Clinical Manifestations and Diagnosis of Idiopathic Pulmonary Fibrosis - UpToDate

29/11/2020 Clinical manifestations and diagnosis of idiopathic pulmonary ﬁbrosis - UpToDate
Author: Talmadge E King, Jr, MD

Section Editor: Kevin R Flaherty, MD, MS
Deputy Editor: Helen Hollingsworth, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2020. | This topic last updated: Dec 17, 2019.
INTRODUCTION
Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), previously known as

cryptogenic fibrosing alveolitis (CFA) in Europe, is the most common type of idiopathic
interstitial pneumonia (IIP). IIPs are spontaneously occurring (ie, idiopathic) diffuse
parenchymal lung diseases. IPF is defined as a spontaneously occurring (idiopathic) specific
form of chronic fibrosing interstitial pneumonia limited to the lung and associated with a
pattern of UIP on high resolution computed tomography or histologic appearance on surgical
(thoracoscopic or open) lung biopsy [1-3].
The other IIPs include nonspecific interstitial pneumonia (NSIP), desquamative interstitial
pneumonia (DIP), respiratory bronchiolitis associated interstitial lung disease (RB-ILD), acute
interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP), and cryptogenic
organizing pneumonia (COP).
The clinical manifestations, evaluation, and diagnosis of IPF will be reviewed here. The
evaluation of interstitial lung disease in general; the diagnosis of the other IIPs; and the
treatment, monitoring, and prognosis of IPF are discussed separately. (See "Approach to the
adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with
interstitial lung disease: Diagnostic testing" and "Idiopathic interstitial pneumonias:
Classification and pathology" and "Treatment of idiopathic pulmonary fibrosis" and "Prognosis
and monitoring of idiopathic pulmonary fibrosis".)
EPIDEMIOLOGY
Reported prevalence and incidence data for IPF vary and depend on ascertainment and
reporting methods, and also the age and geographic location of the population. Both
prevalence and incidence increase with advancing age, with presentation commonly occurring
https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/clinical-manifestations-and-diagnosis-of-idiopathic-pulmonary-ﬁbrosis?search=HYPERSENSITIVE … 1/23
in the sixth and seventh decades; rarely is IPF seen in patients aged less than 50 years [1,2].
The prevalence and incidence are higher in men than women [4].
In a systematic review, the reported prevalence of IPF ranged from 0.5 to 27.9/100,000 and the
incidence ranged from 0.22 to 8.8/100,000 [5]. In the United States, IPF incidence estimates
range from 7 to 16 cases per 100,000 overall [6]. In contrast, among a random sample of
Medicare beneficiaries (largely ≥65 years old), the prevalence of IPF was 494 cases per
100,000, and the incidence was 94 cases per 100,000 person years [7]. In the United Kingdom,
the IPF incidence in 2008 was 7.4 per 100,000 person-years [8]. In Europe, IPF prevalence
ranged from 1.25 to 23.4 cases per 100,000 population, and the annual incidence ranged
between 0.22 and 7.4 per 100,000 population [9]. Overall, the incidence of IPF is increasing
worldwide and conservative estimates of the incidence range from 3 to 9 cases per 100,000
per year for Europe and North America [10].
PATHOGENESIS AND GENETIC PREDISPOSITION
The pathogenesis of IPF/usual interstitial pneumonia (UIP) is complex and likely involves
cycles of epithelial cell injury and dysregulated repair. The pathogenesis of IPF is discussed
separately. (See "Pathogenesis of idiopathic pulmonary fibrosis".)
Most cases of IPF are sporadic, but familial cases have been described. Familial pulmonary
fibrosis, Hermansky-Pudlak syndrome (HPS), and the short telomere syndromes usually
present at a younger age than IPF. While a number of genetic polymorphisms have been
reported among patients with sporadic cases of IPF, none are well-established [1]. (See
"Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)
● Familial pulmonary fibrosis – Familial pulmonary fibrosis (FPF) accounts for less than 5
percent of patients with IPF. Inheritance appears to follow an autosomal dominant
pattern with variable penetration. Within a family, affected patients may have different
interstitial lung diseases [11]. FPF has no distinct distinguishing features and requires a
thorough family history. A number of genetic variants have been associated with FPF, for
example the genes for surfactant-associated proteins A (SFTPA2), surfactant protein C
(SFTPC), and mucin 5B (MUC5B). (See "Pathogenesis of idiopathic pulmonary fibrosis",
section on 'Genetic predisposition'.)
FPF appears to be associated with an increased incidence of bronchogenic carcinoma [12].
● Hermansky-Pudlak syndrome – HPS, an autosomal recessive disorder characterized by

