Relationship between Histopathologic Features and Mortality |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Keywords: idiopathic pulmonary fibrosis; usual interstitial pneumonia; prospective studies; pulmonary fibrosis physiopathology; smoking physiopathology; survival rate
Idiopathic pulmonary fibrosis (IPF) is a common interstitial lung disease (ILD) of unknown etiology. Clinical deterioration in IPF is expected; 5-yr survival ranges from 30 to 50% (1). Few studies have identified features of IPF that are associated with an increased risk of disease progression and death (2). Reported indicators, at presentation, of longer survival include: younger age (< 50 yr), female, a shorter symptomatic period prior to diagnosis, less dyspnea, preserved lung function, extent of ground-glass and reticular opacities on high-resolution computed tomography (HRCT) scan, lymphocytosis (20 to 25%) in bronchoalveolar lavage fluid (BAL), and a beneficial response or stable disease 3 to 6 mo after initial corticosteroid therapy (2). Features associated with shortened survival include: increased neutrophils (> 5%) (6) or eosinophils (> 5%) (2) in the BAL, a failure to respond to immunosuppression therapy, and the extent of "fibrosis" on HRCT scan (5).
The diagnosis of IPF is best confirmed by the identification of usual interstitial pneumonia (UIP) on surgical lung biopsy. The UIP pattern is characterized by heterogeneity that includes patchy chronic inflammation (alveolitis), progressive injury (small aggregates of proliferating myofibroblasts and fibroblasts, termed fibroblastic foci) and fibrosis (dense collagen and honeycomb change) (7).
The correlation between lung pathology and survival is controversial and inadequately defined (7). The most widely held hypothesis suggests that the prognosis and response to therapy of patients with IPF is determined by the extent of cellularity versus fibrosis present on lung tissue examination (8). We carried out a semiquantitative grading of histopathologic abnormalities found on surgical lung biopsy (9). The purpose of this article is to report the relative roles of specific histopathologic alterations in determining prognosis in patients with IPF.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Study Population
The study cohort consisted of 87 patients prospectively enrolled in an ILD Study at the National Jewish Medical and Research Center between 1982 and 1993. The diagnosis of IPF was established according to previously described clinical and histologic criteria (7, 12). Patients with a defined connective tissue disease, left ventricular failure, an occupational and/or environmental exposure that resulted in ILD, or a history of ingestion of a drug or an agent known to cause pulmonary fibrosis were excluded from the study. There were 54 men and 33 women, 89% were white and their ages ranged from 36 to 77 yr (Table 1). Informed consent was obtained from each patient; and the Institutional Human Subject Review Committee approved the protocol. All subjects had clinical, radiographic, and lung function evaluation. Subjects were designated as current smokers (if they smoked cigarettes regularly within the previous year), former smokers (if they had not smoked cigarettes in the previous year but had smoked in the past), and never smokers. Twenty-three were never cigarette smokers, and 64 were ever smokers, including 21 current smokers and 43 former smokers. There were differences in age, sex, and race among the smoking groups.
|
A modified American Thoracic Society (ATS) questionnaire was used to collect demographic and medical information (13). Information regarding the course of the patient's illness was obtained from the initial history obtained at the time of evaluation and from a follow-up questionnaire. Disease onset was defined as the patient's first recollection of the appearance of cough (coughing throughout the day) or dyspnea (breathlessness walking up inclines) or the first documented chest roentgenogram showing ILD. When a subject had both cough and dyspnea, the onset of the earliest symptom was considered the date respiratory symptoms began. The type and amount of exertion determined the severity of dyspnea required to induce distressful breathing using a previously described dyspnea scale (13).
Pulmonary Function Assessment
The methods used for the pulmonary function, volume-pressure relationship, and exercise testing have been described previously (11).
Physiologic assessment included measurement of thoracic gas volume
(Vtg) and TLC, FVC, and FEV1, the volume-pressure relationship of
the lungs, and the single-breath diffusing capacity for carbon monoxide
(DLCO). The coefficient of elastic retraction was calculated by dividing
maximal static transpulmonary pressure by TLC. The normal value in
our laboratory is 3 to 8 cm H2O/L. The volume-pressure data were also
subjected to an exponential curve fit where volume is expressed as a
percentage of observed TLC, and the exponential K, a constant that is
proportional to the total incremental compliance was derived from the
equation: V = A 
Be Kp, where V is the volume at a given pressure
(p), A is the maximal theoretical volume at infinite pressure, and B is
A minus the intercept of the fitted exponential on the volume axis (11).
Respiratory frequency, tidal volume, expired gas concentrations,
heart rate, and blood pressure and arterial blood gas tensions were
determined at rest and while exercising on an electrically braked bicycle ergometer during incremental work loads (maximal exercise testing), and during steady-state exercise at 50% of the maximum work
load achieved during the incremental exercise testing. Arterial blood
gases were determined with blood electrodes. The AaPO2 was calculated from the simplified alveolar air equation. Because approximately half of the patients required supplemental oxygen during exercise, the steady-state exercise PaO2 and AaPO2 were corrected for FIO2,
using the equation: PO2 (corr) = (PaO2/ FIO2) × 21, and AaPO2 (corr) = AaPO2/ FIO2) × 21. Dead space to tidal volume ratio (VD/VT) was calculated using the Bohr equation and corrected for the additional mechanical dead space imposed by the experimental apparatus: VD = ((PaCO2 PECO2)/PaCO2) × VT minus (mechanical dead space of apparatus). Oxygen consumption (
O2) and maximal work load achieved
were expressed as percent of predicted reference values obtained
from the age- and sex-adjusted equations of Jones and Campbell (14).
As seen in Table 2, there was a considerable range of functional disturbances.
|
Pathologic Assessment
All patients underwent open thoracotomy or video-assisted thoracoscopic lung biopsy. The method for collection, processing, and review of the pathologic specimens has been previously described (9, 10). Tissue was obtained from two sites, the upper and lower lobes of the same lung (when technically feasible). Immediately after the biopsy, all specimens were gently inflated with formalin, using a syringe and needle and injecting through the pleura. The specimens were then processed in routine fashion, and multiple-step sections showing representative pathology, as selected by one observer (J.W.), were cut and distributed among the four pathologists. Each pathologist received five slides from each block recut. The pathologists were unaware of the clinical, radiologic, or physiologic findings. Cases in which there were differing diagnoses were reevaluated by the pathology panel at periodic meetings and a consensus diagnosis was agreed upon. The 87 patients in whom there was a consensus for the diagnosis of UIP formed the basis of this study (7, 9, 12). Patients whose histopathologic findings were consistent with the following patterns were excluded from this analysis: nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis associated with ILD (RBILD), lymphoid interstitial pneumonia (LIP), acute interstitial pneumonia (AIP, diffuse alveolar damage), eosinophilic granuloma, hypersensitivity pneumonitis, sarcoidosis, or idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic BOOP).
