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INVITED REVIEW SERIES:

IDIOPATHIC INTERSTITIAL PNEUMONIA
PART 2: SPECIFIC DISEASE ENTITIES
SERIES EDITORS: TAMERA J CORTE, ATHOL U WELLS AND HAROLD R COLLARD

Idiopathic pulmonary fibrosis: Diagnosis, epidemiology and

natural history

GIACOMO SGALLA,1 ALICE BIFFI1,2 AND LUCA RICHELDI1

1
National Institute for Health Research, Southampton Respiratory Biomedical Research Unit, Southampton University
Hospital, Southampton, UK, and 2Clinic of Respiratory Medicine, Department of Health Science, University Hospital San
Gerardo, Monza, Italy

ABSTRACT ration (acute exacerbations) being unpredictable. A

deeper understanding of the mechanisms responsible
Idiopathic pulmonary fibrosis (IPF) is a chronic, pro-
for an accelerated course of the disease and the identi-
gressive fibrosing lung disorder of unknown aetiology
fication of biomarkers of progression would lead to a
whose diagnosis involves the careful exclusion of sec-
better stratification of the disease, essential for deliver-
ondary causes for pulmonary fibrosis and the presence
ing individualized therapeutic strategies.
of a pattern of usual interstitial pneumonia (UIP) at
either high-resolution computed tomography (HRCT) Key words: diagnosis, epidemiology, idiopathic pulmonary
scan or surgical lung biopsy. Despite great efforts made fibrosis, interstitial lung disease, natural history.
in establishing precise, universally acknowledged diag-
nostic criteria for IPF, its ascertainment remains a Abbreviations: 6MWD, 6-min walking test distance; AE-IPF,
challenge, especially in those individuals presenting acute exacerbation of idiopathic pulmonary fibrosis; ALAT, Latin-
with atypical HRCT patterns. With new drugs emerg- American Thoracic Society; ATS, American Thoracic Society; CT,
computed tomography; CTD, connective tissue diseases; DLCO,
ing, establishing a precise diagnosis is becoming a
diffusion lung capacity for carbon monoxide; ERS, European
clinically relevant issue. Although regarded as a rare
Respiratory Society; FVC, forced vital capacity; GAP, Gender,
disease, IPF epidemiology is controversial due to Age, Physiology; GERD, gastro-oesophageal reflux disease;
studies relying on old data and adopting mixed, incom- HRCT, high-resolution computed tomography; IIP, idiopathic
parable methodologies for cases definition. Overall, the interstitial pneumonias; ILA, like interstitial lung abnormalities;
prevalence and incidence appear to be increasing over ILD, interstitial lung disease; INPULSIS, Efficacy and Safety of
the last decades, suggesting that in earlier studies they Nintedanib in Idiopathic Pulmonary Fibrosis; IPF, idiopathic pul-
might have been underestimated because of diagnostic monary fibrosis; JRS, Japanese Respiratory Society; MDD, mul-
uncertainty. IPF is invariably progressive, although its tidisciplinary discussion; MMP, matrix metalloproteinases;
clinical course might greatly vary on an individual MUC5B, mucin 5B; PROFILE, Prospective Observation of Fibrosis
basis, with episodes of severe acute respiratory deterio- in the Lung Clinical Endpoints; SLB, surgical lung biopsy; TBLC,
transbronchial lung cryobiopsy; TOLLIP, Toll-interacting protein;
Correspondence: Giacomo Sgalla, National Institute for Health TOMORROW, To Improve Pulmonary Fibrosis with BIBF 1120;
Research, Southampton Respiratory Biomedical Research Unit, UIP, usual interstitial pneumonia.
Southampton Centre for Biomedical Research, Mailpoint 810, D
Level, South Block, University Hospital Southampton NHS Foun-
dation Trust, Tremona Road, Southampton SO16 6YD, UK. Email: INTRODUCTION
[email protected]
The Authors: Giacomo Sgalla is a Specialist in Respiratory Idiopathic pulmonary fibrosis (IPF) is a chronic and
Medicine and a Clinical Research Fellow in Interstitial Lung
Disease at the NIHR Respiratory Biomedical Research Unit of the
progressive disorder characterized by the aberrant
University Hospital of Southampton, UK. Alice Biffi is a Registrar deposition of extracellular matrix leading to extensive
in Respiratory Medicine at the University Hospital San Gerardo lung remodelling.1 It accounts for about 20% of all
of Monza, Italy, and a Research Fellow in Interstitial Lung Disease cases of interstitial lung disease (ILD) and represents
at the NIHR Respiratory Biomedical Research Unit of the Univer- the most frequent and severe among the idiopathic
sity Hospital of Southampton, UK. Luca Richeldi is a Professor of interstitial pneumonias (IIP), a group of ILD of
Respiratory Medicine and Chair of Interstitial Lung Disease at the
University of Southampton, UK.
unknown cause characterized by various patterns of
Received 18 June 2015; invited to revise 10 August 2015; inflammation and fibrosis.2
revised 21 August 2015; accepted 5 October 2015. Although IPF is considered a rare disease, its social,
Article first published online: 23 November 2015 healthcare and economic burden is far from
2015 Asian Pacific Society of Respirology Respirology (2016) 21, 427437
doi: 10.1111/resp.12683
428 G Sgalla et al.

