This document provides a historical overview and update on the management of idiopathic pulmonary fibrosis (IPF). It discusses the evolution of IPF diagnosis and classification over time based on clinical and pathological criteria. Key risk factors for IPF like older age, family history, smoking and genetics are summarized. The document also reviews prognostic indicators, comorbidities, current pharmacological therapies including pirfenidone and nintedanib, and the multidisciplinary approach to diagnosis and management of IPF.

1. An update on the management of
Idiopathic Pulmonary Fibrosis
Sarfraz Saleemi MD
Pulmonary Medicine
King Faisal Specialist Hospital & Research Center
Riyadh, Saudi Arabia

2. Historical aspects of ILD
Year/author publication Reference
1872 von Buhl desquamative pneumonia
chronic interstitial pneumonia
Oldenburg, Munich, 1872: 56-67
1898 Rindfleisch cirrhosis cystica pulmonum Verh Ges Dtsch Nat] Forsch Arzt 1898; 69
1907 Sandoz Necropsy findings in twin sisters - fetal
bronchiectasis
likely the first description of familial IPF
Beitr Pathol Anat Allg Pathol 1907; 41:
495-516
1912 von Hansemann five cases
lymphangitis reticularis pulmonum
ViIrhows Arch [Pathol
Anaq 1912; 220: 311-321
1933
Hamman & Rich
first published their observations of IPF
acute diffuse interstitial fibrosis
Int Clin 1933; 1: 196-231
1945 Eder et al. clubbing of the fingers
and toes as a clinical feature of the disease
Bull Johns Hopkins Hosp
1945; 76: 163-171
1948 Potter & Gerber Subacute diffuse interstitial fibrosis of the
lungs
Awrh Intern Med 1948; 82: 113-124
1954 Vanek1 necropsy findings in 16 cases
interstitial nonpurulent pneumonia
Zentralbl Allg Pathol 1954; 92: 405-416
1952 Rubin et al. First open thoracotomy with lung biopsy Ann Intem Med 1952; 36: 827-844
1964 Livingstone 45 histologically proven cases QJMed 1964; 33: 71-103
1964 Scadding suggested the term Br MedJ 1964; 2: 686
1933
Hamman & Rich
first published their observations of IPF
acute diffuse interstitial fibrosis
Int Clin 1933; 1: 196-231
fibrosing alveolitis

3. Revised Classification of Interstitial Lung Disease (ILD)
ILD of known
cause e.g.
CTD, drugs,
exposure etc.
Idiopathic
interstitial
pneumonia
(IIP)
Granulomatous
interstitial
pneumonias
e.g. Sarcoidosis
Other ILD e.g.
LAM, PLCH,
PAP etc.
Major IIPs Rare IIPs
Non-specific interstitial
pneumonia (NSIP)
Acute interstitial
pneumonia (AIP)
Desquamatous
Interstitial pneumonia (DIP)
Respiratory Bronchiolitis
ILD (RB-ILD)
Lymphoid interstitial
pneumonia
Cryptogenic organizing
pneumonia (COP)
Idiopathic
pulmonary fibrosis
(IPF)
Unclassified
IIPs
55%
25%
Pleuroparenchymal
fibroelastosis
Travis WD et al. Am J Resp Crti Care Med. 2013;188:733-748.

4. Major Idiopathic Interstitial Pneumonias
Category Clinical Diagnosis Pathologic pattern
Chronic
fibrosing
IPF UIP
Idiopathic nonspecific interstitial
Pneumonia (iNSIP)
NSIP
Smoking-
related
Respiratory bronchiolitis-ILD (RB-ILD) Respiratory bronchiolitis
Desquamative interstitial pneumonia (DIP)
Desquamative interstitial
pneumonia
Acute/
subacute
Cryptogenic organizing pneumonia (COP) Organizing pneumonia
Acute interstitial pneumonia (AIP) Diffuse alveolar damage
Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.