oculocutaneous albinism and platelet abnormalities, is a rare cause of UIP and presents at
an earlier age (eg, thirties) than IPF [13,14]. These patients are often easily diagnosed by
the presence of oculocutaneous albinism, although patients with HPS who are of Puerto
Rican descent may have brown hair and varying amounts of skin melanin. Photophobia
and nystagmus are common in HPS. (See "Pathogenesis of idiopathic pulmonary fibrosis",
section on 'Genetic predisposition' and "Idiopathic interstitial pneumonias: Classification
and pathology", section on 'Differential diagnosis' and "Congenital and acquired disorders
of platelet function", section on 'Storage pool disorders'.)
● Telomeropathies – The short telomere syndromes are caused by mutations in the genes
responsible for maintaining telomere length (eg, TERT, TERC, PARN, DKC1, TINF2, RTEL1) [15].
The disorder is characterized by severely short telomeres (below the first percentile for
age), combined with dysfunction of one or more target organs, including the bone
marrow, liver, skin, and lung. Clinical features suggestive of short telomere syndromes
include a family history of pulmonary fibrosis (in adulthood, short telomere syndromes
most commonly present as an autosomal dominant trait), a personal or family history of
premature greying, transaminitis or evidence of liver dysfunction, cytopenias or an
unexplained macrocytosis. The short telomere syndromes also include dyskeratosis
congenita, bone marrow failure, and liver disease [16-18]. (See "Pathogenesis of idiopathic
pulmonary fibrosis", section on 'Genetic predisposition' and "Dyskeratosis congenita and
other short telomere syndromes".)
Short telomeres have been identified in about 25 percent of sporadic IPF and in about 15
percent of families with familial pulmonary fibrosis [19]. Exome-based surveys suggest
that up to 11 percent of patients with sporadic IPF have short telomere-associated gene
variants [20]. The prevalence of short telomere syndromes may be higher in IPF patients
referred for lung transplantation (estimated 16 percent in one study) [17].
POTENTIAL RISK FACTORS
While IPF, by definition, lacks a known cause, certain risk factors have been identified [1].
Cigarette smoking is most strongly associated with IPF. Exposure to stone, metal, wood, and
organic dusts has also been suggested as a risk factor [21-23]. Gastroesophageal reflux may
contribute to lung injury via microaspiration, although this association is more difficult to
interpret given the high frequency of gastroesophageal reflux in the general population
[24,25].
CLINICAL MANIFESTATIONS
Patients with IPF typically present at age 60 years or older [26,27]. The majority of patients
have a history of cigarette smoking [1]. Patients commonly report a gradual onset of dyspnea
on exertion and nonproductive cough over several months. Fatigue, fever, myalgias, and
arthralgias are rarely reported.
As with all patients who present with interstitial lung disease, the history should include
questions about any family history of lung disease; symptoms suggestive of rheumatic
disease (eg, arthralgias, dry eyes, dry mouth, muscle weakness, numbness, Raynaud
phenomenon, tingling); current and recent medications; and exposure to fumes, dusts (eg,
asbestos, silica), or therapeutic irradiation. (See "Approach to the adult with interstitial lung
disease: Clinical evaluation", section on 'History'.)
On physical examination bibasilar crackles are usually audible, but rarely they may be absent
or only heard unilaterally in early disease. Patients with more advanced disease may have end-
inspiratory "squeaks" due to traction bronchiectasis. While early reports describe finger
clubbing in 45 to 75 percent of patients, our clinical impression is that clubbing is a
manifestation of advanced IPF [28].
EVALUATION
The evaluation of a patient with suspected IPF requires a combination of steps and includes
the following:
● Exclusion of identifiable causes of interstitial lung disease (ILD) based on the history,
physical, and laboratory testing.
● An assessment of the pattern and severity of respiratory impairment on pulmonary

function testing.
● High resolution computed tomography (HRCT) of the chest to confirm the presence of ILD
and characterize the distribution and pattern of opacities.
● A multidisciplinary clinical, radiologic, and pathologic discussion is useful in arriving at the

most accurate final diagnosis [3,29-32].
Clinical assessment — Patients with newly diagnosed ILD should have a detailed assessment
for potential causes of interstitial lung disease ( table 1):
● Medications (eg, amiodarone, bleomycin, long-term nitrofurantoin, biologic therapies)

● Exposure at home or at work to agents that cause hypersensitivity pneumonitis
● Work exposure to asbestos, silica, other fumes, vapors, dusts, or mold

● Signs or symptoms of rheumatic disease (eg, joint pain or inflammation, digital ulcers, dry
eyes, dry mouth, fatigue, fever, hair loss, muscle weakness or pain, photosensitivity,
Raynaud phenomenon, skin thickening, telangiectasia)
● Family history (eg, ILD, premature graying, cryptogenic cirrhosis, aplastic anemia, other
bone marrow diseases)
Laboratory — No laboratory tests are specific for a diagnosis of IPF, so the role of laboratory
testing in patients with newly identified ILD is to identify or exclude processes in the
differential diagnosis. The role of laboratory testing in patients being evaluated for ILD is
discussed separately. (See "Approach to the adult with interstitial lung disease: Diagnostic
testing", section on 'Laboratory tests'.)
For patients undergoing an initial evaluation for possible IPF, serologic studies may be of
benefit in identifying subclinical rheumatic disease [3]. We typically obtain tests for antinuclear
antibodies, anti-cyclic citrullinated peptide antibodies, and rheumatoid factor. C-reactive
protein (CRP) and erythrocyte sedimentation rate are nonspecific measures of inflammation
and are obtained by some experts. Other tests, such as antisynthetase and other myositis
panel antibodies (eg, anti-Jo-1, anti-PL7, anti-melanoma differentiation associated gene
[MDA]-5), creatine kinase, aldolase, Sjögren's antibodies (anti-SS-A, anti-SS-B), and scleroderma
antibodies (anti-topoisomerase [scl-70], anti-PM-1), may be helpful in selected cases with
suggestive symptoms or signs [3].
● Role of screening for myositis antibodies unclear – The possibility that screening tests
for myositis antibodies might identify unsuspected inflammatory myositis was examined
in a case series that included 45 patients with a pattern of UIP on high resolution
computed tomography (HRCT) and no known rheumatic disease [33]. Myositis antibody
testing (Jo-1, PL-7, PL-12, MDA-5, Ro52) was positive in 15 patients, although a change in
diagnosis only occurred in 5. Anti-Ro52 was least likely to be associated with a change in
diagnosis. In the larger group that included patients with other patterns of ILD,
approximately 60 percent of patients with myositis antibodies had negative antinuclear
antibody, rheumatoid factor, and anti-cyclic citrullinated peptide antibody testing. Further
study is needed to determine the best panel for identifying underlying rheumatic disease.
● Antinuclear antibodies and rheumatoid factor – Among patients with IPF documented
by surgical lung biopsy or HRCT with multidisciplinary review and no symptoms or signs of
rheumatic disease, circulating antinuclear antibodies (≥1:40) are present in 17 to 25
percent and a positive rheumatoid factor in 5 to 18 percent, depending on the population
studied [34,35].
● Hypersensitivity pneumonitis panels – For patients with suspected IPF, the utility of
screening panels for hypersensitivity pneumonitis (HP) is unclear due to problems with
specificity. We typically reserve serologic testing for HP for patients with a historical risk
factor (eg, occupational or environmental exposures) or features that are atypical for IPF
(eg, younger age, centrilobular nodules on HRCT imaging). (See "Hypersensitivity
pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section
on 'Laboratory tests'.)
● Biomarkers – Measurement of biomarkers, such as serum matrix metalloproteinase