irrelevant. It is estimated that in Europe approxi- and management of IPF.6 This document provided an
mately 40 000 new cases are being diagnosed each update of the diagnostic criteria, 10 years after the
year, with more than 5000 in the UK only.3 Despite previous statement,11 which now consists of the fol-
being a clinically heterogeneous disease with multi- lowing: (i) exclusion of other known causes of ILD
ple variable courses, the prognosis of patients with (e.g. domestic and occupational environmental expo-
IPF is overall poor, with a 5-year survival, which is sures, CTD and drug toxicity); (ii) presence of an usual
worse than several cancer types.4 As a consequence, interstitial pneumonia (UIP) pattern on high-
the total direct treatment cost for IPF is estimated to resolution computed tomography (HRCT) of the
be around 25 000 USD/person-year, more than the chest in individuals where surgical lung biopsy (SLB)
direct cost for breast cancer.5 is not indicated or available; (iii) and specific combi-
nations of HRCT and biopsy pattern in individuals
undergoing SLB. Finally, a multidisciplinary discus-
DIAGNOSIS sion involving ILD specialists, radiologists and
pathologists is recommended to reach a consensus
Clinical presentation of IPF diagnosis of IPF.
IPF generally occurs after the age of 60 years and is The new criteria originated from the evidence that
more prevalent in men.6 The initial clinical presenta- in an appropriate clinical setting, the presence of a
tion is not specific, consisting of progressive dysp- classical (or definite) UIP pattern on the HRCT scan
noea on exertion combined with dry cough. Bibasilar has a very high positive predictive value (between
inspiratory velcro-type crackles are constant and 90% and 100%) for a histological diagnosis of UIP,12
appear early in the disease.7 Finger clubbing is and has been therefore considered sufficient for a
present in 2550% of cases, whereas weight loss and diagnosis of IPF to be made. If honeycombing on
alteration of the general status are less common. Cya- HRCT is absent, then the diagnosis of IPF is regarded
nosis and signs of right ventricular failure may occur as possible, and further diagnostic evaluation on SLB
in more advanced stages together with respiratory is required.
failure, ultimately causing death in these patients.8 The HRCT and histological features for a UIP
The pulmonary function tests typically show a pattern are fully reported in Table 1, while the guid-
restrictive pattern at spirometry with reduced forced ance for diagnosis of IPF based on the different com-
vital capacity (FVC), and there is an impairment of gas binations of patterns is reported in Table 2.
exchange reflected by the reduction of the diffusion
lung capacity for carbon monoxide (DLCO), which may
represent the only functional abnormality in mild dis- Pitfalls and evolving concepts
eases. However, it is important to note that in patients The main challenge in achieving an accurate diagno-
with concomitant emphysema the predicted FVC sis of IPF is represented by discerning those cases
values may appear falsely normal due to the con- where ascertainment by histopathology is really
comitance of restrictive and obstructive defects. needed. Because the risks of SLB may outweigh the
Laboratory findings are usually non-specific and benefits of establishing a secure diagnosis of IPF (in
are mostly used to rule out alternative diagnosis such particular when the disease is more advanced) and
as connective tissue diseases (CTD), although some many individuals may refuse to undergo a surgical
patients with IPF may present low-positive rheuma- procedure, only a minority of patients with suspected
toid factor and anti-nuclear antibodies titres. It is still IPF reaches diagnosis via SLB.13 It is estimated that up
debated whether these IPF patients with features of a to 10% of ILD cases remains unclassifiable, the main
subclinical autoimmune disorder have a different reason being missing histopathology.14 Patients with a
clinical course and response to treatments. On the possible (or atypical) UIP at HRCT do not fall in any
other hand, some patients with suspected CTD- diagnostic category as per current guidelines, and the
related ILD and low titres of autoantibodies do not need of making a secure diagnosis in these patients
fulfil the criteria for any specific autoimmune disease, without recurring to surgery is still unmet. The
making the differential diagnosis problematic.9 Very urgency of classifying these individuals with a pos-
recently, a joint European Respiratory Society/ sible disease has been underlined shortly after the
American Thoracic Society (ERS/ATS) task force pro- publication of the 2011 statement,13 and it has
posed the term interstitial pneumonia with become more than ever compelling now that safe and
autoimmune features to describe individuals with effective pharmacological treatments for IPF are
both ILD and combinations of other clinical, serologic available.15
and/or pulmonary morphologic features suggestive Undoubtedly, the definition of radiological UIP as
of an underlying systemic autoimmune condition, reported in the current guidelines is not without
but not meeting current rheumatologic criteria for a flaws. Although honeycombing represents the main-
characterized CTD.10 stay of established fibrosis, the smaller cysts that are
visible on pathological samples and are referred to as
microscopic honeycombing, cannot be seen at the
Current diagnostic criteria HRCT of the chest for being beyond the limits of reso-
In 2011, ATS, ERS, the Japanese Respiratory Society lution.16 As such, the absence of radiological honey-
(JRS) and the Latin-American Thoracic Society combing does not translate automatically into the
(ALAT) jointly published an evidence-based state- absence of its histological equivalent. Moreover, the
ment providing recommendation for the diagnosis inter-observer agreement in recognizing honeycomb-
Respirology (2016) 21, 427437 2015 Asian Pacific Society of Respirology
IPF: Diagnosis, epidemiology, course 429

Table 1 Diagnostic criteria for IPF: HRCT and histological patterns

High-resolution computed tomography criteria for UIP pattern

Possible UIP pattern Inconsistent with UIP pattern

UIP pattern (all four features) (all three features) (any of the seven features)

