Automated computer-based CT stratification as a predictor of outcome in hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) has a variable clinical course. Modelling of quantitative CALIPER-derived CT data can identify distinct disease phenotypes. Mortality prediction using CALIPER analysis was compared to the interstitial lung disease gender, age, physiology (ILD-GAP) outcome model. METHODS: CALIPER CT analysis of parenchymal patterns in 98 consecutive HP patients was compared to visual CT scoring by two radiologists. Functional indices including forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLco) in univariate and multivariate Cox mortality models. Automated stratification of CALIPER scores was evaluated against outcome models. RESULTS: Univariate predictors of mortality included visual and CALIPER CT fibrotic patterns, and all functional indices. Multivariate analyses identified only two independent predictors of mortality: CALIPER reticular pattern (p = 0.001) and DLco (p < 0.0001). Automated stratification distinguished three distinct HP groups (log-rank test p < 0.0001). Substitution of automated stratified groups for FVC and DLco in the ILD-GAP model demonstrated no loss of model strength (C-Index = 0.73 for both models). Model strength improved when automated stratified groups were combined with the ILD-GAP model (C-Index = 0.77). CONCLUSIONS: CALIPER-derived variables are the strongest CT predictors of mortality in HP. Automated CT stratification is equivalent to functional indices in the ILD-GAP model for predicting outcome in HP. KEY POINTS: • Computer CT analysis better predicts mortality than visual CT analysis in HP. • Quantitative CT analysis is equivalent to functional indices for prognostication in HP. • Prognostication using the ILD-GAP model improves when combined with quantitative CT analysis.

Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension.

OBJECTIVE: To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH). METHODS: High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified. RESULTS: Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0. CONCLUSION: Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD.

Advances in radionuclide imaging of cardiac sarcoidosis.

INTRODUCTION: Radionuclide imaging for the diagnosis and monitoring of cardiac involvement in sarcoidosis has advanced significantly in recent years. SOURCES OF DATA: This article is based on published clinical guidelines, literature review and our collective clinical experience. AREAS OF AGREEMENT: Gallium-67 scintigraphy is among the diagnostic criteria for cardiac involvement in systemic sarcoidosis, and it is strongly associated with response to treatment. However, fluorine-18, 2-fluoro-deoxyglucose (FDG) positron emission tomography (PET) is now preferred both for diagnosis and for assessing prognosis. AREAS OF CONTROVERSY: Most data are from small observational studies that are potentially biased. GROWING POINTS: Quantitative imaging to assess changes in disease activity in response to treatment may lead to FDG-PET having an important routine role in managing cardiac sarcoidosis. AREAS TIMELY FOR DEVELOPING RESEARCH: Larger prospective studies are required, particularly to assess the effectiveness of radionuclide imaging in improving clinical management and outcome.

Recent advances in the pathogenesis and clinical evaluation of pulmonary fibrosis.

Interstitial lung diseases (ILDs) are a group of heterogeneous disorders, either idiopathic or associated with injurious or inflammatory causes, in which the major site of damage is the lung interstitium. For a long time, knowledge regarding pathogenesis was trivial and there were difficulties in diagnosing and subsequently treating these diseases. During the past decade, however, there has been an impressive development in the field of ILDs. Idiopathic pulmonary fibrosis, the most common and fatal form of ILD, was initially believed to be due to an inflammatory response to unknown lung injury, whereas nowadays it is believed to be the result of multiple injuries at different sites of the lung followed by aberrant repair. The integration of clinical, radiological and histological data, namely a multidisciplinary team (MDT) approach, has provided grounds for a more accurate diagnosis of ILDs, and helped the identification of different entities and development of different therapeutic approaches. However, because of the complexity of ILDs, even this approach may fail to establish a confident diagnosis. How should the clinician behave in this case and what are the pitfalls of the MDT approach? In addition, since diagnosis is the major predictor of prognosis, are there any other tools available to predict prognosis?

Significance of connective tissue disease features in idiopathic interstitial pneumonia.

In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979-2005) were studied (nonspecific interstitial pneumonia (NSIP), n = 45; idiopathic pulmonary fibrosis, n = 56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21-33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud's phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14-0.85; p = 0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.

Elevated nocturnal desaturation index predicts mortality in interstitial lung disease.

BACKGROUND: Nocturnal desaturation may contribute to long-term pulmonary vascular stress in interstitial lung disease (ILD). We study the prevalence, severity and prognostic utility of nocturnal desaturation across ILD. METHODS: ILD patients with overnight oximetry (June 2006-August 2008) were reviewed (n = 134). Significant nocturnal desaturation was considered as > 10% of sleep with SpO2 < 90%. Desaturation index (DI) was defined as the number of desaturation events > 4%/hr. Covariates, including indices of nocturnal desaturation, were evaluated against mortality. RESULTS: Nocturnal desaturation was present in 49 (37%) patients. 31% of patients had pulmonary hypertension (PH) on echocardiography. Increased DI was associated with higher mortality independent of age, gender and BMI (HR 1.04; 95% CI 1.00, 1.06; p = 0.009). In separate models, DI and a) elevated brain natriuretic peptide (BNP; HR 1.04; 95% CI 1.00, 1.08; p = 0.04); b) moderate-severe PH on echocardiography (HR 3.15; 95% CI 1.24, 8.00; p = 0.02); and c) daytime resting SpO2 (HR 0.92; 95% CI 0.85, 0.99; p = 0.04) independently predicted mortality following adjustment for age, gender and BMI. CONCLUSION: Nocturnal desaturation is common and may be severe in ILD. Elevated nocturnal DI predicts higher mortality across ILD, independent of other vascular parameters. This finding may have important implications for the pathogenesis of PH in IPF.

Endpoints for clinical trials of sarcoidosis.

Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life.

Optimal scoring of serial change on chest radiography in sarcoidosis.

BACKGROUND: The optimal means of quantifying change on chest radiography in sarcoidosis is uncertain. In current guidelines, the role of serial measurement of carbon-monoxide diffusing capacity (DLco) remains undefined and the prevalence of discordance between serial chest radiographic change and pulmonary function tends is unknown. OBJECTIVE: To identify and explore key uncertainties in the monitoring of sarcoidosis by serial pulmonary function tests and chest radiography. DESIGN: 354 patients with sarcoidosis and concurrent tests (chest radiography and PFTs within three months at baseline, two years and/or four years) were studied. Chest radiographs were assessed by two radiologists for changes in stage and disease extent. Radiographic change and pulmonary function trends were quantified and compared. RESULTS: Change in radiographic extent of lung disease was always more frequent than change in stage (p < 0.0001) and there was poor agreement between change in stage and change in radiographic extent (Kw = 0.21 at two years; Kw = 0.23 at four years). Change in disease extent on chest radiography was linked to PFT trends on analysis of variance (p < 0.0005 for FEV1, FVC, DLco), whereas change in radiographic stage was not. Changes in gas transfer were often isolated or discordant with other serial data. Discordance between pulmonary function data and chest radiographic data was observed in 50% of cases. CONCLUSIONS: Change in radiographic extent is more applicable to routine monitoring in sarcoidosis than change in radiographic stage. In future guidelines, the role of serial gas transfer estimation and reconciliation of divergent chest radiographic and functional trends might usefully be addressed.

Chest radiography patterns in 75 adolescents with vertically-acquired human immunodeficiency virus (HIV) infection.

AIM: To evaluate lung disease on chest radiography (CR), the relative frequency of CR abnormalities, and their clinical correlates in adolescents with vertically-acquired human immunodeficiency virus (HIV) infection. MATERIALS AND METHODS: CRs of 75 patients [59 inpatients (33 males; mean age 13.7±2.3 years) and 16 outpatients (eight males; mean age 14.1±2.1 years)] were retrospectively reviewed by three independent observers. The overall extent of disease (to the nearest 5%), its distribution, and the proportional extents (totalling 100%) of different radiographic patterns (including ring/tramline opacities and consolidation) were quantified. CR features and clinical data were compared. RESULTS: CRs were abnormal in 51/75 (68%) with "extensive" disease in 38/51 (74%). Ring/tramline opacities and consolidation predominated (i.e., proportional extent >50%) in 26 and 21 patients, respectively. Consolidation was significantly more common in patients hospitalized primarily for a respiratory illness than patients hospitalized for a non-respiratory illness or in outpatients (p<0.005, χ(2) for trend); by contrast, ring/tramline opacities did not differ in prevalence across the groups. On stepwise logistic regression, predominant consolidation was associated with progressive dyspnoea [odds ratio (OR) 5.60; 95% confidence intervals (CI): 1.60, 20.1; p<0.01] and was associated with a primary respiratory cause for hospital admission (OR: 22.0; CI: 2.7, 181.1; p<0.005). Ring/tramline opacities were equally prevalent in patients with and without chronic symptoms and in those admitted to hospital with respiratory and non-respiratory illness. CONCLUSION: In HIV-infected adolescents, evaluated in secondary practice, CR abnormalities are prevalent. The presence of ring/tramline opacities, believed to reflect chronic airway disease, is not linked chronic respiratory symptoms.

Increased epithelial permeability in pulmonary fibrosis in relation to disease progression.

Epithelial injury contributes to pathogenesis in idiopathic pulmonary fibrosis (IPF) but its role in the interstitial lung disease (ILD) of systemic sclerosis (SSc) is uncertain. We quantified the prognostic significance of inhaled technetium-99m ((99m)Tc)-labelled diethylene triamine pentacetate (DTPA) pulmonary clearance, a marker of the extent of epithelial injury, in both diseases. Baseline (99m)Tc-DTPA pulmonary clearance was evaluated retrospectively in patients with SSc-ILD (n = 168) and IPF (n = 97) against mortality and disease progression. In SSc-ILD, the rapidity of total clearance (hazard ratio (HR) 1.02, 95% CI 1.01-1.03; p = 0.001) and the presence of abnormally rapid clearance (HR 2.10; 95% CI 1.25-3.53; p = 0.005) predicted a shorter time to forced vital capcity (FVC) decline, independent of disease severity. These associations were robust in both mild and severe disease. By contrast, in IPF, delayed clearance of the slow component, an expected consequence of honeycomb change, was an independent predictor of a shorter time to FVC decline (HR 1.01, 95% CI 1.00-1.02; p<0.01). Epithelial injury should be incorporated in pathogenetic models in SSc-ILD. By contrast, outcome is not linked to the overall extent of epithelial injury in IPF, apart from abnormalities ascribable to honeycombing, suggesting that core pathogenetic events may be more spatially focal in that disease.

The clinical utility of bronchoalveolar lavage in diffuse parenchymal lung disease.

Bronchoalveolar lavage (BAL) has been used in diagnostic and prognostic evaluation in diffuse parenchymal lung disease for three decades and has a central role in the diagnosis of a number of rare disorders and in excluding opportunistic infection in treated patients. It also has an important place in the personal diagnostic algorithms of many experienced clinicians in the diagnosis of the more prevalent disorders, including sarcoidosis, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. This use of BAL is not well captured in the medical literature, as most published studies pre-date changes in disease classification and fail to integrate BAL data with other clinical and radiological information. Further studies to quantify the value added by bronchoalveolar lavage in routine practice are urgently required.

Elevated brain natriuretic peptide predicts mortality in interstitial lung disease.

Elevated pulmonary vascular resistance portends a poor prognosis across interstitial lung disease (ILD), irrespective of the histospecific diagnosis. Currently, no noninvasive surrogate prognostic marker exists. We explore the prognostic value of brain natriuretic peptide (BNP) and echocardiography across ILD. ILD patients with BNP concentrations performed during 2005-2007 were reviewed (n = 90). Echocardiography tapes were reviewed by a cardiologist blinded to other results. Outcome was evaluated for survival against BNP and echocardiograph parameters. A priori threshold values and composite markers were evaluated against survival. During follow-up (20±9 months) there were 28 deaths (31%). BNP correlated with right heart echocardiographic indices, including right ventricular systolic pressure (RVSP) (R(2) = 0.18, p = 0.0002) but not with parameters of left heart function. Nonsurvivors had higher BNP and RVSP levels than survivors. BNP ≥20 pmol·L(-1) (hazard ratio (HR) 2.93, 95% CI 1.28-6.73; p = 0.01) and moderate-severe pulmonary hypertension (HR 2.53, 95% CI 1.15-5.57; p = 0.02) were associated with increased mortality, independent of age, sex and pulmonary function. Patients with BNP ≥20 pmol·L(-1) had a 14-fold increased mortality over those with BNP <4 pmol·L(-1). Increased BNP levels and/or echocardiographic markers of right ventricular dysfunction were associated with increased mortality across ILD. The link between vascular parameters and mortality supports the concept that pulmonary vascular disease contributes to the final common pathway seen across ILD.

Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study.

BACKGROUND: Systemic sclerosis (SSc) has high mortality and morbidity. Current management focuses on early detection and treatment of organ-based manifestations. AIM: To determine whether the ascertainment of major organ complications of SSc has changed over time and if this is associated with better survival. DESIGN: Retrospective cohort analysis. METHODS: A total of 520 SSc patients, 234 with disease onset between 1990 and 1993 (historical cohort) and 286 with disease onset between 2000 and 2003 (contemporary cohort), were included. Survival and frequency of internal organ complications were compared between the two cohorts. RESULTS: Five-year survival among diffuse cutaneous SSc (dcSSc) patients has improved from 69% in the 1990-93 cohort to 84% in the 2000-03 cohort (P = 0.018), whereas 5-year survival among the limited cutaneous SSc (lcSSc) patients has remained unchanged-93 and 91%, respectively. Sixteen per cent of the lcSSc subjects and 38% of the dcSSc subjects from the contemporary cohort were diagnosed for the clinically significant pulmonary fibrosis compared with 3 and 7%, respectively, of the historical cohort (P < 0.001). Similarly, the diagnosis of pulmonary arterial hypertension was more frequent in the patients from the contemporary cohort (8 and 7% for lcSSc and dcSSc, respectively) compared with [ < 1% (P = 0.002) and 1% (P = 0.148), respectively] the historical cohort. There was no significant difference between the two cohorts in terms of scleroderma renal crisis and cardiac involvement. CONCLUSION: Survival has substantially improved for the diffuse cutaneous subset of SSc with better and more complete ascertainment of lung complications as a result of systematic annual screening.

CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.

Sarcoidosis and Crohn's disease are heterogeneous systemic diseases characterised by granulomatous inflammation. Caspase recruitment domain (CARD)15 is a major susceptibility gene for Crohn's disease, and specifically for ileal and fibrostenotic subtypes. The C-C chemokine receptor (CCR)5 gene has been associated with both parenchymal pulmonary sarcoidosis and perianal Crohn's disease. This study explored associations between CARD15 polymorphisms, CCR5 haplotype and distinct pulmonary sarcoidosis subtypes. 185 Caucasian sarcoidosis patients were genotyped for CARD15 and CCR5 polymorphisms. The genetic data were compared with 347 healthy controls and were examined for associations with serial pulmonary function tests and chest radiographs. CARD15 genotypes did not differ between the unselected sarcoidosis cohort and controls. However, patients carrying the functional 2104T (702W) polymorphism were more likely to have radiographic stage IV disease at 4-yr follow-up. All patients possessing both CARD15 2104T and CCR5 HHC haplotype had stage IV disease at presentation. Carriage of 2104T was associated with worse forced expiratory volume in 1 s, whereas carriage of the CARD15 1761G (587R) polymorphism was associated with better lung function. For the first time, an association between two CARD15 polymorphisms and specific sarcoidosis phenotypes has been demonstrated, as well as an additive effect of possessing CARD15 2104T and CCR5 HHC haplotype.

Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis.

In therapeutic studies in idiopathic pulmonary fibrosis (IPF), the low prevalence of significant change in pulmonary functional tests (PFTs) has been a major constraint. The prognostic value of "marginal" changes in PFTs in IPF and fibrotic non-specific interstitial pneumonia (NSIP) was evaluated. In patients with biopsy-proven IPF (n = 84) and NSIP (n = 72), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D( L,CO)) trends at 6 months were categorised as "significant" (FVC >10%; D(L,CO) >15%) or "marginal" (FVC 5-10%; D(L,CO) 7.5-15%). Proportional hazards analysis and time-dependent receiver operating characteristic methodology were used to examine PFT trends against mortality. In IPF, reductions in FVC were significant in 22 cases (26%) and marginal in 19 cases (23%). Mortality was higher in patients with a significant decline in FVC (hazard ratio (HR) 2.80, 95% CI 1.54-5.06; p<0.001) and those with a marginal decline in FVC (HR 2.31, 95% CI 1.19-4.50; p = 0.01) than in those with stable disease. Progression-free survival was lower when the decline in FVC was marginal than in stable disease (HR 2.34, 95% CI 1.19-4.60; p = 0.01). Marginal changes in D(L,CO) in IPF and marginal changes in FVC and D (L,CO) in fibrotic NSIP did not provide useful prognostic information. Marginal change in FVC in IPF denotes a poor outcome. These findings are applicable to clinical practice and to the selection of patients with more progressive disease for therapeutic studies.