Less common findings include small, ill-defined peribronchial or centrilobular nodules64,70; large nodular or mass-like areas of consolidation71; areas of ground-glass opacity surrounded by a ring-like or crescentic opacities (reversed halo or atoll sign) (approximately 20% of patients);72,73 and irregular linear opacities (reticulation) (7% to 29%).64,66,73 Irregular linear opacities (reticulation) in patients with COP are usually associated with consolidation and located in the subpleural or peribronchial regions of the lower lung zones. Occasionally, the reticular opacities may be the predominant HRCT finding.68
Extrapulmonary findings in patients who have COP include small pleural effusions, present in 10% to 30% of patients,64,66,73 and mild right paratracheal or subcarinal lymphadenopathy, observed in 20% to 40% of cases.30,73 The pleural effusions are small and may be unilateral or bilateral.66
AIP is a fulminant disease of unknown etiology that usually occurs in a previously healthy person and is characterized by histologic findings of DAD (Table 1).1,74 Because the clinical presentation and the histologic features are identical to those of ARDS, AIP has also been referred to as idiopathic ARDS.75 The average age at presentation is approximately 59 years (range 7 to 83 y).176 It has no sex predominance and no association with cigarette smoking. There is often a prodromal illness associated with symptoms of a viral upper respiratory infection followed by dry cough and rapidly progressive severe dyspnea and respiratory failure. The majority of patients have symptoms for less than 1 week before diagnosis.77 The prognosis is poor, the mortality being 50% or more and most deaths occurring between 1 and 2 months of presentation.74,75,77
The HRCT findings in the early stages of AIP (exudative phase) consist primarily of bilateral ground-glass opacities and areas of consolidation (Fig. 11) (Table 1).18,78–80 The ground-glass opacities may be patchy or diffuse; focal sparing of lung lobules is frequently present, resulting in a geographic distribution.81 Smooth septal thickening and intralobular lines are often observed superimposed on the ground-glass opacities (“crazy-paving” pattern).79 The ground-glass opacities usually involve all lung zones, but may have lower or, less commonly, upper lobe predominance.79 The airspace consolidation may be patchy or confluent, and tends to involve mainly the dependent lung regions (Fig. 11).79
The proliferative (organizing) phase and the fibrotic stages of AIP are characterized by the presence of architectural distortion and traction bronchiectasis. In a study by Akira,78 these findings were observed only on CT scans obtained more than 7 days after the onset of symptoms. Honeycombing, present in a small percentage of patients with AIP, correlates with the presence of dense interstitial fibrosis and restructuring of distal airspaces.80,81
The main role and clinical utility of HRCT is in the diagnosis of IPF and the distinction of IPF from other IIPs. It is currently widely accepted that a confident diagnosis of IPF can often be made on the basis of a combination of clinical and HRCT findings.5,18,50 The high specificity of HRCT in the diagnosis of UIP and IPF was initially shown in several retrospective studies82–84 and subsequently confirmed in 2 prospective studies, both of which only included patients with biopsy-proven diagnosis and used histologic features as gold standard.85,86 The first prospective study was by Raghu et al,85 who assessed the accuracy of a clinical diagnosis of IPF and interstitial lung diseases other than IPF in 59 patients who were referred for evaluation of new-onset interstitial lung disease. A specific clinical diagnosis was independently made by a clinician who was an expert in interstitial lung diseases after a thorough clinical assessment that included evaluation of the HRCT findings. The chest radiographs and CT scans were separately reviewed by the thoracic radiologist, who made a radiologic diagnosis independently. The sensitivity and specificity of the IPF diagnosis by the clinical expert were 62% and 97%, respectively. The sensitivity and specificity of the radiologic first-choice diagnosis of IPF were 78% and 90%, respectively.85 Hunninghake et al86 performed a prospective multicenter investigation of 91 patients, including 54 patients with biopsy-proven IPF. The sensitivity of HRCT for a confident diagnosis of IPF by experienced chest radiologists was 48% and the specificity and positive predictive values were 95% and 96%, respectively.86 On the basis of these studies, it is now well accepted that in the appropriate clinical setting the presence of characteristic HRCT findings allows confident noninvasive diagnosis of IPF, obviating lung biopsy.1,87 It should be noted, however, that diagnostic HRCT findings of UIP/IPF are only present in 50% to 70% of patients (Fig. 2). When the HRCT findings do not allow a confident diagnosis or when the clinical findings are atypical (eg, potential exposure to an antigen, raising the possibility of HP), surgical lung biopsy is indicated.