For each patient, the four pathologists (JW, TC, AF, and WT) performed a semiquantitative assessment of inflammatory/exudative changes, fibrotic/reparative changes, and airway alterations, in addition to an overall assessment of cellularity and fibrosis (see Table 4) (9). For each patient, the four pathologists graded 14 specific histopathologic features from slides stained with (1) hematoxylin-eosin, (2) pentachrome (which provided differential staining of elastic tissue, collagenized connective tissue, and mucopolysaccharide-rich stroma), (3) prussian blue (for iron), and (4) toludine blue. The parameters, which were scored in a semiquantitative fashion, included inflammatory/exudative changes, fibrotic/reparative changes, and airway alterations. A grade of zero to 5 was applied to (1) the extent and (2) the severity of cellularity in the alveolar wall (interstitium); (3) metaplastic cells lining the air spaces, including foci of honeycomb lung; (4) the extent and (5) the severity of cellularity in the alveolar space (so-called "desquamation"); (6) interstitial "young connective tissue," i.e., rich in fibroblasts and metachromatic stroma, and relatively poor in mature collagen in the small airways; (7) interstitial fibrosis (including the percent of lung involved by honeycomb cysts, and foci with young connective tissue); (8) honeycomb cysts; (9) metaplastic smooth muscle in the stroma (as distinct from normal smooth muscle associated with airways and vasculature); (10) myointimal mural thickening in the vessel walls. In addition, a score of zero to 2 (absent = 0; present = 1; marked = 2) was used to assess (11) small airway lumenal granulation tissue; (12) intraalveolar granulation tissue; (13) airway wall inflammation; and (14) airway wall fibrosis.
|
As previously described (9), the principal component factor analysis of the means of the ratings of the four pathologists for each of these histologic features resulted in derivation of four factor scores:
1. The fibrosis factor (maximum score = 25), which is composed of interstitial fibrosis, honeycomb cysts, alveolar wall metaplastic cells lining the air spaces, metaplastic smooth muscle in the stroma, and myointimal mural thickening in the vessel walls.
2. The cellularity factor (maximum score = 10), which is composed of the severity and extent of cellular infiltration of the alveolar walls.
3. The alveolar space cellularity factor (maximum score = 10), which is composed of the severity and extent of cellularity within the alveolar space.
4. The granulation and young connective tissue factor (maximum score = 9), which comprises interstitial "young connective tissue" and granulation tissue in the lumens of small airways and alveoli.
Each factor score was derived from the sum of the scores assigned to its components, and the total pathology score was derived from the sum of the four factor scores. The maximum total pathology score was 54.
Treatment Protocol
At entry, most patients had never received treatment directed at IPF (n = 62, 71% of patients); 12 (14%) were not receiving treatment at the time of lung biopsy but had been receiving short courses of corticosteroid treatment more than 30 d prior to the lung biopsy; 13 (15%) had been treated within 30 d of the biopsy. None of the patients had received significant doses of corticosteroid therapy (defined as a total of 2,700 mg of prednisone in any 90-d period) before diagnosis and entry into the study.
Data Analysis
Patients were considered censored if they (1) were still alive when last contacted (censored at the last status date), (2) had received a lung transplant (censored at the time of the transplant), or (3) died from a cause other than ILD (censored at the expiration date). Survival time was calculated as the time since surgical lung biopsy.
The Kruskal-Wallis test was used to compare the three smoking groups for the continuous variables of interest, followed by pairwise comparisons using Wilcoxon's rank sum test. Dichotomous variables were compared using chi-square tests. Fisher's protected method was used to correct for multiple comparisons. Pathology variables were dichotomized (for plots only) by considering values below the median to be "low" and those above the median to be "high."
The survival function was estimated using the Kaplan-Meier method (15). Estimates of the survival function were stratified by smoking status and the four pathology factors. The log-rank statistic was used to compare survival among groups (15). The effect of each variable on the risk of death after controlling for age, sex, and smoking status was modeled using Cox proportional hazards regression (15). Risk ratios are reported for these analyses. Influential points were identified through the use of the likelihood displacement and lmax statistics (16). Patients who accounted for more than 10 times the expected variability of the elements of the lmax statistic or had an likelihood displacement statistic of 0.5 or greater were excluded from the statistical analysis. Points that were considered influential were excluded from the Cox proportional hazards regression analyses. Multivariable models were developed on the subset of patients with complete data for the variables of interest. Akaike's Information Criteria (AIC) (17) was used to compare the multivariable models.
Descriptive statistics were generated using JMP statistical software (SAS Institute Inc., Cary, NC). All other statistical analysis was performed using the SAS statistical package (SAS). Unless otherwise noted, all tests were two-sided and performed at the 0.05 significance level.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Patient Outcome
At the time of the initial visit, the median time that patients had experienced shortness of breath was 24 mo. The duration of symptoms was not affected by smoking status. The median length of follow-up from the onset of symptoms was 65 mo; current smokers had the longest duration of follow-up (94 mo). The median length of follow-up from the time of the biopsy was 40 mo, with longest follow-up time in the current smoker group (63 mo) and the shortest follow-up time in the former smokers group (32 mo). Survival was assessed through September 30, 1999.
After entry into the study, 80 subjects received treatment for their illness with immunosuppressive or cytotoxic therapy: 44 received prednisone alone (one received prednisolone only intravenously); three received cyclophosphamide alone; 26 received prednisone and cyclophosphamide; five received prednisone, cyclophosphamide, and colchicine; one each received prednisone and colchicine, or cyclophosphamide and colchicine. Seven patients received no treatment.
Sixty-three patients (72%) died during the study period. In the analysis, we censored those patients who died because of an illness other than IPF (n = 6) or underwent lung transplantation (n = 4). The median survival time for all subjects was 47.5 mo (95% CI: 33.4-73.4) from the time of lung biopsy. There was a tendency for a greater risk of death for men (approximately 47% greater risk than for women, p = 0.18) and patients with older age (p = 0.0667). The age, sex, and smoking-adjusted survival analysis for the individual clinical and physiologic variables are shown in Table 3. The patient's race (white versus nonwhite) and time since onset of symptoms were not significantly related to the risk of death. An increased risk of death was associated with the number of pack-years of smoking (p = 0.0218) and the degree of dyspnea (p = 0.0029), with a one-unit increase in the dyspnea score being associated with a 10% increase in the risk of death. Vtg, TLC, FVC, FEV1, SGaw, the log of the K value, coefficient of retraction, DLCO, and PaO2 at maximal exercise were significantly related to survival (Table 3). Patients with more normal PaO2 at the end of maximal exercise survived longer (p = 0.0057). The Kaplan-Meier survival estimates stratified by smoking status are shown in Figure 1.
