Materials and Methods	Choose Top of pageABSTRACTMaterials and Methods <<ResultsDiscussionReferencesCITING ARTICLES

Our institutional review board approved this study. We retrospectively searched the electronic pathology records at our institution for diagnoses of UIP from 2000 to 2009. Our facility is an urban regional tertiary referral center of moderate size without a lung transplantation program. We excluded patients with connective tissue disease and those who underwent lobectomy or wedge resection for focal disease. We included only patients with HRCT (section thickness, 1.0 or 1.5 mm at 5- or 10-mm intervals with 1.0- or 1.5-mm prone sections through the lower half of the chest and also at 5- or 10-mm intervals) performed within 3 months before biopsy (n = 44). No IV contrast material was administered. These images were either acquired directly using axial scanning or reconstructed from a full volumetric helical acquisition depending on the preference of the radiologist on duty at the time of the examination. The axial scanning technique used a 10-mm scanning interval and was performed before 2006; after 2006, the helical scanning mode was used and the scanning interval was 5 mm. Patients who underwent preoperative imaging at outside institutions were excluded.

One of three pulmonary pathologists confirmed the diagnosis on the basis of review of video-assisted thoracoscopic surgery specimens obtained from two or more lobes according to American Thoracic Society-European Respiratory Society guidelines. The pathologists work together on a daily basis and freely consult one another on difficult cases; none of the final diagnostic pathology reports were ambiguous, uncertain, or suggested other possible diagnoses. One of the authors was involved with creating the 2011 consensus criteria for the histopathologic diagnosis of UIP, and these criteria were applied at the time of the original diagnoses in our cases.

Two experienced subspecialists in thoracic imaging jointly reviewed the images. They recorded findings known to occur in UIP, including ground-glass attenuation, reticulation, intralobular lines, lobular distortion, traction bronchiolectasis, and honeycombing and the distribution (upper, middle, and lower thirds of each lung and central or peripheral half) of each finding. The HRCT findings of reticulation, intralobular lines, lobular distortion, and traction bronchiolectasis all indicate underlying fibrosis and can occur together or independently; honeycombing represents severe, end-stage fibrosis with cystic destruction of lung architecture. We defined honeycombing as round subpleural cystic spaces of uniform size occurring in vertical stacks with shared walls. In contrast, we considered cystic spaces to be traction bronchi-ectasis if there was intervening lung parenchyma between the cystic spaces without shared walls. Traction bronchiectasis also typically spared the immediate subpleural lung. We classified ground-glass attenuation, hazy increased lung attenuation through which the pulmonary vessels remain visible, as either superimposed on findings of fibrosis or independent of such findings. On the basis of assessment of the entire examination, the readers also classified the abnormalities as heterogeneous (findings of variable severity and appearance alternating with more normal lung) or homogeneous (findings of similar or identical appearance, with or without intervening normal lung).

According to this initial analysis, we defined four patterns. First was classic UIP (cUIP), defined by the presence of honeycombing with lower lobe predominance (Fig. 1). Other findings of fibrosis were also present in variable extent. The second pattern was fibrosis without honeycombing (FnoH). Findings of fibrosis were present in variable amounts, but honeycombing was absent (Fig. 2). In all patients placed in either the cUIP or FnoH pattern, we required the abnormalities to be heterogeneous in appearance and distribution, reflecting the gross pathology of UIP. The third pattern was minimal fibrosis (Fmin). These patients had findings of fibrosis without traction bronchiolectasis or honeycombing (Fig. 3) or a homogeneous appearance of fibrosis without honeycombing (Fig. 4). The final pattern was ground glass opacity present (GGOp). This group had ground-glass attenuation present away from the peripheral areas of fibrosis in the more central lungs (Fig. 5). In the other patterns, ground-glass attenuation was minimal and was superimposed on the findings of fibrosis. We placed each patient into one group on the basis of the predominant pattern and assessed serial change on follow-up examinations. We reviewed the electronic medical record for outcome information.

View larger version (166K)

Fig. 1A —64-year-old man with usual interstitial pneumonia (UIP). A, Supine (A) and prone (B) high-resolution CT images show classic UIP (cUIP) pattern. There is peripheral heterogeneous fibrosis with reticulation, intralobular lines (arrowhead, A), lobular distortion, and traction bronchiolectasis (arrows). Honeycombing is present in costophrenic angle (circle, B). Ground-glass attenuation is confined to and superimposed on areas of obvious fibrosis.

