Idiopathic Pulmonary Fibrosis (IPF) Workup

Results from routine laboratory studies are nonspecific for the diagnosis of idiopathic pulmonary fibrosis; however, some laboratory studies may be helpful for ruling out other causes of interstitial lung disease. Reportedly, up to 30% of patients with idiopathic pulmonary fibrosis (IPF) have positive tests for antinuclear antibodies or rheumatoid factor; however, these titers are generally not high. ^[5] The presence of high titers of antinuclear antibodies or rheumatoid factor may suggest the presence of a connective-tissue disease. The C-reactive protein value and erythrocyte sedimentation rate can be elevated in patients with idiopathic pulmonary fibrosis; however, this finding is nondiagnostic. Although chronic hypoxemia is a common finding in patients with idiopathic pulmonary fibrosis, polycythemia is a rare finding on laboratory studies.

It is strongly recommended to not measure matrix metalloproteinase (MMP)–7, surfactant protein D (SPD), chemokine ligand (CCL)–18, or Krebs von den Lungen-6 for the purpose of distinguishing IPF from other interstitial lung diseases. ^[3]

Chest radiography

The chest radiograph lacks diagnostic specificity for idiopathic pulmonary fibrosis. Virtually all patients with idiopathic pulmonary fibrosis (IPF) have an abnormal chest radiograph at the time of diagnosis. The typical findings are peripheral reticular opacities (netlike linear and curvilinear densities) predominantly at the lung bases (see image below). Honeycombing (coarse reticular pattern) and lower lobe volume loss can also be seen. ^[8]

High-resolution computed tomography

High-resolution computed tomography (HRCT) findings are significantly more sensitive and specific for the diagnosis of idiopathic pulmonary fibrosis and are an essential component of the diagnostic pathway of idiopathic pulmonary fibrosis. ^[41] On HRCT images, idiopathic pulmonary fibrosis is characterized by patchy, peripheral, subpleural, and bibasilar reticular opacities (see image below).

Reticular opacities refer to the fine network of lines that sometimes include interlobular septal thickening and/or intralobular lines. Areas that are severely involved with reticular markings may also demonstrate traction bronchiectasis. Subpleural honeycombing (< 5-mm round translucencies with a density equal to that of air) is also a common finding (see image below).

Ground-glass opacities can be found but are less extensive than reticular abnormalities. ^[8] Reticular opacities and honeycombing seen on HRCT imaging correlates histologically with fibrosis and honeycombing. The presence of subpleural honeycombing, traction bronchiectasis, and thickened interlobular septae increase the specificity of HRCT for diagnosing idiopathic pulmonary fibrosis. ^[8] Patients with typical changes of idiopathic pulmonary fibrosis on HRCT imaging have a worse prognosis compared with patients with biopsy-proven usual interstitial pneumonia and atypical changes of idiopathic pulmonary fibrosis on HRCT imaging. ^[32]

Multiple studies have documented that the accuracy of a confident diagnosis of usual interstitial pneumonia made on the basis of HRCT imaging findings by an experienced observer exceeds 90%. ^[8] However, several clinical conditions may be associated with the radiologic or histologic pattern of usual interstitial pneumonia and must therefore be considered in the differential diagnosis of usual interstitial pneumonia diagnosed on the basis of HRCT imaging.

The differential diagnosis of ground-glass opacities on HRCT imaging include heart failure, nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and hypersensitivity pneumonitis. Fine nodules are suggestive of hypersensitivity pneumonitis, granulomatous infection, or metastatic malignancy. Upper lobe disease is the predominant pattern in hypersensitivity pneumonitis, a variety of pneumoconioses, sarcoidosis, and eosinophilic pneumonia. ^[5] Lymphadenopathy is associated with sarcoidosis and other granulomatous disease. Idiopathic pulmonary fibrosis and NSIP can have indistinguishable clinical presentations, and understanding how HRCT imaging can help to distinguish between these two entities is important (see image below).

The abnormalities in NSIP usually predominate in the middle and lower lungs. NSIP is less likely to have a subpleural distribution compared with usual interstitial pneumonia. Ground-glass opacities are a frequent feature of NSIP and are reported to be found in 76-100% of cases. ^[8] Finally, honeycombing is less common than in usual interstitial pneumonia, with the prevalence ranging from 0-30% in different series. ^[8] Honeycombing is mainly seen in patients with purely fibrotic NSIP.

Based on an updated review by Lynch et al for the diagnosis of idiopathic pulmonary fibrosis, four radiologic diagnostic categories are recommended for use in interpreting HRCT patterns. ^[42]

See the image below.

