Subclinical Interstitial Lung Disease Research Articles

Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis

BackgroundAdults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD...

High-resolution CT and pulmonary function tests in rheumatoid arthritis patients with subclinical interstitial lung disease in Kuwait

BackgroundInterstitial lung disease (ILD) is a frequent extra-articular manifestation of RA and can cause significant morbidity and mortality. Aim of the workTo characterize and define the frequency of radiological and functional abnormalities capable of identifying “subclinical” RA-ILD with particular concern to the effect of methotrexate (MTX) therapy. Patients and methodsSixty patients with RA were recruited with no respiratory manifestations. They were classified into two groups: group 1 included 35 patients receiving MTX and group 2 included 25 patients receiving only nonsteroidal anti-inflammatory drugs. Patients were also classified according to chest high resolution CT (HRCT) as RA-ILD or RA-noILD. Pulmonary function test (PFT) abnormalities were also used to further characterize occult respiratory defects. Results38.3% of RA patients had subclinical ILD (25% in group 1 and 13.3% in group 2), while 61.7% were RA-no ILD. The percentage of patients with RA-ILD was insignificantly more in group 1 than group 2 (42.9% and 32% respectively). HRCT score revealed minimal to mild involvement in both groups. Long-standing RA with mean articular duration >50months carries a significant risk for ILD. Other variables as age, gender, smoking, disease activity or rheumatoid factor seropositivity were not significant risk factors for development of RA-ILD. ConclusionsLung involvement should always be considered in patients with RA particularly those on MTX therapy even in the absence of chest symptoms. A tight control by PFTs, chest radiography and/or HRCT is necessary. Further studies evaluating the potential effect of MTX on progressive ILD with RA are needed.

Functional Impact of a Spectrum of Interstitial Lung Abnormalities in Rheumatoid Arthritis

Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older (P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history (P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs. We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.

Radiotherapy for thoracic tumors: association between subclinical interstitial lung disease and fatal radiation pneumonitis

We evaluated the association between subclinical interstitial lung disease (ILD) and fatal radiation pneumonitis (RP) in patients with thoracic tumors treated with thoracic radiotherapy (RT). Sixty-two consecutive patients with thoracic tumors treated with thoracic RT were retrospectively analyzed. According to our protocols, patients with subclinical ILD (untreated and asymptomatic) were considered to be indicated for thoracic RT, while patients with clinical ILD (post- or during treatment) were not considered candidates for thoracic RT. The presence, extent and distribution of subclinical ILD on CT findings at pre-thoracic RT were reviewed and scored by two chest radiologists. The relationships between RP and clinical factors, including subclinical ILD, were investigated. Subclinical ILD was recognized in 11 (18 %) of the 62 patients. Grade 2-5 RP was recognized in eight (13 %) of the 62 patients, with Grade 5 in three patients and Grade 2 in five patients. Grade 2-5 RP was observed in four (36 %) of the 11 patients with subclinical ILD. Subclinical ILD was found to be a significant factor influencing the development of Grade 2-5 RP (p = 0.0274). Subclinical ILD tended to be significant for the occurrence of Grade 5 RP (p = 0.0785). Regarding the CT score, more extensive ILD (bilateral fibrosis in multiple lobes) was recognized in two of the three patients with Grade 5 RP. In this study, fatal RP tended to be more common in the patients with subclinical ILD. In particular, the presence of extensive fibrosis on CT may be a contraindication for thoracic RT.

Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: The potential risk of extensive radiation pneumonitis

PurposeTo evaluate the toxicity and efficacy of thoracic stereotactic body radiotherapy (SBRT) in patients with subclinical interstitial lung disease (ILD). Methods and materialsOne hundred patients with 124 lung tumors were treated with SBRT at our institution according to our own protocols; patients with subclinical (untreated and oxygen-free) ILD were treated with SBRT, while those with clinical ILD (post- or under treatment) were not. The administration of 48Gy in four fractions was used in 103 (83%) of the 124 tumors. The presence of subclinical ILD in the pre-SBRT CT findings was reviewed by two chest radiologists. The relationships between radiation pneumonitis (RP) and clinical factors were investigated. ResultsSubclinical ILD was recognized in 16 (16%) of 100 patients. Grade 2–5 RP was recognized in 13 (13%) of 100 patients. Grade 2–5 RP was observed in three (19%) of 16 patients with subclinical ILD. Subclinical ILD was not found to be a significant factor influencing Grade 2–5 RP; however, extensive RP beyond the irradiated field, including the contralateral lung, was recognized in only three patients with subclinical ILD, and the rate of extensive RP was significantly high in the patients with subclinical ILD. Grade 4 or 5 extensive RP was recognized in only two patients with subclinical ILD. Dosimetric factors of the lungs (V5, V10, V15, V20, V25, MLD) were significantly associated with Grade 2–5 RP. The three-year overall survival and local control rates of all patients were 53% and 86%, respectively. No significant differences were seen in either overall survival or local control rates between the patients with ILD and those without ILD. ConclusionsSubclinical ILD was not found to be a significant factor for Grade 2–5 RP or clinical outcomes in the current study; however, uncommon extensive RP can occur in patients with subclinical ILD.