(MMP)-7, surfactant protein-D (SPD), chemokine ligand (CCL)-18, and Krebs von den
Lungen (KL)-6, has high rates of false positive and false negative results when
differentiating IPF from other ILDs and is not advised [3].
Pulmonary function tests — Complete pulmonary function testing (PFT; spirometry, lung

volumes, diffusing capacity for carbon monoxide [DLCO]) and resting and ambulatory pulse
oximetry are obtained in virtually all patients with suspected ILD. These tests are helpful in
establishing the pattern of lung involvement (eg, restrictive, obstructive, or mixed) and
assessing the severity of impairment. In patients with IPF, PFTs typically demonstrate a
restrictive pattern (eg, reduced forced vital capacity [FVC], but normal ratio of forced
expiratory volume in one second [FEV1]/FVC), a reduced DLCO, and, as the disease progresses,
a decrease in the six-minute walk distance. (See "Approach to the adult with interstitial lung
disease: Diagnostic testing", section on 'Pulmonary function testing' and "Overview of
pulmonary function testing in adults", section on 'Restrictive ventilatory defect'.)
Chest imaging
● Chest radiograph – A chest radiograph is typically obtained in adults with cough and/or
progressive shortness of breath. The most common findings in IPF are an increase in
reticular markings, although this is a nonspecific finding that is also associated with other
interstitial lung diseases and heart failure.
● High resolution computed tomography – HRCT should be obtained in all patients

suspected of having IPF [3]. Technical requirements for HRCT scanning of patients with
ILD are described in the 2018 American Thoracic Society (ATS), European Respiratory
Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society
(ALAT) guideline and include submillimetric collimation, reconstruction of thin-section
(≤1.5 mm) images, supine inspiratory (full inspiration) and expiratory images, and reduced
radiation dose (1 to 3 mSv, but not <1 MSv) [3]. The presence of certain specific HRCT
features in the appropriate clinical setting, may be sufficient to establish the diagnosis of
IPF ( table 2) [27,36,37].
A diagnosis of IPF cannot be made based on HRCT appearance alone [38]. The
characteristic HRCT features of IPF include peripheral, basilar predominant opacities
associated with honeycombing and traction bronchiectasis-bronchiolectasis ( image 1)
[39-41]. Honeycombing refers to clusters of cystic airspaces approximately 3 to 10 mm in
diameter, usually in a subpleural location ( image 2). While honeycombing is essential to
making a definite HRCT diagnosis of usual interstitial pneumonia (UIP), it is absent in
probable and indeterminate UIP [26,42].
Up to 30 percent of cases with a histopathological diagnosis of UIP may have HRCT

findings more consistent with an alternate diagnosis [43]. (See "High resolution computed
tomography of the lungs", section on 'Idiopathic interstitial pneumonias' and "Approach
to the adult with interstitial lung disease: Diagnostic testing", section on 'Imaging'.)
Ground glass opacities that are superimposed on a fine reticular pattern can be present in
UIP [39], but ground glass opacities without an associated reticular pattern and extensive
ground glass opacities that are more prominent than the reticular changes are
inconsistent with UIP. However, in the setting of an acute exacerbation of IPF, bilateral
ground glass opacities and/or consolidation can be present on a background of a UIP
pattern. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)
Pleural disease is uncommon in IPF, so its presence should raise the possibility of an
alternate or comorbid diagnosis such as rheumatoid arthritis, systemic lupus
erythematosus, asbestosis, heart failure, drug-induced lung disease, or lymphangitic
carcinomatosis. Nodular pleural abnormalities affecting the upper lung zones may be
caused by idiopathic pleuropulmonary fibroelastosis [44].
Flexible bronchoscopy
Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) has a limited role in the