Subpleural, basal predominance Subpleural, basal predominance Upper- or mid-lung predominance

Reticular abnormality Reticular abnormality Peribronchovascular predominance
Honeycombing with or without Absence of features listed as Extensive ground glass abnormality
traction bronchiectasis inconsistent with UIP pattern (see (extent > reticular abnormality)
Absence of features listed as third column) Profuse micronodules (bilateral,
inconsistent with UIP pattern (see predominantly upper lobes)
third column) Discrete cysts (multiple, bilateral,
away from areas of honeycombing)
Diffuse mosaic attenuation/air-trapping
(bilateral, in three or more lobes)
Consolidation in bronchopulmonary
segment(s)/lobe(s)

Histopathological criteria for UIP pattern

UIP pattern (all four Possible UIP pattern Not UIP pattern
criteria) Probable UIP pattern (all three criteria) (any of the six criteria)

Evidence of marked Evidence of marked Patchy or diffuse Hyaline membranes

fibrosis/architectural fibrosis/architectural involvement of lung Organizing pneumonia
distortion, distortion, parenchyma by fibrosis, Granulomas
honeycombing in a honeycombing with or without interstitial Marked interstitial
predominantly Absence of either patchy inflammation inflammatory cell infiltrate
subpleural/paraseptal involvement or Absence of other criteria away from honeycombing
distribution fibroblastic foci, but not for UIP (see the first Predominant
Presence of patchy both column on UIP pattern) airway-centred changes
involvement of lung Absence of features Absence of features Other features suggestive
parenchyma by fibrosis against a diagnosis of UIP against a diagnosis of UIP of an alternate diagnosis
Presence of fibroblast foci suggesting an alternate suggesting an alternate
Absence of features diagnosis (see fourth diagnosis (see fourth
against a diagnosis of UIP column) column)
suggesting an alternate Or
Honeycomb changes
diagnosis (see fourth only
column)

Can be associated with acute exacerbation of idiopathic pulmonary fibrosis.

An isolated or occasional granuloma and/or a mild component of organizing pneumonia pattern may rarely be coexisting in lung
biopsies with an otherwise UIP pattern.

This scenario usually represents end-stage fibrotic lung disease where honeycombed segments have been sampled but where a UIP
pattern might be present in other areas. Such areas are usually represented by overt honeycombing on HRCT and can be avoided by
preoperative targeting of biopsy sites away from these areas using HRCT.
Reprinted with permission of the American Thoracic Society. Copyright 2015 American Thoracic Society. From Raghu et al.6 The
American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; UIP, usual interstitial pneumonia.

ing is far from ideal even among expert chest radiolo- disease and in chronic hypersensitivity pneumoni-
gists, with the presence of emphysema and peripheral tis.19,20 These studies also reported a good inter-
traction bronchiectasis being indicated as the main observer agreement for the identification of traction
confounding factors for its ascertainment.17 On the bronchiectasis, as opposed to honeycombing. Trac-
other hand, prognosis in histologically confirmed UIP tion bronchiectasis, currently regarded as an optional
cases has been recently demonstrated being influ- feature in the radiological criteria for UIP, may there-
enced more by the presence and severity of traction fore have a major role in future diagnostic algorithms.
bronchiectasis than by a definite UIP pattern at the The presence of radiological features of fibrosis other
HRCT.18 The high predictive value of traction bronchi- than honeycombing weighs even more if clinical
ectasis in regard to poor survival has been confirmed parameters are taken into account: a retrospective
by two recent studies exploring the HRCT prognostic study has demonstrated that patients older than 70
determinants both in CTD-related fibrotic lung years with some extent of reticular abnormalities at
2015 Asian Pacific Society of Respirology Respirology (2016) 21, 427437
430 G Sgalla et al.

Table 2 Combination of HRCT and surgical lung biopsy mated. Nevertheless, the study succeeded in
patterns for the diagnosis of IPF6 demonstrating the efficacy of nintedanib in reducing
the rate of decline of FVC in these patients. More
Surgical lung biopsy pattern Diagnosis recently, data from a pre-defined subgroup analysis of
HRCT pattern (when performed) of IPF? the phase 3 INPULSIS (Efficacy and Safety of
Nintedanib in Idiopathic Pulmonary Fibrosis) trials of
UIP UIP Yes
nintedanib, which adopted the same eligibility cri-
Probable UIP
teria as the phase 2 study, have confirmed that the
Possible UIP
treatment effect of nintedanib in terms of FVC decline
Non-classifiable fibrosis
is not different between patients with honeycombing
Not UIP No
and/or biopsy confirmation of UIP and patients with
Possible UIP UIP Yes
a possible UIP and no biopsy. Interestingly, these two
Probable UIP
groups of patients showed identical rates of lung
Possible UIP Probable
function decline in the placebo groups.24
Non-classifiable fibrosis
Not UIP No
Inconsistent UIP Possible Future perspectives
with UIP Probable UIP No
Possible UIP Transbronchial lung cryobiopsy
Non-classifiable fibrosis In real-life clinical practice and based on current
Not UIP guidelines, approximately in half of patients with sus-

pected IPF, a histology confirmation of UIP pattern
Non-classifiable fibrosis: some biopsies may reveal a pattern
would be required to make a confident diagnosis of
of fibrosis that does not meet the above criteria for UIP pattern
and the other idiopathic interstitial pneumonias. These biopsies
IPF, using tissue samples obtained by SLB.6 However,
may be termed non-classifiable fibrosis. such procedure carries appreciable risks, with a mor-

