Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC.
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ABSTRACT:
SUBMITTER: Crossno PF
PROVIDER: S-EPMC2851554 | biostudies-other | 2010 Apr
REPOSITORIES: biostudies-other
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Project description:Identification of early, asymptomatic interstitial lung disease (ILD) in populations at risk of developing idiopathic pulmonary fibrosis (IPF) may improve the understanding of the natural history of IPF.To determine clinical, radiographic, physiologic, and pathologic features of asymptomatic ILD in family members of patients with familial IPF.One hundred sixty-four subjects from 18 kindreds affected with familial IPF were evaluated for ILD. Bronchoalveolar lavage fluid cells were analyzed using flow cytometry. Lung biopsies were performed in six subjects with asymptomatic ILD.High-resolution computed tomography abnormalities suggesting ILD were identified in 31 (22%) of 143 asymptomatic subjects. Subjects with asymptomatic ILD were significantly younger than subjects with known familial IPF (P < 0.001) and significantly older than related subjects without lung disease (P < 0.001). A history of smoking was identified in 45% of subjects with asymptomatic ILD and in 67% of subjects with familial IPF; these percentages were significantly higher than that of related subjects without lung disease (23%) (P = 0.02 and P < 0.001, respectively). Percentages of activated CD4(+) lymphocytes were significantly higher in bronchoalveolar lavage fluid cells from subjects with asymptomatic ILD compared with related subjects without lung disease (P < 0.001). Lung biopsies performed in subjects with asymptomatic ILD revealed diverse histologic subtypes.Asymptomatic ILD in individuals at risk of developing familial IPF can be identified using high-resolution computed tomography scan of the chest, especially in those with a history of smoking. Lung biopsies from individuals in this cohort with early asymptomatic lung disease demonstrate various histologic subtypes of ILD.
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Project description:Specific genetic causes for children's interstitial lung disease (chILD) have been identified within the past decade. These include deletions of or mutations in genes encoding proteins important in surfactant production and function (SP-B, SP-C, and ABCA3), surfactant catabolism (GM-CSF receptor), as well as transcription factors important for surfactant production (TTF1) or lung development (Fox F1), with heterozygous deletions or loss-of-function mutations of the latter resulting in alveolar capillary dysplasia (ACD) with misalignment of the pulmonary veins. Familial pulmonary fibrosis in adults may result from mutations in genes encoding components of telomerase and SP-A2. While not yet reported in children, the expression of these genes in alveolar type II epithelial cells supports a key role for the disruption of normal homeostasis in this cell type in the pathogenesis of interstitial lung disease. The identification of specific genetic causes for chILD now allows for the possibility of non-invasive diagnosis, and provides insight into basic cellular mechanisms that may allow the development of novel therapies.
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Project description:PurposeTo determine the accuracy of computed tomography (CT) in identifying the histopathologic usual interstitial pneumonia (UIP) pattern in rheumatoid arthritis-associated interstitial lung disease (RA-ILD).Materials and methodsAll patients were enrolled into institutional review board-approved longitudinal cohorts at their respective institution, and informed consent was obtained at the time of enrollment. Images of patients with surgical lung biopsy-proved RA-ILD (n = 69) were collected from three tertiary care centers. Two experienced thoracic radiologists independently reviewed the CT scans. The CT pattern was categorized as definite UIP, possible UIP, or inconsistent with UIP in accordance with published criteria. Findings of biopsies were reviewed by an experienced lung pathologist. The sensitivity and specificity of definite CT UIP pattern to histopathologic UIP pattern were determined. The agreement between radiologists was assessed by calculating a ? score.ResultsThe histopathologic UIP pattern was present in 42 of 69 (61%) patients. Men were more likely than women to have a histopathologic UIP pattern (P = .02). Twenty patients (29%, 20 of 69) had a definite UIP pattern on CT scans. The specificity of CT UIP pattern was 96% (26 of 27; 95% confidence interval [CI]: 81%, 100%), with a negative predictive value of 53% (26 of 49). The sensitivity of CT UIP pattern was 45% (19 of 42; 95% CI: 30%, 61%), with a positive predictive value of 95% (19 of 20). The agreement between radiologists for definite UIP pattern versus not was 87% (? = 0.67, P < .0001).ConclusionDefinite UIP pattern on a CT scan in RA-ILD is highly specific and moderately sensitive for histopathologic UIP pattern. CT can therefore help accurately identify the UIP pattern in RA-ILD.
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Project description:Interstitial lung disease (ILD) in childhood is a heterogeneous group of rare pulmonary conditions presenting chronic respiratory disorders. Many clinical features of ILD still remain unclear, making the treatment strategies mainly investigative. Guidelines may provide physicians with an overview on the diagnosis and therapeutic directions. However, the criteria used in different clinical studies for the classification and diagnosis of ILDs are not always the same, making the development of guidelines difficult. Advances in genetic testing have thrown light on some etiologies of ILD, which were formerly classified as ILDs of unknown origins. The need of genetic testing for unexplained ILD is growing, and new classification criteria based on the etiology should be adopted to better understand the disease. The purpose of this review is to give an overview of the clinical and genetic aspects of ILD in children.
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Project description:Systemic sclerosis (SSc) is a connective tissue disease that is characterized by tissue fibrosis, microvasculopathy, and autoimmunity. Interstitial lung disease (ILD) is a common complication of SSc and is one of the frequent causes of mortality in SSc. Although the exact etiology of SSc remains unknown, clinical and experimental investigations have suggested that genetic and environmental factors are relevant to the pathogenesis of SSc and SSc-ILD. More than 30 genes have been identified as susceptibility loci for SSc, most of which are involved in immune regulation and inflammation. It is thought that the key pathogenesis of SSc-ILD is caused by the release of profibrotic mediators such as transforming growth factor ?1 and connective tissue growth factor from lung cells induced by a persistent damage. This review presents the genetic susceptibility to SSc-ILD, including human leukocyte antigen and non-human leukocyte antigen genes, especially focusing on connective tissue growth factor.
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Project description:Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice.
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Project description:ObjectiveTocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement.MethodsThe focuSSced trial was a phase III randomized placebo-controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high-resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5-10%), moderate (>10-20%), and severe (>20%).ResultsOf 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate-to-severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were -4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were -10.0 ± 2.6% (n = 11), -5.7 ± 1.6% (n = 26), and -6.7 ± 2.0% (n = 16), respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity.ConclusionTCZ in early SSc-associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD.
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