evaluation of patients with an HRCT that suggests UIP, because broad and overlapping ranges
of cell counts make differentiation among interstitial lung diseases difficult. The general role
of BAL in the diagnosis of ILD is discussed separately. (See "Role of bronchoalveolar lavage in
diagnosis of interstitial lung disease".)
The ATS/ERS/JRS/ALAT guideline advises against BAL cellular analysis when the clinical
impression is IPF and the HRCT pattern is UIP [3]. On the other hand, when the clinical
impression suggests IPF, but the HRCT pattern is probable UIP, indeterminate for UIP, or an
alternate diagnosis, cellular analysis of BAL fluid to exclude eosinophilic pneumonia,

sarcoidosis, or infection is suggested. (See "Basic principles and technique of bronchoalveolar
lavage".)
Transbronchial lung biopsy and transbronchial cryobiopsy
● Transbronchial lung biopsy (TBLB) – TBLB uses forceps to obtain tissue samples that are
a few millimeters in size and generally too small to secure a definitive diagnosis of UIP. It
is estimated that approximately one-third of TBLB performed for newly diagnosed ILD of
unknown cause will provide a clear diagnosis, while two-thirds will be nondiagnostic and
require a surgical lung biopsy. The decision to perform TBLB should be individualized and
generally limited to patients with reasons to suspect a non-UIP diagnosis. The technique
of transbronchial biopsy is discussed separately. (See "Role of lung biopsy in the diagnosis
of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible
bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on
'Transbronchial biopsy'.)
● Transbronchial cryobiopsy (TBCB) – TBCB shows promise as a diagnostic technique for

ILD, but further work is needed to standardize the technique [3,45,46]. In a series of 21
patients in whom multidisciplinary assessment determined a need for histology,
sequential TBCB and surgical biopsies from two lobes each had poor concordance and
TBCB was nondiagnostic in four patients [47]. It is possible that the more proximal nature
of TBCB compared with surgical biopsy contributes to the low concordance. The technique
of TBCB and its general role in the diagnosis of ILD are discussed separately. (See "Role of
lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial
cryobiopsy' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy'.)
Lung biopsy — For patients who require histopathologic confirmation of suspected IPF, a

surgical lung biopsy is preferred over the bronchoscopic procedures TBLB or TBCB described
above [1,3]. (See 'Transbronchial lung biopsy and transbronchial cryobiopsy' above.)
Patient selection — When the results of the clinical evaluation, laboratory testing, and
HRCT do not allow the clinician to make a confident diagnosis of IPF, surgical lung biopsy may
be indicated [1,3]. The decision requires assessment of the benefits of having a definitive
diagnosis relative to the risks of the surgical procedure. The ATS/ERS/JRS/ALAT guideline and
Fleischner Society systematic review advise that the decision about lung biopsy be made in the
context of a multidisciplinary discussion [3,38]. The ATS/ERS/JRS/ALAT guideline also suggests
the following:
● For patients with newly detected ILD of uncertain etiology and an HRCT pattern of
probable UIP, indeterminate UIP, or an alternate diagnosis, the benefits of surgical lung
biopsy generally outweigh the risks (eg, mortality [<2 percent], bleeding, prolonged air
leak, pain), unless the patient has severe physiologic impairment (eg, requires
supplemental oxygen) or substantial comorbidity.
● For patients with newly detected ILD and an HRCT pattern of UIP, surgical lung biopsy is
unlikely to identify an alternate diagnosis and thus is deemed not to be worth the risk.
IPF is rare among patients <50 years of age, so a lung biopsy may be useful in the evaluation
of such patients. On the other hand, in patients with severe physiologic impairment or
substantial comorbidity, the risks of surgical lung biopsy may outweigh the benefits of
establishing a secure diagnosis of IPF [3,48]. (See "Role of lung biopsy in the diagnosis of
interstitial lung disease".)
Procedure — Surgical lung biopsy may be done via a video-assisted thoracoscopic

approach (VATS, also called minimally-invasive thoracic surgery) or thoracotomy, depending
on the expertise and preference of the surgeon [3]. Ideally, biopsies are obtained from more
than one lobe of the lung and from areas of varying severity. Lung biopsy samples are ideally
greater than 4 cm in the greatest dimension when inflated and include a depth from the
pleural surface of 3 to 5 cm. Surgical lung biopsy virtually always yields an adequate specimen,
and a definitive diagnosis (in combination with clinical assessment and HRCT) is made in
approximately 89 percent of patients [3]. The technique and general role in the diagnosis of
ILD are discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung
disease" and "Overview of minimally invasive thoracic surgery".)
Complications — While data are not available for suspected IPF in specific, the risk of
mortality following surgical lung biopsy for ILD depends on several factors. As examples,
nonelective procedures are associated with higher mortality than elective procedures (20
versus 2 percent), and older age, male sex, higher comorbidity, long-term oxygen therapy, and
open thoracotomy are associated with greater mortality [48,49].
Complications of surgical lung biopsy and video-assisted lung biopsy are discussed separately.
(See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Morbidity
and mortality' and "Overview of minimally invasive thoracic surgery", section on
'Complications'.)
Histopathology — UIP is the histopathologic pattern associated with the clinical diagnosis of