A confident HRCT diagnosis of IPF requires clinical exclusion of known causes of UIP and the presence of all the following 3 HRCT criteria: presence of a reticular pattern in a predominantly peripheral and basal distribution, presence of honeycombing in a predominantly peripheral and basal distribution, and absence of atypical features (eg, centrilobular nodules, peribronchovascular nodules, extensive consolidation, or extensive ground-glass opacities).15,86 If only the first and third criteria are present, namely, if honeycombing is absent, the findings can only be interpreted as “probable IPF”.15 The strongest predictors of IPF on HRCT are lower-lung honeycombing (odds ratio, 5.36) and upper-lung reticulation (odds ratio, 6.28).14 Although basal and peripheral honeycombing is a strong predictor of IPF, there is surprisingly considerable interobserver disagreement in the diagnosis of honeycombing.15 Confident diagnosis of honeycombing requires the presence of clustered cystic airspaces measuring 2 mm to 1 cm in diameter that have well-defined thick walls and are located adjacent to the pleura. They must be distinguished from traction bronchiolectasis, which may have a similar appearance but typically is located a few mm or more from the pleura.
It should be noted that surgical lung biopsy also has limitations. Most importantly, it is invasive and usually assesses only a small part of the lung. Thus, the region sampled may not be representative of the lung as a whole, and the presence of inflammation may be missed. Furthermore, different lobes may show different pathology. For example, in one review of the surgical lung biopsy specimens obtained from 2 or more lobes in 109 patients with a clinical syndrome of IPF and a histologic pattern of either UIP or NSIP, 51 patients had a histologic UIP pattern in all lobes (concordant UIP), 33 patients had NSIP in all lobes sampled, and 28 (26%) had both NSIP and UIP (ie, discordant UIP).88 In another review of the multiple surgical lung biopsy specimens obtained in 64 patients with suspected IPF, 39% had concordant UIP, 48% had concordant NSIP, and 13% had both UIP and NSIP (discordant UIP).49 Only by correlating the CT with the pathologic findings can an overall evaluation of the pattern and extent of lung disease be adequately assessed.
Although a confident diagnosis of IPF can often be made on the basis of the clinical and HRCT findings, there is considerable overlap between the HRCT findings in NSIP and those present in other interstitial lung diseases, particularly IPF and HP, precluding confident diagnosis of NSIP on HRCT.53,89 For example, Johkoh et al89 reviewed the HRCT findings in 129 patients who had various IIPs, including 27 patients who had NSIP. Two independent observers made a correct first-choice diagnosis, on average, in 71% of cases of UIP, 79% of cases of COP, and 63% of cases of DIP, but in only 9% of cases of NSIP. In none of the cases of NSIP was the diagnosis made with a high degree of confidence on HRCT. More recent studies, however, have shown a higher accuracy of HRCT in distinguishing between NSIP and UIP. For example, MacDonald et al13 compared the HRCT findings of UIP and NSIP in 53 consecutive patients who had a clinical presentation consistent with IPF and who underwent lung biopsy. The final diagnosis was IPF in 32 patients and NSIP in 21. HRCT had a sensitivity of 63% and a specificity of 70% for UIP and a sensitivity of 70% and a specificity of 63% for NSIP. The most helpful finding in distinguishing NSIP from UIP was the greater extent of ground-glass opacities (odds ratio: 1.04 for each 1% increase in the proportion of ground-glass opacities).13 Elliot et al90 reviewed the HRCT scans of 47 patients with biopsy-proven IPF (n=22) and NSIP (n=25). A confident CT diagnosis of IPF and NSIP was correct in 88% and 73% of cases, respectively. The presence of honeycombing as a predominant feature had a specificity of 96%, sensitivity of 41%, and a positive predictive value of 90% for