View larger version (100K)

Fig. 1B —64-year-old man with usual interstitial pneumonia (UIP). B, Supine (A) and prone (B) high-resolution CT images show classic UIP (cUIP) pattern. There is peripheral heterogeneous fibrosis with reticulation, intralobular lines (arrowhead, A), lobular distortion, and traction bronchiolectasis (arrows). Honeycombing is present in costophrenic angle (circle, B). Ground-glass attenuation is confined to and superimposed on areas of obvious fibrosis.

View larger version (128K)

Fig. 1C —64-year-old man with usual interstitial pneumonia (UIP). C, Scanning power microscopy images show that lung biopsy is entirely replaced by honeycomb change with honeycomb foci measuring up to 3 mm in greatest dimension (upper left, C). Occasional fibroblast foci are present (D). H and E stain.

View larger version (200K)

Fig. 1D —64-year-old man with usual interstitial pneumonia (UIP). D, Scanning power microscopy images show that lung biopsy is entirely replaced by honeycomb change with honeycomb foci measuring up to 3 mm in greatest dimension (upper left, C). Occasional fibroblast foci are present (D). H and E stain.

View larger version (201K)

Fig. 2A —69-year-old man with usual interstitial pneumonia (UIP). A, Supine (A) and prone (B) high-resolution CT images show heterogeneous fibrosis without honeycombing (FnoH pattern). Note peripheral reticulation (circle, A), intralobular lines (arrowhead, B), lobular distortion, and traction bronchiolectasis (arrow, B). Ground-glass attenuation is confined to areas where it is superimposed on findings of fibrosis. Some lobules, rather than appearing distorted, are hyperinflated, indicating degree of air trapping (circle, B). This occurs variably in patients with UIP.

View larger version (106K)

Fig. 2B —69-year-old man with usual interstitial pneumonia (UIP). B, Supine (A) and prone (B) high-resolution CT images show heterogeneous fibrosis without honeycombing (FnoH pattern). Note peripheral reticulation (circle, A), intralobular lines (arrowhead, B), lobular distortion, and traction bronchiolectasis (arrow, B). Ground-glass attenuation is confined to areas where it is superimposed on findings of fibrosis. Some lobules, rather than appearing distorted, are hyperinflated, indicating degree of air trapping (circle, B). This occurs variably in patients with UIP.

View larger version (177K)

Fig. 2C —69-year-old man with usual interstitial pneumonia (UIP). C, Scanning power microscopy images show patchy fibrosing process with microscopic foci of honeycomb change (lower left, C). These honeycomb spaces would be too small (< 1 mm) to be apparent radiologically. Occasional fibroblast foci are present (D). H and E stains.

View larger version (186K)

Fig. 2D —69-year-old man with usual interstitial pneumonia (UIP). D, Scanning power microscopy images show patchy fibrosing process with microscopic foci of honeycomb change (lower left, C). These honeycomb spaces would be too small (< 1 mm) to be apparent radiologically. Occasional fibroblast foci are present (D). H and E stains.

View larger version (147K)

Fig. 3A —52-year-old woman with usual interstitial pneumonia. A, Supine (A) and prone (B) high-resolution CT images show minimal fibrosis (Fmin) pattern. Note peripheral reticulation with lobular distortion (arrows, A). There are intralobular lines within some of distorted lobules (circles, B). Appearance is heterogeneous, but there is no traction bronchiolectasis or honeycombing.

View larger version (117K)

Fig. 3B —52-year-old woman with usual interstitial pneumonia. B, Supine (A) and prone (B) high-resolution CT images show minimal fibrosis (Fmin) pattern. Note peripheral reticulation with lobular distortion (arrows, A). There are intralobular lines within some of distorted lobules (circles, B). Appearance is heterogeneous, but there is no traction bronchiolectasis or honeycombing.

View larger version (158K)

Fig. 4A —70-year-old woman with usual interstitial pneumonia. A, Supine (A) and prone (B) high-resolution CT (HRCT) images show mild peripheral upper lobe reticulation (A) with homogeneous reticulation, lobular distortion, intralobular line formation, and traction bronchiolectasis in lower lungs (arrows, B). Honeycombing is absent. Homogeneous appearance of HRCT findings places patient in minimal fibrosis (Fmin) category, and appearance is difficult to differentiate from that of nonspecific interstitial fibrosis.