|
|
Histopathologic Findings
A wide range of pathology factor scores was observed in our patients with UIP. The median score for each factor score for the entire group was: cellularity, 6.3 (25th, 75th percentile; 5.5-7.1); alveolar space cellularity, 4.5 (3.5-5.5); fibrosis, 12.9 (9.8- 16.5); granulation/connective tissue, 1.8 (1.0-2.7); and total pathology score, 26.0 (22.3-30.8). Current smokers had significantly lower degrees of cellularity and granulation/connective tissue and higher alveolar space cellularity than did former and never smokers (Figure 2). The amount of fibrosis did not differ by smoking status.
|
In the age-, sex-, and smoking-adjusted survival analyses, only the granulation/connective tissue score was a significant predictor of survival in patients with IPF (Table 4). A one-unit increase in the granulation/connective tissue factor was associated with a 1.74-fold greater risk of death. Of the specific components that comprise this factor, the degree of alveolar space granulation tissue and the fibrotic/reparative changes in young connective tissue were each significantly associated with survival. A one grade level increase of fibrotic/reparative changes in young connective tissue increases the risk of death almost twofold. On the other hand, the airway lumenal granulation tissue extent of involvement was not associated with an increased risk of death. The Kaplan-Meier survival analysis for each factor score dichotomized at the median for entire group is shown in Figure 3.
|
Multivariable survival model. Multiple independent variables were studied in Cox proportional hazards models to assess survival (Table 5). The importance of the multivariable analysis is that it allows identification of those manifestations that are independently and significantly related to outcome (survival) while controlling for the other factors in the model. Age, sex, level of dyspnea, smoking status, TLC, DLCO, coefficient of retraction, and the four pathology factors were included in the multivariable model. FVC and Vtg were excluded since they strongly correlated with TLC (0.82 and 0.76, respectively). Dyspnea, coefficient of retraction, and granulation/connective tissue factor, were significantly related to the risk of death. In this model, current smokers had a 22% greater risk of death than did never smokers and former smokers had an 88% greater risk of death than did never smokers. A change in two levels on our dyspnea scale results in a 49% increased risk of death. An increase of one grade of the granulation tissue factor is associated with a two-fold risk of death.
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The objective of this study was to determine whether or not specific histopathologic features of UIP predicted survival in patients with IPF. We prospectively evaluated the largest number of untreated, surgical lung biopsy-proven, cases of IPF reported to date (7). In addition, the present study provided an improved method of grading the degree of cellularity and fibrosis (9, 11). We found that the extent of granulation/connective tissue present on lung tissue examination was the only histopathologic feature predictive of survival in IPF. By contrast, the extent and severity of interstitial fibrosis or cellularity on lung biopsy were not predictive of survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival in this population.
Influence of Histopathologic Features on Survival in IPF
Previous correlative studies of outcome and histopathology have shown that prognosis and response to therapy in the idiopathic interstitial pneumonias (IIPs) was determined by the extent of interstitial fibrosis and cellularity on biopsy (8). However, this widely held view that predominantly "cellular" biopsies in patients with IPF are associated with a greater likelihood of response to corticosteroids and a better prognosis appears to have little support (1, 7). First, most studies involved a small number of cases of IPF. Second, the pathologic findings were often assessed from tissue samples obtained by percutaneous needle or transbronchial rather than from surgical lung biopsy specimens. Histopathologic confirmation of UIP and grading of specific features is difficult in the small lung biopsy specimens obtained by these methods (1, 7). Third, it is now recognized that histopathologic subtypes other than UIP were commonly included among the patients evaluated in these studies (e.g., DIP, RB-ILD, NSIP, and idiopathic BOOP) (1, 18, 19). These are distinct clinical, radiographic, and histopathologic entities with different responses to therapy and survival rates. Importantly, data show that the UIP pattern is associated with a substantially worse survival than other chronic IIPs (1, 18, 19). Fourth, no single histologic finding, other than end-stage fibrosis and honeycombing, has been shown to correlate with treatment response or prognosis in UIP (7). A positive correlation between the extent of overall cellularity, or a negative correlation with the extent of fibrosis, has been shown to correlate with responsiveness to corticosteroid therapy (3, 8, 20). Fifth, the term "cellularity" was used indiscriminately for interstitial inflammation, intraalveolar macrophage accumulation, or a combination of both. Sixth, the term "fibrosis" has included all manner of fibroblastic proliferation and collagen deposition. More recently, a distinction has been made between fibrotic areas of the lesion characterized by "old," relatively acellular collagen bundles and small aggregates of fibroblasts in myxoid connective tissue, so-called "fibroblastic foci" (1, 7). Until the present study, the relative roles of the stage of fibrosis (mature collagen versus fibroblast foci) in determining prognosis had not been examined (7).
Fibroblastic Foci, Site Ongoing Lung Injury
In IPF, it is hypothesized that early stages of the disease involve less of the lung and is characterized predominantly by cellularity and minimal fibrosis, whereas in advanced disease a large number of alveoli are destroyed by fibrosis with varying degrees of cellularity. This hypothesis has been challenged and it has been proposed that the earliest changes in UIP are fibroblastic foci, a manifestation of ongoing lung injury (7). In this study, a distinction was made between interstitial fibrosis with extensive collagen deposition (which includes honeycomb change) and fibroblastic foci recognized as young connective tissue or connective tissue with granulation tissue type appearance. We have shown that when individual pathologic variables were assessed and quantified, only the granulation/connective tissue factor score was a significant predictor of survival time in patients with IPF. Moreover, the specific features that predicted survival were the degree of alveolar space granulation tissue deposition and extent of young connective tissue present within the fibroblastic foci. Interestingly, when this form of connective tissue appears as an air space process in conditions such as bronchiolitis obliterans organizing pneumonia, it appears to be potentially reversible. However, when identified in IPF, this form of connective tissue has a detrimental impact on prognosis. On the other hand, the extent and severity of interstitial cellularity, alveolar space cellularity, or fibrosis did not predict survival. In fact, it appears that the interstitial inflammation and intraalveolar macrophage accumulation ("desquamation") are most likely secondary events (7).
These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the apparently ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Recent experimental data support an important role for fibroblastic proliferation in the lung injury and repair process in pulmonary fibrosis. It has been proposed that incomplete or delayed alveolar repair after lung injury leads to an acceleration of collagen deposition and lung fibroblast proliferation. Fibroblasts isolated from fibrotic lung induce apoptosis of alveolar epithelial cells in vitro (28). Further, epithelial cell death is most prominent immediately adjacent to underlying foci of fibroblasts (29). These data suggest that the epithelium of the fibrotic lung contain dying and proliferating cells and that alveolar epithelial cell death is induced by abnormal lung fibroblasts (29). Thus, controlling the fibrogenesis (evident in the regions of fibroblastic foci), rather than the "alveolitis," appears most important in arresting the progressive disease and preventing the fatal outcome so common in IPF.
