Is It Idiopathic Pulmonary Fibrosis or Not?

Mary Salvatore, MD; Genta Ishikawa, MD; Maria Padilla, MD

Disclosures

J Am Board Fam Med. 2018;31(1):151-162. 

In This Article

UIP/IPF

Clinical

UIP/IPF is classified as a fibrosing IIP and is the most common subtype of IIPs. UIP is the radiographic pattern and IPF is the clinical diagnosis associated with a UIP pattern. It is limited to the lungs and has the worst prognosis with median survival estimate of 3.8 years.[6–8] It is defined as a chronic fibrosing interstitial pneumonia of unknown cause with a UIP pattern on surgical lung biopsy or on high-resolution Computer Tomography (CT) scan (histologic UIP pattern: variegated pattern of alternating areas of normal or near-normal lung, juxtaposed to areas of lung remodeling with temporal heterogeneity of fibrosis consisting of scattered fibroblastic foci in the background of dense acellular collagen, and honeycombing).[9] It frequently occurs in the elderly male population (median age, 66 years). Risk factors for disease include cigarette smoking and gastroesophageal disease.[8] Most patients with IPF demonstrate a gradual worsening of lung function over years, whereas some patients experience episodes of acute respiratory worsening despite previous stability (ie, acute exacerbation).[8] On physical examination the patients have crackles at the posterior lung bases. Pulmonary function tests demonstrate restrictive physiology with diminished Diffusion Capacity of Lungs for Carbon Monoxide (DLCO) and Forced Vital Capacity (FVC). According to the ATS/ERS/JRS/ALAT 2011 revised diagnostic criteria, the IPF diagnosis is securely established based on high-resolution computed tomography (HRCT) findings of UIP, and/or pathologic criteria, in the absence of known cause of lung fibrosis such as collagen vascular disease, drug toxicity, sarcoidosis, and various environmental exposures (i.e., CHP).[8] In some patients with definitive HRCT findings (ie, UIP pattern; discussed in the following "Radiology" section), surgical lung biopsy can be avoided in the diagnosis of IPF. The multidisciplinary discussion among pulmonologists, radiologists, and pathologists experienced in the diagnosis of interstitial lung disease (ILD) increases the accuracy of the diagnosis. Most ILD centers in the United States have a dedicated ILD multidisciplinary conference, as vital part of the diagnosis and referring patients to those centers would expedite the diagnosis.[10]

Until recently, it had been believed that UIP/IPF was driven by uncontrolled inflammation, therefore many anti-inflammatory medications (prednisone, azathioprine, N-acetylcysteine, interferon-γ, etc.) were previously administered or tested in patients with UIP/IPF.[11,12] However, recent evidence has demonstrated inefficacy or harm from these and they are not recommended therapy in the treatment of IPF.[8] In the past decade, therapeutic modalities have been targeted at mechanisms involved in the wound healing cascade (ie, antifibrotic mechanism). In late 2014, 2 drugs, pirfenidone and nintedanib, were approved by the Food and Drug Administration (FDA) for treatment of IPF based on their ability to slow disease progression. Pirfenidone, an antifibrotic drug that reduces lung fibrosis through down-regulation of the production of growth factors and procollagens I and II, was shown to reduce the rate of FVC decline as well as a statistically significant improvement in progression-free survival in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) trial,[11] which followed the PIPF004 and PIPF006 trials.[13] Likewise, nintedanib, a tyrosine kinase inhibitor, originally developed as an antivascular agent for oncology indications, was tested for efficacy against IPF in several trials,[14,15] and these showed a significant impact in rate of FVC decline relative to placebo. These trials were not powered to answer effect on survival and given the lack of the data of long-term efficacy of these agents; UIP/IPF remains a refractory disease with guarded prognosis for which further investigation of new innovative therapies is necessary.

Radiology

Radiology plays an important role in the early and correct diagnosis of UIP. HRCT scans of the chest should be performed in the supine position in full inspiration. Intravenous contrast is not indicated. Slice thickness should be between 1 and 1.25 mm. Prone CT images can be acquired if the patient has early disease and there is a concern that the findings may represent dependent atelectasis. Expiratory images can be obtained on initial imaging if hypersensitivity pneumonitis is in the differential diagnosis because expiratory imaging demonstrates air trapping, one of the radiographic hallmarks of hypersensitivity pneumonitis.

In 2011, the ATS/ERS/JRS/ALAT published evidence based guidelines for the diagnosis of IPF.[8] A "UIP pattern" radiographically was defined as subpleural basilar predominant fibrosis, reticulations, honeycombing, and absence of features that would support an alternate diagnosis (Figure 1). The correct diagnosis of honeycombing is important and as such it deserves extra attention. The definition of honeycombing described by Webb et al[16] is "rounded lucencies with shared walls in vertical stacks that are subpleural and occur in association with other findings of fibrosis." The inter-reader agreement for honeycombing (HC) is low ranging, from 0.21 to 0.31 in previous reports[17] due to mimickers of honeycombing, which include bronchiolectasis, paraseptal emphysema, and cystic bronchiectasis. If there is no honeycombing but other criteria are met, the diagnosis is a "possible UIP pattern" radiographically as per the ATS criteria (Figure 2). Recent articles support that the possible UIP pattern likely represents an early UIP pattern.[18,19]

Figure 1.

A "Usual interstitial pneumonitis (UIP) pattern" radiographically was defined by American Thoracic Society as subpleural basilar predominant fibrosis, reticulations, honeycombing, and absence of features that would support an alternate diagnosis.

Figure 2.

If there is no honeycombing but other criteria for a usual interstitial pneumonitis (UIP) pattern are met, the diagnosis is a "possible UIP pattern" radiographically as per the American Thoracic Society (ATS) criteria.

Features that would suggest an alternative diagnosis include consolidation as can be seen in organizing pneumonia (Figure 3), air trapping that is seen in hypersensitivity pneumonitis, and nodules, which are also seen in hypersensitivity pneumonitis and sarcoidosis. Ground glass opacities are frequently seen in patients with desquamative interstitial pneumonitis or respiratory bronchiolitis interstitial lung disease. Cysts occur in lymphocytic interstitial pneumonitis and lymphangioleimyomatosis among others. Bronchovascular distribution is consistent with hypersensitivity pneumonitis and NSIP and sarcoidosis. Upper lobe–predominant fibrosis is not typical of UIP and is more common with hypersensitivity pneumonitis and sarcoidosis.[8]

Figure 3.

Features that would suggest an alternative diagnosis include consolidation as can be seen in organizing pneumonia, which follows the bronchovascular bundles in this example.

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