View larger version (85K)

Fig. 4B —70-year-old woman with usual interstitial pneumonia. B, Supine (A) and prone (B) high-resolution CT (HRCT) images show mild peripheral upper lobe reticulation (A) with homogeneous reticulation, lobular distortion, intralobular line formation, and traction bronchiolectasis in lower lungs (arrows, B). Honeycombing is absent. Homogeneous appearance of HRCT findings places patient in minimal fibrosis (Fmin) category, and appearance is difficult to differentiate from that of nonspecific interstitial fibrosis.

View larger version (157K)

Fig. 4C —70-year-old woman with usual interstitial pneumonia. C, Scanning power microscopy images show patchy chronic scarring with architectural distortion without obvious honeycomb change (C). Occasional fibroblast foci are present (D). H and E stain.

View larger version (180K)

Fig. 4D —70-year-old woman with usual interstitial pneumonia. D, Scanning power microscopy images show patchy chronic scarring with architectural distortion without obvious honeycomb change (C). Occasional fibroblast foci are present (D). H and E stain.

View larger version (234K)

Fig. 5A —75-year-old man with usual interstitial pneumonia with ground-glass opacity present (GGOp) pattern at initial presentation. A, Supine (A) and prone (B) high-resolution CT images. Note that there are numerous areas of hazy increased lung attenuation in both central and peripheral lung. There is some peripheral reticulation and lobular distortion (arrow), but ground-glass opacity is diffuse in distribution, although superimposed on areas of distortion and traction bronchiolectasis (circles).

View larger version (150K)

Fig. 5B —75-year-old man with usual interstitial pneumonia with ground-glass opacity present (GGOp) pattern at initial presentation. B, Supine (A) and prone (B) high-resolution CT images. Note that there are numerous areas of hazy increased lung attenuation in both central and peripheral lung. There is some peripheral reticulation and lobular distortion (arrow), but ground-glass opacity is diffuse in distribution, although superimposed on areas of distortion and traction bronchiolectasis (circles).

View larger version (209K)

Fig. 5C —75-year-old man with usual interstitial pneumonia with ground-glass opacity present (GGOp) pattern at initial presentation. C, Scanning power microscopy images show patchy scarring that is subpleural in distribution (C). Honeycomb change is not prominent. Occasional fibroblast foci are present (D). H and E stain.

View larger version (211K)

Fig. 5D —75-year-old man with usual interstitial pneumonia with ground-glass opacity present (GGOp) pattern at initial presentation. D, Scanning power microscopy images show patchy scarring that is subpleural in distribution (C). Honeycomb change is not prominent. Occasional fibroblast foci are present (D). H and E stain.

Results	Choose Top of pageABSTRACTMaterials and MethodsResults <<DiscussionReferencesCITING ARTICLES

There were eight patients with the cUIP pattern, and only one of these patients underwent biopsy after 2005 (a 54-year-old man due to his young age). Seven patients were men, and the patients were 54–76 years old at the time of biopsy (mean age, 71 years). Five died of respiratory failure at 12, 14, 27, 30, and 72 months after diagnosis. One patient was lost to follow-up after hospital discharge. One had slow clinical decline over 40 months but was last seen in 2008. This patient also had acute diffuse alveolar damage 6 days after the biopsy and remained hospitalized for 2 weeks. One cUIP patient remains alive and clinically stable at 32 months. Serial CT information was available only in the patient who survived 72 months: This showed progression in the size of the honeycomb cysts and the extent of fibrosis. Extensive ground-glass attenuation was present throughout both lungs, suggesting diffuse alveolar damage as a preterminal event.

There were 21 patients with the FnoH pattern. Only two of these biopsies occurred after 2006. There were 16 men and five women (age 50–90 years; mean age, 75 years). Nine FnoH patients died of respiratory failure at 9, 9, 21, 34, 54, 54, 72, 80, and 84 months after diagnosis (Fig. 6). A 10th developed diffuse alveolar damage 2 weeks after biopsy and died 1 month after the procedure. Two died of other causes (lung cancer at 36 months, cirrhosis at 24 months). Four were lost to follow-up 1 week to 4 months after diagnosis. Five remain alive at 60, 66, 66, 78, and 102 months, four with clinical and radiographic progression of disease (Fig. 7). One patient is clinically stable at 60 months.

