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* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Ryu, Douglas, and Vassallo) and Biostatistics (Mr. Decker), and the Department of Laboratory Medicine and Pathology (Dr. Myers), Mayo Clinic, Rochester, MN; and the Baptist Hospital (Dr. Capizzi), Nashville, TN.
Correspondence to: Jay H. Ryu, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Desk East 18, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail ryu.jay{at}mayo.edu
| Abstract |
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Study objectives: To further characterize the clinical features and course of subjects with DIP and RB-ILD.
Design: Retrospective study.
Setting: Tertiary care, referral medical center.
Patients: Twenty-three subjects with DIP and 12 subjects with RB-ILD seen over a 12-year period between 1990 and 2001.
Interventions: None.
Results: The study population included 19 men (54%) and 16 women (46%). The mean (± SD) age at diagnosis was 46 ± 10 and 43 ± 7 years, respectively, for patients with DIP and RB-ILD. All subjects were either current or previous smokers except for three subjects with DIP. The diagnosis was confirmed in all cases by surgical lung biopsy. Bronchoscopy with transbronchial lung biopsy had been performed in 12 patients and was nondiagnostic in all. The most common pulmonary function abnormality was a reduced diffusing capacity of the lung for carbon monoxide. A CT scan of the chest revealed ground-glass opacities bilaterally in most patients who had DIP and RB-ILD. No differences were observed between subjects with DIP and RB-ILD with respect to clinical features, radiologic findings, or pulmonary function test results. The clinical course was characterized by relative stability in the majority of patients in both groups and a partial response to corticosteroid therapy. Five deaths were observed, including three resulting from progressive diffuse lung disease, all in subjects with DIP.
Conclusions: We concluded that DIP and RB-ILD are chronic disease processes that in most patients are related to smoking. Persistent abnormalities can be seen on pulmonary function testing and radiologic studies despite smoking cessation and corticosteroid therapy. Corticosteroid therapy appeared to be associated with modest clinical benefit but usually not with resolution of disease. Progressive disease with eventual death can occur in subjects with DIP, especially with continued cigarette smoking.
Key Words: desquamative interstitial pneumonia interstitial lung disease respiratory bronchiolitis
| Introduction |
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In an effort to further characterize these two disorders, we identified 35 patients with clinicoradiologic evidence of interstitial lung disease (ILD) and DIP or RB-ILD patterns identified on lung biopsy specimens. We examined the clinical and radiologic presentation of these subjects, as well as their clinical course.
| Materials and Methods |
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RB-ILD was defined by the presence of clinical and radiologic evidence of ILD occurring in a patient with histologically proven respiratory bronchiolitis (RB) seen on a surgical lung biopsy specimen. The histologic diagnosis of RB required the presence of yellow-brown-pigmented macrophages in the lumens of respiratory bronchioles, alveolar ducts, and peribronchiolar alveolar spaces without significant associated interstitial pneumonia. Similarly, DIP was diagnosed in patients with clinical and radiologic evidence of ILD, and a histologic pattern of DIP on surgical lung biopsy specimens. Several investigators45910 have highlighted the histologic overlap between RB and DIP. For the purposes of our study, DIP was defined by the presence of pigmented macrophages diffusely involving alveolar spaces in at least one low-magnification field (x40) without a bronchiolocentric distribution and accompanied by diffuse alveolar septal thickening due to alveolar septal inflammation with or without fibrosis. Patients with incidental RB or DIP noted on their lung specimen obtained for an unrelated purpose (eg, lung cancer resection) were excluded from this study.
Medical records were examined in detail to gather clinical, radiologic, and pulmonary function data at presentation. Follow-up data regarding their clinical course, results of subsequent radiologic and pulmonary function studies, response to treatment, and clinical outcome also were extracted. The eventual clinical outcome was assessed at the time of the last available follow-up visit and was categorized as improved, stable, or worsened using the criteria published in a American Thoracic Society (ATS)/European Respiratory Society (ERS) statement.11 These criteria include the assessment of changes in respiratory symptoms, radiologic findings, and pulmonary function measurements (ie, total lung capacity, vital capacity, diffusing capacity of the lung for carbon monoxide [DLCO], and oxygen saturation or PaO2).11
Spirometry and measurements of lung volumes and DLCO were performed in our laboratory using standard techniques.12 Pulmonary function data included plethysmographically determined total lung capacity, FVC, FEV1, FEV1/FVC ratio, and DLCO.
This study was approved by the Mayo Foundation institutional review board. Patients who did not authorize the use of their medical records for research were excluded from this study (two patients).
Statistical Analysis
Patient characteristics were compared between groups using the two-sample rank sum test for continuous variables and an exact test for categoric variables. The log-rank test was used to compare the survival of groups of patients. In all cases, two-tailed p values of < 0.05 were considered to be statistically significant.
| Results |
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Nineteen subjects (54%) were men and 16 subjects (46%) were women (Table 1
). The mean age at diagnosis was 46 ± 10 and 43 ± 7 years, respectively, for patients with DIP and RB-ILD. Thirty-two patients (91%) were either current or past smokers. Three subjects with DIP were nonsmokers, and no environmental exposure or underlying disease was identified in these three subjects. The most common symptoms at presentation were dyspnea (83% of all patients) followed by cough (46% of all patients). There were no significant differences when comparing the DIP and RB-ILD groups with respect to gender, age, smoking status, smoking history, or presenting symptoms (p
0.183).