Multidisciplinary discussion should include discussions of the tality estimated between 2% and 6% within 90 days.25
potential for sampling error and a re-evaluation of adequacy of As such, a possible role for transbronchial lung biop-
technique of HRCT. Note: in cases with an inconsistent with UIP sies has been advocated; however, current guidelines
HRCT pattern and a UIP surgical lung biopsy pattern, the pos- do not recommend their use in the evaluation of IPF
sibility of a diagnosis of IPF still exists and clarification by MDD in the majority of individuals, mainly due to the
among interstitial lung disease experts is indicated. current uncertainty about their diagnostic accuracy,
Reprinted with permission of the American Thoracic Society. the best location to biopsy and the number of biop-
Copyright 2015 American Thoracic Society. From Raghu et al.6
sies to be taken. A recent prospective study in 69
The American Journal of Respiratory and Critical Care Medicine
is an official journal of the American Thoracic Society.
patients with a HRCT pattern of fibrotic ILD has
HRCT, high-resolution computed tomography; IPF, idiopathic shown that transbronchial lung cryobiopsy (TBLC) is
pulmonary fibrosis; MDD, multidisciplinary discussion; UIP, usual feasible and safe in these patients, and pathologists
interstitial pneumonia. were able to identify the criteria sufficient to define a
specific pattern in 63 patients (93%), including 47
UIP.26 However, given the considerable costs and
HRCT has the 95% of positive predictive value of UIP burden on patients related to TBLC, further studies
on SLB, and it becomes 100% for people older than 75 are needed to assess the usefulness of this technique
years.21 as a potential alternative to SLB in the evaluation of
Recently, late phase randomized clinical trials in ILD and especially IPF.
IPF have also offered some new interesting insights. A
study conducted in a cohort of patients from the Early detection of IPF
ARTEMIS trial22 (a placebo controlled trial of Due to the subtle, invariably progressive course, the
Ambrisentan in idiopathic pulmonary fibrosis) has late onset of symptoms and the non-specificity of
shown a positive predictive value of possible UIP on clinical and physiological signs, the diagnosis of IPF is
HRCT toward histological confirmation of 94%. often delayed, with a median duration of symptoms
Despite the limitation represented by the retrospec- before diagnosis of more than 24 months.27 The delay
tive nature of the study and the potential selection in referral of patients to a tertiary care centre special-
bias due to the fact that subjects screened for the trial izing in ILD has been found to correlate with poorer
already received a diagnosis of IPF, confirmed by a survival,28 which makes diagnosing IPF at an early
UIP pattern at histology, these data suggest that SLB stage an urgent matter, especially now that safe and
might not be necessary to reach a diagnosis of IPF if effective treatments are available.
HRCT scans are being assessed by experts. The phase However, defining what early means in a context
2 TOMORROW (To Improve Pulmonary Fibrosis with where current diagnostic criteria require the evidence
BIBF 1120) study,23 evaluating the safety and efficacy of established lung scarring might generate some
of nintedanib in IPF patients, included patients confusion. The reality is that what happens before the
having both definite and probable IPF, the latter scar, in a presumably asymptomatic phase, is largely
being defined by a possible (or atypical) UIP pattern unknown. Terms like interstitial lung abnormalities
at HRCT scan. These patients represented more than (ILA) or subclinical ILD have been used to describe
half the study cohort (62%), suggesting that the preva- the whole of the patterns of interstitial lung altera-
lence of honeycombing in UIP might be overesti- tions that can be found on HRCT in the absence of a
Respirology (2016) 21, 427437 2015 Asian Pacific Society of Respirology
IPF: Diagnosis, epidemiology, course 431