View larger version (140K)

Fig. 6A —75-year-old man with usual interstitial pneumonia and fibrosis without honeycombing (FnoH) pattern and subsequent acute diffuse alveolar damage. A, Prone high-resolution CT (HRCT) images (A and B) and supine HRCT image 9 months later (C). Prone images show reticulation and lobular distortion with intralobular lines (circles, A and B). There is traction bronchiolectasis (arrow, A and B) without honeycombing. Note heterogeneous appearance. Follow-up HRCT image (C) shows new ground-glass opacity away from areas of fibrosis that correlated with acute and fatal exacerbation. Note that ground-glass attenuation is superimposed on lobular distortion and reticulation; some intralobular lines (circles, C) are also visible indicating organization and fibrosis.

View larger version (82K)

Fig. 6B —75-year-old man with usual interstitial pneumonia and fibrosis without honeycombing (FnoH) pattern and subsequent acute diffuse alveolar damage. B, Prone high-resolution CT (HRCT) images (A and B) and supine HRCT image 9 months later (C). Prone images show reticulation and lobular distortion with intralobular lines (circles, A and B). There is traction bronchiolectasis (arrow, A and B) without honeycombing. Note heterogeneous appearance. Follow-up HRCT image (C) shows new ground-glass opacity away from areas of fibrosis that correlated with acute and fatal exacerbation. Note that ground-glass attenuation is superimposed on lobular distortion and reticulation; some intralobular lines (circles, C) are also visible indicating organization and fibrosis.

View larger version (181K)

Fig. 6C —75-year-old man with usual interstitial pneumonia and fibrosis without honeycombing (FnoH) pattern and subsequent acute diffuse alveolar damage. C, Prone high-resolution CT (HRCT) images (A and B) and supine HRCT image 9 months later (C). Prone images show reticulation and lobular distortion with intralobular lines (circles, A and B). There is traction bronchiolectasis (arrow, A and B) without honeycombing. Note heterogeneous appearance. Follow-up HRCT image (C) shows new ground-glass opacity away from areas of fibrosis that correlated with acute and fatal exacerbation. Note that ground-glass attenuation is superimposed on lobular distortion and reticulation; some intralobular lines (circles, C) are also visible indicating organization and fibrosis.

View larger version (171K)

Fig. 7A —80-year-old man with usual interstitial pneumonia (UIP). A, Supine high-resolution CT images show fibrosis without honeycombing (FnoH) pattern (A) and clinical and radiographic progression 42 months later to classic UIP (cUIP) pattern (B). Heterogeneous findings of fibrosis show progression in severity and extent, with new subtle honeycombing on later scan in area with traction bronchiolectasis at time of diagnosis (circle). Similar findings were present in lower lobes (not shown). New areas of traction bronchiolectasis are also visible at follow-up (arrows, B). Patient is alive 78 months after diagnosis but with clinically and radiographically progressive disease.

View larger version (158K)

Fig. 7B —80-year-old man with usual interstitial pneumonia (UIP). B, Supine high-resolution CT images show fibrosis without honeycombing (FnoH) pattern (A) and clinical and radiographic progression 42 months later to classic UIP (cUIP) pattern (B). Heterogeneous findings of fibrosis show progression in severity and extent, with new subtle honeycombing on later scan in area with traction bronchiolectasis at time of diagnosis (circle). Similar findings were present in lower lobes (not shown). New areas of traction bronchiolectasis are also visible at follow-up (arrows, B). Patient is alive 78 months after diagnosis but with clinically and radiographically progressive disease.

Sixteen FnoH patients underwent at least one follow-up CT; half still had the FnoH pattern months to years after biopsy, although all had progression in HRCT extent and severity (Fig. 8). Four progressed from the FnoH to the cUIP pattern at 18–48 months (Fig. 9). The other four developed the GGOp pattern (including the patient who died in the postoperative period), and these were all associated with mortality within 60 days due to diffuse alveolar damage.

