INTERSTITIAL LUNG DISEASE

1. IDIOPATHIC PULMONARY FIBROSIS:
An Update
Dr. Sushant Kumar Nanda
1st yr DM Resident
SCB MCH, Cuttack

2. 0UTLINE
• Introduction
• New recommendations on diagnosis
• New recommendations on treatment
• Future prospectives
• conclusion

3. INTRODUCTION
• IPF is a chronic, fibrosing
interstitial pneumonia of unknown
cause associated with radiological
and histologic features of usual
interstitial pneumonia (UIP).
• It occurs primarily in older adults,
characterized by progressive
worsening of dyspnea and lung
function and has a poor prognosis

4. 2018
2022

5. Update on Diagnosis and Treatment
of IPF
Reassess several topics from the previous guidelines
1. radiological and histopathological features of UIP
2. diagnostic criteria
3. diagnostic and treatment approaches
4. prior evidence based recommendations about antacid
medications and transbronchial lung cryobiopsy (TBLC)
In addition, addresses new questions about
1. Antireflux surgery
2. genomic classifier testing

6. Spectrum of HRCT findings in IPF
.
Lung fibrosis is confidently recognized when traction
bronchiectasis/bronchiolectasis and/or honeycombing are identified,
although honeycombing must be distinguished from paraseptal
emphysema and airspace enlargement with fibrosis

7. Traction bronchiectasis/bronchiolectasis
• represents irregular bronchial
and/or bronchiolar dilatation
caused by surrounding retractile
fibrosis
• Distorted airways are thus
identified in a background of
reticulation and/or ground-glass
attenuation.
• On contiguous HRCT sections, the
dilated bronchi or bronchioles can
be tracked back toward more
central bronchi.
• The pattern in this patient
represents the probable usual
interstitial pneumonia pattern

8. Honeycombing
• Honeycombing is defined by
clustered, thick-walled, cystic
spaces of similar diameters,
measuring between 3 and 10 mm
but up to 2.5 cm in size.
• The size and number of cysts often
increase as the disease progresses.
• Often described in the literature as
being layered, a single layer of
subpleural cysts is also a
manifestation of honeycombing
• Honeycombing is an essential HRCT
criterion for typical (“definite”) UIP-
IPF pattern when seen with a basal
and peripheral predominance.

9. Paraseptal
emphysema
• subpleural cysts are
relatively larger than
honeycomb cysts
• Occur mainly in the
upper lobes
• a/w Centrilobular
emphysema
• usually occur in a single
layer

10. Airspace enlargement
with fibrosis (AEF)
• Aka smoking-related interstitial
fibrosis, in a cigarette smoker
• clustered asymmetric cysts that
are larger and more irregular
than typical honeycomb cysts,
without traction bronchiectasis
or other signs of fibrosis
• Emphysema is also present.
• AEF is not regarded as a distinct
form of idiopathic interstitial
pneumonia but results from the
presence of a greater amount of
fibrosis than usually described in
the classic definition of
emphysema.

11. Honeycombing vs Traction bronchiectasis
• Pathologic–HRCT correlations have demonstrated that honeycombing and
traction bronchiolectasis are closely related. Typical UIP and honeycombing
on HRCT correlate best with bronchiolectasis histologically.
• Honeycombing corresponds to bronchiolar cysts, developed after collapse
of fibrotic alveolar septa and dilatation of terminal airways.
• Honeycombing cysts consist of both dilatation of peripheral airspaces due
to surrounding alveolar septal fibrosis and tangentially viewed traction
bronchiolectasis.
• Recent observations have underlined that in IPF, the remodeling process
appears to be a continuum from traction bronchiectasis to honeycombing
and that conceptual separation of the two processes may be misleading.

12. Differential diagnosis of UIP
• The UIP pattern is a hallmark of IPF (IPF-UIP), but it can
also be seen in patients with fibrotic HP, connective
tissue disease (CTD-UIP), or exposure- related ILDs.
• HP-UIP and CTD-UIP may sometimes be suspected on
the basis of imaging appearance but are often
indistinguishable radiologically from IPF-UIP.
• Pleuroparenchymal fibroelastosis may be seen in 6–
10% of cases of IPF. It may be associated with more
rapid decline in lung function, higher risk of
pneumothorax and pneumomediastinum, and poorer
survival.