Typical radiologic UIP pattern is as follows:

• Subpleural and basal predominant; distribution is often heterogeneous
• Honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis

Probable UIP pattern is as follows:

• Subpleural and basal predominant; distribution is often heterogeneous
• Reticular pattern with peripheral traction bronchiectasis or bronchiolectasis
• May have mild ground-glass opacities

Indeterminate pattern for UIP is as follows:

• Subpleural and basal predominant
• Subtle reticulation; may have mild ground-glass opacities or distortion ("early UIP pattern")
• CT features and/or distribution of lung fibrosis that do not suggest any specific etiology ("truly indeterminate")

Alternative diagnosis pattern is findings suggestive of another diagnosis based on (1) CT features, (2) predominant distribution, and (3) others.

CT features include the following:

• Cysts
• Marked mosaic attenuation
• Predominant ground-glass opacities
• Profuse micronodules
• Centrilobular nodules
• Nodules
• Consolidation

Predominant distribution is as follows:

• Peribronchovascular
• Perilymphatic
• Upper or mid lung

Other findings are as follows:

• Pleural plaques (consider asbestosis)
• Dilated esophagus (consider connective-tissue disease)
• Distal clavicular erosions (consider rheumatoid arthritis)
• Extensive lymph node enlargement (consider other etiologies)
• Pleural effusions, pleural thickening (consider connective-tissue disease/drugs)

Pulmonary function testing

The typical findings on pulmonary function tests in patients with idiopathic pulmonary fibrosis are a restrictive ventilatory defect and a reduced diffusion capacity for carbon monoxide. ^[6] These findings are nonspecific and should be used in conjunction with clinical, radiologic, and pathologic information to ensure an accurate diagnosis of idiopathic pulmonary fibrosis (IPF).

In patients with idiopathic pulmonary fibrosis, a restrictive ventilatory defect is typically present. Vital capacity, functional residual capacity, total lung capacity, and forced vital capacity (FVC) all are reduced. Additionally, the static pressure-volume curve is shifted downward and to the right as a result of decreased lung compliance. ^[6] Obstructive ventilatory defects are not common. However, if present, they may suggest the coexistence of chronic obstructive pulmonary disease.

Prognostication in idiopathic pulmonary fibrosis relies on serial assessments of FVC. Patients who have a greater than 10% decline in FVC (percent predicted) over 6 months, have a 2.4-fold increased risk of death. Additionally, in patients who do not desaturate to less than 88% during a 6-minute walk test (6MWT), the only strong predictor of mortality is a progressive decline in FVC (>10% after 6 mo). ^[33] As a result of these findings, change in FVC is being used more frequently as a primary end point in clinical trials.

A large study was completed in 2012 to estimate the minimal clinically important difference (MCID) of FVC in patients with IPF. In this study, data was used from 1,156 patients included in two clinical trials investigating IFN-γ1β. This study found that the hazard ratio for the one-year risk of death was 2.14 (1.43-3.20) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%. ^[43]

Impaired gas exchange is demonstrated by the decreased diffusion capacity of carbon monoxide (DL_CO). In idiopathic pulmonary fibrosis, the reduced DL_CO may precede the development of abnormal lung volumes. Additionally, DL_CO is reduced to a greater extent in idiopathic pulmonary fibrosis compared with other idiopathic interstitial pneumonias. ^[6] Prognostication in idiopathic pulmonary fibrosis also relies on serial assessments of DL_CO. A baseline DL_CO below 35% is correlated with increased mortality. Additionally, a decline in DL_CO greater than 15% over 1 year is also associated with increased mortality. ^[33]

6-Minute walk testing

The 6MWT is a marker of functional exercise capacity that is being increasingly used in the initial and longitudinal clinical assessment of patients with idiopathic pulmonary fibrosis. Desaturation below the threshold of 88% during the 6MWT has been associated with an increased mortality. ^[33] Additionally, in patients with idiopathic pulmonary fibrosis who desaturate to less than 88% during a 6MWT, a progressive decline in DL_CO (>15% after 6 mo) is a strong predictor of increased mortality. ^[7]

Heart rate recovery (HRR), specifically the failure of the heart rate to decline at 1 or 2 minutes postexercise, is associated with increased mortality. A 2009 retrospective analysis found that the failure of the heart rate to decline after exertion (by >13 beats at 1 min or by >22 beats at 2 min) is a strong predictor of increased mortality. ^[44]

A study by du Bois and colleagues estimated the minimal clinically important difference in the 6MWT in 822 patients with idiopathic pulmonary fibrosis. For patients who had a decline in 6MWT of 26-50 meters at 24 weeks, the hazard ratio for death at 1 year was 3.59 (1.95-6.63). For patients who had a decline in the 6MWT of more than 50 meters at 24 weeks, the hazard ratio for death at 1 year was 4.27 (2.57-7.10). The minimal clinically important difference in 6MWT was distance is 24-45 meters. ^[45]

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) has been an immensely useful research tool in idiopathic pulmonary fibrosis. However, the role of BAL in the clinical diagnosis of idiopathic pulmonary fibrosis remains limited. Increased numbers of neutrophils in BAL fluid are found in 70-90% of all patients with idiopathic pulmonary fibrosis, and increased numbers of eosinophils in BAL fluid are found in 40-60% of all patients with idiopathic pulmonary fibrosis. Previous studies have demonstrated that the absence of BAL fluid lymphocytosis is important for the diagnosis of idiopathic pulmonary fibrosis. A 2009 study suggests that BAL fluid analysis has an additional benefit for the diagnosis of idiopathic pulmonary fibrosis. The study demonstrated the discriminating power of a cut-off level of less than 30% lymphocytosis in BAL fluid in distinguishing idiopathic pulmonary fibrosis from nonidiopathic pulmonary fibrosis diagnoses. ^[46]

BAL is not required for the diagnosis of idiopathic pulmonary fibrosis and is not recommended for patients with newly detected interstitial lung disease of apparently unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of UIP. ^[3] However, BAL fluid analysis can be useful to exclude other alternative diagnoses. Appropriate analysis of BAL fluid may demonstrate the presence of infection, malignancy, alveolar proteinosis, eosinophilic pneumonia, or occupational dusts.

Cellular analysis of BAL fluid is suggested (conditional recommendation) for patients with new detected interstitial lung disease who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis. ^[3]

BAL fluid neutrophilia has been demonstrated to predict early mortality. One study demonstrated a linear relationship between increasing neutrophil percentage and the risk of mortality. Each doubling in baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of death or transplantation in the first year after presentation. ^[34] Additionally, studies of BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with idiopathic pulmonary fibrosis and that MMP7 levels may correlate with disease severity. ^[1]

Transthoracic echocardiography

Studies have demonstrated that pulmonary hypertension is present at rest in approximately 20-40% of idiopathic pulmonary fibrosis patients who are listed for lung transplantation. ^[4] The US National Institutes of Health (NIH) definition of pulmonary arterial hypertension is a mean pulmonary artery pressure greater than 25 mmHg at rest with a normal pulmonary capillary wedge pressure measured by right-sided heart catheterization. Generally, transthoracic echocardiography is an excellent modality to detect pulmonary hypertension. However, in patients with chronic lung disease, including idiopathic pulmonary fibrosis, studies have shown a variable performance for transthoracic echocardiography to detect pulmonary hypertension. ^[4]

Bronchoscopy

As previously stated, bronchoscopy with BAL and/or transbronchial biopsy is not required for the diagnosis of idiopathic pulmonary fibrosis. However, it can be used to ensure that alternative diagnoses are excluded. In cases requiring histopathology, the specificity and positive predictive value of UIP pattern identified by transbronchial biopsy has not been rigorously studied. ^[1]

BAL is not required for the diagnosis of idiopathic pulmonary fibrosis and is not recommended for patients with newly detected interstitial lung disease of apparently unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of UIP. ^[3]

Cellular analysis of BAL fluid is suggested (conditional recommendation) for patients with newly detected interstitial lung disease who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis. ^[3]

The 2018 guidelines made no recommendation for or against transbronchial lung biopsy for patients with newly detected interstitial lung disease of unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis. ^[3]

Transbronchial cryobiopsy

A detailed search of the current evidence was concluded in the 2018 guidelines regarding the use of transbronchial cryobiopsy, and this search indicated enthusiasm regarding the current evidence suggesting a positive role for it in the workup of patients with interstitial lung disease with probable, indeterminate, or compatible with alternative pattern to UIP; however, this was offset by concern about the lack of standardized procedure and approach and the heterogeneous rates of adverse events noted in previous studies. ^{[47, 48, 49]} Therefore, the panel identified many questions that need to be answered before recommending widespread use of cryobiopsy, including the number of samples that should be obtained, the location from which the biopsies should be obtained, and the duration of time the Cryo probe should be cooled, among others, and it concluded the urgent need for standardization of this procedure to balance its diagnostic yield compared with its complications.

Surgical lung biopsy

A surgical lung biopsy specimen can be obtained through either an open lung biopsy or video-assisted thoracoscopic surgery (VATS). A surgical lung biopsy provides the best sample for which to distinguish usual interstitial pneumonia from other idiopathic interstitial pneumonias. VATS is preferred because it is associated with less morbidity and a shorter hospital stay compared with open lung biopsy.

Given the high-quality evidence regarding HRCT specificity for the recognition of histopathologic UIP pattern, surgical lung biopsy is not essential in making the diagnosis. ^[1] In patients with UIP pattern on HRCT a surgical lung biopsy is not needed for the diagnosis of idiopathic pulmonary fibrosis.

