Open access peer-reviewed chapter - ONLINE FIRST

Diagnosis of IPF

Written By

Pahnwat T. Taweesedt, Kejal Gandhi, Reena Shah and Salim Surani

Submitted: August 14th, 2021 Reviewed: February 1st, 2022 Published: March 9th, 2022

DOI: 10.5772/intechopen.102992

IntechOpen
Idiopathic Pulmonary Fibrosis Edited by Salim Surani

From the Edited Volume

Idiopathic Pulmonary Fibrosis [Working Title]

Dr. Salim Surani and Dr. Venkat Rajasurya

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung fibrosis with an unknown cause commonly seen in the elderly. Obtaining histories such as past medical history, exposure history, occupational history, and family history can be crucial parts to help to find other pulmonary fibrosis causes. Not only that, but thorough physical examination can rule out pulmonary fibrosis related to other diseases. Several diagnostic modalities have helped to improve the IPF assessment, including computer tomographic scan, histopathology, bronchoscopy lavage, serological testing, and serum biomarkers. Diagnostic of exclusion is required. The consensus from multidisciplinary IPF experts’ discussion from various societies recommends the clinical practice for IPF diagnosis to help define this condition. In this book chapter, we will discuss the evidence for each of the diagnostic techniques for IPF.

Keywords

  • pulmonary fibrosis
  • IPF
  • telomere-related mutation
  • Hermansky-Pudlak syndrome
  • HRCT
  • UIP
  • IPF diagnosis
  • familial IPF
  • cryobiopsy

1. Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, fibrotic lung disease with unidentifiable etiology. IPF is commonly seen in the elderly aged group [1]. IPF associates with high morbidity and mortality. It is crucial to diagnose IPF, as specific antifibrotic therapy may improve survival from 2 to 5 years to 6.9–7.9 years [2].

In 2000, the American Thoracic Society (ATS), the European Respiratory Society (ERS), and American College of Chest Physician (ACCP) first collaborated and published a consensus statement for IPF diagnosis and treatment based on an experts’ opinions. This initial definition of IPF included criteria such as usual interstitial pneumonia (UIP) finding on thoracic or open lung biopsy, restrictive lung function in patients with chronic fibrosing interstitial pneumonia after excluding other causes [3].

Eleven years later, ATS, ERS, the Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) updated the guidelines with clinical, imaging, and histopathological findings in IPF diagnostic criteria based on the international evidence-based data [4]. Among patients for whom IPF was suspected, three high-resolution computed tomography (HRCT) pattens were reported; “UIP,” “possible UIP,” and “inconsistent with UIP” [4]. Surgical lung biopsy (SLB) was recommended in patients with suspected IPF who have the last two HRCT patterns [4]. SLB pattern is primarily divided into “UIP,” “probable UIP”, “possible UIP”, “unclassifiable fibrosis,” and “not UIP” [4]. Recommendations from French, German and Swiss have been proposed in 2013 and 2017, respectively [5].

In 2018, the consensus statement from Fleischner Society and clinical practice guideline ATS/ERS/JRS/ALAT for UIP/IPF diagnosis were published with numbers of similar main components (Table 1) [6, 7]. With more support data from observational studies and randomized controlled trials than 2011 guidelines, diagnosis and treatment recommendations were improved from 2011. Recently, the German respiratory society updated the German guidelines for the diagnosis of IPF in 2021 [8].

Fleischner Society consensus statementATS/ERS/JRS/ALAT 2018 CPG
HRCT findingsTypical UIPUIP
LocationSubpleural & basal predominance
PatternHoneycombing ± traction bronchiectasis
BiopsyNot recommended
Probable UIP
LocationSubplerual & basal prodominance
PatternTraction bronchiectasis
BiopsyNot recommendedRecommended (conditional)
Indeterminate for UIP
LocationDiffuse or variableSubpleural & Basal predominant
PatternNon-UIP featuresDistortion, groud glass opacity
BiopsyRecommended
Non-IPFAlternative diagnosis
PatternFeature of other diseases
BiopsyRecommended
Histological findingsDefinite UIPUIP
LocationSubplerual & paraseptal prodominance
PatternArchitecture remodeling, dense/patchy fibrosis, fibroblast foci
Probable UIP
PatternHoneycombing ± fibroblastic foci
Indeterminate for UIP
PatternCentrilobular injury/scarring foci
Mild lymphoid hyperplasia/diffuse inflammation
Diffuse homogenous fibosis
Fibrosis ± architectural distortion
Some UIP
Alternative diagnosis
PatternUIP + finding highly suggestive of another diagnosis
or non-UIP
Feature of other diseases

Table 1.