Influence of Cigarette Smoking on Survival in IPF
Many studies have shown a high percentage of ever cigarette smokers among persons with IPF (3, 4, 20, 30) and case control studies suggest that smoking is a risk factor for the development of IPF (31). However, earlier studies showed that being an ever smoker did not affect survival in IPF (3, 4, 34, 35). In the present study, smoking status at the time of biopsy was a significant prognostic variable in that current smokers had a markedly improved survival compared with never or former smokers.
Interestingly, not only does cigarette smoking play a role in
the development of IPF (33) and alters lung function (2, 11), it
also alters the histopathologic appearance of the disease. We
found that current smokers have less overall interstitial cellularity but greater alveolar space inflammation
likely reflecting increased inflammation secondary to ongoing accumulation of macrophages as a result of smoking. The fibrotic
changes were similar among the current, former, and never
smoker groups; however, there were significantly lower granulation/connective tissue scores among the current smokers.
There were no differences in any of the pathology factor
scores between never and former smokers. It is probably the
decreased granulation/connective tissue that is responsible for
the longer survival in current smokers. Conversely, some factor in cigarette smoke may be contributing to decrease granulation/connective tissue. However, multivariable model suggests that if the other factors in the model were held constant
(for example, granulation/connective tissue, dyspnea, and coefficient of retraction), current smokers and former smokers
would tend to have an increased risk of death as opposed to
never smokers. However, this difference is not statistically significant. These findings suggest that the ongoing epithelial damage and repair processes associated with persistent fibroblastic proliferation is less among current smokers.
The current literature argues that in the absence of a surgical (thoracoscopic or open) lung biopsy, the diagnosis of IPF remains uncertain. Further, the separation of the four distinct histologically forms of the IIPs (UIP, DIP, NSIP, AIP) is essential because these patterns differ in clinical presentations, responses to therapy, and clinical course. The present study has shown that careful analysis and quantification of the specific histopathologic features found in UIP is useful in defining the prognosis of patients with IPF. Somewhat surprisingly, the specific histopathologic features that predicted survival were the degree of alveolar space granulation tissue deposition and extent of young connective tissue present within the fibroblastic foci rather than the extent and severity of interstitial cellularity or fibrosis. The full implications of these findings remain to be determined. However, given the disappointing therapeutic results achieved with immunosuppressive or anti-inflammatory agents, these data suggest that future therapies should be aimed at preventing or inhibiting the fibroproliferative response.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Talmadge E. King, Jr., M.D., San Francisco General Hospital, Room 5H22, 1001 Potrero Avenue, San Francisco, CA 94110. Email: tking{at}medsfgh.ucsf.edu
(Received in original form January 19, 2000 and in revised form May 23, 2001).
Acknowledgments: The writers thank Drs. L.C. Watters, T.L. Dunn, A. Shen, and R.L. Mortenson for their role in enrolling patients; Alma (Dolly) Kervitsky, S. Arlene Niccoli, Martin Wallace, Trudy McDermott, and Janet Henson for their technical assistance; Becki Bucher Bartelson for her assistance with the data analysis; William Kastner and David Ikle for the design and maintenance of the computerized data for the ILD study; the referring physicians; and a special thanks to the patients for allowing the investigators to participate in their care. We would like to remember and express our appreciation to the late William (Whitey) Thurlbeck for his contributions to this and other studies.
Supported by a SCOR Grant No. HL-27353 from the National Heart, Lung and Blood Institute.
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1. Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR, Offord KP. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 157: 199-203 .
2. Schwartz DA, Van Fossen DS, Davis CS, Helmers RA, Dayton CS, Burmeister LF, Hunninghake GW. Determinants of progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149: 444-449 [Abstract].
3.
Turner-Warwick M,
Burrows B,
Johnson A.
Cryptogenic fibrosing alveolitis: clinical features and their influence on survival.
Thorax
1980;
35:
171-180
4. Schwartz DA, Helmers RA, Galvin JR, Van Fossen DS, Frees KL, Dayton CS, Burmeister LF, Hunninghake GW. Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149: 450-454 [Abstract].
5.
Gay SE,
Kazerooni EA,
Toews GB,
Lynch III.
J, Gross BH, Cascade PN,
Spizarny DL, Flint A, Schork MA, Whyte RI, Popovich J, Hyzy R,
Martinez FJ. Idiopathic pulmonary fibrosis: predicting response to
therapy and survival.
Am J Respir Crit Care Med
1998;
157:
1063-1072
6. Rudd RM, Haslam PL, Turner-Warwick M. Cryptogenic fibrosing alveolitis relationships of pulmonary physiology and bronchoalveolar lavage to treatment and prognosis. Am Rev Respir Dis 1981; 124: 1-8 [Medline].
7.
Katzenstein ALA,
Myers JL.
Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.
Am J Respir Crit Care Med
1998;
157:
1301-1315
8. Selman M, King Jr TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136-151.
9. Cherniack RM, Colby TV, Flint A, Thurlbeck WM, Waldron JA, King Jr TE, and BAL Cooperative Group Steering Committee. Quantitative assessment of lung pathology in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1991;144:892-900.
10. Hyde DM, King Jr TE, McDermott T, Waldron Jr JA, Colby TV, Thurlbeck WM, Flint A, Ackerson L, Cherniack RM. Idiopathic pulmonary fibrosis: the quantitative assessment of lung pathology. Comparison of a semiquantitative versus a morphometric histopathologic scoring system. Am Rev Respir Dis 1992;146:1042-1047.
11. Cherniack RM, Colby TV, Flint A, Thurlbeck WM, Waldron Jr JA, Ackerson L, Schwarz MI, King Jr TE. Correlation of structure and function in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1995;151:1180-1188.
12. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.
13. Watters LC, King TE, Schwarz MI, Waldron JA, Stanford RE, Cherniack RM. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis 1986; 133: 97-103 [Medline].
14. Jones NL, Campbell EJM. Clinical exercise testing. Philadelphia: W. B. Saunders Co; 1982. p. 249.
15. Collett D. Modelling survival data in medical research. London: Chapman & Hall; 1994.
16. Pettitt AN, Bin Daud I. Case-weighted measures of influence for proportional hazards regression. Appl Statist 1989;38:51-67.
17. Akaike H. A new look at the statistical model identification. IEEE Trans Auto Control 1974;AC-19:716-723.
18.
Daniil ZD,
Gilchrist FC,
Nicholson AG,
Hansell DM,
Harris J,
Colby TV,
du Bois RM.
A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial
pneumonia in patients with cryptogenic fibrosing alveolitis.
Am J
Respir Crit Care Med
1999;
160:
899-905
19. Nagai S, Kitaichi M, Itoh H, Nishimura K, Izumi T, Colby TV. Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Eur Respir J 1998; 12: 1010-1019 [Abstract].
20. Carrington CB, Gaensler EA, Coutu RE, Fitzgerald MX, Gupta RG. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298: 801-809 [Abstract].