Update on the diagnosis and classification of ILD

The purpose of this review is to provide an update on the diagnosis and classification of interstitial lung disease (ILD), with a specific focus on newly described ILD subtypes and phenotypes. In addition, the strengths and limitations of the current approach to ILD diagnosis and management are discussed. Idiopathic pleuroparenchymal fibroelastosis and acute fibrinous and organizing pneumonia are new entities that have been described in small case series. Undifferentiated connective tissue disease-associated ILD, smoking-related interstitial fibrosis, familial ILD, unclassifiable ILD, and subclinical ILD have also been better characterized in recent publications. New data regarding these conditions are summarized in this review. The multidisciplinary approach to ILD is reviewed, and complementary classification schemes are described that may help direct the management and improve prognostication of some ILDs. ILDs are a large and heterogeneous group of diseases with several newly characterized subtypes and phenotypes. The current approach to ILD classification has limitations in some patients that can be minimized by considering complementary classification schemes.

AB0689 Interstitial lung disease in severe connective tissue diseases (CTD)

BackgroundWe here report the incidence, the clinical features and treatment response of interstitial lung disease (ILD) associated to idiopathic inflammatory myopathies (IIM), Sjogren’s Syndrome (SS) and systemic lupus erythematosus (SLE).MethodsWe...

Update in Diffuse Parenchymal Lung Disease 2012

In 2012, relevant articles were published in the area of diffuse parenchymal lung diseases (DPLDs). Most of them were focused on idiopathic pulmonary fibrosis (IPF), the most aggressive DPLD, others on sarcoidosis, and some on less common disorders such as lymphangioleiomyomatosis. Studies in IPF revealed novel pathogenic mechanisms, putative biomarkers to predict outcome, and recently completed clinical trials, whereas in sarcoidosis most studies dealt with the identification of gene variants associated with increased risk. The concept of subclinical interstitial lung disease (ILD), meaning the presence of functional restriction or chest tomographic abnormalities in asymptomatic subjects, was underlined by two population-based studies, and our journal housed an important debate on the clinically meaningful endpoints needed to evaluate the treatment of IPF. This update highlights the advancesmade over the past year, primarily focused on those published in this journal.

Neglected evidence in idiopathic pulmonary fibrosis: from history to earlier diagnosis

This perspective highlights some evidence that has hitherto been neglected, especially because it may not have been sufficiently explicated in the clinical respiratory medicine literature. Idiopathic pulmonary fibrosis (IPF) has appeared only in the second half of the 20th century and, like lung cancer and chronic obstructive pulmonary disease, may be a direct consequence of the cigarette smoking epidemic. It is a disease of lung ageing, with most affected patients being >70 years of age. The relationship between lung ageing and pulmonary fibrosis is further illustrated in the bleomycin mouse model, in which older males develop more fibrosis than young female mice. Earlier diagnosis of IPF is a prerequisite for significant progress to be made in the long-term outcome and prognosis. We consider that only two different yet complementary and realistic approaches could lead to earlier diagnosis of IPF and possibly to allowing more efficient disease management: 1) investigating any patients with early Velcro crackles at lung auscultation through proactive education of, and commitment from, primary care physicians; and 2) using current large-scale lung cancer screening strategies with low-dose high-resolution computed tomography in smokers for the detection of subclinical interstitial lung disease and especially early IPF.

Reply: Subclinical Interstitial Lung Disease: No Place for Crackles?

From the Authors: We thank Professors Cottin and Cordier for their thoughtful response to our perspective of subclinical interstitial lung disease (ILD) (1). We agree with the authors that the physical exam is an important skill to be taught and refined and not to be supplanted by more complex physiologic testing but rather supplemented by it. However, the only data addressing the significance of crackles in subclinical ILD that we are aware of is what we have previously shown in individuals with subclinical rheumatoid arthritis–associated ILD (RA-ILD) (2). In this study, we found a statistically significant difference in the percentage of subjects having audible crackles on physical exam when comparing those with subclinical RA-ILD (24%) to those with only RA (4.7%, P = 0.02) or to those with clinically significant RA-ILD (100%, P < 0.001). We did not include physical exam in our diagnostic algorithm as it is unclear if these findings can be extrapolated to other groups affected with subclinical ILD. Despite the above, we agree with Cottin and Cordier that the presence of crackles could improve the assessment of populations at risk of developing subclinical ILD. We agree with Cottin and Cordier that the identification of subjects with subclinical ILD may come with increased psychological and financial burdens and with a risk of additional radiation exposure. As outlined in our perspective, we believe that future research into subclinical ILD can be structured to minimize these risks while maximizing the benefit of early identification. Longitudinal studies will be crucial in determining which subset of patients with subclinical ILD will go on to develop clinically significant ILD and which individuals may have reversible causes, such as hypersensitivity pneumonitis; it is in this population that a work-up for subclinical ILD would be most justified. More sensitive noninvasive metrics to assess subclinical ILD, such as clinical predictive modeling and biomarker and genetic assays, can also work to reduce the indiscriminate use of imaging. Additionally, an improved understanding of subclinical ILD will hopefully lead to a better understanding of the pathophysiology of ILD and the development of more effective treatments targeted at earlier stages of disease. Our hope is that efforts targeted at early identification will ultimately have a positive impact on the morbidity and mortality of ILD.