Comparison of the 2018 Fleischner society consensus statement and clinical practice guideline from ATS/ERS/JRS/ALAT 2018 for UIP/IPF diagnosis [6, 7].

ATS: American Thoracic Society; CPG: clinical practice gruidline, ERS: European Respiratory Society; IPF: idiopathic pulmonary fibrosis, JRS: Japanese Respiratory Society; ALAT: Latin American Thoracic Society; HRCT: high-resolution computed tomography; UIP: usual interstitial pneumonia.

Not only HRCT and SLB, but clinical manifestations, history, and other diagnostic modalities have also been proposed to help with IPF diagnosis. Multidisciplinary discussion is of utmost importance. Due to the rapidly growing of new data in the IPF field, guidelines from worldwide pulmonary societies consensus are necessary. We will discuss the current evidence that has been used to improve the diagnosis of IPF.

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2. Clinical presentation, risk factors, and history

2.1 Clinical presentation and past medical history

IPF is typically present at age above 50 years and is predominant in men [1, 9]. Lungs are the only organ involvement in IPF. Gradual onset of shortness of breath on exertion is the most common symptom that accounts for up to 86% of the patients with IPF, which can progress to shortness of breath at rest. Chronic nonproductive cough can be found in up to 75% of the cases [10]. Other symptoms include fatigue and decreased appetite. As IPF requires the diagnosis of exclusion, autoimmune diseases, connective tissue disease-related symptoms (e.g., arthralgia, dry eyes, Raynaud phenomenon), medications, radiation history, environment exposure (e.g., home, workplace, frequent visit places, hobbies), occupation, family history should be inquired in detailed to rule out any identifiable conditions. The physical exam is usually remarkable for bibasilar crackles and rales [6]. Digital clubbing was described in 20–30% of IPF cases [8].

Smoking is an undeniable risk factor of IPF in several studies [11]. Up to 70% of patients with IPF have a smoking history. Ever tobacco smoking or even secondhand smoking cases had a higher risk of developing IPF, although the latter had lower odds [9]. The pathogenesis of smoking as the risk factor of IPF is suggested to be due to oxidative stress [12].

Chronic obstructive pulmonary disease, co-morbidity that smoking is a potent risk factor, was found in one-third of the IPF cases. Gastroesophageal reflux disease (GERD) was noted in 60–90% of the patients with IPF and was thought to cause micro-aspiration that may precipitate IPF and acute exacerbation. The majority of GERD in IPF patients are asymptomatic. Nonetheless, the relationship between GERD and IPF remains controversial as there was no significant relationship after controlling for smoking in meta-regression [13]. Diabetes was positively correlated with IPF, but causal relationships still cannot determinate [14]. The presence of obstructive sleep apnea in patients with IPF was noted to be more than 50%, but true prevalence still cannot be concluded due to the small number of participants in those studies [15]. Chronic human herpes virus-7, human herpes virus-8, Ebstein-Barr virus, and cytomegalovirus infection could increase the risk of IPF [2]. However, acute infection of these viruses did not associate with IPF [2].

2.2 Environmental and occupational risk factors

The environmental exposure was reported in up to 27% [10]. Various occupational exposure has been revealed to be associated with IPF (Table 2). Silica, wood dust, metal dust/fumes, and vapors/gases/dust/fume had population attributable fractions of 3,4, 8, and 26%, respectively [16]. Deposition of dust and fumes from metal in the lung may give rise to the disturbance in the immune system. IPF risk has been reported to be increased with the longer duration of work exposure. In a meta-analysis of case–control studies by Park et al., metal dust, wood dust, pesticide had a high odds ratio (OR) in the IPF group [11]. However, textile dust, stone, and sand dust did not significantly increase the risk of IPF in this meta-analysis study [11]. The agriculture sector and farming workers showed an increased risk of IPF with an OR of 1.88 (95% CI 1.17–3.04). In contrast, demolition and building construction, and woodworker carpentry did not significantly increase the risk of IPF [11].