21. Dreisin RB, Schwarz MI, Theofilopoulos AN, Stanford RE. Circulating immune complexes in the idiopathic interstitial pneumonias. N Engl J Med 1978; 298: 353-357 [Abstract].
22. Winterbauer RH, Hammar SP, Hallman KO, Hays JE, Pardee NE, Morgan EH, Allen JD, Moores KD, Bush W, Walker JH. Diffuse interstitial pneumonitis: clinicopathologic correlations in 20 patients treated with prednizone/azathioprine. Am J Med 1978; 65: 661-672 [Medline].
23. Wright PH, Heard BE, Steel SJ, Turner-Warwick M. Cryptogenic fibrosing alveolitis: assessment by graded trephine lung biopsy histology compared with clinical, radiographic, and physiological features. Br J Dis Chest 1981; 75: 61-70 [Medline].
24.
Tukiainen P,
Taskinen E,
Holsti P,
Korhola O,
Valle M.
Prognosis of
cryptogenic fibrosing alveolitis.
Thorax
1983;
38:
349-355
25.
Selman M,
Carrillo G,
Salas J,
Padilla RP,
Pérez-Chavira R,
Sansores R,
Chapela R.
Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial.
Chest
1998;
114:
507-512
26. Raghu G, Depaso WJ, Cain K, Hammar SP, Wetzel CE, Dreis DF, Hutchinson J, Pardee NE, Winterbauer RH. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective, double-blind randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991; 144: 291-296 [Medline].
27. Watters LC, Schwarz MI, Cherniack RM, Waldron JA, Dunn TL, Stanford RE, King Jr TE. Idiopathic pulmonary fibrosis: pretreatment bronchoalveolar lavage cellular constituents and their relationships with lung histopathology and clinical response to therapy. Am Rev Respir Dis 1987;135:696-704.
28. Uhal BD, Joshi I, True AL, Mundle S, Raza A, Pardo A, Selman M. Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro. Am J Physiol 1995;269(6 Pt 1):L819-828.
29. Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol 1998;275(6 Pt 1):L1192-1199.
30.
Johnston IDA,
Prescott RJ,
Chalmers JC,
Rudd RM.
the Fibrosing
Alveolitis Subcommittee of the Research Committee of the British
Thoracic Society. British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management.
Thorax
1997;
52:
38-44
31. Iwai K, Mori T, Yamada N, Yamaguchi M, Hosoda Y. Idiopathic pulmonary fibrosis. Epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med 1994; 150: 670-675 [Abstract].
32. Hubbard R, Lewis S, Richards K, Johnston I, Britton J. Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitis. Lancet 1996; 347: 284-289 [Medline].
33. Baumgartner KB, Samet J, Stidley CA, Colby TV, Waldron JA. the Collaborating Centers. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997; 155: 242-248 [Abstract].
34.
de Cremoux H,
Bernaudin JF,
Laurent P,
Brochard P,
Bignon J.
Interactions between cigarette smoking and the natural history of idiopathic
pulmonary fibrosis.
Chest
1990;
98:
71-76
35.
Hubbard R,
Johnston I,
Britton J.
Survival in patients with cryptogenic
fibrosing alveolitis: a population-based cohort study.
Chest
1998;
113:
396-400
This article has been cited by other articles:
 |
|
 |
|
  O. Eickelberg and G. J. Laurent The Quest for the Initial Lesion in Idiopathic Pulmonary Fibrosis: Gene Expression Differences in IPF Fibroblasts Am. J. Respir. Cell Mol. Biol., January 1, 2010; 42(1): 1 - 2. [Full Text] [PDF]
|
|
|
|
 |
|
 A Jayachandran, M Konigshoff, H Yu, E Rupniewska, M Hecker, W Klepetko, W Seeger, and O Eickelberg SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis Thorax, December 1, 2009; 64(12): 1053 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Guo, B. Shan, R. C. Klingsberg, X. Qin, and J. A. Lasky Abrogation of TGF-{beta}1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L864 - L870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Swigris, J. Swick, F. S. Wamboldt, D. Sprunger, R. du Bois, A. Fischer, G. P. Cosgrove, S. K. Frankel, E. R. Fernandez-Perez, D. Kervitsky, et al. Heart Rate Recovery After 6-Min Walk Test Predicts Survival in Patients With Idiopathic Pulmonary Fibrosis Chest, September 1, 2009; 136(3): 841 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Kinder, K. K. Brown, F. X. McCormack, J. H. Ix, A. Kervitsky, M. I. Schwarz, and T. E. King Jr Serum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis Chest, June 1, 2009; 135(6): 1557 - 1563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Liu, B. Hu, Y. Y. Choi, M. Chung, M. Ullenbruch, H. Yu, J. B. Lowe, and S. H. Phan Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation Am. J. Pathol., May 1, 2009; 174(5): 1745 - 1755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Behr and V. J. Thannickal Update in Diffuse Parenchymal Lung Disease 2008 Am. J. Respir. Crit. Care Med., March 15, 2009; 179(6): 439 - 444. [Full Text] [PDF]
|
|
|
|
|
|
C. D. Fell, L. X. Liu, C. Motika, E. A. Kazerooni, B. H. Gross, W. D. Travis, T. V. Colby, S. Murray, G. B. Toews, F. J. Martinez, et al. The Prognostic Value of Cardiopulmonary Exercise Testing in Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., March 1, 2009; 179(5): 402 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kreider and R. M. Kotloff Selection of Candidates for Lung Transplantation Proceedings of the ATS, January 15, 2009; 6(1): 20 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. D. Tazelaar Pathology of Diffuse and Neoplastic Disease ACCP Pulmonary Med Brd Rev, January 1, 2009; 25(0): 501 - 512. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Lynch III Idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia/Fibrosis, and Sarcoidosis ACCP Pulmonary Med Brd Rev, January 1, 2009; 25(0): 635 - 686. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mozaffarian, A. W. Brewer, E. S. Trueblood, I. G. Luzina, N. W. Todd, S. P. Atamas, and H. A. Arnett Mechanisms of Oncostatin M-Induced Pulmonary Inflammation and Fibrosis J. Immunol., November 15, 2008; 181(10): 7243 - 7253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Horowitz and A. H. Limper Stress in the ER (Endoplasmic Reticulum): A Matter of Life and Death for Epithelial Cells Am. J. Respir. Crit. Care Med., October 15, 2008; 178(8): 782 - 783. [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Ding, C. L. Gladson, H. Wu, H. Hayasaka, and M. A. Olman Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner J. Biol. Chem., October 3, 2008; 283(40): 26839 - 26849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Arakawa, K. Fujimoto, K. Honma, N. Suganuma, H. Morikubo, Y. Saito, H. Shida, and Y. Kaji Progression from Near-Normal to End-Stage Lungs in Chronic Interstitial Pneumonia Related to Silica Exposure: Long-Term CT Observations Am. J. Roentgenol., October 1, 2008; 191(4): 1040 - 1045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Rogliani, M. Mura, M. Assunta Porretta, and C. Saltini Review: New perspectives in the treatment of idiopathic pulmonary fibrosis Therapeutic Advances in Respiratory Disease, April 1, 2008; 2(2): 75 - 93. [Abstract] [PDF]