IPF. This pattern was identified in only a single patient (by both readers) with fibrotic NSIP. Conversely, predominant ground-glass opacity and/or reticular opacity with minimal or no honeycombing was identified in 48 (96%) of 50 readings in patients with NSIP, and in 26 (59%) of 44 readings in patients with UIP, giving a sensitivity of 96% and a specificity of 41% for the diagnosis of NSIP.90 Sumikawa et al21 compared the HRCT findings of various IIPs in 92 patients with biopsy-proven diagnosis. Two independent observers made the correct diagnosis in 79% of readings. Multivariate logistic regression analysis showed that the most useful finding for distinguishing IPF from NSIP was the extent of honeycombing. The average extent of honeycombing was 4.4% of the parenchyma in IPF, 0.3% in cellular NSIP and 0.6% in fibrotic NSIP.21 Another helpful finding in distinguishing NSIP from IPF is the relative subpleural sparing in the dorsal regions of the lower lobes observed at 2 or more levels in up to 65% of patients with NSIP compared with only 4% of patients with UIP25 (Fig. 12). In summary, these studies show that in many patients HRCT allows distinction of NSIP from IPF. However, while the presence of predominantly peripheral and basal honeycombing in the appropriate clinical setting often allows a confident diagnosis of IPF on HRCT, a confident diagnosis of NSIP requires surgical biopsy.
Although a definitive diagnosis of NSIP usually requires surgical biopsy, in clinical practice surgical biopsy is underused and performed in fewer than 15% of patients with chronic interstitial lung disease.91,92 Even if patients undergo lung biopsy, there is considerable disagreement among pathologists over the diagnosis of interstitial lung diseases, particularly NSIP.93 Furthermore, a histologic diagnosis of NSIP often does not constitute a final diagnosis, because NSIP is a common reaction pattern to various drugs; is commonly associated with collagen vascular diseases, particularly scleroderma; and can be a histologic manifestation of HP.1,10 These conditions need to be excluded by careful clinical assessment before making a diagnosis of idiopathic NSIP. Moreover, in many cases even expert clinicians, pathologists, and radiologists fail to reach a consensus as to the diagnosis. Churg and Müller94 therefore proposed an alternative approach to the IIPs and morphologically and radiologically related conditions such as HP, interstitial lung disease in collagen vascular disease, and drug-related interstitial lung disease. Their approach is based on dividing the radiologic or histologic findings into 3 types: (a) purely cellular processes, with or without a component of organizing pneumonia; (b) processes that show the type of linear fibrosis (fibrosis that follows the original alveolar walls) without architectural distortion as observed in fibrotic NSIP, some cases of chronic HP, and some drug reactions, with or without a cellular component; and (c) processes that show the fibrotic architectural distortion of UIP, namely, honeycombing.94 Processes that are purely cellular, including RB-ILD, DIP, cellular NSIP, COP, and subacute (nonfibrotic) HP, usually respond to corticosteroid therapy. Thus, regardless of the specific diagnosis or label of the disease, if the process is purely cellular it usually responds to treatment. Linear fibrosis without architectural distortion is associated with a distinctly worse prognosis than purely cellular lesions. This has been well documented for patients with NSIP,95 and patients with chronic HP and fibrosis.96 This classification is particularly practical and helpful for cases in which the clinical, histologic, and radiologic features do not fit neatly into the ATS/ERS classification of IIPs, nor with a diagnosis of HP.94
