Diagnosis

The first international guideline for diagnosing IPF was published in 2000 (53). It recommended that a thorough physical examination should be performed for every patient suspected with ILD and a careful history, including information on medications, exposures, family history and comorbidities should be taken (53). Serologic testing should be performed in patients less than 50 years of age, especially in females, since there is a high possibility of the manifestation of a CTD (53). In some cases, ILD may be the first manifestation of CTD (53). It was also recommended that a thorough history of exposures should be taken, e.g. hypersensitivity pneumonitis (HP) and asbestosis may mimic IPF (53).

In addition to typical clinical and HRCT features, the diagnosis of IPF required that there is an abnormality in lung function parameters (53). It was recommended that transbronchial biopsy (TBB) or bronchoalveolar lavage (BAL) procedures be performed in order to exclude alternative diagnoses in patients who did not undergo surgical lung biopsy (SLB) (53).

Analysis of BAL has been commonly used in the investigations of patients with ILD and IPF. An increase in the percentage of neutrophils (over 5 %) in BAL fluid has been noted in the majority of IPF patients and approximately half of the patients have an increase (over 5

%) in eosinophils (53,72). Instead, an increase in the numbers of lymphocytes has been reported to be uncommon in IPF (53,72). However, these features are not specific for IPF, since similar findings have been seen in a wide variety of other ILDs (53,73). The increases in the percentage of eosinophils, neutrophils or both in BAL fluid have been associated with worse survival in some studies (53). When the diagnostic criteria were updated in 2011, BAL and TBB were no longer required for diagnosing IPF, but BAL was considered to be feasible for excluding HP, in which more than 40 % lymphocytosis would be suggestive of HP diagnosis (1). When the diagnostic guidelines were again updated in 2018, BAL was recommended for patients with different radiological patterns other than UIP (51). The 2018 guidelines did not provide any recommendation for or against TBB (51).

Table 3 presents the radiological criteria for HRCT scanning patterns according to 2011 and 2018 criteria.

Table 3. Radiological criteria for high-resolution computed tomography (HRCT) patterns (adapted from Raghu et al. 2011 (1) and 2018 (51)).

HRCT scanning patterns according to 2011 diagnostic criteria

UIP Pattern Possible UIP Inconsistent with UIP Pattern

Subpleural, basal predominance Subpleural, basal

predominance Upper or mid-lung predominance Reticular abnormality Reticular abnormality Peribronchovascular predominance Honeycombing with or without

traction bronchiectasis Absence of features

inconsistent with UIP Extensive ground glass abnormality (extent > reticular abnormality)

HRCT scanning patterns according to 2018 diagnostic criteria

UIP Probable UIP Indeterminate for UIP Alternative diagnosis Subpleural, basal

opacity may exist CT features and/or distribution of fibrosis not HRCT,high-resolution computed tomography; UIP, usual interstitial pneumonia; CT, computed tomography

Figure 1. High-resolution computed tomography images of a patient with definite UIP pattern. Reticular pattern is basal and peripheral.

Some bronchiectasis and honeycombing are evident.

According to the 2011 guidelines, the diagnosis of IPF required A) the exclusion of other known causes of ILD B) the presence of a UIP pattern in HRCT (Table 3) and C) the specific combination of HRCT and lung biopsy pattern in patients subjected to lung biopsy (Tables 4 and 5, Figure 2) (1). In uncertain cases, the accuracy of an IPF diagnosis increases in a multidisciplinary discussion (MDD) and the MDD group should include at least experienced pulmonologists, pathologists and radiologists (1,74). In addition, a rheumatologist or occupational physician may provide supplemental expertise in some cases (51,75).

Several studies have reported that the radiological diagnosis of UIP confirms the diagnosis of IPF with 90 – 100 % certainty (1,76,77). It has been suggested that approximately one third of patients with IPF need to undergo a lung biopsy if one wishes to make an accurate diagnosis (78). The lung biopsy can be taken surgically by an open thoracotomy procedure, but currently less invasive methods i.e. VATS and transbronchial cryobiopsy, are more commonly used (1,47,79,80). In the new 2018 recommendations, the taking of a SLB is conditional i.e. SLB should be performed in HRCT patterns other than UIP for the majority of the patients, but not for a sizeable minority (51,81). The benefits of taking the SLB should outweigh the potential risks (51). The decision to perform a SLB should be made in the MDD (51). The new recommendation did not provide any recommendation for or against transbronchial cryobiopsy (51).

