© 2002 American Thoracic Society
Acute Interstitial PneumoniaComparison of High-Resolution Computed Tomography Findings between Survivors and NonsurvivorsFirst Department of Internal Medicine and Department of Radiology, Kumamoto University School of Medicine, Kumamoto; Department of Respiratory Medicine, Tosei General Hospital, Seto, Aichi; Department of Radiology, National Kinki chuo Hospital for Chest Disease, Sakai City; Department of Radiology, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Radiology, Vancouver Hospital and Health Sciences Center and University of British Columbia, Vancouver, British Columbia, Canada Correspondence and requests for reprints should be addressed to Kazuya Ichikado, M.D., Ph.D., First Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860-0811, Japan. E-mail: ichikado{at}kaiju.medic.kumamoto-u.ac.jp
This study compared high-resolution computed tomography (CT) findings between 10 survivors and 21 nonsurvivors of acute interstitial pneumonia and evaluated whether the CT findings were predictive of patients' response to treatment. The survivor and nonsurvivor groups with pathologically or clinically diagnosed acute interstitial pneumonia were similar in age, sex, disease duration, and lung injury score. Retrospective, subjective evaluations of the CT scans were conducted by two independent observers without knowledge of patient outcomes. CT findings were graded on a one to six scale corresponding to consecutive pathologic phases as follows: areas of (1) normal attenuation, (2) ground-glass attenuation, (3) consolidation, (4) ground-glass attenuation associated with traction bronchiolectasis or bronchiectasis, (5) consolidation associated with traction bronchiolectasis or bronchiectasis, and (6) honeycombing. An overall score was obtained by quantifying the extent of each abnormality in three lung zones in each lung. The extent of ground-glass attenuation or consolidation associated with traction bronchiolectasis or bronchiectasis was less in survivors than nonsurvivors (p = 0.004 and p = 0.009, respectively). Architectural distortion was less frequent, and ground-glass attenuation or consolidation without traction bronchiolectasis or bronchiectasis was more extensive in survivors than in nonsurvivors (p = 0.007, p = 0.002, and p = 0.029, respectively). Overall CT scores of survivors were significantly lower than those of nonsurvivors (p = 0.0003). A CT score of less than 245 had an 80% positive and a 90% negative predictive value for survival. There was good interobserver agreement in the assessment of the CT findings (Kappa 0.75). The results indicate that CT assessment is potentially helpful in predicting patient prognosis in acute interstitial pneumonia regardless of the degree of physiologic abnormality.
Key Words: high-resolution computed tomography • acute interstitial pneumonia • diffuse alveolar damage • high-dose corticosteroid therapy
Acute interstitial pneumonia (AIP) is a rapidly progressive condition of unknown cause that occurs in a previously healthy individual and produces the histologic findings of diffuse alveolar damage (1). Because of its acute presentation and histologic features similar to those of acute respiratory distress syndrome (ARDS), AIP has been considered an idiopathic form of ARDS (1, 2). The pathologic hallmark of AIP is the presence of diffuse alveolar damage, which as in ARDS can be categorized into three phases: the acute exudative, subacute proliferative, and chronic fibrotic phases (3–6). Determination of these phases is dependent on the timing of the lung biopsy in relationship to the original lung insult, and combinations of these features are often seen from field to field throughout the lung. After investigating the histology from open-lung biopsy in 12 survivors and 12 nonsurvivors of AIP, Olson and colleagues (2) concluded that no histopathologic feature was predictive of prognosis. Bilateral areas of ground-glass attenuation with or without airspace consolidation, architectural distortion, or traction bronchiectasis were seen on high-resolution computed tomography (HRCT) scans in patients with AIP (7, 8). Ichikado and colleagues (9, 10) observed that certain HRCT findings correlate with the stages of diffuse alveolar damage. Although they detected areas of ground-glass attenuation and consolidation in the acute exudative as well as in the proliferative and fibrotic phases, architectural distortion and traction bronchiectasis or bronchiolectasis were almost invariably associated with the late proliferative or fibrotic phases of AIP. Furthermore, they emphasized the ability of HRCT to assess the overall pathologic stage, an ability that is a major advantage over open-lung biopsy. The aim of this study was to compare the HRCT findings between survivors and nonsurvivors of AIP and to evaluate whether HRCT findings were predictive for patient prognosis in AIP.