IPF. A UIP-like pattern of injury can also be seen in other fibrotic lung diseases, eg, associated
with rheumatic diseases, chronic hypersensitivity pneumonitis, drug-toxicity, and

pneumoconioses (eg, asbestosis) ( table 3).
The histologic hallmark and chief diagnostic criterion for UIP is a heterogeneous appearance
with alternating areas of normal lung, fibrosis, fibroblast foci, and honeycomb change [3]. The
peripheral subpleural parenchyma is most severely affected. Fibroblastic foci, which are areas
of active fibroproliferation characterized by clusters of fibroblasts and myofibroblasts that lie
in continuity with the established fibrosis, are a hallmark feature of IPF. Features to suggest an
alternate diagnosis (eg, granulomas, prominent airway-centered changes, inflammation
separate from areas of honeycombing) should be absent.
The pathology of IPF/UIP is described in detail separately. (See "Idiopathic interstitial

pneumonias: Classification and pathology", section on 'Pathology'.)
DIAGNOSIS
The diagnosis of IPF requires exclusion of other known causes of interstitial lung disease (ILD)
and either definite features of usual interstitial pneumonia (UIP) on high resolution computed
tomography (HRCT) or certain combinations of HRCT and histopathologic features of UIP [3].
Multidisciplinary discussion including specialists from pulmonary, pathology, radiology, and
sometimes rheumatology can help improve diagnostic accuracy [3,29-32]. The following
sections describe the diagnostic criteria.
Diagnosis without lung biopsy — The diagnosis of IPF/UIP can be made on the basis of a
characteristic presentation (eg, insidious onset of dyspnea in a patient over age 60) in
combination with definite features of UIP on HRCT ( table 2), and exclusion of other known
causes of UIP, including environmental exposure (eg asbestos, causes of hypersensitivity
pneumonitis), medications, and rheumatic disease ( table 4) [3]. The Fleischner Society white
paper suggests that a lung biopsy is not necessary in patients with an HRCT pattern
considered probable for UIP when a multidisciplinary discussion yields a confident diagnosis
of IPF. In contrast, the American Thoracic Society, European Respiratory Society, Japanese
Respiratory Society, and Latin American Thoracic Society (ATS/ERS/JRS/ALAT) guideline favors
histopathologic confirmation [3]. (See 'Diagnosis with lung biopsy' below.)
Prediction rules are being developed to help diagnose IPF in patients without definite UIP on
HRCT (ie, no honeycombing) in the absence of lung biopsy. In such patients, it has been
suggested that clinical variables of increasing age and higher total HRCT interstitial score can
predict a biopsy confirmation of IPF [27]. A further analysis has shown that for patients with an
HRCT classified as possible UIP (2011 criteria with basilar predominant reticular opacities,
traction bronchiectasis, but no honeycombing) [1], demographic information (eg, age, sex)
and other radiographic features (eg, extent of reticular versus ground glass opacities) can help
predict the presence of UIP [50]. In this analysis, age ≥60 years and extent of reticular density
one-third or more of total lung volume had high specificity for IPF (80 percent probability). In
an exploratory study, a clinical prediction rule (age, sex, total traction bronchiectasis score)
improved the positive predictive value to >90 percent for a UIP pattern on surgical biopsy [26].
With further validation, the prediction tool may enable a confident diagnosis of UIP for those
with an HRCT classified as possible UIP, without surgical lung biopsy. However, the prediction
rule is not useful for those with an HRCT pattern considered inconsistent with UIP.
Diagnosis with lung biopsy — When performed, surgical lung biopsy results need to be
correlated with the HRCT findings, preferably in the context of a multidisciplinary discussion
(MDD) ( table 3) [3,32,51]. (See 'Chest imaging' above and 'Histopathology' above.)
● HRCT shows UIP – If the HRCT shows a UIP pattern and the lung histopathology pattern
is UIP, probable UIP, or indeterminate for UIP, then the diagnosis is IPF, unless the
histopathology demonstrates a definite alternate diagnosis (eg, poorly formed
granulomas indicating chronic hypersensitivity pneumonitis).
● HRCT shows probable UIP – If the HRCT shows probable UIP and the histopathology
shows UIP or probable UIP, then the diagnosis is IPF; and if the lung histopathology
pattern is indeterminate for UIP, the diagnosis is likely IPF.
● HRCT is indeterminate for UIP – If the HRCT is indeterminate for UIP (eg, mild ground
glass opacities or distortion, distribution of fibrosis that is not typical for a specific ILD),
but the histopathology shows definite or probable UIP, then the diagnosis is IPF or likely
IPF, respectively. If the histopathology is also indeterminate for UIP, the diagnosis remains
indeterminate unless MDD reclassifies to a more specific diagnosis.
● HRCT suggests an alternate diagnosis – If the HRCT demonstrates features suggestive

of an alternate diagnosis, but the histopathology shows UIP, MDD may determine that the
diagnosis is likely IPF. Otherwise, for histopathology findings that are probable,
indeterminate, or suggest an alternate diagnosis, the final diagnosis would be not IPF.
In all of the various HRCT scenarios, the histopathology may identify a specific non-IPF
diagnosis that becomes the final diagnosis.
Discordant findings have been described among samples from different lobes in a single
patient. When lung biopsy findings are discordant among lobes, for example UIP in one lobe
and nonspecific interstitial pneumonia (NSIP) in another lobe, the convention is to classify and
manage that patient as IPF because the disease trajectory tends to follow that of patients with
UIP in all lobes.
Post-diagnostic evaluation — The possibility of short telomere syndrome (STS) should be

