Interstitial lung disease: time to rethink the snapshot diagnosis?

An accurate and early diagnosis of idiopathic pulmonary fibrosis (IPF) is critically required for patients and care providers because it dictates very specific management decisions that include referral to transplant, access to new approved drugs, avoidance of immunosuppression and potential referral to palliative care. While the original diagnosis of IPF was highly dependent on patterns observed on histology, in 2002 the American Thoracic Society (ATS)/European Respiratory Society (ERS) guideline altered the approach to diagnosis so as to include a clinical–radiological–pathological multidisciplinary diagnosis. A careful history, searching for subtle evidence of connective tissue disease, exposures and other known causes for interstitial lung disease (ILD), was emphasised. A radiographic pattern of usual interstitial pneumonia (UIP) on highresolution CT (HRCT) was described, characterised by basal-predominant fibrosis with peripheral reticular markings, traction airway change, architectural distortion and honeycombing. With this new classification system, it was proposed, characteristic HRCT findings could lead to a confident diagnosis of IPF without the need for a biopsy. The advantage of using HRCT patterns as a surrogate for pathological findings was particularly appealing given data describing increased risk for acute exacerbation and death following lung biopsy. Support for such an approach was increased by studies demonstrating agreement between radiographic and pathological findings. Raghu et al found that the specificity of HRCT for UIP was 90%. Flaherty et al found that the HRCT interpretation of definite UIP in biopsy-proven UIP and non-specific interstitial pneumonia (NSIP) had 100% specificity. Hunninghake et al found that in a blinded prospective evaluation of patients with surgical lung biopsies, a confident HRCT diagnosis of UIP was 95% specific for the pathological finding of UIP. HRCT appearance was also predictive of survival: a definite UIP pattern on HRCT (having all the features described above) was associated with a lower survival than for those patients with radiographic findings that were indeterminate or suggestive of another diagnosis. Despite this apparently high predictive power, however, these same studies reported low agreement regarding a specific diagnosis (kappa of 0.54) on HRCT and other authors have also found only modest agreement (kappa of 0.48) for the finding of honeycombing, suggesting that even this key finding is not easily interpreted. Community physicians are more likely to assign a diagnosis of IPF and to be in agreement on it than physicians at tertiary referral centres. Subsequent iterations of the ATS/ERS guidelines have attempted to refine the definition of IPF, and, in particular, the radiographic features of UIP. In 2011, ATS consensus statement specifically defined three categories of radiographic criteria: UIP pattern, possible UIP pattern and inconsistent with UIP pattern. The final diagnosis of IPF rested on a combination of radiographic and pathological features (when lung biopsy was obtained), which, in combination with multidisciplinary discussion, would lead to one of several possible diagnostic statements: IPF, probable IPF, possible IPF or not IPF. This classification scheme was designed to allow for the uncertainty that is often present in pathological and radiographic interpretations and to permit less-than-confident definitions of IPF. However, these categories were never validated, either retrospectively or prospectively, nor were studies performed to assess the reproducibility of these diagnostic assessments in actual practice. In Thorax, Walsh et al address this latter issue in an elegant manner. The authors designed a two-part study. CTs from consecutive patients in a tertiary referral centre were obtained. All patients carried a multidisciplinary team diagnosis of idiopathic fibrotic lung disease, chronic hypersensitivity pneumonitis (HP) or fibrotic lung disease associated with a connective tissue disease, excluding sarcoidosis. All CTs were performed at full inspiration as high-resolution scans. Observers were invited to participate from a variety of radiographic societies. In the first stage of the study, an internetbased viewing application allowed radiologists to view 15 sections from each CT and to assign a diagnostic category: UIP, possible UIP or inconsistent with UIP. Raters were asked to score honeycombing, traction bronchiectasis and emphysema as definitely present, possibly present or absent. In the second stage of the study, chest radiologists were randomly selected from the initial participant group, one subset with >20 years of experience and another with <10 years. These thoracic radiologists were given the full thinsection CTs of a new cohort of patients and scored CTs with the same criteria. Kappa values were calculated for interobserver agreement for diagnostic category and for honeycombing. Surprisingly, agreement on overall diagnosis category was only moderate (ranging from 0.48 for general radiologists to 0.52 for chest radiologists). The agreement between radiologists did not even improve if the approach was simplified into a binary comparison of definite/possible UIP versus inconsistent with UIP. When interpreting the presence of honeycombing by use of a scoring system, the agreement scores ranged from 0.56 to 0.65, though the higher agreement scores were found in less experienced observers (fellows), possibly suggesting that there was agreement but not necessarily accuracy. This study demonstrates that the problem of inter-reader reliability, which has long been a concern in the study of IPF, has not been fully addressed by the recent ATS/ERS consensus revision. Reliably phenotyped subjects are key to interpreting data from clinical trials and translational studies. Similarly, clinical decision-making regarding the use of novel antifibrotic medications and immunosuppressive therapies increasingly hinges on CT interpretation as fewer patients are undergoing surgical lung biopsy. Several possible approaches could be considered to address these issues. The first is to further refine the current criteria by better identifying the reasons for uncertainty in CT interpretation. One of the limitations to this study is that we do not know why the radiologists called certain scans inconsistent. Are these discrepancies due to areas of lucency that are variably interpreted as emphysema or honeycombing? Would addition of expiratory images help improve overall results by highlighting air trapping or would they Section of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, Yale University, New Haven, Connecticut, USA; Division of Respirology, Department of Medicine and Pathology/Molecular Medicine, McMaster University Hamilton, Ontario, Canada