely distinguish ILD patients from healthy controls and can accurately discriminate between different ILD subgroups. Hence, exhaled breath analysis using eNose technology could be a novel biomarker in ILD, enabling timely diagnosis in the future.

Trends and seasonal variation of hospitalization and mortality of interstitial lung disease in the United States from 2006 to 2016

BackgroundIn the recent years, the overall trends in hospital admission and mortality of interstitial lung disease (ILD) are unknown. In addition, there was some evidence that interstitial lung disease death rate highest in the winter but this finding was only available in one study. This study will investigate the trend and seasonal variations in hospital admission and mortality rates of ILD from 2006 to 2016.MethodFrom the Nationwide Inpatient Sample database, we collected all cases with the International Classification of Diseases (ICD)-9 or ICD-10 codes of ILD excluding identifiable external causes (drug, organic or inorganic dusts) from 2006 to 2016. Hospitalization rates of each year were calculated based on U.S Census population data. Monthly hospitalization and in-hospital mortality rates were analyzed by seasonal and trend decomposition. Subgroups of idiopathic interstitial fibrosis (IPF), acute respiratory failure (ARF), pneumonia were analyzed.ResultsFrom 2006 to 2016, all-cause hospital admission rate of patients with interstitial lung disease (ILD) and IPF-only subgroup declined but their overall mortality remained unchanged (except IPF subgroup and acute respiratory failure subgroup). Acute respiratory failure related admission account for 23% of all causes and pneumonia 17.6%. Mortality of ILD in general and subgroup of ILD with ARF was highest in winter, up to 8.13% ± 0.60 and 26.3% ± 10.2% respectively. The seasonal variations of hospital admission and mortality of ILD in general was not changed when infectious pneumonia cases were ruled out. All cause admission rates were highest in months from January to April. Subgroup analysis also showed seasonal variations with highest hospitalization rates for all subgroups (IPF, ARF, pneumonia) in the months from December to April (winter to early Spring).ConclusionFrom 2006 to 2016, admission rates of ILD of all causes and IPF subgroup declined but in-hospital mortality of ILD of all causes remained unchanged. Mortality of IPF subgroup and acute respiratory failure subgroup trended down. All-cause hospital admissions and mortality of ILD have a strong seasonal variation. Hospitalization rates for all subgroups (IPF, ARF, pneumonia) were highest in the months from December to April.

Picking interstitial lung disease out of the myositis haystack

Interstitial lung disease (ILD) is a common manifestation of the connective tissue disease (CTD) associated idiopathic inflammatory myopathies (IIM). Although patients may be diagnosed as having polymyositis (PM) or dermatomyositis (DM) under the IIM spectrum, it is quite clear that risk, pattern of ILD and disease course between subgroups of patients is different. The natural history may be asymptomatic and slowly progressive or stable, chronically progressive or fulminant rapidly progressive depending on ILD subtype. ILD can be the initial presenting feature and this can make recognition of an underlying CTD-IIM overlap more difficult with some patients initially misdiagnosed with idiopathic pulmonary fibrosis. Therefore, early recognition and characterization of patients can influence management and prognosis. It is clear than certain clinical and serological features phenotype patients into more specific CTD-IIM ILD subgroups. A number of myositis-CTD overlap associated antibodies and their clinical patterns have been described over the last few years. The hallmark CTD-IIM ILD subgroup is antisynthetase syndrome, characterized by autoantibodies to tRNA synthetases. Muscle weakness is not universally present and parenchymal lung disease can predominate. Anti-MDA5 DM has a distinct cutaneous pulmonary phenotype and is significantly associated with the development of ILD with different patterns seen in different ethnic groups. Other autoantibodies associated with ILD include those targeting nucleolar autoantigens such as anti-PM-SCL, again with characteristic syndromes. Picking ILD out of the “myositis haystack” can be complex. This heterogeneous disease group requires robust multidisciplinary collaboration between rheumatologists, pulmonologists, thoracic radiologists, and histopathologists to bring together clinical assessment to reach a diagnostic conclusion so optimal outcomes can be achieved.

Exploring the Ability of Electronic Nose Technology to Recognize Interstitial Lung Diseases (ILD) by Non-Invasive Breath Screening of Exhaled Volatile Compounds (VOC): A Pilot Study from the European IPF Registry (eurIPFreg) and Biobank.