significant clinical presentation. Although a few odologies have been used for the cases ascertainment
patients presenting with ILA can progress to a UIP in the populations examined, ranging from the use of
pattern (thus to definite IPF) over some years, most different diagnostic ICD codes, to death registries and
subject with ILA will not develop IPF, either going surveys of clinicians with varying degree of specialty,
toward resolution, keeping on with stable or mini- or a mix of both. Finally, studies adopted different
mally progressive ILA or evolving to other forms of designs, and the results are not easily comparable.
ILD/IIP.29 Over the last years, several genome-wide A recent study collecting data from US Medicare
associations studies have identified several common beneficiaries aged 65 years or older between 2001 and
and rare genetic variants in more than a dozen loci on 2011 has shown much higher rates than previously
different chromosomes that appear to contribute to described (incidence of 93.7 cases per 100 000/year,
the risk of developing IPF. The most consistent and prevalence ranging from 202.2 cases per 100 000 in
reproducible genetic finding in IPF is represented by a 2001 to 494.5 cases per 100 000 in 2011). In the
common single nucleotide polymorphism in the pro- observed period incidence has remained stable,
moter of the gene encoding for mucin 5B (MUC5B) whereas prevalence appears on the rise.36 In the UK, a
located on the chromosome 11, which has been first study37 reported an incidence of 4.6 per 100 000/
found to be associated with a six to eightfold year by retrieving cases from a longitudinal primary
increased risk for both sporadic and familiar forms of care database between 1991 and 2003. A higher inci-
IPF.30 However, this variant is estimated to be present dence of 7.4 per 100 000/year has been reported in a
in 20% of the general population and has been follow-up study using data from same database (but
reported as a risk factor also for asymptomatic ILA,31 slightly different methods for case inclusion) for the
confirming a large genetic effect for this variant. Even period of 20002009.38 Importantly, both studies have
if ILA and IPF seem to share some common genetic showed an increase of incidence rates throughout the
grounds, it is still impossible to conclude with cer- observed periods. Overall, recent data suggest an
tainty the biological effect of the single genetic vari- increasing prevalence and a stable or increasing inci-
ants isolated so far, and most importantly, to dence of IPF in western countries. When data have
determine the influence of environmental factors on been stratified per sex and age, the majority of the
such variants in the development of a progressive studies have showed higher prevalence and incidence
fibrosis. Large, longitudinal studies are needed to rates among men and with increasing age, especially
determine which combination of genetic variants and after 75 years.
clinical, physiologic and imaging features predict an As noted above, there have been few epidemiologic
increased risk of progression to IPF, thus defining an studies in Asian communities. Recently, a Japanese
early IPF phenotype.29 study39 has explored the certificates of medical ben-
More realistically, at present, a prompt recognition efits for IPF in the Hokkaido prefecture between 2003
of signs and symptoms suggestive of IPF operated by and 2007, reporting a prevalence and incidence of
healthcare practitioners remains the most valuable 10.0 and 2.23 per 100 000/year respectively. Although
approach for limiting the diagnostic delay. It has been male predominance and an increase of frequency
advocated that the careful assessment of velcro-type with age are confirmed in these studies, prevalence
crackles by lung auscultation, if supported by a con- and incidence rates appear lower than those
sistent clinical picture, represent a practical, reliable described in western countries, suggesting a possible
and cost-effective way for prompting a proper diag- role of ethnic differences in IPF epidemiology
nostic process.7 In light of the evidence of significant between Asian and Western populations.
findings of interstitial and fibrotic lung abnormalities
in lung cancer screening programs conducted using
low-dose computed tomography (CT) scan of the Mortality
chest,32 another advisable approach for earlier diag- IPF-related mortality data share some common limi-
nosis of IPF might be the adoption of screening strat- tations with prevalence and incidence evaluations.
egies for detecting ILD as a by-product of cancer Being derived from national registries built on infor-
screening, taking advantage of shared risk factors mation provided by death certificates, IPF-related
such as age and smoking.33 mortality is largely affected by IPF under-recognition
and misdiagnosis and is likely to be underestimated.40
Several studies have pointed out that similar to
EPIDEMIOLOGY prevalence and incidence, IPF-related mortality is
higher in men, increases with age41,42 and seems to
Incidence and prevalence of IPF increase over time. Olson et al.,43 looking at IPF-
IPF is known for being the most common among the related deaths in the US from 1992 to 2003, have cal-
IIP. Data from existing registries suggest that IPF culated an age- and sex-adjusted mortality of 50.8 per
accounts for 1737% of all ILD diagnoses.34,35 Never- 100 000/year, with an increment rate of 28.4% for men
theless, its prevalence and incidence still remain and 41.3% for women over the study period. In the
unclear, with a large variability across reports due to a UK, mortality has also steadily increased from 1968 to
number of reasons. First, a precise knowledge of IPF 2008.3 The reasons behind the observed increase in
epidemiology is hurdled by the lack of a uniform defi- IPF-related mortality are not fully clear, although it
nition of IPF in the studies conducted so far, as the can be hypothesized that an improvement in recog-
older ones included cases diagnosed before the 2000 nition of the disease, more than a real increase in
consensus statement on IPF.11 Second, different meth- mortality, plays a major role. In terms of causes of
2015 Asian Pacific Society of Respirology Respirology (2016) 21, 427437
432 G Sgalla et al.