5. Idiopathic Pulmonary Fibrosis (IPF)
• Chronic, progressive fibrosing interstitial
pneumonia of unknown cause.
• Occurring primarily in older adults
• limited to the lungs
• and associated with the histopathologic and/or
radiologic pattern of Usual Interstitial Pneumonia
(UIP)
Am J Respir Crit Care Med. 2011;183(6):788-824.
progressive
irreversible
lethal disease

6. Proposed mechanism of lung fibrosis in IPF
Growth factors (TGF-β1) and other
products of epithelial cell injury
Fibroblasts
1. Susceptible host
- genetics
- Old age
2. Injury to alveolar epithelium
- cigarette smoke
- industrial dust
- GE reflux
- viral infection
4. Release of pro-
fibrotic cytokines
6. Increased
extracellular
matrix
deposition
5. Recruitment,
proliferation and
activation of
fibroblasts and
differentiation of
myofibroblasts
7. Impaired gas exchange leading to respiratory failure
3. Aberrant wound
healing response
- recruitment and
activation of
immune cells
- Increase vascular
permeability
- increased
apoptosis

7. Risk factors and possible causes of IPF
Older age
Family
history
Cigarette
smoking
Male
genderIPF

8. Genetics of IPF
Possible candid gene polymorphisms
– SFTPA2 or SFTPC mutations (Surfactant proteins C or A2)
– TERT mutations (Telomerase reverse transcriptase)
– MUC5B (MUCIN 5B)promoter gene
– ABCA3
familial

9. MUC5B promoter gene
• Discovered by genomewide linkage scan
• Increased expression of MUC5B on the p-terminus
of Chromosome 11
• More associated w/ patients older than >50yrs
(Framingham cohort, NEJM 2013)
• Associated with IPF but not scleroderma or
sarcoidosis fibrosis (Thorax 2013)
• Hypothesized Mechanisms: by increased Mucin5B
production
– Increased epithelial injury
– Slowed clearance of airway toxins
Nusair 2013

10. Telomere factor in IPF
• Telomere is a repeated sequence of TTAGGG at the end of
chromosome.
• Telomeres protect genetic information by acting as a buffer
against the chromosomal shortening during replication.
• Critical shortening of the telomeres leads to cell-cycle arrest.
• Maintaining telomere length is necessary for ongoing cell
proliferation.
• Loss in telomere length can be restored by the
ribonucleoprotein telomerase

11. Telomere length in Interstitial Lung Diseases
• 359 patients with various ILD
• 173 healthy subjects
• TL in all cases of ILD was
significantly shorter compared
with those of control subjects
• TL in patients with idiopathic
pulmonary fibrosis (IPF) was
significantly shorter than in
patients with other ILDs
CHEST 2015; 148(4): 1011 - 1018

12. Effect of telomere length on survival in patients with
idiopathic pulmonary fibrosis:
An observational cohort study with independent validation
• 370 patients
• 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths
than did the 195 healthy controls (mean age-adjusted log-transformed ratio of
telomere to single copy gene was −0·16 [SD 0·23] vs 0·00 [0·18]; p<0·0001);
• The association between telomere length and survival in patients with idiopathic
pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing
capacity of carbon monoxide, and was replicated in the two independent
idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0·11 [0·03–
0·39], p=0·00066; San Francisco cohort, HR 0·25 [0·07–0·87], p=0·029).
The Lancet Respiratory Medicine , Volume 2 , Issue 7 , 557 - 565
Telomere length was independently associated with transplant-free
survival in patients with IPF
(HR 0·22 [95% CI 0·08–0·63]; p=0·0048)

13. 500
Incidence Prevalence
400
300
200
100
0
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Time (y)
Adapted from Raghu G et al. Lancet Respir Med. 2014;2(7):566-72.
Casesper100,000person-years
Incidence and Prevalence of IPF

14. Incidence of IPF
Am J Respir Crit Care Med 2006;175: 810-816
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
Male
Female
18-34 35-44 45-54 55-64 65-74 >75
Age group (years)
Per100,1000

15. Diagnosis of IPF
IPF diagnostic team

16. Multi-disciplinary approach improves diagnostic
agreement and confidence

17. Survival related to delay in referral to tertiary care center
Am J Respir Crit Care Med. 2011;184:842-847

18. AND
Definite UIP pattern
on HRCT without
surgical biopsy
OR
Definite/possible
UIP pattern on HRCT
+
surgical
lung biopsy showing
definite/probable UIP
Exclusion of
known causes of
Interstitial Lung
Disease
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.
Diagnosis of IPF – current guidelines

19. CT scan criteria for UIP
Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824.
UIP Pattern Possible UIP Pattern Inconsistent With UIP Pattern
(All Four Features) (All Three Features) (Any of the Seven Features)
Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824.