However, for patients with newly diagnosed interstitial lung disease of unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis, a surgical lung biopsy is suggested (conditional recommendation). ^[3]

The previously described major and minor criteria for the clinical diagnosis of idiopathic pulmonary fibrosis have been eliminated. ^[10]

The diagnosis of idiopathic pulmonary fibrosis now requires the following ^{[1, 3]} :

• The exclusion of other known causes of interstitial lung disease (ILD), including domestic and occupational environmental exposures, connective tissue disease, and drug toxicity

• The presence of a UIP pattern on HRCT in patients not subjected to a surgical lung biopsy

• Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy

The histopathological lesion associated with idiopathic pulmonary fibrosis is usual interstitial pneumonia. Usual interstitial pneumonia is characterized by a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycomb change, which results in a patchwork appearance at low magnification (see image below). ^[13]

Fibrosis predominates over inflammation in usual interstitial pneumonia. Fibroblastic foci represent microscopic zones of acute lung injury and are randomly distributed within areas of interstitial collagen deposition and consist of fibroblasts and myofibroblasts arranged in a linear fashion within a pale-staining matrix. ^[13] Although fibroblastic foci are not specific for usual interstitial pneumonia, they represent an important diagnostic criterion.

Another important diagnostic criterion for usual interstitial pneumonia is honeycomb change. Microscopically, honeycomb change is defined by cystically dilated bronchioles lined by columnar respiratory epithelium in scarred, fibrotic lung tissue. ^[13] Dense eosinophilic collagen without associated honeycomb change signifies fibrotic scars and is also characteristic of usual interstitial pneumonia. Interstitial inflammation, consisting of patchy alveolar septal infiltrates of mononuclear cells, is not predominant in usual interstitial pneumonia.

The usual interstitial pneumonia histologic pattern can be associated with other diseases besides idiopathic pulmonary fibrosis. These include asbestosis, collagen-vascular disease, fibronodular sarcoidosis, hypersensitivity pneumonitis, and toxic drug reactions (eg, to amiodarone, bleomycin, or nitrofurantoin). Correlation with clinical history is needed to identify these conditions.

In pathology specimens taken during acute exacerbations of idiopathic pulmonary fibrosis, microscopy reveals a combination of usual interstitial pneumonia with superimposed diffuse alveolar damage. Alveolar septa are expanded by more extensive fibroblast proliferation than is seen in conventional fibroblast foci. Additionally, marked hyperplasia of type 2 pneumocytes and hyaline membrane remnants is present. ^[13]

UIP histopathology patterns and features are as follows ^[3] :

• Dense fibrosis with architectural distortion (ie, destructive scarring and/or honeycombing)
• Predominant subpleural and/or paraseptal distribution of fibrosis
• Patchy involvement of lung parenchyma by fibrosis
• Absence of features to suggest an alternate diagnosis

Probable UIP histopathology patterns and features are as follows ^[3] :

• Some histologic features from UIP are present but to an extent that precludes a definite diagnosis of UIP AND
• Absence of features to suggest an alternative diagnosis OR honeycombing only

Indeterminate for UIP histopathology patterns and features are as follows ^[3] :

• Fibrosis with or without architectural distortion, with features favoring either a pattern other than UIP or features favoring UIP secondary to another cause
• Some histologic features of UIP but with other features suggesting an alternative diagnosis

Alternative diagnosis histopathology patterns and features are as follows ^[3] :

• Features of other histologic patterns of idiopathic interstitial pneumonias (eg, absence of fibroblast foci or loose fibrosis) in all biopsy specimens
• Histologic findings indicative of other diseases (eg, hypersensitivity pneumonitis, Langerhans cell histiocytosis, sarcoidosis, lymphangioleiomyomatosis)

If the HRCT pattern is consistent with an alternative diagnosis but histopathology demonstrates UIP, then idiopathic pulmonary fibrosis is likely. ^[3]

If the HRCT pattern is consistent with an alternative diagnosis and histopathology demonstrates probable UIP or indeterminate UIP, then the diagnosis is likely not IPF. ^[3]

If the HRCT pattern is indeterminate and histopathology is probable UIP, then the diagnosis is likely idiopathic pulmonary fibrosis. ^[3]

If the HRCT pattern is probable UIP and histopathology is indeterminate for UIP, the diagnosis is likely idiopathic pulmonary fibrosis. ^[3]

If the HRCT pattern is indeterminate and histopathology is indeterminate for UIP, the diagnosis is indeterminate. ^[3]

Any pattern on HRCT associated with a surgical lung biopsy finding of alternative diagnosis is not consistent with the diagnosis of idiopathic pulmonary fibrosis. ^[3]

Multidisciplinary discussion amongst pulmonologists, radiologists, and pathologists experienced in the diagnosis of interstitial lung disease is of utmost importance to an accurate diagnosis. ^{[1, 3]}