13. UIP pattern due to connective tissue disease (CTD-UIP)
CTD-UIP should be considered
when
• honeycomb cysts are extensive,
occupying >70% of the fibrotic
portions of the lung (exuberant
honeycombing sign)
• fibrotic abnormality is sharply
demarcated on coronal images
from the relatively normal upper
lungs (straight-edge sign)
• there is relative increase in
fibrosis in the anterior upper lobes
(anterior upper lobe sign).

14. UIP pattern due to HP
HP-UIP should be considered when
• fibrosis and honeycomb cysts predominate in the upper or mid lungs
• mosaic attenuation or three-density sign is present
• when the fibrosis appears diffuse in the axial plane.

15. Combined pleuroparenchymal fibroelastosis
and UIP patterns
• dense subpleural fibrosis
at the lung apices with
traction bronchiectasis
and upper lobe volume
loss.
• subpleural reticular
abnormality and
honeycombing in both
lower lobes.

16. Definite UIP
UIP pattern
associated with
some paraseptal and
centrilobular
emphysema in the
upper lobes

17. Probable UIP
probable UIP pattern
with fibrotic features in
the lung periphery and
some centrilobular
emphysema in the upper
lobes

18. Indeterminate for UIP pattern
peribronchovascular and
subpleural ground-glass
opacities, intermingled
with fine reticulation but
no honeycombing or
traction bronchiectasis

19. Probable UIP pattern in the diagnostic
approach to IPF
Reasons to merge definite UIP and
probable UIP
• There is increasing evidence that patients with
the probable UIP pattern and UIP pattern on
HRCT have similar disease behavior and clinical
courses
• the likelihood of histologic confirmation of UIP
in patients with the probable UIP pattern ranges
from 80% to 85%
• in the appropriate clinical context,
histopathological confirmation of the UIP
pattern is not required to ascertain the
diagnosis of IPF in patients with either the
probable UIP pattern or the UIP pattern
Reasons to maintain the differentiation
• studies describing the correlation of
probable UIP with histopathological UIP are
from expert settings, and correlation in
alternative settings is unknown
• there is evidence suggesting that patients
with probable UIP might have better
survival
• the predictive value of the probable UIP CT
pattern for histologic UIP is slightly lower
than for the UIP CT pattern, suggesting that
the probable UIP CT pattern may show more
overlap with other fibrotic lung diseases
such as fibrotic HP
• there is evidence that the predictive value of
a probable UIP pattern for histologic UIP is
lower in individuals with relatively mild
fibrosis and in younger individuals

20. • Merging UIP and probable UIP patterns into a single category was
considered; however, the guideline committee decided to retain the four
categories with minor modifications for the purpose of clarity
• Although the UIP pattern and probable UIP pattern remain separate, the
diagnostic approaches for these entities are similar and histologic
confirmation is usually unnecessary unless there is clinical concern for an
alternative diagnosis

21. Histopathological Features of UIP
Diagnosis of UIP on biopsy is suggested by a combination of the following:
1) patchy dense fibrosis with architectural distortion (i.e., destructive
scarring and/or honeycombing)
2) a predilection for subpleural and paraseptal lung parenchyma
3) fibroblast foci
4) the absence of features that suggest an alternative diagnosis
When all of these features are present, a UIP pattern can be established with
confidence.
“Probable UIP” refers to biopsies in which some of these findings are present
in the absence of features to suggest an alternative diagnosis.

22. Commentary on use of TBLC
Application of the histopathological criteria for UIP is more challenging with TBLC
specimens because
1) the subpleural predominance of pathologic changes may not be readily
appreciated
2) the potential for sampling error results in less confident exclusion of features that
may suggest an alternative diagnosis.
Compared with surgical lung biopsy (SLB), TBLC is more likely to demonstrate a
probable UIP pattern than a definite UIP pattern given the limited sampling of
subpleural lung parenchyma in most cases.
Nevertheless,a combination of patchy fibrosis, fibroblast foci, and the absence of
features to suggest an alternative diagnosis is usually sufficient to establish a probable
UIP pattern on TBLC.
Combining UIP and probable UIP patterns in the context of multidisciplinary discussion
(MDD) results in comparable rates of diagnostic agreement for SLB and TBLC in patients
with IPF

23. Evidence-based Recommendations
for Diagnosis of IPF
“We suggest that TBLC be regarded as an
acceptable alternative to SLB for making a
histopathological diagnosis in patients with ILD
of undetermined type in medical centers with
experience performing and interpreting TBLC”
(conditional recommendation,
very low quality evidence)

24. Role of genomic classifier
A genomic classifier was developed with machine learning and
whole transcriptome RNA sequencing using lung tissue obtained
by SLB. More recently, it was introduced and validated for lung
tissue obtained by transbronchial forceps biopsy.
“We make no recommendation for or against the
addition of genomic classifier for the purpose of
diagnosing UIP in patients with ILD of undetermined
type who are undergoing transbronchial forceps
biopsy, because of insufficient agreement among the
committee members.”

25. primary change to the diagnostic algorithm is that patients with an HRCT pattern
of probable UIP are now managed similarly to patients with UIP, meaning that
lung sampling after initial MDD is less likely
2018 2022
Patient suspected of having IPF
Potential cause/associated condition
No Yes
No
Chest HRCT pattern
Confirmation of specific
diagnosis (including w ith HRCT)
Yes
UIP or Indeterminate for UIP or
probable UIP* alternate diagnosis
MDD
BAL†
± TBLC‡
SLB‡
MDD
IPF Alternative diagnosis
No Yes
UIP
No
Yes
BAL
MDD
Not IPF
MDD
probable UIP,
indeterminate for UIP,
alternative diagnosis
Chest HRCT pattern Specific diagnosis
Further evaluation
(including HRCT)
Surgical lung
biopsy*
Potential cause/associated condition
Patient suspected to have IPF
IPF per Figure 8

26. Diagnosis based upon HRCT and
biopsy patterns
• The key change to the figure describing combinations
of HRCT and histologic patterns is that an HRCT pattern
suggestive of an alternative diagnosis combined with
a histopathology pattern of probable UIP is now
considered indeterminate for IPF rather than non-IPF.
• The rationale : Patients with this combination of
findings can have heterogeneous patterns of disease
behavior and outcomes, including sometimes being
similar to patients with IPF; therefore, labeling this as
“indeterminate” seems preferable to the more limiting
guidance provided in the previous guideline.

27. 2018
2022
IPF suspected*
Histopathology pattern†
UIP Probable UIP
Indeterminate
for UIP or
biopsy not
performed
Alternative
diagnosis
HRCT pattern
UIP IPF IPF IPF Non-IPF dx
Probable UIP IPF IPF IPF (Likely)‡
Non-IPF dx
Indeterminate IPF IPF (Likely)‡
Indeterminate§
Non-IPF dx
Alternative
diagnosis IPF (Likely)‡
Indeterminate§
Non-IPF dx Non-IPF dx
IPF suspected* Histopathology pattern
UIP Probable UIP
Indeterminate for
UIP
Alternative
diagnosis
UIP IPF IPF IPF Non-IPF dx
Probable UIP IPF IPF IPF (Likely)** Non-IPF dx
HRCT
pattern Indeterminate
for UIP IPF IPF (Likely)**
Indeterminate
for IPF*** Non-IPF dx
Alternative
diagnosis
IPF (Likely)**
/non-IPF dx
Non-IPF dx Non-IPF dx Non-IPF dx

28. Schematic pathway for clinical management

29. Role of antacid medication
• ‘’We suggest not treating patients with IPF
with antacid medication for the purpose of
improving respiratory outcomes’’
(conditional recommendation, very low quality evidence)
• Remarks: Antacid medication and other interventions may be appropriate
for patients with both IPF and symptoms of gastroesophageal reflux
disease (GERD) for the purpose of improving gastroesophageal reflux
(GER)–related outcomes in accordance with GER-specific guidelines.

30. Role of antireflux surgery
• ‘’We suggest not referring patients with IPF for
antireflux surgery for the purpose of improving
respiratory outcomes”
(conditional recommendation, very low quality evidence)
Remarks: Antireflux surgery may be appropriate for patients with
both IPF and symptoms of GERD for the purpose of improving
GER-related outcomes in accordance with GER-specific
guidelines.

32. Current therapies
Treatment Mechanism of action Clinical effects
Pirfenidone Antifibrotic
anti-inflammatory
Slows rate of decline in FVC
Nintedanib Antifibrotic
anti-inflammatory Slows rate of decline in FVC
Oral corticosteroids, opioids Antitussive Decrease cough—improve
quality of life
Anti-acids, proton pump
inhibitors
Reduces GERD Benefits unclear
Lung transplantation Surgical replacement of
one lung or both lungs
Only available potentially
curative therapy

33. Therapies in development
Treatment Mechanism of action Clinical effects
PRM-151 Recombinant human pentraxin-2;
Acts as an antifibrotic agent
Slows rate of decline in FVC
Pamrevlumab Fully human recombinant monoclonal
antibody against CTGF
Slows rate of decline in FVC
TD139 Small molecule inhibitor of galectin-3 Decreases plasma biomarkers of
inflammation. Study in progress to
asses effect on FVC
PLN-74809 Blocks activation of the TGFβ pathway Study in progress with end-points of
safety, tolerability, pharmacokinetics
TRK-250 Suppresses expression of TGFβ Study in progress to assess safety
and tolerability of single and
multiple inhaled doses

34. BIOMARKERS AND ASSESSING
TREATMENT RESPONSE
• Predicting the clinical course of IPF based on respiratory function and
radiologic imaging is unreliable and, at this time, we cannot predict
disease trajectory accurately.
• Monitoring of IPF progression is most commonly accomplished by
measuring change in FVC over 12 months, and a decline in FVC≥10% is
generally considered the threshold for affirming progression.
• Developing a blood based biomarker for clinical use is a high priority that
would be useful in early diagnosis and assessment of treatment efficacy.
• Possible biomarkers:
 receptor for advanced glycation end products (RAGE)
 serum MMPs that break down collagens type I and III

36. CONCLUSION
Update of IPF:
• Radiological and histopathological criteria for IPF were
updated by consensus.
• A conditional recommendation was made to regard TLC as
an acceptable alternative to surgical lung biopsy in centers
with appropriate expertise.
• No recommendation was made for or against genomic
classifier testing.
• Conditional recommendations were made against antacid
medication and antireflux surgery for the treatment of IPF.

37. • Pirfenidone and nintedanib are the two antifibrotic
agents currently available for the treatment of IPF. At
this time, only lung transplant can alter its relentless
course.
• There is an urgent need for research into targeted
treatments that prolong life and improve quality of life
for patients with IPF.
• As we try new treatment approaches, the development
of reliable and accurate biomarkers to monitor the
efficacy for clinical trial and real-world application will
be increasingly important.

38. References
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American Thoracic Society, European Respiratory Society, Japanese Respiratory
Society, and Latin American Thoracic Society. Idiopathic Pulmonary Fibrosis (an
Update) and Progressive Pulmonary Fibrosis in Adults: An Official
ATS/ERS/JRS/ALAT Clinical Practice Guideline, guideline.Am J Respir Crit Care Med
Volume 205 Number 9 | May 1 2022
• Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ,et al.;
American Thoracic Society, European Respiratory Society, Japanese Respiratory
Society, and Latin American Thoracic Society.Diagnosis of idiopathic pulmonary
fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline.Am J Respir Crit
Care Med2018;198:e44–e68
• Glass DS, Grossfeld D,Renna HA, et al. Idiopathic pulmonary fibrosis:Current and
future treatment.Clin Respir J. 2022;16(2):84-96. doi:10.1111/crj.13466
• White ES, Thomas M, Stowasser S and Tetzlaff K (2022) Challenges for Clinical Drug
Development in Pulmonary Fibrosis. Front. Pharmacol. 13:823085.doi:
10.3389/fphar.2022.823085

39. Thank you