Background: There is an increasing interest in employing electronic nose technology in the diagnosis and monitoring of lung diseases. Interstitial lung diseases (ILD) are challenging in regard to setting an accurate diagnosis in a timely manner. Thus, there is a high unmet need in non-invasive diagnostic tests. This single-center explorative study aimed to evaluate the usefulness of electronic nose (Aeonose®) in the diagnosis of ILDs. Methods: Exhaled volatile organic compound (VOC) signatures were obtained by Aeonose® in 174 ILD patients, 23 patients with chronic obstructive pulmonary disease (COPD), and 33 healthy controls (HC). Results: By dichotomous comparison of VOC’s between ILD, COPD, and HC, a discriminating algorithm was established. In addition, direct analyses between the ILD subgroups, e.g., cryptogenic organizing pneumonia (COP, n = 28), idiopathic pulmonary fibrosis (IPF, n = 51), and connective tissue disease-associated ILD (CTD-ILD, n = 25) were performed. Area under the Curve (AUC) and Matthews’s correlation coefficient (MCC) were used to interpret the data. In direct comparison of the different ILD subgroups to HC, the algorithms developed on the basis of the Aeonose® signatures allowed safe separation between IPF vs. HC (AUC of 0.95, MCC of 0.73), COP vs. HC (AUC 0.89, MCC 0.67), and CTD-ILD vs. HC (AUC 0.90, MCC 0.69). Additionally, to a case-control study design, the breath patterns of ILD subgroups were compared to each other. Following this approach, the sensitivity and specificity showed a relevant drop, which results in a poorer performance of the algorithm to separate the different ILD subgroups (IPF vs. COP with MCC 0.49, IPF vs. CTD-ILD with MCC 0.55, and COP vs. CT-ILD with MCC 0.40). Conclusions: The Aeonose® showed some potential in separating ILD subgroups from HC. Unfortunately, when applying the algorithm to distinguish ILD subgroups from each other, the device showed low specificity. We suggest that artificial intelligence or principle compound analysis-based studies of a much broader data set of patients with ILDs may be much better suited to train these devices.

Phenotypic Clusters Predict Outcomes in a Longitudinal Interstitial Lung Disease Cohort

The current interstitial lung disease (ILD) classification has overlapping clinical presentations and outcomes. Cluster analysis modeling is a valuable tool in identifying distinct clinical phenotypes in heterogeneous diseases. However, this approach has yet to be implemented in ILD. Using cluster analysis, novel ILD phenotypes were identified among subjects from a longitudinal ILD cohort, and outcomes were stratified according to phenotypic clusters compared with subgroups according to current American Thoracic Society/European Respiratory Society ILD classification criteria. Among subjects with complete data for baseline variables (N= 770), four clusters were identified. Cluster 1 (ie, younger white obese female subjects) had the highest baseline FVC and diffusion capacity of the lung for carbon monoxide (Dlco). Cluster 2 (ie, younger African-American female subjects with elevated antinuclear antibody titers) had the lowest baseline FVC. Cluster 3 (ie, elderly white male smokers with coexistent emphysema) had intermediate FVC and Dlco. Cluster 4 (ie, elderly white male smokers with severe honeycombing) had the lowest baseline Dlco. Compared with classification according to ILD subgroup, stratification according to phenotypic clusters was associated with significant differences in monthly FVC decline (Cluster 4, -0.30%vsCluster 2, 0.01%; P< .0001). Stratification by using clusters also independently predicted progression-free survival (P<.001) and transplant-free survival (P< .001). Among adults with diverse chronic ILDs, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might better predict meaningful clinical outcomes than current ILD diagnostic criteria.

The utility of comprehensive autoantibody testing to differentiate connective tissue disease associated and idiopathic interstitial lung disease subgroup cases.

Interstitial lung disease (ILD) comprises many heterogeneous disease groups, the largest being CTD-associated and those labelled as idiopathic out of necessity. The mechanisms causing ILD are poorly understood, but most CTD- and idiopathic-ILD cases can respond to immunosuppression, clearly suggesting a pathological role for inflammation. By contrast, corticosteroid immunosuppression causes harm without benefit in the feared idiopathic pulmonary fibrosis, suggesting that inflammation plays little pathological role, and where ILD progresses rapidly to lethal outcome even with anti-fibrotic drug use. Given the treatment response differences apparent between ILD subgroups, and the dangers and costs of corticosteroid and anti-fibrotic drug use, respectively, it has become vital in every ILD patient to make an accurate subgroup diagnosis, to optimize treatment selections. This review discusses why differentiating CTD- and idiopathic-ILD subgroup cases remains so problematic, and why existing comprehensive CTD-specific serology would, if generally available, represent an ideal biomarker tool to enhance ILD subgroup diagnostic accuracy.