Subclinical Interstitial Lung Disease: No Place for Crackles?

T.J.D. is supported by NIH Grant number 5T32 HL007633-25. G.M.H. is supported by NIH grant K08 HL092222. I.O.R. is supported by NIH Grant number K23 HL087030. Author Contributions: Drafting the manuscript for important intellectual content: T.J.D., G.M.H., I.O.R. Author disclosures are available with the text of this letter at www.atsjournals.org.

Subclinical Interstitial Lung Disease

The widespread use of high-resolution computed tomography in clinical and research settings has increased the detection of interstitial lung abnormalities (ILA) in asymptomatic and undiagnosed individuals. We reported that in smokers, ILA were present in about 1 of every 12 high-resolution computed tomographic scans; however, the long-term significance of these subclinical changes remains unclear. Studies in families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease have shown that asymptomatic and undiagnosed individuals with ILA have reductions in lung volume, functional limitations, increased pulmonary symptoms, histopathologic changes, and molecular profiles similar to those observed in patients with clinically significant interstitial lung disease (ILD). These findings suggest that, in select at-risk populations, ILA may represent early stages of pulmonary fibrosis or subclinical ILD. The growing interest surrounding this topic is motivated by our poor understanding of the inciting events and natural history of ILD, coupled with a lack of effective therapies. In this perspective, we outline past and current research focused on validating radiologic, physiological, and molecular methods to detect subclinical ILD. We discuss the limitations of the available cross-sectional studies and the need for future longitudinal studies to determine the prognostic and therapeutic implications of subclinical ILD in populations at risk of developing clinically significant ILD.

Smoking and Subclinical Interstitial Lung Disease

The relationships between cigarette smoking and heart disease, lung cancer, and chronic obstructive pulmonary disease (COPD) are well known; in contrast, the topic of the relationship between smoking and interstitial lung disease is almost obscure. Despite its lack of a public persona, this relationship is important, since smoking plays a key role in the pathobiology of several interstitial lung diseases — respiratory bronchiolitis, desquamative interstitial pneumonia, pulmonary Langerhans'-cell histiocytosis, and perhaps idiopathic pulmonary fibrosis.1 It is widely known that in asymptomatic smokers with normal lung function, chest radiography reveals the presence of interstitial opacities (also known as dirty lung).2 The . . .

MMP1 and MMP7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression.Methods and FindingsWe analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins—MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A—that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%–100%) and specificity of 98.1% (95% CI 89.9%–100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%–100%) and specificity of 87.2% (95% CI 72.6%–95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%).ConclusionsOur experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.

Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease.

The reported prevalence of interstitial lung disease in patients with rheumatoid arthritis has varied from 10% to 50%, yet less than 5% of patients with arthritis develop severe fibrosing interstitial lung disease. This suggests that subclinical disease may not always presage progressive disease. Bronchoalveolar lavage fluid from patients with rheumatoid arthritis and either clinically evident interstitial lung disease or subclinical disease was examined for the presence of factors with a putative role in the development of interstitial fibrosis. Patients with subclinical disease were identified by prospective radiographic and lung function screening of 93 patients with rheumatoid arthritis. Fourteen patients were identified in this manner and an association between subclinical disease and smoking history was noted. Eleven patients with established interstitial lung disease had increased neutrophils (p less than 0.05), collagenase, and type III procollagen N terminal peptide levels (p less than 0.01) in the bronchoalveolar lavage fluid. Preliminary characterisation of the bronchoalveolar lavage collagenase suggested that it originated from neutrophils. Ten patients with subclinical interstitial lung disease underwent bronchoalveolar lavage. Of these, one had increased neutrophils and two had increased collagenase concentrations--abnormalities associated with advanced interstitial lung disease and a poor prognosis. These results suggest that in arthritis patients with evidence of subclinical pulmonary interstitial disease bronchoalveolar lavage might be useful in identifying those who may require careful monitoring in the hope that early treatment will prevent severe fibrosis.