Potential risk factors for IPF
Tobacco Smoking
Chronic viral infection
(human herpes virus-7, human herpes virus-8, Ebstein-Barr virus, cytomegalovirus)
Exposure (e.g., metal dust, wood dust, pesticide)
Agriculture and farming worker
Family history of pulmonary fibrosis

Table 2.

Potential risk factors for IPF.

2.3 Family history

Although IPF cases occur sporadically, familial cases have been reported, such as familial pulmonary fibrosis (FPF), Hermansky-Pudlak syndrome (HPS), and telomere-related mutation (Table 3). Genetic testing is recommended in patients with early-onset (less than 50 years old) pulmonary fibrosis and positive family history.

Family history related to IPF
Familial pulmonary fibrosis
Hermansky-Pudlak syndrome
Telomere-related mutation

Table 3.

Family history related to IPF.

FPF is defined by two or more people in the family with a confirmed history of pulmonary fibrosis [17]. It accounts for less than five to up to 25 percent of IPF cases [18]. Pulmonary fibrosis in the family had a significant association with IPF cases with an OR of 12.6 (95% confidence interval 6.5–24.2) [9]. In addition to aiding diagnosis, family history helps predict survival. Transplant-free survival in patient-reported FPF is less in patients with IPF than patients with interstitial lung disease (ILD) other than IPF [18].

HPS, an autosomal recessive disorder, was first described in 1959 by Frantisek Hermansky and Paulus Pudlak [19]. This syndrome is characterized by oculocutaneous albinism, inflammatory bowel disease, platelet dysfunction, and pulmonary fibrosis. Pulmonary fibrosis is commonly found in HPS-1, HPS-2, and HPS-4 genetic types and affected middle-aged (HPS-1 and HPS-4) or children (HPS-2) [19].

Telomere-related mutation in IPF includes TERT, TERC, TINF2, NAF1, PARN, DKC1, and RTEL1 [20]. Premature shortening of the telomere, a region at the ends of the chromosome with repetitive DNA sections, may lead to the accelerated aging process in IPF. Screening for short telomeres should be done in patients with extrapulmonary organ involvements associated with short telomere syndrome, especially patients considered for a lung transplant. Patients with shortened telomeres have decreased lung transplant-free survival and faster disease progression [20].

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3. Imaging

High-resolution CT scan (HRCT) plays a central role in the diagnosis of IPF. As described earlier, diagnosis of IPF requires exclusion of other known causes of ILD in addition to the presence of UIP pattern on HRCT. If HRCT shows a definitive UIP pattern, further surgical lung biopsy is not required for diagnosis. HRCT patterns in suspected IPF patients can be divided into four patterns: UIP, intermediate UIP, probable UIP, and alternative diagnosis (Table 4). All the patterns are characterized by their distribution and lung parenchymal appearance [6].

UIPProbable UIPIndeterminate UIPAlternative diagnosis
  • Basal and subpleural predominance with heterogenous distribution

  • Honeycombing with or without traction bronchiectasis and bronchiolectasis, with superimposed mild GGO, reticular pattern

  • Basal and subpleural predominance with heterogenous distribution

  • Reticular pattern with traction bronchiectasis

  • ± Mild GGO

  • No honeycombing

  • The basal and subpleural predominance

  • Subtle reticular pattern, with mild GGO or early distortion

  • No honeycombing

  • CT features and/or distribution does not suggest an alternative diagnosis

  • Parenchymal features:

    • Cysts

    • Predominant GGO

    • Nodules

    • Diffuse/Centrilobular nodules

    • Consolidation

    • Marked mosaic attenuation

  • Predominant Distribution:

    • Peribronchovascular

    • Perilymphatic

    • Upper/mid-lung

  • Other:

    • Pleural plaques (asbestosis)

    • Pleural thickening/effusions (CTD)

    • Distal clavicular erosions (RA)

    • Extensive lymph node involvement

Table 4.

HRCT pattern categories.

