ANNOTATED IPF GUIDELINES

An Official 2022 ATS/ERS/JRS/ALAT Clinical Practice Guideline.

Raghu G, Remy-Jardin M, Richeldi L et al. Am J Respir Crit Care Med. 2022;205(9):e18-e47.

Note: text in italics are excerpts from Raghu G, Remy-Jardin M, Richeldi L et al. Am J Respir Crit Care Med. 2022;205(9):e18-e47.

DEFINITION OF IPF^1,2

Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and histologic features of usual interstitial pneumonia (UIP).

The definition of IPF requires the exclusion of other forms of interstitial pneumonia including other idiopathic interstitial pneumonias and interstitial lung disease (ILD) associated with environmental exposure, medication, or systemic disease.

IPF (n.):^3,4 a chronic, progressive form of fibrotic interstitial pneumonia of unknown cause; associated with UIP patterns on high-resolution computed tomography (HRCT) and histopathology; requires exclusion of other forms of interstitial pneumonia (IP).

CLINICAL PRESENTATION^1,2,5,6

[IPF] occurs primarily in older adults, is characterized by progressive worsening of dyspnea and lung function, and has a poor prognosis.

It should be considered in all adult patients with unexplained chronic exertional dyspnea, cough, bibasilar inspiratory crackles, and/or digital clubbing.

The incidence of IPF increases with older age, with presentation typically occurring in the sixth and seventh decades.

Patients with IPF aged less than 50 years are rare; such patients may subsequently manifest avert features of an underlying connective tissue disease that was subclinical at the time IPF was diagnosed.

More men have been reported with IPF than women, and the majority of patients have a history of cigarette smoking.

CONSIDER IPF IN PATIENTS WITH^1,2,5,6

• Chronic, exertional dyspnea 
• Cough
• Bibasilar crackles
• Digital clubbing

DIAGNOSTIC CRITERIA^1,2

The diagnosis of IPF requires the following:

1. Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity) and either #2 or #3.
2. The presence of the HRCT pattern of UIP
3. Specific combinations of HRCT and histopathologic patterns in patients subjected to lung tissue sampling.

MEDICAL HISTORY²

Should patients with newly detected ILD of unknown cause who are clinically suspected of having IPF undergo a detailed, prompted history to exclude potential causes of the ILD?

Patients with suspected IPF should have a detailed history of medications, exposures, and family history performed to rule out other causes of lLD.²

SEROLOGIC TESTING²

Should patients with newly detected ILD of unknown cause who are clinically suspected of having IPF undergo serological testing to exclude connective tissue diseases (CTDs) as potential causes of the ILD?

Ruling out other known causes of ILD (e.g., CTD) is critical to diagnosing IPF.² The guidelines recommend performing testing for CTD in patients with positive clinical manifestations, serologies, or other characteristics atypical for IPF.²

BRONCHOALVEOLAR LAVAGE (BAL)^1,2

Should patients with newly detected ILD of unknown cause who are clinically suspected of having IPF undergo cellular analysis of their BAL fluid?

Cellular analysis of BAL fluid may be appropriate in patients with newly detected ILD of apparently unknown cause who are clinically suspected of having IPF, if they have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis. BAL may be performed before multidisciplinary discussion (MDD) in select patients being evaluated in experienced centers.^1,2

Patients with suspected ILD who have a pattern other than UIP on HRCT may benefit from analysis of BAL fluid to rule out potential other ILDs, most notably eosinophilic pneumonia and sarcoidosis.²

HRCT PATTERNS IN IPF^1,2,7

The guidelines recommend the use of 4 categories for HRCTs in diagnosing IPF.

• UIP
• Probable UIP
• Indeterminate for UIP
• Alternative diagnosis

The UIP pattern is a hallmark of IPF, but it can also be seen in patients with fibrotic hypersensitivity pneumonitis (HP), connective tissue disease, or exposure-related ILDs.

The presence of an HRCT pattern of UIP is diagnostic for IPF when combined with the exclusion of other known causes of ILD.

HRCT features frequently seen in UIP include honeycombing with or without traction bronchiectasis/bronchiolectasis in a subpleural and basal distribution with the concurrent presence of mild ground-glass opacification and fine reticulation.

A definite UIP pattern on HRCT has a 90%-100% positive predictive value (PPV) for IPF.^8-13

LUNG BIOPSY^1,2

For patients with newly detected ILD of unknown cause who are clinically suspected of having IPF, should lung biopsy be performed to ascertain the histopathology diagnosis of UIP pattern?