|
|
|
|
|
|
B. W. Kinder, K. K. Brown, M. I. Schwarz, J. H. Ix, A. Kervitsky, and T. E. King Jr Baseline BAL Neutrophilia Predicts Early Mortality in Idiopathic Pulmonary Fibrosis Chest, January 1, 2008; 133(1): 226 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kitowska, D. Zakrzewicz, M. Konigshoff, I. Chrobak, F. Grimminger, W. Seeger, P. Bulau, and O. Eickelberg Functional role and species-specific contribution of arginases in pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L34 - L45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Konigshoff, A. Wilhelm, A. Jahn, D. Sedding, O. V. Amarie, B. Eul, W. Seeger, L. Fink, A. Gunther, O. Eickelberg, et al. The Angiotensin II Receptor 2 Is Expressed and Mediates Angiotensin II Signaling in Lung Fibrosis Am. J. Respir. Cell Mol. Biol., December 1, 2007; 37(6): 640 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kabuyama, K. Oshima, T. Kitamura, M. Homma, J. Yamaki, M. Munakata, and Y. Homma Involvement of selenoprotein P in the regulation of redox balance and myofibroblast viability in idiopathic pulmonary fibrosis. Genes Cells, November 1, 2007; 12(11): 1235 - 1244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Scotton and R. C. Chambers Molecular Targets in Pulmonary Fibrosis: The Myofibroblast in Focus Chest, October 1, 2007; 132(4): 1311 - 1321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kono, T. Nishiuma, Y. Nishimura, Y. Kotani, T. Okada, S.-i. Nakamura, and M. Yokoyama Sphingosine Kinase 1 Regulates Differentiation of Human and Mouse Lung Fibroblasts Mediated by TGF-beta1 Am. J. Respir. Cell Mol. Biol., October 1, 2007; 37(4): 395 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. O. Rosas, P. Ren, N. A. Avila, C. K. Chow, T. J. Franks, W. D. Travis, J. P. McCoy Jr., R. M. May, H.-P. Wu, D. M. Nguyen, et al. Early Interstitial Lung Disease in Familial Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 698 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Hunninghake and M. I. Schwarz State of the Art. Does Current Knowledge Explain the Pathogenesis of Idiopathic Pulmonary Fibrosis?: A Perspective Proceedings of the ATS, August 15, 2007; 4(5): 449 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Liu, A. M. Das, J. Seideman, D. Griswold, C. N. Afuh, T. Kobayashi, S. Abe, Q. Fang, M. Hashimoto, H. Kim, et al. The CC Chemokine Ligand 2 (CCL2) Mediates Fibroblast Survival through IL-6 Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 121 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Mueller-Mang, C. Grosse, K. Schmid, L. Stiebellehner, and A. A. Bankier What Every Radiologist Should Know about Idiopathic Interstitial Pneumonias RadioGraphics, May 1, 2007; 27(3): 595 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. U. Wells and C. M. Hogaboam Update in Diffuse Parenchymal Lung Disease 2006 Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 655 - 660. [Full Text] [PDF]
|
|
|
|
|
|
K. Hamada, S. Nagai, S. Tanaka, T. Handa, M. Shigematsu, T. Nagao, M. Mishima, M. Kitaichi, and T. Izumi Significance of Pulmonary Arterial Pressure and Diffusion Capacity of the Lung as Prognosticator in Patients With Idiopathic Pulmonary Fibrosis Chest, March 1, 2007; 131(3): 650 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. O. Villalba, P. D. Sampaio-Barros, M. C. Pereira, E. M. F. P. Cerqueira, C. A. Leme Jr, J. F. Marques-Neto, and I. A. Paschoal Six-Minute Walk Test for the Evaluation of Pulmonary Disease Severity in Scleroderma Patients Chest, January 1, 2007; 131(1): 217 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Greenlee, Z. Werb, and F. Kheradmand Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted Physiol Rev, January 1, 2007; 87(1): 69 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L Tiitto, R Bloigu, U Heiskanen, P Paakko, V L Kinnula, and R Kaarteenaho-Wiik Relationship between histopathological features and the course of idiopathic pulmonary fibrosis/usual interstitial pneumonia Thorax, December 1, 2006; 61(12): 1091 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gauldie, M. Kolb, K. Ask, G. Martin, P. Bonniaud, and D. Warburton Smad3 Signaling Involved in Pulmonary Fibrosis and Emphysema Proceedings of the ATS, November 1, 2006; 3(8): 696 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Flaherty, A.-C. Andrei, S. Murray, C. Fraley, T. V. Colby, W. D. Travis, V. Lama, E. A. Kazerooni, B. H. Gross, G. B. Toews, et al. Idiopathic Pulmonary Fibrosis: Prognostic Value of Changes in Physiology and Six-Minute-Walk Test Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 803 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Nakagome, M Dohi, K Okunishi, R Tanaka, J Miyazaki, and K Yamamoto In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-{beta} in the lung Thorax, October 1, 2006; 61(10): 886 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Kelly, R. Leigh, S. E. Gilpin, E. Cheng, G. E. M. Martin, K. Radford, G. Cox, and J. Gauldie Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 557 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. du Bois Fibroblastic foci: time to be counted? Chest, July 1, 2006; 130(1): 3 - 5. [Full Text] [PDF]
|
|
|
|
|
|
N. Enomoto, T. Suda, M. Kato, Y. Kaida, Y. Nakamura, S. Imokawa, M. Ida, and K. Chida Quantitative analysis of fibroblastic foci in usual interstitial pneumonia. Chest, July 1, 2006; 130(1): 22 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Lettieri, S. D. Nathan, S. D. Barnett, S. Ahmad, and A. F. Shorr Prevalence and Outcomes of Pulmonary Arterial Hypertension in Advanced Idiopathic Pulmonary Fibrosis Chest, March 1, 2006; 129(3): 746 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kuwano PTEN as a New Agent in the Fight against Fibrogenesis Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 5 - 6. [Full Text] [PDF]
|
|
|
|
|
|