20. Histology criteria of UIP
UIP pattern Probable UIP Possible UIP NOT UIP Pattern
1. Evidence of marked
fibrosis/architectural
distortion +/-
honeycombing in a
predominantly
subpleural/paraseptal
distribution
2. Presence of patchy
involvement by
fibrosis
3. Presence of
fibroblast foci
4. Absence of
features against a
diagnosis of UIP
1. Evidence of marked
fibrosis /architectural
distortion +/-
honeycombing
2. Absence of either
patchy involvement or
fibroblastic foci, but
not both
3. Absence of
features against a
diagnosis of UIP
1. Patchy or diffuse
involvement of lung
parenchyma by
fibrosis, with or
without
interstitial
inflammation
2. Absence of other
criteria for UIP
3. Absence of
features against a
diagnosis of UIP
1. Hyaline membranes
2. Organizing
pneumonia
3. Granulomas
4. Marked interstitial
Inflammatory cell
Infiltrate away from
honeycombing
5. Predominant airway
centered changes
6. Other features
suggestive of an
alternate diagnosis

21. Histology of IPF (UIP)
Normal lung
Fibroblastic
foci
Honeycombing
Interstitial fibrosis

22. Diagnosis of IPF
integrating CT and pathology
Histopathological pattern
UIP Probable
UIP
Possible
UIP
Non-
classifiable
fibrosis
Non-UIP
HRCT
Pattern
UIP
Yes Yes Yes Yes No
Possible
UIP
Yes Yes Probable Probable No
Not
consistent
with UIP
Possible No No No No

23. Clinical conditions other than IPF associated with
usual interstitial pneumonia pattern(UIP)
• Collagen vascular disease
• Drug toxicity
• Chronic hypersensitivity pneumonitis
• Asbetosis
• Familial idopathic pulmonary fibrosis
• Hermansky-Pudlak syndrome

24. Suspected interstitial lung disease
High resolution CT scan of chest
IPF IPF/Not IPF
NOT IPF
MDD
Diagnostic Algorithm
Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824.
Identifiable Causes for ILD?
Surgical Lung
biopsy
NO
UIP
pattern
Possible UIP
Inconsistent with UIP
NO UIP
UIP
Probable/possible UIP
Unclassifiable fibrosis
YES
pulmonologist
pathologist
radiologist

25. Disease
Progression
Time
Acute
worsening
Stable
Natural History of IPF
At the time of diagnosis it is not possible to predict whether
patients will have a slower or faster rate of decline

26. 5 year survival rate %
IPF survival

27. IPF survival
Median survival 3 years from the onset of symptoms

28. Cause of Death in IPF
IPF
[N=543]
1-7 year FU
60% Died
[N=326]
Respiratory
failure
39%
Lung
cancer
10%
Pulmonary
embolism
3%
Pulmonary
infection
3%
Cardiovascular
disease
27%
Other
18%
Panos RJ et al. Am J Med. 1990;88:396.