Similar to the radiological criteria, also a change in the histological categorization of UIP was recommended in the 2018 guideline (Table 4) (51). The histological terms are consistent with radiological terms i.e. UIP, probable UIP, indeterminate for UIP and alternative diagnosis (51). Indeterminate for UIP is characterized by a fibrosing process that does not meet the criteria for a UIP pattern or other forms of fibrotic interstitial pneumonia (Table 4) (51). Similarly to the 2011 guidelines, IPF can be diagnosed when appropriate combinations of the HRCT pattern and the histological pattern are present (Tables 5 and 6) (51).

Ascertainment or exclusion of the diagnosis of IPF should be made in the MDD (51).

Figure 2 presents the diagnostic criteria of IPF which evolved between the years 2000 – 2018.

Histological UIP pattern according to 2011 diagnostic criteria

UIP pattern Probable UIP pattern Possible UIP pattern Not UIP pattern Marked

criteria for UIP OP (can be associated with AEx) Histological UIP pattern according to 2018 diagnostic criteria

UIP Probable UIP Indeterminate for UIP Alternative diagnosis Dense fibrosis with

architectural distortion Features of other IIPs

Distribution of fibrosis

UIP, usual interstitial pneumonia; AEx, acute exacerbation of idiopathic pulmonary fibrosis; OP, organizing pneumonia; IIP, idiopathic interstitial pneumonia

Table 4. Histological criteria for UIP pattern (adapted from Raghu et al. 2011 (1) and 2018 (51) statements).

Table 5. Diagnosis of idiopathic pulmonary fibrosis with the 2011 criteria (adapted from Raghu et al. 2011(1)).

HRCT Pattern Histology pattern Diagnosis

UIP UIP IPF

Inconsistent with UIP UIP Possible IPF

Probable UIP Possible IPF

HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis

Table 6. Diagnosis of idiopathic pulmonary fibrosis with the 2018 criteria (adapted from Raghu et al. 2018 (51)).

HRCT Pattern Histology pattern Diagnosis

UIP UIP IPF

Indeterminate for UIP UIP IPF

Probable UIP Likely IPF

Indeterminate for UIP Indeterminate Alternative diagnosis Not IPF

Alternative diagnosis UIP Likely IPF or not IPF

Probable UIP Not IPF

Indeterminate for UIP Not IPF Alternative diagnosis Not IPF

HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis

12 2000 ATS/ERS International consensus statement (53): Majorcriteria: *Exclusionofotherknowncausesof ILD *Abnormalpulmonaryfunctionstudies includingevidenceofrestrictionand imparedgasexchange *Bibasilarreticularabnormalitieswith minimalgroundglassopacitiesinHRCT *Nofeaturestosupportalternative diagnosisinTBBorBAL Minorcriteria: *age>50years *Unexplaneddyspneaonexcertionwith incidousonset *Durationofsymptomsover3months *Bibasilarinspiratorycrakcles

2011: An official ATS/ERS/JRS/ALAT Statement (1): ThediagnosisofIPFrequires: *Exclusionofotherknowncausesof ILD *UIPpatterninHRCTinpatientsnot subjectedtoSLB *SpesificcombinationsofHRCTand SLBpatternifSLBperformed *InunclearcasesMDDwith experiencedpulmonologist, pathologistandradiologist Themajorandminorcriteriaproposed in2000ATS/ERSconsensusstatement wereeliminated

2018:ATS/ERS/JRS/ALATclinical practiceguideline(51): *Exclusionofotherknowncausesof ILDwithdetailedhistoryof medicationsandenvironmental exposuresaswellasserologictesting toexcludeCTDs *UIPpatterninHRCTOR *SpesificcombinationsofHRCTand histopathologicpatternifSLBis performed *BAL,SLB,TBBandcryobipsynot recommendedwhenHRCTpatternis UIP *MDDsuggestedfordecisionmaking DistiguishedrecommendationsonBAL andSLBinpatientswithUIPHRCT patternandotherpatterns Figure 2. Diagnostic criteria of idiopathic pulmonary fibrosis. ATS, American Thoracic Society; ERS, European Respiratory Society; JRS, Japanese Respiratory Association; ALAT, Latin American Thoracic Association; IPF idiopathic pulmonary fibrosis; ILD, interstitial lung disease; HRCT, high-resolution computed tomography; TBB, transbronchial biopsy; BAL, bronchoalveol lavage; UIP, usual interstitial pneumonia; SLB, surgical lung biopsy; MDD, multidisciplinary discussion; CTD, connective tissue disease

2.4 RISK FACTORS OF IPF