D. S. Kim, H. R. Collard, and T. E. King Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proceedings of the ATS, January 1, 2006; 3(4): 285 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Martinez and K. Flaherty Pulmonary function testing in idiopathic interstitial pneumonias. Proceedings of the ATS, January 1, 2006; 3(4): 315 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Visscher and J. L. Myers Histologic spectrum of idiopathic interstitial pneumonias. Proceedings of the ATS, January 1, 2006; 3(4): 322 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. N. Lama and S. H. Phan The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proceedings of the ATS, January 1, 2006; 3(4): 373 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Willis, R. M. duBois, and Z. Borok Epithelial Origin of Myofibroblasts during Fibrosis in the Lung. Proceedings of the ATS, January 1, 2006; 3(4): 377 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E S Choi, E M Pierce, C Jakubzick, K J Carpenter, S L Kunkel, H Evanoff, F J Martinez, K R Flaherty, B B Moore, G B Toews, et al. Focal interstitial CC chemokine receptor 7 (CCR7) expression in idiopathic interstitial pneumonia J. Clin. Pathol., January 1, 2006; 59(1): 28 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Doran and J. J. Egan Herpesviruses: a cofactor in the pathogenesis of idiopathic pulmonary fibrosis? Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L709 - L710. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Bouros and K. M. Antoniou Current and future therapeutic approaches in idiopathic pulmonary fibrosis Eur. Respir. J., October 1, 2005; 26(4): 693 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A Pacanowski and G. W Amsden Interferon Gamma-1b in the Treatment of Idiopathic Pulmonary Fibrosis Ann. Pharmacother., October 1, 2005; 39(10): 1678 - 1686. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Grijm, H. J. Verberne, F. H. Krouwels, F. R. Weller, H. M. Jansen, and P. Bresser Semiquantitative 67Ga Scintigraphy as an Indicator of Response to and Prognosis After Corticosteroid Treatment in Idiopathic Interstitial Pneumonia J. Nucl. Med., September 1, 2005; 46(9): 1421 - 1426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Noble and R. J. Homer Back to the Future: Historical Perspective on the Pathogenesis of Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., August 1, 2005; 33(2): 113 - 120. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Hagood, P. Prabhakaran, P. Kumbla, L. Salazar, M. W. MacEwen, T. H. Barker, L. A. Ortiz, T. Schoeb, G. P. Siegal, C. B. Alexander, et al. Loss of Fibroblast Thy-1 Expression Correlates with Lung Fibrogenesis Am. J. Pathol., August 1, 2005; 167(2): 365 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Chunn, J. G. Molina, T. Mi, Y. Xia, R. E. Kellems, and M. R. Blackburn Adenosine-Dependent Pulmonary Fibrosis in Adenosine Deaminase-Deficient Mice J. Immunol., August 1, 2005; 175(3): 1937 - 1946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. King Jr. Clinical Advances in the Diagnosis and Therapy of the Interstitial Lung Diseases Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 268 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Lynch, W. D. Travis, N. L. Muller, J. R. Galvin, D. M. Hansell, P. A. Grenier, and T. E. King Jr Idiopathic Interstitial Pneumonias: CT Features Radiology, July 1, 2005; 236(1): 10 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Halkos, A. A. Gal, F. Kerendi, D. L. Miller, and J. I. Miller Jr Role of Thoracic Surgeons in the Diagnosis of Idiopathic Interstitial Lung Disease Ann. Thorac. Surg., June 1, 2005; 79(6): 2172 - 2179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Lee, J. H. Ryu, M. H. Wittmer, T. E. Hartman, J. F. Lymp, H. D. Tazelaar, and A. H. Limper Familial Idiopathic Pulmonary Fibrosis: Clinical Features and Outcome Chest, June 1, 2005; 127(6): 2034 - 2041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Eaton, P. Young, D. Milne, and A. U. Wells Six-Minute Walk, Maximal Exercise Tests: Reproducibility in Fibrotic Interstitial Pneumonia Am. J. Respir. Crit. Care Med., May 15, 2005; 171(10): 1150 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Azuma, T. Nukiwa, E. Tsuboi, M. Suga, S. Abe, K. Nakata, Y. Taguchi, S. Nagai, H. Itoh, M. Ohi, et al. Double-blind, Placebo-controlled Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., May 1, 2005; 171(9): 1040 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bonniaud, P. J. Margetts, M. Kolb, J. A. Schroeder, A. M. Kapoun, D. Damm, A. Murphy, S. Chakravarty, S. Dugar, L. Higgins, et al. Progressive Transforming Growth Factor {beta}1-induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 889 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Watts, E. M. Sampson, G. S. Schultz, and M. A. Spiteri Simvastatin Inhibits Growth Factor Expression and Modulates Profibrogenic Markers in Lung Fibroblasts Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 290 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ito, S. Nagai, M. Kitaichi, A. G. Nicholson, T. Johkoh, S. Noma, D. S. Kim, T. Handa, T. Izumi, and M. Mishima Pulmonary Manifestations of Primary Sjogren's Syndrome: A Clinical, Radiologic, and Pathologic Study Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 632 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. B. Moore, J. E. Kolodsick, V. J. Thannickal, K. Cooke, T. A. Moore, C. Hogaboam, C. A. Wilke, and G. B. Toews CCR2-Mediated Recruitment of Fibrocytes to the Alveolar Space after Fibrotic Injury Am. J. Pathol., March 1, 2005; 166(3): 675 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Vittal, J. C. Horowitz, B. B. Moore, H. Zhang, F. J. Martinez, G. B. Toews, T. J. Standiford, and V. J. Thannickal Modulation of Prosurvival Signaling in Fibroblasts by a Protein Kinase Inhibitor Protects against Fibrotic Tissue Injury Am. J. Pathol., February 1, 2005; 166(2): 367 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Pilewski, L. Liu, A. C. Henry, A. V. Knauer, and C. A. Feghali-Bostwick Insulin-Like Growth Factor Binding Proteins 3 and 5 Are Overexpressed in Idiopathic Pulmonary Fibrosis and Contribute to Extracellular Matrix Deposition Am. J. Pathol., February 1, 2005; 166(2): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Hallstrand, L. J. Boitano, W. C. Johnson, C. A. Spada, J. G. Hayes, and G. Raghu The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis Eur. Respir. J., January 1, 2005; 25(1): 96 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Swigris, W. G. Kuschner, J. L. Kelsey, and M. K. Gould Idiopathic Pulmonary Fibrosis: Challenges and Opportunities for the Clinician and Investigator Chest, January 1, 2005; 127(1): 275 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhou, R. Song, C. L. Fattman, S. Greenhill, S. Alber, T. D. Oury, A. M.K. Choi, and D. Morse Carbon Monoxide Suppresses Bleomycin-Induced Lung Fibrosis Am. J. Pathol., January 1, 2005; 166(1): 27 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kitasato, T. Hoshino, M. Okamoto, S. Kato, Y. Koda, N. Nagata, M. Kinoshita, H. Koga, D.