death, respiratory failure from IPF accounted for the tifiable cause (such as infections, left heart failure,
60% of IPF-related deaths in a US-based study,43 fol- pulmonary embolism, etc.), and are referred to as
lowed by cardiovascular diseases (8.5%) and lung AE-IPF. These events represent an acceleration of the
cancer (2.9%). Such proportion is even higher than in underlying fibrotic process; they have no effective
previous reports,41 confirming IPF as the major treatments and usually lead to a poor outcome. Mor-
underlying cause of death in these patients. Interest- tality from AE-IPF is >50%52,53 during hospitalization,
ingly, a recent study39 has reported a percentage of and it can reach 80% after 1 year of follow up. The
death from acute exacerbation of idiopathic pulmo- typical histological finding in AE-IPF is diffuse alveo-
nary fibrosis (AE-IPF) of 40%, much higher than pre- lar damage superimposed on the underlying UIP
viously described.44 pattern.54 The incidence of AE-IPF is still unclear,
varying from 5% to 15% per year in retrospective
studies on the placebo arm populations enrolled in
NATURAL HISTORY clinical trials15,55,56 and might increase with time,
reaching 20.7% at 3 years from diagnosis.52 Lower FVC
Patterns of disease progression and DLCO have been shown to correlate with a higher
Notwithstanding the advances in understanding the risk of AE-IPF,52 and the concomitant presence of
underlying pathogenic mechanisms and the discov- emphysema or pulmonary hypertension is also asso-
ery of two agents effective in reducing the decline of ciated with an increased risk.57
pulmonary function, IPF remains a progressive Collard et al. in 2007 proposed a consensus defini-
disease with unfavourable prognosis. Median survival tion for AE-IPF58 based on the following criteria: acute
from diagnosis is only 23 years,6 reportedly varying and unexplained onset or worsening of dyspnoea
from 27.4 months for patients with severe disease (within 30 days or less), new bilateral opacities at the
(FVC < 55% predicted) to 55.6 months for patients HRCT of the chest superimposed on a background
with mild disease (FVC 70% predicted).45 UIP pattern, and no evidence of infection on BAL or of
The rate of progression of IPF is highly variable, any other identifiable cause in patients with previous
both between patients and between different periods or concurrent diagnosis of IPF. However, procedures
in a single individual. Many patients have a slow but such as bronchoscopy and BAL are not feasible in the
progressive clinical course over a period of years, most critical patients, and this definition is excluding
whereas in 1015% of patients the course of the a priori patients with a rapid decline occurring for
disease is much more rapid, leading to death from more than 30 days. For those patients with respiratory
respiratory failure in few months. Finally, a minority worsening of unknown cause but not fulfilling all the
of patients present relative stability over long periods, criteria, a definition of suspected AE-IPF was there-
punctuated by episodes of rapid acute deterioration fore proposed.58
(AE-IPF), either fatal or leading to a step down in pul- Nevertheless, this definition seems to be too strict
monary function.6,46 However, it is impossible at to be used in clinical practice and has made experts
present to predict, at the time of the diagnosis, how argue about of the current classification of AE-IPF,
the disease will behave in the single individual, which might represent an artificial construct.59,60
although it has been noted that male smokers tend to First, the clinical picture does not seem to differ
have an accelerated clinical course.47 much between these entities. Suspected AE-IPF and
The presence of several comorbidities indeed influ- definite AE-IPF are both associated with high risk of
ences prognosis in IPF. Emphysema and secondary short-term mortality. As such, suspected exacerba-
pulmonary arterial hypertension, commonly present tions have been proposed as an outcome measure in
in IPF patients, are both associated with poor sur- clinical trials, where the low rate of observed AE-IPF
vival.48,49 Lung cancer is also frequently associated makes it difficult to capture a potential reduction in
with IPF and has a significant impact on survival.50 As the incidence of these events as determined by an
mentioned above, gastro-oesophageal reflux disease investigational therapy.61 A study has also reported no
has been proven an important factor both in the difference of outcome between hospitalized patients
pathogenesis and progression of the disease.51 As with idiopathic acute exacerbation of fibrotic ILD and
such, comorbidities should be timely evaluated to those for whom aetiologies were identified.53
identify those patients at higher risk, and a proper Second, although AE-IPF is considered an idi-
treatment should be delivered whenever possible. opathic event, the role of potential triggers in driving
As new and more targeted therapies are being occult injuries to the lung has been progressively rec-
developed, clarifying the heterogeneity of IPF ognized. It has been demonstrated that at least 9% of
becomes more than ever compelling and tools for AE-IPF may be caused by clinically silent viral infec-
stratification of patients are strongly needed to tailor tions according to molecular or microarray findings
personalized treatments to those patients who could in BAL.62 Increased exposure to ozone and nitrogen
benefit the most. dioxide has also been shown to be associated with an
increased risk of AE-IPF.63 Elevated pepsin levels have
been found in the BAL of patients with AE-IPF, sug-
Acute exacerbation of IPF gesting that aspiration of gastric contents may have a
Every IPF patient may experience, at any point during causative role for disease worsening in a subgroup of
the course of the disease and regardless of its severity, IPF patients.64 The reduction in the rate of AE-IPF
episodes of acute respiratory deterioration. Some of observed in patients treated with proton pump
these are idiopathic, as they do not recognize an iden- inhibitors also supports this hypothesis.51 Finally,
Respirology (2016) 21, 427437 2015 Asian Pacific Society of Respirology
IPF: Diagnosis, epidemiology, course 433

Table 3 Proposed prognostic predictors in IPF

Category Parameter Evidence

Demographic/clinical Age Older age27

Sex Male42
Dyspnoea and oxygen level Baseline68
Changes at 6 months67
Comorbidities Pulmonary hypertension49
Pulmonary emphysema48
GERD51
Lung cancer50
Physiological FVC Baseline FVC < 55%45
6 months decline > 10% or 510%69
DLCO Baseline45
6 or 12 months decline >15%67,69
6MWD Baseline <250 m71
24-week decline >50 m71
Radiological Fibrosis score Baseline and changes at follow-up18,72,73
Traction bronchiectasis Extent of traction bronchiectasis18
Biomarkers Serum and plasma biomarkers Baseline levels of: SPA, SPD, KL6/MUC1, alfa1
defensins, CCL18, YKL40, CXCL13, anti-HSP70 IgG,
MMP7, MMP1, osteopontin, periostin79
MMP collagen fragments (neoepitopes) Baseline levels and changes at 3 months81
Fibrocytes >5% (Total leucocytes)82
v6 integrin Extent of immunostaining on lung IPF tissue86
Microbiome Members of Staphylococcus and Higher concentration in BAL at diagnosis87
Streptococcus genera
Bacterial burden Higher bacterial burden in BAL at diagnosis88
Genetic MUC5B promoter polymorphism Minor risk allele (improved survival)84
rs35705950
TOLLIP polymorphism Major risk allele (improved survival)85
rs5743890

6MWD, 6-min walking test distance; DLCO, diffusion lung capacity for carbon monoxide; FVC, forced vital capacity; GERD, gastro-
oesophageal reflux disease; IPF, idiopathic pulmonary fibrosis; MMP, matrix metalloproteinases; MUC5B, mucin 5B; TOLLIP, Toll-
interacting protein.

