Articles
Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial

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Summary

Background

Present guidelines for the diagnosis of idiopathic pulmonary fibrosis require histological confirmation of surgical lung biopsy samples when high-resolution CT images are not definitive for usual interstitial pneumonia. We aimed to assess the predictive value of high-resolution CT in a cohort of patients with suspected idiopathic pulmonary fibrosis from a previous randomised trial.

Methods

ARTEMIS-IPF was a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial of ambrisentan for adults aged 40–80 years with well-defined idiopathic pulmonary fibrosis and 5% or less honeycombing on high-resolution CT. In December, 2010, an interim analysis showed lack of efficacy and the trial was stopped. In the present follow-on analysis, we assessed patients who were screened for ARTEMIS-IPF who underwent high-resolution CT as part of screening and surgical lung biopsy as part of standard clinical care. A radiologist and a pathologist from a central panel independently assessed anonymised CT scans and biopsy samples. We calculated the positive and negative predictive value of high-resolution CT (classified as usual interstitial pneumonia, possible usual interstitial pneumonia, and inconsistent with usual interstitial pneumonia) for confirmation of histological patterns of usual interstitial pneumonia. This study is registered with ClinicalTrials.gov, number NCT00768300.

Findings

315 (29%) of 1087 consecutively screened patients in ARTEMIS-IPF had both high-resolution CT and surgical lung biopsy samples. 108 of 111 patients who met high-resolution CT criteria for usual interstitial pneumonia had histologically confirmed usual interstitial pneumonia (positive predictive value 97·3%, 95% CI 92·3–99·4), as did 79 of 84 patients who met high-resolution CT criteria for possible usual interstitial pneumonia (94·0%, 86·7–98·0). 22 of 120 patients had an inconsistent high-resolution CT pattern for usual interstitial pneumonia that was histologically confirmed as not or possible usual interstitial pneumonia (negative predictive value 18·3%, 95% CI 11·9–26·4).

Interpretation

In the appropriate clinical setting, for patients with possible usual interstitial pneumonia pattern on high resolution CT, surgical lung biopsy sampling might not be necessary to reach a diagnosis of idiopathic pulmonary fibrosis if high-resolution CT scans are assessed by experts at regional sites familiar with patterns of usual interstitial pneumonia and management of idiopathic interstitial pneumonia.

Funding

Gilead Sciences.

Introduction

Idiopathic pulmonary fibrosis is characterised by worsening respiratory symptoms and pulmonary function and usually leads to death from respiratory failure within 5 years of diagnosis.1 Accurate diagnosis of the disease is essential to provide clinical guidance for treatment decisions, stratify enrolment into clinical trials, and establish prognosis and priority for lung allograft allocation. Diagnosis is made with the highest degree of confidence when clinical, radiological, and pathological data are reviewed by a multidisciplinary discussion team, consisting of a clinician, a radiologist, and a pathologist who all have expertise in the diagnosis of interstitial lung diseases.1, 2 Assessment of surgical lung biopsy samples in patients with idiopathic pulmonary fibrosis will show a pattern classified as usual interstitial pneumonia with increased diagnostic accuracy if specimens are obtained from more than one lobe.3 With the advent of high-resolution CT, characteristic patterns of abnormalities have been identified in patients with idiopathic pulmonary fibrosis.4, 5, 6 Evidence-based guidelines provide specific criteria for the radiological pattern of usual interstitial pneumonia and, in the appropriate clinical setting, histological confirmation is not needed when a confident diagnosis is made with high-resolution CT.1, 7 The usual interstitial pneumonia pattern on high-resolution CT has a high positive predictive value for the presence of a histological pattern of usual interstitial pneumonia. The appropriate clinical setting is defined as, typically, a male patient older than 60 years with unexplained dyspnoea on exertion and pulmonary fibrosis of unknown cause, including absence of collagen vascular disease and absence of identifiable cause or environmental factor attributable to the manifested pulmonary fibrosis.1 To classify a high-resolution CT as showing usual interstitial pneumonia, honeycombing and reticular abnormalities in a predominantly basilar and subpleural distribution need to be present. In addition, the high-resolution CT should not show any atypical features for usual interstitial pneumonia, including prominent ground glass abnormalities, nodules, air trapping, and peribronchovascular or upper lung predominant patterns of distribution. If such atypical features are prominent, the high-resolution CT pattern is designated as inconsistent with usual interstitial pneumonia1 and procurement of a surgical lung biopsy should be considered. The guidelines recognise a third potential radiological diagnosis: possible usual interstitial pneumonia pattern, which is characterised by the presence of bilateral lower lobe subpleural reticular abnormalities without honeycombing and without atypical features. In patients with this pattern, the guidelines1 require surgical lung biopsy evidence of usual interstitial pneumonia to confirm the diagnosis of idiopathic pulmonary fibrosis.

We aimed to assess the value of high-resolution CT showing a possible usual interstitial pneumonia pattern for prediction of a histological pattern consistent with usual interstitial pneumonia in a subgroup of participants who were screened for inclusion in a multicentre trial8 of ambrisentan.

Section snippets

Study design and participants

ARTEMIS-IPF was a randomised, double-blind, placebo-controlled, multicentre, event-driven phase 3 trial8 to assess whether the selective endothelin receptor antagonist ambrisentan was effective for reduction of the rate of progression of idiopathic pulmonary fibrosis. All participants provided written, informed consent, and the study was approved by local ethics committees. After 1087 patients had been screened between Jan 21, 2009, and Dec 21, 2010, and 494 patients randomly allocated to study

Results

Of 1087 consecutive participants screened for enrolment in ARTEMIS-IPF study (figure 1), 315 patients had both a high-resolution chest CT (a required study procedure) and a surgical lung biopsy sampling (not a required study procedure but obtained as part of standard clinical care before enrolment) that was interpreted by the local radiologists and pathologists. Figure 2 shows representative examples of high-resolution CT images. Six screened participants had surgical lung biopsy data but not

Discussion

For assessment of patients with interstitial lung disease, presence of unambiguous honeycombing on a high-resolution CT has a valuable positive predictive value for usual interstitial pneumonia.1, 3, 4, 5, 6, 7, 10, 11, 12 When honeycombing is not present or minimal, diagnosis of idiopathic pulmonary fibrosis is challenging. Present guidelines recommend that patients suspected to have idiopathic pulmonary fibrosis with possible usual interstitial pneumonia pattern on high resolution CT also

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