The diagnosis of HP can often be strongly suggested by a combination of history of exposure to a known offending antigen; recurrent episodes of symptoms; symptoms occurring 4 to 8 hours after exposure; and characteristic HRCT findings of bilateral ground-glass opacities, lobular areas of decreased attenuation with air-trapping on expiratory images, and poorly defined centrilobular nodules.97,98 However, in up to 40% of histologically proven cases of HP, the offending antigen is not identified.96,97 Furthermore, in patients with chronic HP the HRCT findings may mimic those of IPF and NSIP.98,99 Silva et al25 compared the HRCT findings of 18 patients with proven chronic HP, 23 with IPF, and 25 with NSIP. Two independent chest radiologists assessed the HRCT images, made a first-choice diagnosis, and noted the degree of confidence in the diagnosis. The CT features that best differentiated chronic HP were lobular areas with decreased attenuation and vascularity, poorly defined centrilobular nodules, and absence of lower-zone predominance of abnormalities (P≤0.008). The features that best differentiated NSIP were relative subpleural sparing, absence of lobular areas with decreased attenuation, and lack of honeycombing (P≤0.002). The features that best differentiated IPF were basal predominance of honeycombing, absence of relative subpleural sparing, and absence of centrilobular nodules (P≤0.004). A confident diagnosis was made in 70 (53%) of 132 readings by the 2 observers. This diagnosis was correct in 66 (94%) of 70 readings. The authors concluded that the characteristic CT features of chronic HP, IPF, and NSIP allow confident distinction among these entities on HRCT in approximately 50% of patients.
The HRCT findings of COP are relatively nonspecific, and may be observed in a variety of infections and neoplastic diseases.18,71 However, COP can usually be readily distinguished from other chronic interstitial and airspace lung diseases on HRCT. Johkoh et al89 reviewed the HRCT findings in 129 patients who had various IIPs, including 24 with COP. On average, on the basis of the pattern and distribution of abnormalities on HRCT, 2 independent observers made a correct first-choice diagnosis in 79% of 24 cases of COP.89 In patients with clinical and CT findings consistent with COP, the diagnosis can usually be readily confirmed by transbronchial biopsy showing characteristic histologic features of organizing pneumonia and exclusion of other causes of organizing pneumonia by clinical history and laboratory tests.
The predominant subpleural distribution of COP resembles that of chronic eosinophilic pneumonia (CEP). Arakawa et al100 compared the HRCT findings in 38 patients with COP and 43 patients with CEP. Air-space consolidation was the most frequent HRCT finding in both COP (87%) and CEP (74%), and it had a predominately peripheral distribution in 66% of patients with COP and 56% of patients with CEP. A peribronchial distribution of consolidation was observed more frequently in COP than in CEP (29% vs. 9%). There was no appreciable difference in the cephalocaudal distribution of the consolidation between COP and CEP. The most helpful distinguishing feature on CT was the presence of nodules, observed in 32% of patients with COP and only 5% of patients with CEP. On the basis of the HRCT findings, 2 independent chest radiologists made a correct first choice of COP or CEP in 67% and 72% of cases, respectively.100 In clinical practice, the differential diagnosis can be readily made on the basis of clinical history and laboratory tests. Approximately 50% of patients with CEP have asthma and the vast majority has peripheral eosinophilia.101
The HRCT findings of AIP reflect the presence of DAD, and are therefore similar to those of ARDS of known etiology. However, Tomiyama et al102 showed that patients with AIP are more likely to have a symmetric lower-lobe distribution of abnormalities and a greater prevalence of honeycombing (26% of patients vs. 8%). In clinical practice, the vast majority of patients with DAD have a known etiology, the diagnosis of AIP requiring careful clinical evaluation to eliminate less common causes of DAD such as drug reaction or collagen vascular disease.