mechanical stress of the lungs secondary to surgery are contrasting data about smoking status.27,66 Also
and BAL has been advocated as a potential inductor dyspnoea scores and oxygen levels at baseline and
of AE-IPF in a subset of individuals.65 their longitudinal changes have shown to predict
The identification of such triggers as likely causes of survival.67,68
diffuse damage in lungs with the inability to undergo Among the physiology variables, FVC and DLCO
a normal repair, together with the evidence of similar values at baseline have been extensively used to
clinical characteristics and outcomes irrespectively of assess disease severity and inform about prognosis in
a recognized aetiology, have resulted to the proposal IPF;45 however, their changes over time provide more
of a new, broader conceptual framework for AE-IPF, accurate prognostic information than baseline
where it is accepted that acute worsening of IPF rec- values.67 Mortality has been found being higher in IPF
ognizes secondary causes, some of which are not patients with significant (>10%) or also marginal
identifiable, sometimes leading to an acceleration of (510%) absolute decline in FVC at 6 months.69
the disease with the development of diffuse lung According to a recent study, using the relative change
injury.60 in % predicted FVC rather than the absolute change
may increase the chance of identifying a 10% decline
without affecting prognostic accuracy.70 A significant
Predicting prognosis in IPF decline (>15%) in DLCO has been found to predict
increased risk of mortality at 12 and at 6 months.67,69 A
Individual predictors of survival distance walked at the 6-min walking test distance
Many clinical and physiological parameters have (6MWD) <250 m at baseline and a 24-week decline in
been proposed as predictors of poor outcome in IPF, 6MWD of >50 m have been also reported to be inde-
although most of the available data come from retro- pendent predictors of mortality.71
spective studies or post-hoc analysis of clinical trials, The prognostic value of both the pattern and the
characterized by relatively short follow-up periods extent of the fibrotic process in IPF shown at the
(Table 3). HRCT have been investigated by several studies. The
Older age and male sex seem to be correlated with extent of pulmonary fibrosis at baseline or its changes
a poorer prognosis in IPF patients,27,46 whereas there at follow up has been demonstrated being a predictor
2015 Asian Pacific Society of Respirology Respirology (2016) 21, 427437
434 G Sgalla et al.

of poor survival in IPF patients.18,72,73 The presence of disease behaviour in a large prospective cohort of well-
traction bronchiectasis, as mentioned previously, has characterized IPF patients to validate biological and
been also found to predict mortality independently.18 clinical end-points. Using cohorts from the PROFILE
study, Jenkins et al. have recently focused their atten-
Risk scoring systems tion on collagen fragments generated by matrix
Several risk models, based on different combinations metalloproteinases81 and have demonstrated that the
of demographic, clinical, physiological and radiologi- 3-month change in the serum levels of some of these
cal parameters, have been proposed to stage IPF and fragments is strongly predictive of overall survival,
predict survival. King et al. first proposed a clinical- suggesting a potential role for these biomarkers as
radiological-physiological scoring system27 integrat- early predictors of poor outcome.
ing seven different parameters, but resulted as too Circulating, bone marrow-derived mesenchymal
complicated for use in clinical practice. The compo- progenitor cells called fibrocytes have been also
site physiologic index developed by Wells et al.74 was investigated as potential biomarkers of progression in
conceived only on three pulmonary function meas- IPF. Fibrocytes levels are higher in the peripheral
urements (DLCO, the forced expiratory volume in 1 s blood of IPF patients as compared with healthy sub-
(FEV1) and FVC) and was proven to correlate with jects, and the cut-off level of >5% (of total leucocytes)
fibrosis extent on HRCT scan of the chest. has been found to be associated with worse survival.82
Ley et al.75 developed a simple, multidimensional The advances in modern omics technologies
prognostic staging system using data from three large (genomics, epigenomics, transcriptomics, proteo-
and geographically distinct cohorts. Four baseline mics etc.) and the application of bioinformatics
variables were included in the model: gender (G), age methodologies (enabling the automated analysis of
(A) and two respiratory physiology variables (P) (FVC large amounts of biological data) are indeed promis-
and DLCO). The Gender, Age, Physiology (GAP) index ing with regard to the definition of a disease finger-
score identifies three stages of severity with 1-year print for IPF. Patients with rapid progression are
mortality risk of 6%, 16% and 39%, respectively. known to present a gene expression profile different
Recently, the same group has proposed a longitudinal from those with longer survival irrespective of clinical
GAP model that incorporates the 24-week relative presentation at the time of diagnosis.47 It has also
change in % predicted FVC and the respiratory hospi- been reported that a molecular expression signature
talizations,76 with significant risk re-classification of 134 gene transcripts at the time of diagnosis has the
improvement. These same authors have also investi- potential to discern relatively stable IPF patients from
gated the prognostic value of the scores for the extent those with a more rapid functional decline.83 The
of fibrosis and emphysema on HRCT in the context of minor allele of the MUC5B polymorphism known to
the GAP model.77 The fibrosis score has been pro- confer an increased risk of developing IPF30 has been
posed as the potential replacement of DLCO in a modi- found to be associated with better survival.84 Simi-
fied GAP model (the CT-GAP model) with comparable larly, IPF cases with the Toll-interacting protein
performance. This could be useful in clinical practice (TOLLIP) major allele have been found to have a
because DLCO is difficult to obtain in the most severe lower mortality risk as compared with minor allele
IPF patients. carriers.85 These results pave way to the stratification
of IPF patients based on a genetically determined risk
A fingerprint for IPF of progression, which might also enhance the design
Stratifying IPF based on different phenotypes of of future clinical trials.
disease progression and response to different treat- Tissue markers identifiable on biological samples
ments remains a challenge due to the complex (such as surgical lung biopsies) might be also used for
network of different pathogenic pathways interacting predicting prognosis and response to specific treat-
together and the unforeseeable influence of environ- ments. v6 Integrin is a key mediator for the activa-
mental exposures on the development of the disease. tion of transforming growth factor and target of a
The establishment of large, longitudinal cohorts of novel monoclonal antibody currently being evaluated
patients and the adoption of a comprehensive in a phase II randomized clinical trial. Recently, it has
approach for their characterization, including demo- been demonstrated that its quantification at
graphic, clinical and biological data, might define a immunostaining in IPF lung tissue is associated with
specific signature for patients with IPF, providing increased mortality.86
valuable information on prognosis and expected Very recently it has been suggested that also the
response to available therapies.78 lung microbiome, i.e. the overall burden of bacteria in
A large number of peripheral blood proteins and the lungs, may have a role in the pathogenesis and
cytokines have been studied in IPF as potential progression of IPF, namely specific members of the
biomarkers of disease progression. The evidence on Staphylococcus and Streptococcus genera to be
the most important plasma and serum biomarkers has involved.87 Molyneaux et al. have reported that a
been extensively discussed in some recent reviews on higher bacterial burden in BAL at the time of diagno-
the topic.79,80 However, most data come from retro- sis allows to identify patients with a more progressive
spective studies and so far none of such biomarkers disease.88 The evidence of reduced mortality in
has been validated for use in the clinical practice. In patients with fibrotic ILD treated with co-trimoxazole
2009, the UK-based PROFILE (Prospective Observa- supports the hypothesis of the influence of respira-
tion of Fibrosis in the Lung Clinical Endpoints) study tory bacterial colonization in the progression of the
was launched with the aim to longitudinally evaluate disease.89
Respirology (2016) 21, 427437 2015 Asian Pacific Society of Respirology
IPF: Diagnosis, epidemiology, course 435