Hypersensitivity pneumonitis: The dug-well lung

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is caused by a variety of environmental agents and may present as occult respiratory illness. HP represents a potentially curable subgroup of interstitial lung disease. This study was designed to examine a group of patients with HP due to a unique mechanism of environmental exposure. Five patients with HP were retrospectively identified, from our hospital records, admitted during the period of March 2007 to February 2011 with history of exposure to dug wells. The mode of exposure was specified as multiple entries into a dug well for different reasons. Other modes of exposure were considered as criteria of exclusion. All of the five patients had subacute HP based on available clinical, radiographic, immunologic, and supportive evidence and exposure. There were additional allergic bronchopulmonary aspergillosis-like features in one patient who did not have antecedent asthma. The evaluation of patient records indicated a fungal etiology. The air and soil from selected wells were tested for fungal organisms. Both settings grew Aspergillus as the predominant species. This novel mechanism of HP is labeled "dug-well lung" because the disease was attributed to exposure to dug wells. Lung disease may result from exposure to a dug well. Farmers or mechanics, climbing down these damp wells for a multitude of reasons, are prone to develop HP. The public health care personnel and farming community should be made aware of this potential occupation-related health hazard.

Interleukin-18 is a key mediator in dermatomyositis: potential contribution to development of interstitial lung disease

To determine whether IL-18 is involved in the inflammation of DM and PM. Thirty-three patients with DM were enrolled in this study, including 25 with interstitial lung disease (ILD). In addition, 16 patients with PM were enrolled, including 6 with ILD. All patients were admitted to our hospital as a result of their condition requiring treatment, and clinical laboratory data including serum IL-18 were recorded on admission. Serum IL-18 was significantly (P < 0.0001) higher in both DM and PM patients than in healthy controls (n = 30). Serum ferritin and IL-18 were significantly (P = 0.003 and 0.0044, respectively) higher in DM than in PM patients. Additionally, ferritin and IL-18 were significantly (P = 0.023 and 0.034, respectively) higher in DM patients with ILD than in DM patients without ILD. Significant positive correlations were found between creatine kinase (CK) and ferritin (r(s) = 0.39, P = 0.024); CK and IL-18 (r(s) = 0.48, P = 0.005); and IL-18 and ferritin (r(s) = 0.54, P = 0.0012) in the DM group as a whole. These findings were different for the DM plus ILD subgroup: significant positive correlations were found between CK and ferritin (r(s) = 0.40, P = 0.047); CK and IL-18 (r(s) = 0.63, P = 0.0008); and IL-18 and ferritin (r(s) = 0.41, P = 0.042). Serum IL-18 was strikingly elevated in patients with DM and was associated particularly with disease activity and ILD complication in DM.

Cytokine gene polymorphisms and BALF cytokine levels in interstitial lung diseases

The aim of our study is to investigate correlations of T(H)1/T(H)2 cytokine gene polymorphisms and bronchoalveolar lavage fluid (BALF) cytokine values in interstitial lung diseases (ILD). In 16 sarcoidosis, 7 idiopathic pulmonary fibrosis (IPF) and 8 hypersensitivity pneumonitis (HP) patients we evaluated IL-1 alpha, -1R, -1RA, -2, -4, -4R alpha, -6, -10, -12, IFN-gamma, TGF-beta1 and TNF-alpha gene polymorphisms in peripheral blood, and MCP-1,MIP-1 alpha, MIP-1 beta, RANTES, ENA-78, FGF, G-CSF, GM-CSF, IFN-gamma, IL-1 alpha, IL-1RA, IL-1 beta, -2, -4, -5, -6, -8, -10, -17, TNF-alpha, Tpo and VEGF values in BALF. We found higher TNF-alpha values in IL-1R pst 1970 TT homozygotes regardless of diagnosis (p=0.0126). In the sarcoidosis group IL-4R alpha(+1902)AA and IL-10(-1082)G allele correlated with higher BALF ENA-78 levels (p=0.0258, p=0.0230). In the HP group the IL-6(-174)CG and IL-6(nt565)AG correlated with higher ENA-78 BALF levels (p=0.0253). In the IPF group the IL-1 beta +3962 CC homozygotes had lower IL-1RA BALF values (p=0.046). BALF chemokine values did not differ between ILD subgroups, except for IL-8, which was higher in stage III sarcoidosis patients compared to stage I. Our results show a probable influence of gene polymorphisms, namely IL-4R alpha and IL-10 on ENA-78 BALF levels in sarcoidosis, IL-6 on ENA-78 BALF levels in HP and IL-1-beta on IL-1RA BALF values in the IPF group. The TNF-alpha BALF values correlated with IL-1R pst 1970 gene polymorphisms.