-Y. Yoon, H. Asao, et al. Enhanced Expression of Interleukin-18 and its Receptor in Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., December 1, 2004; 31(6): 619 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. Wynes, S. K. Frankel, and D. W. H. Riches IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal J. Leukoc. Biol., November 1, 2004; 76(5): 1019 - 1027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Clement and committee members Task force on chronic interstitial lung disease in immunocompetent children Eur. Respir. J., October 1, 2004; 24(4): 686 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Desai, S. Veeraraghavan, D. M. Hansell, A. Nikolakopolou, N. S. L. Goh, A. G. Nicholson, T. V. Colby, C. P. Denton, C. M. Black, R. M. du Bois, et al. CT Features of Lung Disease in Patients with Systemic Sclerosis: Comparison with Idiopathic Pulmonary Fibrosis and Nonspecific Interstitial Pneumonia Radiology, August 1, 2004; 232(2): 560 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakubzick, E. S. Choi, K. J. Carpenter, S. L. Kunkel, H. Evanoff, F. J. Martinez, K. R. Flaherty, G. B. Toews, T. V. Colby, W. D. Travis, et al. Human Pulmonary Fibroblasts Exhibit Altered Interleukin-4 and Interleukin-13 Receptor Subunit Expression in Idiopathic Interstitial Pneumonia Am. J. Pathol., June 1, 2004; 164(6): 1989 - 2001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Hill, O. Fruchter, M. D. Eisner, P. G. Tsoutsou, K. I. Gourgoulianis, J. S. Vourlekis, L. Richeldi, G. Raghu, T. E. King Jr., and A. S. Teirstein Interferon Gamma-1b for Pulmonary Fibrosis N. Engl. J. Med., April 22, 2004; 350(17): 1794 - 1797. [Full Text] [PDF]
|
|
|
|
|
|
D. S. Zander Idiopathic Interstitial Pneumonias and the Concept of the Trump Card Chest, February 1, 2004; 125(2): 359 - 360. [Full Text] [PDF]
|
|
|
|
|
|
H. Monaghan, A. U. Wells, T. V. Colby, R. M. du Bois, D. M. Hansell, and A. G. Nicholson Prognostic Implications of Histologic Patterns in Multiple Surgical Lung Biopsies From Patients With Idiopathic Interstitial Pneumonias Chest, February 1, 2004; 125(2): 522 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. N. Lama, K. R. Flaherty, G. B. Toews, T. V. Colby, W. D. Travis, Q. Long, S. Murray, E. A. Kazerooni, B. H. Gross, J. P. Lynch III, et al. Prognostic Value of Desaturation during a 6-Minute Walk Test in Idiopathic Interstitial Pneumonia Am. J. Respir. Crit. Care Med., November 1, 2003; 168(9): 1084 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chiyo, Y. Sekine, T. Iwata, K. Tatsumi, K. Yasufuku, A. Iyoda, M. Otsuji, S. Yoshida, K. Shibuya, T. Iizasa, et al. Impact of interstitial lung disease on surgical morbidity and mortality for lung cancer: analyses of short-term and long-term outcomes J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1141 - 1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Kamp Idiopathic Pulmonary Fibrosis: The Inflammation Hypothesis Revisited Chest, October 1, 2003; 124(4): 1187 - 1190. [Full Text] [PDF]
|
|
|
|
|
|
J. Cisneros-Lira, M. Gaxiola, C. Ramos, M. Selman, and A. Pardo Cigarette smoke exposure potentiates bleomycin-induced lung fibrosis in guinea pigs Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L949 - L956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. Shorr, D. B. Davies, and S. D. Nathan Predicting Mortality in Patients With Sarcoidosis Awaiting Lung Transplantation Chest, September 1, 2003; 124(3): 922 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Ross The Clinical Diagnosis of Asbestosis in This Century Requires More Than a Chest Radiograph Chest, September 1, 2003; 124(3): 1120 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]
|
|
|
|
|
|
H. R. Collard, T. E. King Jr., B. B. Bartelson, J. S. Vourlekis, M. I. Schwarz, and K. K. Brown Changes in Clinical and Physiologic Variables Predict Survival in Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 538 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Flaherty, J. A. Mumford, S. Murray, E. A. Kazerooni, B. H. Gross, T. V. Colby, W. D. Travis, A. Flint, G. B. Toews, J. P. Lynch III, et al. Prognostic Implications of Physiologic and Radiographic Changes in Idiopathic Interstitial Pneumonia Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 543 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. I. Latsi, R. M. du Bois, A. G. Nicholson, T. V. Colby, D. Bisirtzoglou, A. Nikolakopoulou, S. Veeraraghavan, D. M. Hansell, and A. U. Wells Fibrotic Idiopathic Interstitial Pneumonia: The Prognostic Value of Longitudinal Functional Trends Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 531 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Thabut, H. Mal, Y. Castier, O. Groussard, O. Brugiere, R. Marrash-Chahla, G. Leseche, and M. Fournier Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis J. Thorac. Cardiovasc. Surg., August 1, 2003; 126(2): 469 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Flaherty, T. V. Colby, W. D. Travis, G. B. Toews, J. Mumford, S. Murray, V. J. Thannickal, E. A. Kazerooni, B. H. Gross, J. P. Lynch III, et al. Fibroblastic Foci in Usual Interstitial Pneumonia: Idiopathic versus Collagen Vascular Disease Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1410 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. R. Collard and T. E. King Jr Demystifying Idiopathic Interstitial Pneumonia Arch Intern Med, January 13, 2003; 163(1): 17 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Gong and E. J. Mark Case 40-2002 - A 56-Year-Old Man with Rapidly Worsening Dyspnea N. Engl. J. Med., December 26, 2002; 347(26): 2149 - 2157. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Tobin Compliance (COMmunicate PLease wIth Less Abbreviations, Noun Clusters, and Exclusiveness) Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1534 - 1536. [Full Text] [PDF]
|
|
|
|
|
|
A. G. Nicholson, L. G. Fulford, T. V. Colby, R. M. du Bois, D. M. Hansell, and A. U. Wells The Relationship between Individual Histologic Features and Disease Progression in Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., July 15, 2002; 166(2): 173 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Hagood, A. Mangalwadi, B. Guo, M. W. MacEwen, L. Salazar, and G. M. Fuller Concordant and Discordant Interleukin-1-Mediated Signaling in Lung Fibroblast Thy-1 Subpopulations Am. J. Respir. Cell Mol. Biol., June 1, 2002; 26(6): 702 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Khoshnevis, T. E. King Jr., and J. Tooze Histopathology and prediction of survival in usual interstitial pneumonia Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1451 - 1452. [Full Text] [PDF]
|
|
|
|
|
|
J. Gauldie Inflammatory Mechanisms Are a Minor Component of the Pathogenesis of Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1205 - 1206. [Full Text] [PDF]
|
|
|
|
|
|
R. M. Strieter Inflammatory Mechanisms Are Not a Minor Component of the Pathogenesis of Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1206 - 1207. [Full Text] [PDF]
|
|
|
|
|
|
M. J. TOBIN Tuberculosis, Lung Infections, Interstitial Lung Disease, and Socioeconomic Issues in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 631 - 641. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |