Toews, Galen B.

Abstract Findings of surgical lung biopsy (SLB) are important in categorizing patients with idiopathic interstitial pneumonia (IIP). We investigated whether histologic variability would be evident in SLB specimens from multiple lobes in patients with IIP. SLBs from 168 patients, 109 of whom had multiple lobes biopsied, were reviewed by three pathologists. A diagnosis was assigned to each lobe. A different diagnosis was found between lobes in 26% of the patients. Patients with usual interstitial pneumonia (UIP) in all lobes were categorized as concordant for UIP (n = 51) and those with UIP in at least one lobe were categorized as discordant for UIP (n = 28). Patients with nonspecific interstitial pneumonia (NSIP) in all lobes were categorized as having fibrotic (n = 25) or cellular NSIP (n = 5). No consistent distribution of lobar histology was noted. Patients concordant for UIP were older (63 ± 9 [mean ± SD] yr; p < 0.05 as compared with all other groups) than those discordant for UIP (57 ± 12 yr) or with fibrotic NSIP (56 ± 11 yr) or cellular NSIP (50 ± 9 yr). Semiquantitative high-resolution computed tomography demonstrated a varied profusion of fibrosis (p < 0.05 for all group comparisons), with more fibrosis in concordant UIP (2.13 ± 0.62) than in discordant UIP (1.42 ± 0.73), fibrotic NSIP (0.83 ± 0.58), or cellular NSIP (0.44 ± 0.42). Survival was better for patients with NSIP than for those in both UIP groups (p < 0.001), although survival in the two UIP groups was comparable (p = 0.16). Lobar histologic variability is frequent in patients with IIP, patients with a histologic pattern of UIP in any lobe should be classified as having UIP.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonias (IIPs) have similar clinical and radiographic features, but their histopathology, response to therapy, and natural history differ. A surgical lung biopsy is often required to distinguish between these entities. Objectives We sought to determine if clinical variables could predict a histopathologic diagnosis of IPF in patients without honeycomb change on high-resolution computed tomography (HRCT). Methods Data from 97 patients with biopsy-proven IPF and 38 patients with other IIPs were examined. Logistic regression models were built to identify the clinical variables that predict histopathologic diagnosis of IPF. Measurements and Main Results Increasing age and average total HRCT interstitial score on HRCT scan of the chest may predict a biopsy confirmation of IPF. Sex, pulmonary function, presence of desaturation, or distance walked during a 6-minute walk test did not help discriminate pulmonary fibrosis from other IIPs. Conclusions Clinical data may be used to predict a diagnosis of IPF over other IIPs. Validation of these data with a prospective study is needed.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea, impaired gas exchange, and ultimate mortality. Objectives To test the hypothesis that maximal oxygen uptake during cardiopulmonary exercise testing at baseline and with short-term longitudinal measures would predict mortality in patients with idiopathic pulmonary fibrosis. Methods Data from 117 patients with IPF and longitudinal cardiopulmonary exercise tests were examined retrospectively. Survival was calculated from the date of the first cardiopulmonary exercise test. Measurements and Main Results Patients with baseline maximal oxygen uptake less than 8.3 ml/kg/min had an increased risk of death (n = 8; hazard ratio, 3.24; 95% confidence interval, 1.10–9.56; P = 0.03) after adjusting for age, gender, smoking status, baseline forced vital capacity, and baseline diffusion capacity for carbon monoxide. We were unable to define a unit change in maximal oxygen uptake that predicted survival in our cohort. Conclusions We conclude that a threshold maximal oxygen uptake of 8.3 ml/kg/min during cardiopulmonary exercise testing at baseline adds prognostic information for patients with IPF.

Abstract Rationale Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator. Objectives To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts. Methods Fibroblasts were grown in vitro from well characterized control (n = 7), UIP (n = 17), or other DPLD (n = 13) lung tissue. The effects of PGE2 on fibroblast proliferation and collagen expression were determined. Measurements and Main Results Only 3 of 12 UIP fibroblast lines exhibited PGE2-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE2 resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE2, whereas other DPLD fibroblasts manifested a degree of resistance intermediate to control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A. Conclusions The recognition that UIP fibroblasts manifest variable refractoriness to PGE2 suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.

Abstract The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.

Abstract Rationale Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult. Objectives Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers. Methods Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days. Measurements and Main Results Each observer's diagnosis was coded into one of eight categories. A κ statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (κ = 0.55–0.71) than within community centers (κ = 0.32–0.44). Clinically significant disagreement was present between academic and community-based physicians (κ = 0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians. Conclusions Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.

Abstract Rationale and Hypothesis Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide. Methods One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation ⩽ 88% during a baseline 6MWT. For patients with a baseline saturation ⩽ 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients. Conclusion These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.

Abstract Current guidelines recommend that the clinician, radiologist, and pathologist work together to establish a diagnosis of idiopathic interstitial pneumonia. Three clinicians, two radiologists, and two pathologists reviewed 58 consecutive cases of suspected idiopathic interstitial pneumonia. Each participant was provided information in a sequential manner and was asked to record their diagnostic impression and level of confidence at each step. Interobserver agreement improved from the beginning to the end of the review. After the presentation of histopathologic information, radiologists changed their diagnostic impression more often than did clinicians. In general, as more information was provided the confidence level for a given diagnosis improved, and the diagnoses rendered with a high level of confidence were more likely congruent with the final pathologic consensus diagnosis. The final consensus pathologist diagnosis was idiopathic pulmonary fibrosis in 30 cases. Clinicians identified 75% and radiologists identified 48% of these cases before presentation of the histopathologic information. Histopathologic information has the greatest impact on the final diagnosis, especially when the initial clinical/radiographic diagnosis is not idiopathic pulmonary fibrosis. We conclude that dynamic interactions between clinicians, radiologists, and pathologists improve interobserver agreement and diagnostic confidence.

Abstract Chemokines are increased and may exert effects on both inflammatory and remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we examined the concomitant expression of inflammatory CC chemotactic cytokines or chemokines and their corresponding receptors in surgical lung biopsies obtained at the time of disease diagnosis and pulmonary fibroblasts grown from these biopsies. By gene array analysis, upper and lower lobe biopsies and primary fibroblast lines from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial lung disease, but not patients without IIP, exhibited CCL7 gene expression. TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed at significantly higher levels in UIP lung biopsies compared with biopsies from patients with nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, and from patients without IIP. Higher levels of CCL7 were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts, and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP fibroblasts. Together, these data suggest that CCL7 is highly expressed in biopsies and pulmonary fibroblast lines obtained from patients with UIP relative to patients with other IIP and patients without IIP, and that this CC chemokine may have a major role in the progression of fibrosis in this IIP patient group.

Abstract Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.