Patients Thirty-one patients with histopathologically or clinically diagnosed AIP who had undergone an HRCT scan at one of our five institutions were included in this study. The 18 men and 13 women ranged in age from 29 to 77 years (mean, 60.4 ± 11.1). Seven of the 31 cases were previously reported by the authors (9). These patients with prolonged respiratory failure of unknown etiology had shown bilateral infiltrates on conventional radiographs. The CT scans were obtained to evaluate evidence of reversible complications that may be contributing to the respiratory compromise. Only patients who had been previously healthy, had no known predisposing factors for lung disease such as collagen vascular diseases, and presented no apparent cause for the development of diffuse alveolar damage were included in the study. The pathologic diagnosis of AIP was made by open-lung biopsy in 10 patients and by autopsy in 17 patients. Open-lung biopsy was performed on the day of the CT examination in eight patients; the remaining two patients underwent lung biopsy 6 or 10 days after the CT scans because they were considered too ill to tolerate the surgical procedure on the day of the CT scans. No evidence of viral, bacterial, or fungal infection was found in the pathologic specimens. The remaining four patients were too ill to undergo lung biopsy and were clinically diagnosed. All patients fulfilled the clinical or pathologic criteria of AIP described by Katzenstein and colleagues (1). All patients had an acute onset of symptoms, severe hypoxia, diffuse pulmonary infiltrates on the chest radiograph, and no sign of cardiac failure. All patients had moderate to severe lung injury scores (1.5–4.0; mean, 3.1 ± 0.6) as described by Murray and colleagues (11) and required mechanical ventilation. The lung injury score, which is based on radiologic and physiologic parameters of severity of lung injury, consists of a chest radiographic score of disease extent and a hypoxia score (PaO2/FIO2). A score between 0.1 and 2.5 indicates mild to moderate lung injury, and a score of greater than 2.5 indicates severe injury and a diagnosis of ARDS. All patients received high-dose intravenous corticosteroid (methylprednisolone, 1–2 g/day) for three days after the possibility of infection was ruled out by cultures of sputum and serum titers against Mycoplasma, Chlamydia, and various viruses. Corticosteroid therapy was followed by a tapered dosage and was combined with intravenous or oral administration of cyclophosphamide with the choice dependent on the patient's pulmonary physiologic response. Ten of the 31 patients responded to medical treatment and survived, and the remaining 21 patients died of respiratory failure within 2 weeks to 6 months despite intensive treatment. The 10 survivors included 7 patients who were pathologically proven to have AIP and 3 who were clinically diagnosed. One of the 21 nonsurvivors was clinically diagnosed without a lung biopsy. Ten survivors were followed for 2 to 42 months (mean 18 months).
CT Examination
CT Assessment
Scoring of CT Findings
Data Analysis To analyze the CT score as a predictor of survival, the highest value within the 95% confidence interval for mean CT score from patients who survived was used as a cutoff CT value for distinction between survivors and nonsurvivors. Standard formulas were used to calculate a positive predictive value, a negative predictive value, sensitivity, and specificity.
Patient Characteristics A comparison of background factors such as age, sex, disease duration from the onset of symptoms to CT scans, and lung injury score at the time of CT examination between survivors and nonsurvivors of AIP is summarized in Table 1. Age, sex, duration of symptoms, and lung injury score at the time of CT examination were not significantly different between survivors and nonsurvivors (all p > 0.05).
CT Findings The frequency of each CT finding in survivors and nonsurvivors is summarized in Table 2. Architectural distortion was more commonly seen in nonsurvivors than in survivors (p = 0.007; Figure 1) . Bronchiolectasis and bronchiectasis tended to be more common in nonsurvivors than in survivors, but the differences were not statistically significant (p = 0.09 and p = 0.24, respectively; Figure 2) . The frequencies of areas of ground-glass attenuation, airspace consolidation, interlobular septal thickening, intralobular reticular opacities, and honeycombing were not significantly different between survivors and nonsurvivors.
The extent of either ground-glass attenuation or air-space consolidation combined with traction bronchiolectasis or bronchiectasis was less in survivors than in nonsurvivors (p = 0.004 and p = 0.009, respectively; Table 3 and Figure 1). In contrast, the extent of ground-glass attenuation or of air-space consolidation without traction bronchiolectasis or bronchiectasis was greater in survivors than in nonsurvivors (p = 0.002 and p = 0.029, respectively; Figure 3) . No significant difference was found in the extent of other parenchymal abnormalities.
The overall CT scores of survivors (mean ± SD, 223.5 ± 33.2) were significantly lower than those of nonsurvivors (324.2 ± 55.7, p = 0.0003; Figure 4) . The range of CT scores in survivors was 176.7 to 288.4. To analyze the predictive value of a CT score in terms of survival, we used a cutoff score of 245, which was the highest value within the 95% confidence interval for mean CT score from survivors. Using this cutoff for survival, the sensitivity for predicting survival was 80%, with a specificity of 90%. The positive predictive value for survival of a CT score (less than 245) was 80%, and the negative predictive value was 90% (Table 4).
The observers showed good agreement in their evaluations of the presence of lung abnormalities (Kappa statistic 0.75). Their assessments of the extent of CT findings also correlated well (Spearman rank correlation coefficient, r = 0.78, p < 0.01). Four of the 21 nonsurvivors underwent follow-up CT scans. The follow-up scans of all four showed diffuse ground-glass attenuation, with or without consolidation, associated with traction bronchiectasis and bronchiolectasis and with small cystic lesions.