View larger version (188K)

Fig. 8A —83-year-old man with usual interstitial pneumonia (UIP). A, Supine high-resolution CT images through lower lobes show fibrosis without honeycombing (FnoH) pattern (A) and progressive disease 88 months later (B). Peripheral reticulation, lobular distortion, intralobular line formation, and traction bronchiolectasis (arrows, A) progressed in extent and severity, but there is still no honeycombing. Patient is alive with progressive disease 102 months after diagnosis. Note heterogeneous appearance to fibrosis, with areas of relatively normal lung immediately adjacent to fibrotic changes of variable severity. Areas of lobular hyperinflation due to air trapping (arrows, B) are present adjacent to fibrotic areas.

View larger version (182K)

Fig. 8B —83-year-old man with usual interstitial pneumonia (UIP). B, Supine high-resolution CT images through lower lobes show fibrosis without honeycombing (FnoH) pattern (A) and progressive disease 88 months later (B). Peripheral reticulation, lobular distortion, intralobular line formation, and traction bronchiolectasis (arrows, A) progressed in extent and severity, but there is still no honeycombing. Patient is alive with progressive disease 102 months after diagnosis. Note heterogeneous appearance to fibrosis, with areas of relatively normal lung immediately adjacent to fibrotic changes of variable severity. Areas of lobular hyperinflation due to air trapping (arrows, B) are present adjacent to fibrotic areas.

View larger version (121K)

Fig. 9A —78-year-old man with usual interstitial pneumonia (UIP). A, Prone high-resolution CT images through lower lobes show fibrosis without honeycombing (FnoH) pattern at diagnosis (A) and progression to classic UIP (cUIP) pattern 48 months later (B). Heterogeneous appearance of reticulation, lobular distortion, intralobular lines (circles, A), and traction bronchiolectasis (arrow, A) evident at diagnosis progresses in extent and severity in B. Honeycombing develops in costophrenic angle (circles, B). Patient died of respiratory failure 54 months after diagnosis.

View larger version (140K)

Fig. 9B —78-year-old man with usual interstitial pneumonia (UIP). B, Prone high-resolution CT images through lower lobes show fibrosis without honeycombing (FnoH) pattern at diagnosis (A) and progression to classic UIP (cUIP) pattern 48 months later (B). Heterogeneous appearance of reticulation, lobular distortion, intralobular lines (circles, A), and traction bronchiolectasis (arrow, A) evident at diagnosis progresses in extent and severity in B. Honeycombing develops in costophrenic angle (circles, B). Patient died of respiratory failure 54 months after diagnosis.

We classified 10 patients as Fmin. Biopsies were performed between 2002 and 2009, with all but one after 2006 (four in 2009). There were six women and four men (age, 52–79 years; mean age, 67 years). Three died of respiratory failure 6, 8, and 18 months after diagnosis. Two died of other causes (cirrhosis at 10 months, lung cancer at 82 months). Four patients remain alive at 29, 54, 57, and 63 months after diagnosis; two have clinical and radiographic progression, while two are clinically stable 57 and 63 months after diagnosis. One patient was lost to follow-up after 2 weeks. Serial studies were available in seven patients: two progressed to the FnoH pattern at 12 and 24 months, and one progressed to the cUIP pattern at 75 months. Two remained stable at 57 and 63 months (Fig. 10), and two had the GGOp pattern at 6 and 18 months. Both of these patients died within 2 weeks.

View larger version (126K)

Fig. 10A —66-year-old woman with usual interstitial pneumonia. A, Prone high-resolution CT images of lower lobes show minimal fibrosis (Fmin) pattern at diagnosis (A) and radiographic stability 14 months after diagnosis (B). Patient remains clinically stable 63 months after diagnosis. There is peripheral reticulation and, in some areas, visible lobular distortion and intralobular line formation (arrows, A). Traction bronchiolectasis is minimal or absent (arrowhead, A), and there is no honeycombing. Ground-glass attenuation is superimposed on findings of fibrosis.

View larger version (119K)

Fig. 10B —66-year-old woman with usual interstitial pneumonia. B, Prone high-resolution CT images of lower lobes show minimal fibrosis (Fmin) pattern at diagnosis (A) and radiographic stability 14 months after diagnosis (B). Patient remains clinically stable 63 months after diagnosis. There is peripheral reticulation and, in some areas, visible lobular distortion and intralobular line formation (arrows, A). Traction bronchiolectasis is minimal or absent (arrowhead, A), and there is no honeycombing. Ground-glass attenuation is superimposed on findings of fibrosis.

Five patients had the GGOp pattern at diagnosis. These biopsies were uniformly distributed between 2002 and 2009. There were three men and two women, between 54 and 76 years old (mean age, 68 years). All died of respiratory failure at 19 days, 20 days, 30 days, 8 months, and 40 months after biopsy. Two had follow-up HRCT examinations that showed progressive GGOp. Underlying FnoH was visible in four patients; Fmin was present in one. Only one patient had a prior CT or HRCT; he had the FnoH pattern 2 years before his presentation with GGOp, although he had no specific diagnosis of UIP at presentation.

HRCT findings involved all lobes in all patients. None had an upper zone or central predominance. All but the GGOp patients had peripherally predominant findings. The distribution was nonsegmental and abnormalities crossed fissures. In some cases, the findings were subjectively slightly asymmetric.

Discussion	Choose Top of pageABSTRACTMaterials and MethodsResultsDiscussion <<ReferencesCITING ARTICLES

We identified four unique HRCT patterns in patients who had biopsy-proven UIP between 2000 and 2009. Lynch and colleagues [10] first described the utility of the concept of a “pattern” approach to the idiopathic interstitial lung diseases. Our primary aim was to determine whether any imaging patterns exist in recently biopsy-proven UIP that could obviate biopsy in cases with a concordant clinical history and presentation, particularly in patients without honeycombing. We also wanted to determine how patterns evolve over time and how patterns may affect prognosis or clinical course. The frequency and duration of HRCT was not consistent, however, because there were many different physicians involved in the care of our patients and the patients also received many different treatments and had various comorbid conditions.

The cUIP pattern is well established, and biopsy in such cases is not typically necessary. We had only one patient with cUIP undergo biopsy after 2005 (a 54-year-old man who underwent biopsy because of his young age), and there were only eight patients in this group. Consistent with prior reports, patients with this pattern had poor outcomes, with death or progression of disease in all but one patient, who is currently stable at 32 months. The presence of honeycombing indicates advanced, end-stage disease, yet the finding remains a requirement for diagnosis according to many publications and authors.

The FnoH pattern was the most common pattern in our series. We currently consider this pattern (since roughly 2005) in concert with appropriate clinical findings to be diagnostic. This explains why there were only two biopsies of patients with FnoH after 2006. The pathology of UIP is that of a temporally heterogeneous process, with areas of normal lung and areas of recent fibrosis (fibroblastic foci) immediately adjacent to areas of more advanced collagen-type fibrosis. This heterogeneity is a hallmark of the disease [11]. However, heterogeneity of findings at imaging has not been previously emphasized. HRCT, reflecting the gross pathology of UIP, elegantly shows this heterogeneous appearance, especially in cases without honeycombing but with findings of fibrosis. The pattern of peripheral, patchy, nonsegmental mild ground-glass opacity superimposed on reticulation, lobular distortion, intralobular lines, and traction bronchiectasis, associated with areas of normal intervening lung and variability in the severity of fibrosis between areas of involvement may be diagnostic (Fig. 11). Although the lower lobes are predominantly affected in UIP, the upper lobes were also involved in all of our cases. We agree with Hunninghake and colleagues [5] that some upper lobe involvement is characteristic of UIP even though it may be less severe than that in the lower zone, and we believe the presence of some upper lobe involvement is essential to the diagnosis. Although many prior reports describe ground-glass attenuation in patients with UIP, it must be emphasized that ground-glass opacity superimposed on the findings of fibrosis (reticulation, lobular distortion, intralobular lines, and traction bronchiolectasis) does not represent active alveolitis and has a very different significance from the GGOp pattern [12].

View larger version (177K)

Fig. 11A —79-year-old man with usual interstitial pneumonia and fibrosis without honeycombing (FnoH) pattern at diagnosis. A, Supine (A and B) and prone (C) high-resolution CT images show peripheral reticulation (arrows, A) with lobular distortion, intralobular lines, and traction bronchiolectasis (circles, B and C). Most significant and severe fibrosis is in peripheral lower lung (B and C), but there is some involvement of upper lobes as well (A). Process is heterogeneous, with fibrosis of varying severity and appearance alternating with more normal lung, and distribution is nonsegmental and crosses fissures.

View larger version (194K)

Fig. 11B —79-year-old man with usual interstitial pneumonia and fibrosis without honeycombing (FnoH) pattern at diagnosis. B, Supine (A and B) and prone (C) high-resolution CT images show peripheral reticulation (arrows, A) with lobular distortion, intralobular lines, and traction bronchiolectasis (circles, B and C). Most significant and severe fibrosis is in peripheral lower lung (B and C), but there is some involvement of upper lobes as well (A). Process is heterogeneous, with fibrosis of varying severity and appearance alternating with more normal lung, and distribution is nonsegmental and crosses fissures.

View larger version (116K)

Fig. 11C —79-year-old man with usual interstitial pneumonia and fibrosis without honeycombing (FnoH) pattern at diagnosis. C, Supine (A and B) and prone (C) high-resolution CT images show peripheral reticulation (arrows, A) with lobular distortion, intralobular lines, and traction bronchiolectasis (circles, B and C). Most significant and severe fibrosis is in peripheral lower lung (B and C), but there is some involvement of upper lobes as well (A). Process is heterogeneous, with fibrosis of varying severity and appearance alternating with more normal lung, and distribution is nonsegmental and crosses fissures.

Our patients with the FnoH pattern behaved clinically and radiographically like those with cUIP. They were similar in age and were prone to episodes of acute respiratory decompensation and suffered disease-specific mortality. Our results support those of Sumikawa and colleagues [13], who found no difference in prognosis between UIP patients with “definite UIP” or “probable UIP” HRCT patterns, which, according to the definitions of the authors, mirror our cUIP and FnoH groups.

Our 10 patients with the Fmin pattern had HRCT findings of bilateral fine or coarse reticulation, lobular distortion, and intralobular line formation but without traction bronchiolectasis or honeycombing or had a homogeneous appearance, findings that often overlap with those of fibrotic nonspecific interstitial pneumonitis (NSIP) [14–17]. Peripheral mild or homogeneous fibrosis can also occur in many other conditions, including chronic eosinophilic pneumonia, cryptogenic organizing pneumonia, and chronic aspiration. There is known overlap in the HRCT appearance of UIP and NSIP, in particular, with most due to UIP biopsy diagnosis, with HRCT findings more suggestive of NSIP (as in our Fmin group). Interestingly, the pathologic distinction between UIP and NSIP is not always straightforward, and in patients with more than one biopsy specimen, 12–26% have had UIP in one lobe and NSIP in the other [18, 19]. The clinical behavior in such individuals mimics that of UIP rather than NSIP [19]. We did not observe this variability, but our patients were given one final diagnosis after biopsies from more than one lobe. We did not perform a study with biopsies from different lobes read individually in a blinded fashion. In any event, the Fmin pattern is now the most common to undergo biopsy at our institution because the HRCT findings are more subtle and less definitive than those in cUIP or FnoH. Nonetheless, we observed upper lobe involvement in all Fmin patients.

Interestingly, our patients with the Fmin pattern behaved similarly to patients with cUIP and FnoH: Disease-specific mortality occurred, and patients suffered episodes of acute respiratory decompensation. This is consistent with prior reports: A UIP diagnosis at biopsy has poor prognosis and histology has been reported as the most important factor in determining survival in patients with idiopathic interstitial pneumonia [20]. Other authors have proposed that mortality in patients with proven UIP may actually vary on the basis of HRCT pattern at diagnosis [21]. In the study by Sumikawa and colleagues [13], patients with HRCT findings more suggestive of NSIP than of UIP had a mean survival of 76.9 months compared with 45.7 months in UIP patients with honeycombing and 57.9 months in those with probable UIP. Although these differences were not statistically significant, there was a trend toward longer survival in the NSIP-like fibrosis group. A study by Shin and colleagues [22] also found that a subjective fibrotic score at HRCT was a significant independent prognostic indicator in patients with UIP and NSIP regardless of the specific diagnosis. Jeong et al. [23] reported that patients with UIP but no honeycombing on HRCT and patients with NSIP had a better prognosis than UIP patients with honeycombing.