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0.454). Only three patients (DIP, two patients; RB-ILD, one patient) had a repeat CT scan available after
2 years of follow-up, and all three demonstrated a relatively stable appearance of mostly ground-glass opacities with no honeycombing seen (Fig 1 ).
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| Discussion |
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The clinical and radiologic characteristics of DIP and RB-ILD are not specific. Patients generally present with an insidious onset of dyspnea and cough over a course of weeks or months. In our study population, there were no significant differences in clinical and radiologic presentation when comparing patients with DIP to those with RB-ILD. Most patients in both groups presented with chronic dyspnea and radiologic abnormalities. Inspiratory crackles were present in about one half of patients, and digital clubbing was present in one fourth of those with DIP as well as of those with RB-ILD. These findings are similar to those previously reported by other investigators.910131516
As noted in previous studies,161718192021 ground-glass opacities were the predominant finding on chest imaging by CT scan for our patients with DIP and RB-ILD. Ground-glass opacities have been shown to correlate with macrophage accumulation within the alveolar spaces and alveolar ducts.22 Reticular and consolidative opacities were uncommon. The overlap in radiologic features of DIP and RB-ILD has been described by Heyneman and colleagues,17 who concluded that RB, RB-ILD, and DIP represent varying degrees of severity of the pulmonary reaction to cigarette smoke. Our results tend to support their conclusion.
Although all of our patients who underwent CT scanning had abnormalities noted, chest radiographs demonstrated no parenchymal infiltrates in several of them. Conventional chest radiograph findings are normal in up to 22% of biopsy-proven cases of DIP.923 The higher sensitivity of CT scanning compared to chest radiography in the detection of ILDs has been well-recognized.21
The majority of our patients with DIP and RB-ILD demonstrated a stable clinical course, although radiologic abnormalities tended to persist. Several deaths occurred in patients with DIP from respiratory causes, while no deaths were observed in the RB-ILD group. Carrington and colleagues13 had previously reported a 27.5% mortality rate in a group of 40 patients with DIP who had been followed up for a mean duration of 9 years. Similarly, Yousem and colleagues9 noted a 32% mortality rate in their 36 patients with DIP, which is in contrast to no deaths being observed in 18 patients with RB-ILD. Both studies also noted "improvement" in many of their patients, most of whom had received corticosteroid therapy. Specific criteria by which this improvement was judged were not stated in either study. In addition, the durability of this response was not stated. Based on our data and those of previous reports, RB-ILD appears to be associated with a more benign clinical course compared to that of DIP.
There is some evidence to suggest that smoking cessation may suffice as the initial therapeutic maneuver for patients with RB-ILD. None of the patients in our series who quit smoking had progressive disease, but the majority also received corticosteroid therapy. Yousem and colleagues9 reported that patients with RB-ILD had "resolution of symptoms" after the cessation of smoking. How many of these subjects received corticosteroid therapy is not clear. Six patients with RB-ILD who were initially reported by Myers and colleagues2 had minimal or no symptoms on follow-up, although all but one continued to smoke. Three of these patients had been treated with corticosteroid therapy.
It remains unclear whether corticosteroid therapy favorably alters the natural history of DIP and RB-ILD, particularly since the effect of smoking status on the clinical course of patients with these disorders has not been fully delineated. The majority of DIP patients reported by Carrington et al13 and Yousem et al9 had been treated with corticosteroid therapy and appeared to experience at least temporary symptomatic improvement. The effect of smoking cessation was not specifically explored in these patients with DIP. Akira and colleagues20 described an initial decrease in ground-glass opacities in all DIP cases treated with corticosteroid therapy. In three of their cases, however, ground-glass opacities increased again despite continued treatment with "low-dose" corticosteroid therapy. The smoking status of these three patients was not stated.
Although DIP and RB-ILD are smoking-related in most subjects with these disorders, our data suggest that both of these lesions can persist for long periods even after smoking cessation and attempts at corticosteroid therapy. Fraig and colleagues24 have described the persistence of the RB after many years of smoking abstinence. Several of our patients with DIP and RB-ILD appeared to have a fluctuating course of persistent parenchymal infiltrates and pulmonary function abnormalities, which varied partly with the corticosteroid dose, months to years after smoking cessation. It seems plausible that cigarette smoke antigens or cigarette smoke-induced alterations in the lungs persist for long periods and may continue to provoke a chronic inflammatory reaction.
Due to limited follow-up in many of our patients, we were unable to adequately address the question of whether RB-ILD or DIP can progress to usual interstitial pneumonia. In three of our patients who had a follow-up CT scan after an interval of
2 years, there was no evidence of progression to honeycombing. Akira and colleagues20 studied sequential CT scans in eight patients with DIP over a mean follow-up period of 3.2 years and found no evidence of DIP progressing to usual interstitial pneumonitis. Hartman and colleagues19 noted the development of honeycombing in 1 of their 11 subjects with DIP, which was observed by serial CT scans over a period of 2 to 52 months. Although the number of subjects studied is relatively modest and follow-up data are incomplete, as in our study, on balance, there is little evidence to suggest that DIP progresses to usual interstitial pneumonitis.
We conclude that most patients with DIP or RB-ILD have a relatively stable clinical course, but deaths can occur in those with DIP. Smoking cessation is likely an important component in the management of patients with these smoking-related ILDs, but the influence of smoking on the clinical course of these patients has not been fully delineated. Some of our patients had persistent disease even with smoking cessation and corticosteroid therapy.
| Footnotes |
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This research was supported by Mayo Institutional funds and the Robert N. Brewer Family Foundation.
Received for publication May 5, 2004. Accepted for publication August 2, 2004.
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