SUMMARY 11 American Thoracic Society (ATS) at ERSE. American Thoracic

Society. Idiopathic pulmonary fibrosis: diagnosis and treatment.
International consensus statement. Am. J. Respir. Crit. Care Med.
The 2011 ATS/ERS/ALAT/JRS statement6 proposed for
2000; 161: 64664.
the first time an evidence-based diagnostic algorithm 12 Sundaram B, Gross BH, Martinez FJ, Oh E, Mller NL, Schipper
for IPF. However, a degree of uncertainty remains for M, Kazerooni EA. Accuracy of high-resolution ct in the diagnosis
patients with possible UIP at HRCT who cannot of diffuse lung disease: effect of predominance and distribution
undergo SLB: it is unclear whether these patients of findings. Am. J. Roentgenol. 2008; 191: 10329.
should be treated with approved IPF therapies. 13 du Bois RM. An earlier and more confident diagnosis of idi-
In light of the existing diagnostic criteria and build- opathic pulmonary fibrosis. Eur. Respir. Rev. 2012; 21: 1416.
ing on international collaborations among special- 14 Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD,
ized centres, more efforts are required to improve the Elicker BM, Koth LL, King TE Jr, Wolters PJ et al. Prevalence and
still-limited knowledge on prevalence and incidence prognosis of unclassifiable interstitial lung disease. Eur. Respir. J.
2013; 42: 7507.
of IPF, which nonetheless appears to be on the rise.
15 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel
The involvement in these efforts of centres in coun- U, Cottin V, Flaherty KR, Hansell DM, Inoue Y et al. Efficacy and
tries with little or no data on IPF epidemiology has to safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J.
be encouraged as it would help understand poten- Med. 2014; 370: 207182.
tially relevant racial factors and therefore provide 16 Arakawa H, Honma K. Honeycomb lung: history and current
insights into disease pathogenesis. concepts. Am. J. Roentgenol. 2011; 196: 77382.
Although the natural history of IPF remains unpre- 17 Watadani T, Sakai F, Johkoh T, Noma S, Akira M, Fujimoto K,
dictable in the single patient, some new tools (such as Bankier AA, Lee KS, Muller NL, Song JW et al. Interobserver vari-
the GAP staging system) can help in predicting prog- ability in the CT assessment of honeycombing in the lungs. Radi-
ology 2013; 266: 93644.
nosis. Over the next years, a proper disease stratifica-
18 Sumikawa H, Johkoh T, Colby TV, Ichikado K, Suga M, Taniguchi
tion of IPF, based on the information derived from H, Kondoh Y, Ogura T, Arakawa H, Fujimoto K et al. Computed
biomarkers and the application of modern tech- tomography findings in pathological usual interstitial pneumo-
niques such as genomics and proteomics might nia: relationship to survival. Am. J. Respir. Crit. Care Med. 2008;
determine a paradigmatic shift in both diagnosis and 177: 4339.
management, with the advent of a personalized 19 Walsh SL, Sverzellati N, Devaraj A, Keir GJ, Wells AU, Hansell DM.
approach to IPF. Connective tissue disease related fibrotic lung disease:
high resolution computed tomographic and pulmonary
function indices as prognostic determinants. Thorax 2014; 69:
21622.
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2015 Asian Pacific Society of Respirology Respirology (2016) 21, 427437