UIP = usual interstitial pneumonia; GGO = ground glass opacities; CT = computed tomography; CTD = connective tissue disease; RA = rheumatoid arthritis.

UIP is the hallmark pattern of IPF. It has characteristic bilateral, peripheral, lower lobe predominance with parenchymal findings of honeycombing and traction bronchiectasis along with fine reticular opacities in the absence of extensive ground-glass opacities. Honeycombing is defined as a group of cystic airspaces 3 to 10 mm in diameter, with well-defined, thick walls. It is absent in intermediate and probable UIP patterns. Traction bronchiectasis or bronchiolectasis ranges from non-tapering of the bronchial wall to marked airway dilatation and varicosity in the presence of parenchymal distortion [6]. A typical UIP pattern is only observed in 50% of IPF patients. Thus, the IPF spectrum varies from typical UIP patterns to atypical findings such as ground-glass opacities, nodules, consolidation, or atypical distribution [21]. Mild ground glass opacities and the reticular pattern can be seen in UIP. However, presence of GGO out of proportion to the reticular pattern is inconsistent with UIP.

Acute exacerbation of IPF is characterized by acute onset dyspnea and hypoxemia and development of bilateral ground-glass opacities and/or consolidation on a UIP background. The clinical course of IPF can be correlated with progressive lung parenchymal changes seen on serial HRCT scans. However, there is no consensus on the role of serial HRCT scans in established patients to determine prognosis [22].

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4. Lab assay

Serological testing is recommended in all patients with newly identified ILD to exclude identifiable connective tissue disease (CTD) [6]. CTD-associated ILD investigations include erythrocytes sedimentation rate, C-reactive protein, anti-nuclear antibodies, rheumatoid factors, anti-cyclic citrullinated peptide, myositis panel, muscle enzymes, and anti-neutrophil cytoplasmic antibodies. Other serologic testing may be obtained based on clinical signs and symptoms such as anti-U1 ribonucleoprotein, anti-PM/Scl75 (polymyositis/scleroderma 75), anti-PM/Scl100, anti-Ku, anti-nuclear matrix protein 2, anti-transcriptional intermediary factor 1-gamma, anti-signal recognition particle, anti-small ubiquitin-related modifier-activating enzyme, anti-3-hydroxy-3-methylglutaryl-CoA reductase, and anti-melanoma differentiation-associated protein 5 (Table 5) [8].

Systemic sclerosisanti–Scl70/topoisomerase-1, anti-centromere, anti-RNA polymerase III, anti-Th/To, U3 RNP (fibrillarin), and anti-Ku
Sjögren syndromeanti-Ro and anti-La
MyositisCreatine phosphokinase, myoglobin, aldolase, antisynthetase antibodies (anti-Jo-1 and others), anti-MDA5, anti-PM/Scl75, anti-PM/Scl100, anti-TIF1- γ, anti-SEP, anti-HMGCR, anti NXP2, anti-U1RNP
Rheumatoid arthritisRheumatoid factor, anti-cyclic citrullinated peptide
VasculitisAntineutrophil cytoplasmic antibodies, anti myeloperoxidase antibodies, antiproteinase 3 antibodies

Table 5.

Laboratory workup for common connective tissue disease-related interstitial lung diseases.

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5. Bronchoscopic approach

Cellular analysis from bronchoalveolar lavage (BAL) fluid is suggested in suspected IPF cases with probable UIP, indeterminate UIP, or an alternative diagnosis pattern on HRCT. This work-up is not suggested for patients with HRCT patterns of UIP [6]. BAL is not used for the IPF diagnosis by itself but might support the detection of other conditions (Tables 6 and 7).

BALMacrophagesLymphocytesNeutrophilsEosinophilsCD4/CD8
Healthy individual>85%10–15%<3%≤1%49–83%
IPF49–83%7–27%6–22%2–8%1–3%

Table 6.

Comparison of cellular analysis from bronchoalveolar lavage between a healthy individual and IPF [6].

Lymphocytic predominanceSarcoidosis, HP, NSIP, Drug-induced, Radiation, COP, Lymphoproliferative disorders, CTD
Neutrophilic
predominance
CTD, IPF, aspiration, infection, bronchitis, asbestosis, ARDS/DAD
Eosinophilic
predominance
Eosinophilic pneumonia, Drug-induced, BM transplant, asthma, ABPA, Hodgkin, infection

Table 7.

