Idiopathic pulmonary fibrosis presents a number of diagnostic challenges for clinicians. Clinical labs are part of the continuum that allows for successful diagnosis and management of the disease.

By Chris Wolski

While the exact cause of idiopathic pulmonary fibrosis is not always known, clinicians have a wealth of diagnostic tools at their disposal to help identify the potential causes of the disease and, if it is indeed idiopathic pulmonary fibrosis, potential treatments to help manage it.

Ganesh Raghu, MD, a professor of medicine, laboratory medicine, and pathology and the director of the Center for Interstitial Lung Disease at the University of Washington in Seattle, Washington, recently spoke with CLP about the challenges of diagnosing idiopathic pulmonary fibrosis and the best diagnostic best practices clinicians should follow.

Raghu’s answers have been edited for length and clarity.

CLP: What are some of the risk factors for idiopathic pulmonary fibrosis?

Ganesh Raghu: Idiopathic pulmonary fibrosis (IPF)—a progressive fibrotic lung disease limited to lungs occurring in adults—is more likely to occur in those who are 60 years and older and individuals with a history of smoking. There are additional factors that put thousands of people at higher risk for IPF, including genetic predisposition factors, a family history of interstitial lung disease (ILD), as well as the use of certain medications and environmental exposures.

It is challenging for doctors to figure out what causes pulmonary fibrosis (PF). Sometimes they are able to identify one or more causes of the disease, which can surface during the evaluation process. When the cause of the PF is unknown, it is called “idiopathic.” The term “idiopathic interstitial pneumonia” (IIP) is used to describe a heterogenous group of acute chronic ILD of unknown cause. It is only a subgroup of patients with IIP who have idiopathic pulmonary fibrosis (IPF). IPF is a specific disease entity and is a progressive fibrotic lung disease limited to lungs manifesting in adults, typically in males who are 60-plus years old. The typical clinical setting that raises the index of suspicion for IPF is therefore a 60-plus-year-old male, with unexplained exertional shortness of breath, cough, radiological evidence of pulmonary fibrosis without exposures in the environment, and/or medications known to cause/associated with PF and /or known autoimmune, connective tissue diseases. Thus, it is important to note that not all patients who have PF of unknown cause, i.e., without an identifiable cause and/or systemic clinical conditions such as connective tissue disease, have IPF and they may have other subgroups of idiopathic interstitial pneumonias (IIP).

IPF is a severe respiratory disease characterized by shortness of breath, dry cough, and reduced respiratory function with low levels of oxygen. Diagnosing IPF is challenging because these symptoms are non-specific. They occur with all other interstitial lung diseases and with other respiratory problems, leading to a delay in diagnosis and frequent misdiagnoses. More often than not, IPF is in the late stages of the disease course at diagnosis and has a median survival of 3 to 5 years. Since antifibrotic drugs indicated for treatment of IPF that may slow the rate of progression of IPF are currently available for clinical use, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.

CLP: So, what is the diagnostic process?

Raghu: In 2011, evidence-based clinical practice guidelines were published by an expert international committee representing major respiratory societies in the world, including the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Society (ALAT). The guidelines established diagnostic criteria and treatment strategies for IPF. New treatment recommendations were updated in the 2015 guidelines and the diagnostic criteria was refined and updated in the 2018 guidelines. These guidelines define four radiographic image patterns on the basis of lung imaging, as well as histopathology features of usual interstitial pneumonia (UIP) pattern and characteristic features of IPF, and provide diagnostic algorithm as well as treatment recommendations based on evidence. The diagnostic criteria updated in 2018 was presented at the Pulmonary Fibrosis Foundation (PFF) Summit last year [2021—editor].

And, just recently in May 2022, we updated the IPF guidelines and addressed the progression to pulmonary fibrosis among patients with other interstitial lung diseases (ILDs). Progressive pulmonary fibrosis was defined as meeting two of three criteria of worsening symptoms, radiologic progression, and physiologic progression within the previous year, with no alternative explanation among patients with an ILD other than IPF.

As part of the criteria, diagnosis of IPF requires exclusion of other known causes of ILD, e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity. Therefore, clinicians should first obtain a detailed history of medication use and environmental exposures at home, work, and other places the patient frequently visits to exclude potential causes of ILD. Serologic testing and physical examination should also be conducted to exclude connective tissue disease as a cause.

I cannot overstate the importance of eliciting a detailed medical history. Without this history, a diagnosis of IPF might be made erroneously, since fibrotic hypersensitivity pneumonitis can present with a pattern of UIP, and this is also a recognized feature of connective tissue disease-related interstitial lung disease and thus the UIP pattern is non-specific.

If a potential cause for ILD is identified, the patient should then undergo a thorough evaluation to confirm or exclude the specific disease—hypersensitivity pneumonitis, connective tissue disease (CTD), pneumoconiosis and iatrogenic causes (e.g., drug toxicity, irradiation).

Patients with newly diagnosed ILD should undergo high-resolution computed tomography (HRCT) of the chest to determine whether the images indicate a usual interstitial pneumonia (UIP) pattern, probable UIP, an indeterminate pattern or an alternate diagnosis.

If a specific diagnosis is not made or no potential cause for ILD is identified, further evaluation is influenced by the patterns of HRCT images of the chest and supportive clinical findings surfaced in the course of multidisciplinary discussion (MDD) to ascertain or exclude the diagnosis of IPF. Our current guidelines recommend MDD for the evaluation and diagnosis of IPF, which allows the clinician, radiologist and pathologist to work together to establish an accurate diagnosis.

Sometimes, even after all of the initial diagnostic evaluations are complete, including detailed medical history, laboratory testing (serology), and review of the HRCT image patterns with the radiologist, the physician, guided by the MDD, might need to pursue invasive diagnostic interventions such as bronchoscopy, lung biopsy in the patient who does not have increased risks for procedure-related complications.

CLP: What are some of the clinical diagnostic best practices that pathologists and laboratorians should follow?

Raghu: Consideration of exposure history, ancillary testing for antigen sensitization, e.g., antigen-specific antibodies, HRCT features, and need for demonstration of bronchoalveolar lavage lymphocytosis in individual cases in MDD may be helpful in assigning diagnostic confidence and determining the need for a lung biopsy.

Radiologists play a critical role in the evaluation and diagnosis of suspected IPF. Many forms of pulmonary fibrosis look similar on a CT scan to the untrained eye and mind, but subtle image patterns and distribution of abnormal findings on HRCT scans are critically important when trying to identify the type of pulmonary fibrosis a patient might have. Adult patients greater than 50 years of age with newly detected ILD of apparently unknown cause are clinically suspected of having IPF if they have unexplained symptomatic or asymptomatic patterns of bilateral fibrosis on a chest radiograph or chest CT scan, bibasilar inspiratory crackles and an age typically older than 60 years. In patients with familial pulmonary fibrosis, IPF may manifest in younger patients—middle-aged patients less than 60 years.

Accurate pattern identification of UIP on imaging is key in the multidisciplinary discussions (MDD) and prevents the need for a lung biopsy. When scan patterns point to indeterminate or alternate diagnosis, further diagnostic interventions, such as bronchoalveolar lavage for cellular analyses and lung biopsy, should be considered in patients who do not have increased risks for procedure-related complications. Lung biopsy for histopathology can be obtained by fiberoptic bronchoscopy (transbronchial forceps biopsy, transbronchial cryobiopsy, or surgical lung biopsy). The 2022 guidelines made a conditional recommendation with regard to transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy at centers with appropriate expertise to perform the transbronchial lung cryobiopsy for patients with new onset of ILD of unknown cause. A genomic classifier for a molecular diagnosis of UIP pattern in transbronchial lung biopsy is currently available in clinical practice in the U.S. No recommendation was made in favor of or against genomic classifier testing (GCT) for diagnosing usual interstitial pneumonia in patients with ILD of undetermined type. It is hoped that further studies will provide additional evidence regarding GCT to update the guideline for this new diagnostic intervention for patients suspected with IPF.