In this study, we found that HRCT scans showing abnormalities that suggested the fibroproliferative phase of diffuse alveolar damage predicted poor outcome in our patients with AIP. Ichikado and colleagues (9, 10) compared HRCT findings with histopathologic findings of diffuse alveolar damage and detected a close correlation between CT findings and pathologic phases of diffuse alveolar damage. They determined that patients who had areas of increased attenuation (ground-glass attenuation or airspace consolidation) associated with traction bronchiectasis on CT scans had histologic findings of the late proliferative or fibrotic phases of diffuse alveolar damage, whereas patients who had ground-glass attenuation or consolidation without traction bronchiectasis had histologic features of the exudative or early proliferative phases of diffuse alveolar damage. Lamy and associates (12) correlated the histologic findings at open-lung biopsy or autopsy with prognosis in 45 patients with ARDS. They reported that patients who had extensive parenchymal abnormalities or histologic evidence of extensive fibrosis detected in open-lung biopsy specimens had a worse prognosis than that of patients with predominantly early exudative changes. Similarly, in this study, patients with CT findings suggestive of the late proliferative or fibrotic phases, including architectural distortion and areas of increased attenuation with associated bronchiectasis or bronchiolectasis, were less likely to survive than were patients without evidence of fibroproliferation. Because patients with AIP are often too ill to tolerate surgical lung biopsy, the ability to assess the overall pathologic stage by a noninvasive method such as HRCT would be useful for planning treatment strategies and determining prognosis. As Lamy and colleagues (12) described, the presence of extensive fibrosis on biopsy specimens appears to be associated with the greatest risk of mortality, but in their study, 3 of 13 such patients with ARDS survived with minimal or no residual functional abnormalities. Therefore, even the presence of traction bronchiolectasis or bronchiectasis or architectural distortion suggestive of progression to fibroproliferative diffuse alveolar damage should not preclude continuous treatment with aggressive support measures. Recently, in studies of ARDS patients conducted by Meduri and colleagues (13–15), corticosteroids were found to accelerate the repair processes during the proliferative phase of diffuse alveolar damage and to be most effective during the early proliferative phase before the development of acellular fibrosis with deranged alveolar architecture, which is seen in the late proliferative and the fibrotic phases. In this study, all of our patients with AIP were treated with high-dose methylprednisolone, and we also found corticosteroids to be effective for patients who had limited areas of CT abnormalities suggestive of the late proliferative or fibrotic phases. The results of our present AIP patients with idiopathic cases of ARDS were compatible with those of Meduri and colleagues (13–15). To examine the relationship between the response to corticosteroid and overall disease stage of diffuse alveolar damage evaluated by HRCT scans, further investigation should include a general study of ARDS caused by various etiologic agents such as infection or drug. In this study, we chose the lung injury score of Murray and colleagues (11) to quantify as accurately as possible the degree of physiologic or radiographic abnormality at the time of CT examination. However, we did not find any significant differences in disease duration or lung injury score at the time of CT examination between survivors and nonsurvivors in our patients with AIP. This result shows that the severity of impairment of arterial oxygenation or the extent of opacity on a chest radiograph may not necessarily reflect the prognosis of patients with AIP. Regardless of the difference in CT findings between survivors and nonsurvivors, one possible reason for the lack of significant difference of disease duration at the time of CT scans may be the difficulty in accurately identifying the onset of lung injury. In the Fracica and colleagues (16) examination of pathologic and physiologic features of diffuse alveolar damage/ARDS in baboons, they observed no significant changes in cardiopulmonary physiologic parameters after periods of more than 60 hours of excess oxygen exposure. Our experimental study also showed that the early exudative changes of diffuse alveolar damage induced by hyperoxia were not specifically detected on HRCT scans (10, 17). Our results and those of Lamy and associates (12) differ from those of Olson and colleagues (2) and Vourlekis and colleagues (18), who detected no significant differences in histologic findings at open-lung biopsy between survivors and nonsurvivors of AIP. As those authors acknowledged, a limitation of their studies was the potential sampling error because the findings were obtained with relatively small biopsy specimens that may not accurately reflect the overall pattern and extent of parenchymal abnormalities. A major advantage of HRCT over open-lung biopsy is the ability to assess the entire lung rather than relying on a small biopsy specimen. Therefore, in our study, CT scores were used to quantify as accurately as possible the overall extent or severity of disease, and these scores showed significant differences between survivors and nonsurvivors in our patients with AIP. Furthermore, the cutoff value for the CT score, which was the highest value for the 95% confidence interval for mean CT score from survivors, had prognostic value for survival, with a positive predictive value of 80% and a negative predictive value of 90%. Our study has two main limitations. It is retrospective, and the sample included a small proportion of survivors. The reported mortality rate of AIP is approximately 60–75% (1, 2, 19). It is not surprising, therefore, that we could identify only a small number of patients who survived the disease. Further investigation is required to determine the reliability of CT findings for predicting prognosis in patients with AIP. In conclusion, our results suggest that patients with AIP who have CT findings suggestive of the fibroproliferative phase of diffuse alveolar damage, particularly findings of architectural distortion, and ground-glass attenuation or consolidation associated with traction bronchiectasis, have a worse prognosis than do patients without these findings.
This work was supported by a grant-in-aid for interstitial lung diseases from the Japanese Ministry of Health and Welfare, and a grant-in-aid for scientific research 12670565 from the Japanese Ministry of Education, Culture, Sports, Science and Technology. Received in original form June 29, 2001; accepted in final form March 5, 2002
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