Lung biopsy is recommended in those patients with newly detected ILD of unknown cause who are clinically suspected of having IPF and have an HRCT pattern of probable UIP, indeterminate for UIP, or alternative diagnosis.² Patients in the appropriate clinical setting (e.g., 60 year old, male, smoker) with a probable UIP pattern on HRCT may be diagnosed with IPF after MDD discussion.¹

We suggest that transbronchial lung biopsy (TBLC) be regarded as an acceptable alternative to surgical lung biopsy (SLB) for making a histopathological diagnosis in patients with ILD of undetermined type in medical centers with experience performing and interpreting TBLC (conditional recommendation, very low quality evidence).¹

HISTOPATHOLOGIC PATTERNS IN IPF^1,2,7

The guidelines recommend the use of 4 categories for histopathologic classification in diagnosing IPF. The presence of UIP pattern on histopathology when combined with the exclusion of other known causes of ILD is likely to indicate IPF. Other histopathologic patterns should be considered with the corresponding HRCT patterns and clinical information to help inform the most likely differential diagnosis.

HISTOPATHOLOGY DIAGNOSTIC CATEGORIES^1,2,7

• UIP
• Probable UIP
• Indeterminate for UIP
• Alternative diagnosis

HISTOPATHOLOGY FEATURES OF UIP^1,2,7

A diagnosis of UIP made by biopsy is predicated on a combination of the following:

• Patchy dense fibrosis with architectural distortion (i.e., destructive scarring and/or honeycombing)
• Predilection for subpleural and paraseptal lung parenchyma
• Fibroblast foci
• Absence of features that suggest an alternative diagnosis

Biopsy may also reveal mild inflammation consisting of patchy interstitial infiltrate of lymphocytes and plasma cells associated with hyperplasia of type 2 pneumocytes and bronchiolar epithelium. The fibrotic zones involve deposition of dense collagen with scattered subepithelial foci of proliferating fibroblasts/myofibroblasts (i.e. fibroblast foci).²

COMBINATIONS OF RADIOLOGIC AND PATHOLOGIC DATA CAN POINT TO A DIAGNOSIS¹

Reprinted with permission of the American Thoracic Society. Copyright © 2022 American Thoracic Society. All rights reserved. Raghu G et al. 2022. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 205(9):e18-e47. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

^*“Clinically suspected of having IPF” is defined as unexplained patterns of bilateral pulmonary fibrosis on chest radiography or chest computed tomography, bibasilar inspiratory crackles, and age > 60 years. Middle-aged adults (>40 and <60 yr old) can rarely present with otherwise similar clinical features, especially in patients with features suggesting familial pulmonary fibrosis.

^†Diagnostic confidence may need to be downgraded if histopathological assessment is based on transbronchial lung cryobiopsy given the smaller biopsy size and greater potential for sampling error compared with surgical lung biopsy.

^‡IPF is the likely diagnosis when any of the following features are present: 1) moderate to severe traction bronchiectasis and/or bronchiolectasis (defined as mild traction bronchiectasis and/or bronchiolectasis in four or more lobes, including the lingula as a lobe, or moderate to severe traction bronchiectasis in two or more lobes) in a man >50 years old or in a woman >60 yr old, 2) extensive (>30%) reticulation on HRCT and age > 70 yr, 3) increased neutrophils and/or absence of lymphocytosis in BAL fluid, and 4) multidisciplinary discussion produces a confident diagnosis of IPF.

^§Indeterminate for IPF 1) without an adequate biopsy remains indeterminate and 2) with an adequate biopsy may be reclassified to a more specific diagnosis after multidisciplinary discussion and/or additional consultation.

• A UIP pattern on HRCT in combination with a thorough clinical history is diagnostic for IPF
• In cases where HRCT does not show a UIP pattern, certain combinations of HRCT patterns and histopathologic patterns can help determine the likelihood that a patient has IPF

MULTIDISCIPLINARY DISCUSSION^1,2

Should patients with newly detected ILD of unknown cause who are clinically suspected of having IPF be the subject of MDD for decision-making?

The guidelines recommend the use of an MDD to guide decision making in cases of suspected IPF. It is the most beneficial in those cases where HRCT pattern is indeterminate for UIP or suggestive of alternate diagnosis, or where there is conflicting clinical, radiologic, and/or histologic data to come to a confident diagnosis.