explored in patients with a diagnosis of IPF who have premature graying, cytopenias,
unexplained macrocytosis, or a family history of interstitial lung disease. The diagnosis is
based on the combination of clinical manifestations and telomere length analysis of peripheral
blood leukocytes. Identification of pathogenic variants in known STS-causing genes (in adults,
typically TERT, PARN, TERC, and RTEL1) provides corroborative evidence, but is not essential for
establishing a diagnosis. The diagnosis of STS is discussed separately. (See 'Pathogenesis and
genetic predisposition' above and "Dyskeratosis congenita and other short telomere
syndromes", section on 'Laboratory testing and bone marrow'.)
Patients who are found to have STS need to be screened for bone marrow and liver
dysfunction; at-risk family members may need screening with telomere length analysis.
Patients with bone marrow dysfunction may require treatment (eg, danazol, hematopoietic
cell transplantation). (See "Dyskeratosis congenita and other short telomere syndromes",
section on 'Screening of family members and relatives' and "Dyskeratosis congenita and other
short telomere syndromes", section on 'Management'.)
Patients with IPF and STS have a poorer prognosis following lung transplantation and may
benefit from modified anti-rejection treatment plans to prevent myelotoxicity and
hepatotoxicity. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Telomerase
complex mutations'.)
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of IPF includes other diseases with histopathologic features of usual
interstitial pneumonia (UIP), such as rheumatic diseases (eg, rheumatoid arthritis, systemic
sclerosis), chronic hypersensitivity pneumonitis [52], asbestosis, and certain drug-induced
lung diseases ( table 4) [53,54]. In addition, the differential diagnosis of IPF includes the
other idiopathic interstitial pneumonias, pulmonary Langerhans' cell histiocytosis, combined
pulmonary fibrosis and emphysema, and pleuropulmonary elastosis. The interpretation of
lung biopsy results in interstitial pneumonitis is discussed separately. (See "Interpretation of
lung biopsy results in interstitial lung disease" and "Idiopathic interstitial pneumonias:
Classification and pathology".)
● Nonspecific interstitial pneumonitis – Nonspecific interstitial pneumonia (NSIP) is a

type of idiopathic interstitial pneumonia that is frequently in the differential diagnosis of
IPF. Characteristic features include diffuse ground glass opacities on high resolution
computed tomography (HRCT), a reticular pattern, and traction bronchiectasis;
honeycombing is generally absent. The diagnosis generally requires histopathologic
confirmation by lung biopsy, either via thoracoscopic surgery or thoracotomy. (See
"Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial
pneumonia", section on 'Diagnosis'.)
● Rheumatic disease – Patients with rheumatic disease, most commonly rheumatoid

arthritis (RA), can develop a UIP-like pattern of lung injury, although NSIP is the type of
interstitial lung disease (ILD) among patients with rheumatic disease, including those with
RA. Differentiating rheumatic disease-associated ILD from IPF is largely based on
identifying clinical features that provide clues to the presence of rheumatic disease, such
as arthritis, rheumatoid nodules, Raynaud phenomenon, skin changes (eg, sclerodactyly,
increased skin thickness, digital ulcers), muscle weakness, and abnormal esophageal
motility. On HRCT, features suggestive of rheumatic disease that would be atypical for IPF
include pleural or pericardial effusion and esophageal abnormalities. (See "Interstitial
lung disease in rheumatoid arthritis", section on 'Pathologic types of RA-ILD' and "Clinical
manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis
(scleroderma)", section on 'Pathology'.)
● Drug and irradiation-induced UIP – Distinguishing the idiopathic form of UIP from drug-
induced lung disease is largely a matter of correlation with the clinical information.
Treatments associated with a UIP-like pattern of pulmonary toxicity include
cyclophosphamide, bleomycin, nitrosoureas, methotrexate, nitrofurantoin, and
irradiation, among others. Additional agents associated with pulmonary fibrosis are listed
on the Pneumotox website [55]. (See "Cyclophosphamide pulmonary toxicity" and
"Bleomycin-induced lung injury" and "Methotrexate-induced lung injury" and
"Nitrosourea-induced pulmonary injury" and "Nitrofurantoin-induced pulmonary injury"
and "Radiation-induced lung injury".)
● Asbestosis – Asbestosis is associated with occupational exposures such as mining of

asbestos, shipbuilding, welding, and demolition. The HRCT pattern associated with
asbestosis is similar to IPF, but pleural plaques, particularly with linear bands of
calcification, are a clue to underlying asbestosis. A definitive diagnosis of asbestosis
requires an appropriate occupational history and demonstration of asbestos fibers
(usually in the form of ferruginated asbestos bodies) in the tissue specimen. (See
"Asbestos-related pleuropulmonary disease".)
● Chronic hypersensitivity pneumonitis – Chronic hypersensitivity pneumonitis can

present with imaging or histopathologic features similar to those found in IPF/UIP (
image 3). The typical HRCT appearance is that of centrilobular nodules and lobular
areas of decreased perfusion on HRCT, although these features are not always present (
image 4). The histopathologic finding of poorly formed granulomas or giant cells in the
interstitium, even if rare, should raise suspicion for chronic hypersensitivity pneumonitis.
(See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and
diagnosis", section on 'Diagnosis'.)
● Pulmonary Langerhans' cell histiocytosis – Pulmonary Langerhans' cell histiocytosis