In the appropriate clinical setting, and in a patient suspected to have IPF and without exposure history to raise the index of suspicion for diagnosis of fibrotic hypersensitivity pneumonitis and without clinical or serological evidence for connective tissue disease,  patients with an HRCT pattern of definite usual interstitial pneumonia (UIP) do not need to undergo further diagnostic interventions / lung biopsy because a confident diagnosis can be made on clinical grounds alone (>90% confidence). The confident diagnosis for a clinical diagnosis of IPF following a MDD may also be high in patients with the HRCT pattern of probable UIP pattern, and surgical lung biopsy may not be essential for such patients in the appropriate clinical setting.

In essence, the need for histopathology diagnosis of UIP pattern in lung biopsy in patients with HRCT patterns other than definite UIP must be considered only in patients who do not have increased risks for procedure-related complications and in patients whose diagnosis is uncertain after MDD, utilizing all clinical details that includes exposure and family medical history, radiological, laboratory, and bronchoalveolar cellular analyses. The need for surgical lung biopsy to pursue a histopathological diagnosis must be a last resort for patients who do not have increased risks for surgical complications.  

CLP: More specifically, how are clinical labs involved in the diagnosis of pulmonary fibrosis?

Raghu: Results from routine laboratory studies are non-specific for the diagnosis of IPF. Some tests that may be helpful to pursue further diagnostic interventions to exclude other causes of interstitial lung disease and these include specific Immunoglobulin G (IgG) against antigens known to cause hypersensitivity pneumonitis (“hypersensitivity pneumonitis panel”), serology for connective tissue disease that includes antinuclear antibodies or rheumatoid factor titers (positive results in about 30% of patients with IPF, but the titers are generally not high), ant-CCP (cyclic citrullinated peptide), myositis, and ANCA panel (antineutrophil cytoplasmic antibodies).

CLP: Certainly biopsies or any other invasive sample collection carries risk that should be avoided if it puts the patient at significant risk. Are there any cutting-edge diagnostic technologies or alternatives that are as effective, and also minimally invasive?

Raghu: Surgical lung biopsy has an overall diagnostic yield of approximately 90% for ILD when considered in the context of MDD. However, it is not required to achieve a confident diagnosis in a large proportion of cases of fibrotic interstitial lung disease (fILD), and it is therefore critical that patients undergo a thorough non-invasive evaluation before consideration of a surgical lung biopsy.

The availability of a clinically validated genomic classifier—the Envisia Genomic Classifier for UIP pattern in transbronchial forceps biopsy for patients with fibrotic ILD and IPF—will be a significant step forward in incorporating the results in the MDD, ensuring an accurate and timely diagnosis in the appropriate clinical setting and might avoid the need for surgical lung biopsy in some patients.

CLP: Let’s look ahead, then. Are there any diagnostic technologies on the drawing board or being actively developed that can more effectively and safely diagnose pulmonary fibrosis?

Raghu: Again, one promising tool is the Envisia Classifier, which uses machine learning together with deep RNA sequencing to detect the presence or absence of usual interstitial pneumonia (UIP), the hallmark feature of IPF.

In the clinical utility study, known as CATALYST, researchers found that when the Envisia Classifier was used as a complement to HRCT in an MDT evaluation, there was high agreement (86%) in IPF versus non-IPF diagnoses when evaluating the same patients with HRCT and surgical histopathology results. When paired with HRCT results and patient clinical history, the Envisia Classifier gave the participating physicians a higher level of confidence in making an IPF diagnosis.

The results with molecular classification through machine learning are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses. We are hopeful that this test has the potential to ascertain the diagnosis of IPF with MDD without the need for obtaining larger lung biopsy specimens by transbronchial lung cryobiopsy or surgical lung biopsy.

CLP: Is the 2018 guideline for diagnosis of IPF being updated?

Raghu: Yes, the 2018 guideline has just been updated to clarify the diagnostic interventions, diagnostic algorithm, and management of IPF. The 2022 ATS-ERS-JRS-ALAT guideline recommendations were presented at ATS 2022 in May this year and the ATS-ERS-JRS-ALAT guideline document was published as an official ATS document in the May 1, 2022, issue of the American Journal of Respiratory and Critical Care Medicine (AJRCCM).

Future studies with blood-specific or lung-specific molecular markers, in combination with genetic factors and other clinical, physiological and imaging features to enhance diagnostic efforts, refine prognostic recommendations and influence the initial or subsequent treatment options, are warranted.

Chris Wolski is the chief editor of CLP.