Cellular analysis of bronchoalveolar lavage in different conditions.

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6. Histopathology

Multiple lung biopsies from few lobes are suggested in suspected IPF cases with probable UIP, indeterminate UIP, or alternative diagnosis patterns on HRCT. SLB is preferred over transbronchial lung biopsy and cryobiopsy. SLB be done by video-assisted thoracoscopic surgical (VATS) technique over open thoracotomy. When patients have a UIP pattern on HRCT, lung biopsy is not recommended in clinically suspected IPF patients after excluded other potential ILD etiologies. In these cases, diagnosis of IPF can be made without histopathology proof.

Similar to the HRCT pattern, histopathology patterns in suspected IPF individuals can be categorized into four groups; UIP, probable UIP, indeterminate UIP, and alternative diagnosis (Table 8) [6]. Classic “UIP” is the principal histopathologic feature of IPF. It frequently demonstrates dense fibrosis in paraseptal and subpleural areas of the lung with distortion of architecture, often resulting in microscopic honeycombing pattern accompanied by unaffected lung parenchyma in the low-magnification photomicrograph. For higher-magnification photomicrographs, fibroblast foci and patchy fibrosis are characteristics of UIP. The honeycombing pattern on biopsy is defined as fibrosed cystic airspace.

UIPProbable UIPIndeterminate UIPAlternative diagnosis
  • Predominant subpleural ± paraseptal involvement

  • Distortion of lung architecture with dense fibrosis ± honeycombing

  • Fibroblast foci

  • Patchy fibrosis

  • No features of an alternative diagnosis

  • Honeycombing

----or----
  • Some features of UIP but to the extent that if not possible for UIP diagnosis

+
No features of an alternative diagnosis
  • Fibrosis ± distortion of lung architecture

+
Non-UIP pattern
or
Interstitial inflammation, chronic fibrous pleuritis, OP, granuloma, hyaline membraines, airway-centered
  • Some features of UIP + alternative diagnosis features

  • Other IIPs features in all biopsies

  • Indicative of other disease such as LAM, sarcoidosis, HP

Table 8.

Histopathologic feature of idiopathic pulmonary fibrosis [6].

HP = hypersensitivity pneumonitis; IIPs = Idiopathic interstitial pneumonias; LAM = Lymphangioleiomyomatosis; OP = organizing pneumonia; UIP = usual interstitial pneumonia.

Accurate diagnosis of IPF requires the synopsis consideration of clinical manifestation, HRCT, and biopsy results (Table 9). When the HRCT pattern of clinically suspected IPF patients is not classic UIP or discordant with biopsy result, the multidiscipline decision from different subspecialties discussion such as pulmonologist, radiologist, and pathologist is suggested [6].

Biopsy result
Clinically suspected IPF after exclusion of other ILD causesUIPProbable UIPIndeterminate
for UIP
Alternative diagnosis
HRCT findingUIPIPF
A biopsy is not recommended
Probable
UIP
IPFIPFLikely IPFNot IPF
Indeterminate
for UIP
IPFLikely IPFNot IPFNot IPF
Alternative diagnosisLikely IPFNot IPFNot IPFNot IPF

Table 9.

Diagnosis of IPF using surgical lung biopsy result and high-resolution computed tomography finding [6].

HRCT = high-resolution computed tomography; IPF=Idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia.

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7. Genetic biomarker

Genetic factors affecting the susceptibility to IPF mainly depend on whether a patient has sporadic IPF or familial IPF. With the increase in the use of genome sequencing, multiple gene variants have been associated with IPF. Common variants with modest effects have been associated with sporadic IPF, whereas rare gene variants with more significant impact have been associated with a familial form of IPF.

7.1 Genetic variants associated with sporadic IPF

Mucin 5B (MUC5B) variant is a common variant associated with sporadic IPF. It is a glycoprotein involved in mucociliary clearance. A MUC5B promoter single nucleotide polymorphism (rs35705950) increases the susceptibility to developing IPF four-fold [23]. Despite this, MUC5B promoter SNP is associated with decreased mortality in IPF patients. However, it is not associated with systemic scleroderma-related ILD can increase the risk of ILD in rheumatoid arthritis patients, especially in those having CT findings of UIP.