Our sample size is small, but we also believe that histology remains the most important prognostic indicator. Our patients clearly showed evolution from the Fmin to both the FnoH and cUIP pattern, and patients in all groups had significant mortality due to acute respiratory failure and were prone to episodes of acute decompensation, with diffuse alveolar damage and a high mortality. We believe that regardless of the initial pattern, UIP behaves in a consistent manner. Survival differences between HRCT patterns likely reflect the lead-time bias of early diagnosis rather than true differences in the underlying disease. Indeed, NSIP is also a variable entity; Silva et al. [24] reported that five of 18 patients with NSIP and typical HRCT findings progressed over time to develop HRCT findings more suggestive of UIP [24]. It would seem possible that such cases really represented UIP with the Fmin pattern at HRCT, missed on initial biopsy because of sampling problems. In any event, we emphasize the need to define treatment responses in patients with UIP on the basis of the HRCT pattern and to compare treated and untreated populations clearly stratified not only on the basis of UIP diagnosis but on more specific pattern information.

The GGOp pattern was the least common but is important to recognize. In our patients, this pattern correlated with diffuse alveolar damage superimposed on or associated with histopathologic UIP. Diffuse alveolar damage is the histology of the acute exacerbation of UIP and may also be the initial presentation of the disease [25, 26]. Three of our five patients died within 1 month of biopsy, indicative of the severity of the underlying condition. Of note, diffuse alveolar damage in the postoperative period occurred in three of our patients and was fatal in two. This occurred in one patient with cUIP, one with FnoH, and one with Fmin. Lung biopsy is not without risk in patients with UIP.

Our study has several limitations. Our sample size is small because surgical biopsy is not often performed in these patients due to advanced age, comorbid conditions, and the known risk of precipitating a diffuse alveolar damage flare [9]. We also use HRCT extensively, and we currently consider both the cUIP and FnoH patterns diagnostic in the proper clinical setting without the need for tissue diagnosis. Heterogeneity, some upper lobe involvement, and a lower zone and peripheral predominance, however, are essential, and in this setting, even the Fmin pattern may be diagnostic, particularly in a patient more than 70 years old [27]. We cannot comment on potential false-positive diagnoses of UIP. A separate study of patients with FnoH or Fmin diagnosed and managed as UIP without tissue diagnosis would help in this regard. In addition, our follow-up intervals were fairly short, and we made no attempt to make statistically significant assumptions regarding outcomes or mortality. Of importance, even larger prior studies have not focused on disease-specific mortality; this makes interpretation of survival data on the basis of HRCT severity indexes difficult given the advanced age and comorbidities in these patients. We made no attempt to subjectively or objectively quantify the severity of HRCT abnormalities within the given groups. This could be done with larger populations.

There is some overlap between patterns, with severe FnoH bordering cUIP and advanced Fmin appearing similar to mild FnoH; this is true with any classification system and, in our opinion, does not render it less useful. Our HRCT readers work together at one institution and routinely consult one another; we did not assess interobserver variability but had no significant disagreements as to patient classification. Future larger prospective studies of interobserver variability using readers from multiple institutions would be of interest. Lastly, we did not control for treatment differences between patterns. Future prospective studies of patients on therapy based on HRCT pattern are of importance.

In summary, we believe that the cUIP and FnoH patterns allow specific diagnosis of UIP in the setting of a consistent clinical presentation without the need for biopsy. Some patients with Fmin or GGOp may require biopsy, but in a patient of appropriate age (more than 70 years) with heterogeneous findings of fibrosis with some upper lobe findings, lower zone predominance, and a nonsegmental distribution in whom the clinical features are consistent, we advocate presumptive diagnosis of IPF [27]. UIP with the Fmin pattern appears to behave clinically like UIP with the cUIP or FnoH patterns. There is clearly evolution in some patients from Fmin to FnoH to cUIP over time as alluded to in the classic study by Akira and colleagues [28]. In addition to grouping patients by diagnosis (UIP), we propose that the further stratification of patients on the basis of HRCT pattern will be of use in assessing the effects of therapy, determining prognosis, and more accurately comparing outcomes. Lastly, diffuse alveolar damage may be the initial presentation of UIP, and diffuse alveolar damage as an acute flare of IPF can occur at any time regardless of the initial HRCT pattern.