(also referred to as pulmonary eosinophilic granuloma or pulmonary histiocytosis X) is a
disease of smokers aged 20 to 40 years with characteristic HRCT features including a mid
to upper zone predominance, multiple cysts and nodules, and interstitial thickening. While
lung biopsy is not always needed for the diagnosis, the histopathology typically shows
cysts and aggregates of Langerhans-like dendritic cells (S-100 and CD1a positive on
staining) surrounding smaller bronchioles. (See "Pulmonary Langerhans cell
histiocytosis".)
● Airspace enlargement with fibrosis (AEF) – AEF is a pathologic entity seen in cigarette
smokers that can mimic honeycomb cysts on HRCT [38,56,57]. However, AEF tends to
predominate in the upper to mid lung zones, spare the most peripheral parts of the lung
(subpleural but not abutting pleura), and be characterized by thinner walls than typical
honeycomb cysts [38]. Areas of AEF can be seen in combination with combined pulmonary
fibrosis and emphysema (CPFE) and UIP [58].
● Combined pulmonary fibrosis and emphysema – CPFE is most commonly seen in male
smokers and is characterized by dyspnea, upper-lobe emphysema, lower-lobe fibrosis,
and abnormalities of gas exchange [59]. In a case series, in addition to emphysematous
changes, thick-walled cystic lesions with an internal diameter greater than the cysts of
honeycombing, consistent with AEF noted above, were seen in 16 (73 percent) of the 22
patients with CPFE, but none of the eight patients with IPF [60]. (See "High resolution
computed tomography of the lungs", section on 'Emphysema' and "Idiopathic interstitial
pneumonias: Classification and pathology", section on 'Smoking-related interstitial
abnormalities'.)
● Pleuropulmonary fibroelastosis – Pleuropulmonary fibroelastosis (PPFE), which can be

idiopathic or chemotherapeutic drug-induced, is a rare process that is characterized by
upper lobe pleural and subpleural lung parenchymal fibrosis. The pattern of pleural
thickening and upper lobe predominance should raise suspicion for PPFE. (See
"Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare

histopathologic interstitial pneumonia patterns'.)
FUTURE DIRECTIONS
An investigational technology has been developed that analyzes RNA sequence data of 190
genes from transbronchial biopsy samples to classify patients as having a molecular pattern of
usual interstitial pneumonia (UIP) or not [61,62]. In a validation cohort of 49 patients with new
onset interstitial lung disease, three to five transbronchial biopsies were obtained from each
participant for RNA molecular analysis [63]. The analysis demonstrated 88 percent specificity
(95% CI 70-98) and 70 percent sensitivity (95% CI 47-87) for differentiating UIP from non UIP.
Among patients with possible or inconsistent UIP on high resolution computed tomography
(HRCT), the RNA molecular test showed a positive predictive value of 81 percent (95% CI 54–96)
for biopsy-proven UIP. Further study is needed to clarify whether the test can reduce the need
for surgical biopsies in patients without a pattern of UIP on HRCT or aid in diagnosis when
histopathology is not definitive. It is important to remember that UIP can be found in multiple
settings (eg, hypersensitivity pneumonitis, rheumatoid arthritis, drug-induced lung toxicity),
and this test does not distinguish among causes of UIP.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Interstitial lung
disease".)
SUMMARY AND RECOMMENDATIONS
● Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic fibrosing interstitial pneumonia

with a histopathologic or radiographic pattern of usual interstitial pneumonia (UIP) (
table 5). (See 'Introduction' above.)
● On histopathologic examination, the hallmark and chief diagnostic criterion for UIP is a
heterogeneous appearance with alternating areas of normal lung, interstitial
inflammation, fibroblast foci, and honeycomb change, in a subpleural distribution. (See
'Histopathology' above.)
● The onset of IPF is typically in patients age 60 and older, except among patients with
familial pulmonary fibrosis in whom disease presents earlier. Men appear to be affected
more often than women, and the majority of patients have a history of cigarette smoking.
(See 'Clinical manifestations' above.)
● Patients commonly report a gradual onset (over several months) of dyspnea on exertion
and a nonproductive cough. Fatigue, fever, myalgias, and arthralgias are rarely reported.
On physical examination bibasilar crackles are usually audible, but may be absent or
heard unilaterally early in the disease. (See 'Clinical manifestations' above.)
● When IPF is suspected, the first step is clinical evaluation to identify features of rheumatic
disease, familial pulmonary fibrosis, or exposures that can cause UIP (eg, medications,
antigens associated with hypersensitivity pneumonitis, agents of pneumoconiosis) (
table 1). Laboratory testing includes serologic tests for rheumatic disease and
sometimes serology for hypersensitivity pneumonitis. (See 'Evaluation' above.)
● High resolution computed tomography (HRCT) should be obtained in all patients