Toll interacting protein (TOLLIP) is a regulator of toll-like receptor (TLR), and variation in this gene leads to a decrease in TLR mRNA expression and increased risk of pulmonary infection [24]. TT TOLLIP genotype ((rs3750920) is associated with improved survival with N-acetyl cysteine treatment [25]. However, the other minor allele of TOLLIP (rs5743890) decreases the susceptibility to IPF development but is associated with increased mortality from IPF [26].

Desmoplakin (DSP) encodes for desmoplakin, an adhesion molecule between 2 cells and tethers the cytoskeleton to the cell membrane. Two variants in DSP have been identified in which one variant (rs2744371) is protective, whereas the other variant (rs2076295) increases the susceptibility to IPF [27].

A-kinase Anchoring protein 13 (AKAP13) is a regulator of rhoA, which is involved in the profibrotic signaling pathway. Single nucleotide polymorphism in AKAP13 has also been associated with an increased risk of IPF. AKAP 13 mRNA expression was higher in the lung biopsy section of IPF patients compared to controls [28].

7.2 Genetic factors associated with familial IFP

Various surfactant-producing gene mutations have been identified, such as SFPT-C and SFPT-A2 associated with IPF in families. Transcription and translation of the SFPT-C gene leads to pro-SPC formation, which is further processed in the endoplasmic reticulum before being secreted in the alveolar space. SFPT-C mutation leads to the formation of pro-SPC. However, it cannot be further processed and folded, leading to protein accumulation within the endoplasmic reticulum and thus, activating unfolded protein response (UPR) within the cell. Unfolded protein response helps to protect the cell and also enhances protein folding chaperones. However, prolonged standing activation of UPR system leads to alveolar epithelial cell death through apoptosis [29]. Studies have shown markers for endothelium reticulum stress and UPR pathway activation even in the absence of SFPT-C mutation. These studies demonstrate that this pathway may contribute to the pathogenesis of IPF [30]. Similarly, SFTP-A2 gene mutations have been identified in a family with 15 members who had familial IPF, bronchoalveolar carcinoma, or underlying lung disease. SFTP-A2 also accumulates mutant surfactant protein A within the endoplasmic reticulum, leading to stress and ultimate activation of the apoptotic pathway [31].

Telomerase complex mutations have been identified in families with UIP. Telomeres are the tandem repeats of TTAGGG found at both ends of chromosomes, protecting the end of chromosomes during cell division. Telomerase helps maintain these telomeres length. Telomerase mutation leads to the shortening of telomere in the alveolar epithelial cells, which was found to be involved in the disease process. Telomere shortening has also been observed in peripheral leukocytes in these patients. New studies have shown shortened telomere length in patients with sporadic IPF and non-telomerase complex mutation IPF, indicating it might play a role in the pathogenesis of IPF [32].

Other molecular biomarkers such as elevated levels of matrix metalloproteinase 7 (MMP 7), mucin 1 (KL-6), CC chemokine ligand 18 (CCL 18), cancer antigen have also been associated with disease progression but have limited clinical value at present and requires further studies [33].

Thus, the use of genetic and biologic biomarkers can further help understand the pathogenesis of IPF and develop future targeted therapies. However, currently, more studies are required to use these markers for diagnostic purposes.

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8. Conclusion

When encountering patients with clinical context and tempo of disease compatible with IPF, excluding identifiable causes by acquiring history and serology is recommended. Other investigations such as biomarkers may aid the defining of IPF. After that, IPF diagnosis can be made with the UIP pattern shown by HRCT. In patients with HRCT patterns of non-UIP, a surgical lung biopsy will assist the diagnosis. When a definite diagnosis cannot be concluded by UIP pattern from HRCT or biopsy result, the mutual agreement from the multidisciplinary discussion is recommended to help diagnose IPF.

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Written By

Pahnwat T. Taweesedt, Kejal Gandhi, Reena Shah and Salim Surani

Submitted: August 14th, 2021 Reviewed: February 1st, 2022 Published: March 9th, 2022