Both the long-term survival in IPF and its likelihood of response to treatment with corticosteroids correlate with the histologic and HRCT findings. In the past it was believed that alveolitis played an important role in the development of fibrosis and that the prognosis was influenced by the extent of inflammation histologically103,104 and by the extent of ground-glass opacity on HRCT.105,106 These studies preceded the description of NSIP in 1994,47 and almost certainly included patients with IIPs other than IPF, particularly NSIP. Furthermore, the theory that inflammation eventually leads to widespread pulmonary fibrosis seems to hold true for several of the corticosteroid-responsive IIPs (eg, NSIP), but not for UIP.91 More recent studies have shown that the extent of reticulation and honeycombing are better predictors of prognosis than the extent of ground-glass opacities. For example, a study by Gay et al107 showed that although the extent of ground-glass opacities was higher in corticosteroid responders than in nonresponders, the only CT parameter that statistically predicted death during follow-up of patients with IPF was the extent of lung fibrosis. More recently, in a retrospective study of 167 patients with IPF, Best et al108 showed that visually determined extent of fibrosis on HRCT is a strong independent predictor of mortality in IPF. Flaherty et al109 showed that among patients with IPF, an HRCT showing characteristic features of IPF, namely, honeycombing, was associated with worse survival than an HRCT showing findings more suggestive of NSIP (no honeycombing) (median survival, 2.1 vs. 5.8 y) and worse than patients with a histologic diagnosis of NSIP (median survival >9 y).109 Jeong et al110 found that patients who have IPF and minimal or no honeycombing (ie, honeycombing involving less than 5% of the parenchyma) on HRCT had a mortality rate similar to those with NSIP, and significantly lower than those with UIP and honeycombing. Overall, these studies show that the prognosis of IPF is worse than that of NSIP, and that patients with IPF and honeycombing have worse prognosis than patients with minimal or no honeycombing.
Serial HRCT scans in patients with IPF typically show progressive increase in the extent and severity of fibrosis over several months or years.35,111 Reticulation often progresses to honeycombing and honeycomb cysts increase in size (Fig. 6).35,36 The areas of ground-glass opacities may improve or resolve with treatment or may progress to reticulation and honeycombing.35,37 Serial CT scans in patients with NSIP have shown that patients with predominant ground-glass opacities on the initial CT are more likely to improve with treatment and have a better long-term prognosis than patients with predominant reticulation.112–114 Screaton et al114 performed serial CT scans in 38 patients with histologically proven NSIP, including 4 with cellular NSIP, 13 with mixed cellular and fibrotic NSIP, and 21 with fibrotic NSIP. The predominant initial CT pattern was inflammatory (ground-glass opacities and consolidation) in 6 (16%) patients and fibrotic (reticulation and honeycombing) in 32 (84%). At a mean follow-up of approximately 1 year, all of the patients with an inflammatory predominant pattern on the initial CT improved, whereas of the 32 patients with a fibrotic predominant pattern, 7 (22%) improved, 6 (19%) deteriorated, and 19 (59%) remained stable. Surprisingly, there was no significant association between the histologic findings and the likelihood of improvement on follow-up CT.114
The vast majority of patients with COP has predominant consolidation on HRCT and shows good response to corticosteroids. Predominant reticulation is observed in a small percentage of patients and is associated with worse prognosis. Lee et al68 reviewed the HRCT findings of 26 patients with COP who had radiographic follow-up for a median of 44 weeks after treatment. Of the 26 patients, 17 (65%) had partial or complete resolution of the abnormalities at follow-up and 9 (35%) had persistent or progressive abnormalities. Consolidation was present on the initial CT scan in 14 (82%) of the 17 patients who improved on follow-up, but in only 2 of the 9 patients with persistent or progressive disease (P=0.009). None of the 6 patients who had irregular linear opacities as the predominant pattern on initial HRCT showed complete resolution on follow-up imaging (P=0.02).68
HRCT can also be helpful in predicting likelihood of response to treatment in patients with AIP. Ichikado et al115 compared the HRCT findings of AIP between 10 survivors and 21 nonsurvivors. The extent of ground-glass opacity or air-space consolidation without traction bronchiectasis or bronchiolectasis was greater in survivors than in nonsurvivors, and the extent of either ground-glass opacity or air-space consolidation combined with traction bronchiolectasis or bronchiectasis was greater in nonsurvivors.
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