suspected of having IPF. The characteristic HRCT features of IPF/UIP include peripheral
(subpleural), bibasilar reticular opacities associated with architectural distortion, including
honeycomb changes and traction bronchiectasis or bronchiolectasis ( table 2).
Depending on the features in an individual patient, the pattern may be considered UIP,
probable UIP, indeterminate for UIP, or suggestive of an alternate diagnosis. Ground glass
opacities are occasionally present, but are less prominent than reticular changes, except
in the setting of an acute exacerbation. (See 'Chest imaging' above.)
● Bronchoalveolar lavage (BAL) has a limited role in the evaluation of patients with
suspected IPF, largely to identify alternate diagnoses, such as sarcoidosis. (See
'Bronchoalveolar lavage' above.)
● When the results of the clinical evaluation, laboratory testing, and HRCT do not allow the
clinician to make a confident diagnosis of IPF, surgical lung biopsy may be indicated. The
decision requires assessment of the benefits of having a definitive diagnosis relative to
the risks of the surgical procedure. A surgical biopsy via video-assisted thoracoscopy or
thoracotomy is preferred over a transbronchial lung biopsy, as the larger sample size is
essential to a confident diagnosis. (See 'Lung biopsy' above.)
● The diagnosis of IPF requires exclusion of other known causes of interstitial lung disease
AND either definite features of UIP on HRCT or certain combinations of HRCT and lung
biopsy features of UIP ( table 3). (See 'Diagnosis' above.)
● The differential diagnosis of IPF includes other diseases with histopathologic features of
UIP, such as rheumatic diseases (eg, rheumatoid arthritis, systemic sclerosis), chronic
hypersensitivity pneumonitis, asbestosis, and certain drug-induced lung diseases (
table 4). (See 'Differential diagnosis' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Clinical Manifestations and Diagnosis of Idiopathic Pulmonary Fibrosis - UpToDate

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29/11/2020 Clinical manifestations and diagnosis of idiopathic pulmonary ﬁbrosis - UpToDate

Author: Talmadge E King, Jr, MD

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), previously known as

PATHOGENESIS AND GENETIC PREDISPOSITION

FPF appears to be associated with an increased incidence of bronchogenic carcinoma [12].

● Hermansky-Pudlak syndrome – HPS, an autosomal recessive disorder characterized by

POTENTIAL RISK FACTORS

● An assessment of the pattern and severity of respiratory impairment on pulmonary

● A multidisciplinary clinical, radiologic, and pathologic discussion is useful in arriving at the

● Medications (eg, amiodarone, bleomycin, long-term nitrofurantoin, biologic therapies)

● Work exposure to asbestos, silica, other fumes, vapors, dusts, or mold

● Biomarkers – Measurement of biomarkers, such as serum matrix metalloproteinase

Pulmonary function tests — Complete pulmonary function testing (PFT; spirometry, lung

● High resolution computed tomography – HRCT should be obtained in all patients

Up to 30 percent of cases with a histopathological diagnosis of UIP may have HRCT

Bronchoalveolar lavage — Bronchoalveolar lavage (BAL) has a limited role in the

alternate diagnosis, cellular analysis of BAL fluid to exclude eosinophilic pneumonia,

Transbronchial lung biopsy and transbronchial cryobiopsy

● Transbronchial cryobiopsy (TBCB) – TBCB shows promise as a diagnostic technique for

Lung biopsy — For patients who require histopathologic confirmation of suspected IPF, a

Procedure — Surgical lung biopsy may be done via a video-assisted thoracoscopic

Histopathology — UIP is the histopathologic pattern associated with the clinical diagnosis of

with rheumatic diseases, chronic hypersensitivity pneumonitis, drug-toxicity, and

The pathology of IPF/UIP is described in detail separately. (See "Idiopathic interstitial

● HRCT suggests an alternate diagnosis – If the HRCT demonstrates features suggestive

Post-diagnostic evaluation — The possibility of short telomere syndrome (STS) should be

● Nonspecific interstitial pneumonitis – Nonspecific interstitial pneumonia (NSIP) is a

● Rheumatic disease – Patients with rheumatic disease, most commonly rheumatoid

● Asbestosis – Asbestosis is associated with occupational exposures such as mining of

● Chronic hypersensitivity pneumonitis – Chronic hypersensitivity pneumonitis can

● Pulmonary Langerhans' cell histiocytosis – Pulmonary Langerhans' cell histiocytosis

● Pleuropulmonary fibroelastosis – Pleuropulmonary fibroelastosis (PPFE), which can be

"Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic fibrosing interstitial pneumonia

● High resolution computed tomography (HRCT) should be obtained in all patients

Use of UpToDate is subject to the Subscription and License Agreement.

2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment.

3. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An

5. Kaunisto J, Salomaa ER, Hodgson U, et al. Idiopathic pulmonary fibrosis--a systematic

6. Raghu G, Weycker D, Edelsberg J, et al. Incidence and prevalence of idiopathic pulmonary

9. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic

10. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of

13. Suzuki T, Li W, Zhang Q, et al. Hermansky-Pudlak syndrome is caused by mutations in

14. Vicary GW, Vergne Y, Santiago-Cornier A, et al. Pulmonary Fibrosis in Hermansky-Pudlak

31. Pezzuto G, Claroni G, Puxeddu E, et al. Structured multidisciplinary discussion of HRCT

37. Quadrelli S, Molinari L, Ciallella L, et al. Radiological versus histopathological diagnosis of

44. Oda T, Ogura T, Kitamura H, et al. Distinct characteristics of pleuroparenchymal

51. Yagihashi K, Huckleberry J, Colby TV, et al. Radiologic-pathologic discordance in biopsy-

52. Sahin H, Brown KK, Curran-Everett D, et al. Chronic hypersensitivity pneumonitis: CT

55. Pneumotox. http://www.pneumotox.com/pattern/index/ (Accessed on October 20, 2015).

60. Inomata M, Ikushima S, Awano N, et al. An autopsy study of combined pulmonary

Topic 14870 Version 20.0

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