29. Level of dyspnea Increase in level of dyspnea
DLCO ≤40% Decrease in FVC≥10%
Saturation<88% on 6MWT Decrease in DLco≥15%
Extent of honeycombing on HRCT Decrease >50 m in 6MWT
Pulmonary hypertension Worsening of fibrosis on HRCT
Concomitant Emphysema
Indicators of increased risk of mortality in IPF
Longitudinal factorsBaseline factors

30. GAP prognostic Score
GAP Index for IPF
Factor Points
Gender: Male 1
Age: 61-65 1
>65 2
Physiology: FVC 50-75% pred. 1
< 50% pred. 2
DLCO 36-55% pred. 1
< 36% pred. 2
Pt. cannot perform 3
GAP Staging for IPF
Mortality (%)
Points Stage 1-yr 2-yr 3-yr
0-3 I 5.6 11 16
4-5 II 16 30 42
6-8 III 39 62 77
Eur Respir Rev 2014; 23: 220–224

31. IPF co-morbidities
Extra-pulmonaryPulmonary
•Parenchymal
(e.g., lung cancer; infections.)
• Pulmonary vascular
(e.g., pulmonary embolus, PH)
•Cardiac (e.g., HFpEF, CAD)
• Endocrine (e.g., diabetes mellitus)
• Hematologic
(e.g., anemia , polycythemia)
• GI (e.g., GERD)
• Psychiatric
• Musculoskeletal (e.g., osteoporosis)
• Medications

32. GERD treatment and survival in IPF

33. Fundoplication for GERD and survival in IPF

34. IPF survival in the setting of PH
Cumulativeprobabilityofsurvival
Years

35. IPF management
Risk stratify
Symptom management
Pulmonary rehabilitation
Oxygen
Co-morbidities/complications
Pharmacological
therapy
Enroll in a clinical trial
(Where available and appropriate)
Lung
Transplant
(Where available
and appropriate)

36. Timeline: Therapeutic Approaches to IPF
Colchicine
D-penicillamine
Immunomodulation Future
NAC
Glutathione
Warfarin
IFN-g 1b
Etanercept
Imatinib
Bosentan
FG-3109?
Statins?
LO Inhibitors?
Combo Tx?
BIBF 1120?
QAX576??
Sirolimus?
1950s 1990s 2005
Anti-inflammatory
Immunosuppression
Anti-fibrotic
Anti-oxidant Antiproliferative
Corticosteroids
azathioprine
cyclophosphamide
2014
Pirfenidone
Nintedanib
Next?

37. Traditional treatment of IPF
Prednisone
Azathioprine
N-Acetylcysteine
Warfarin

38. M Turner-Warwick, et al. Thorax. 1980;35:593-599.
G. Raghu, et al. ARRD. 1991;144:291-296.
0 3 6 9 12 15 18
100
80
60
40
20
0
% Survival
Treated (prednisone alone)
Untreated
Prednisone + Imuran
Time (years)
Prednisone +/- Azathioprine in IPF

40. Clinical trials in the new era
2011 2012 2013 2014
CAPACITY trial I &II
(Pirfenidone)
PANTHER Part B
(NAC)
ASCEND
(Pirfenidone)
INPULSIS I & II
(Nintedanib)
PANTHER Part A
(Pred, Aza, NAC)
ACE-IPF
(Warfarin)

41. Noth et al. A placebo controlled randomized trial of
warfarin in idiopathic pulmonary fibrosis
Am J Respir Crit Care Med 2012;186:88
ACE – IPF
(Anticoagulation Effectiveness in IPF)
Stopped early for increased mortality risk
14 treatment vs. 3 placebo deaths

42. Warfarin vs. Placebo: All-cause Mortality and Hospitalization
100
Warfarin
Placebo90
Log-rank P values at 48 weeks: 0.034
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24
Weeks
35
41
28 32 38 40 44 48
# at Risk
Warfarin
Placebo
72
73
63
64
46
48
22
29
14
20
3
3
Noth I et al. Am J Respir Crit Care Med. 2012;186(1):88-95.
Probability(%)

43. WARFARIN

44. PANTHER-IPF
• Prednisone, Azathioprine and N-acetylcysteine:
A Study That Evaluates
Response in IPF
NEJM 2012;366:1968
Randomized to NAC, NAC plus prednisone/azathioprine, or placebo for 60 weeks
IPF
n=341
Placebo
n=131
NAC plus P/A
n=77
NAC alone
n=133
60 weeks
1”ry outcome:
FVC decline
2’ry outcome:
Acute
exacerbation,
disease
progression

45. PANTHER-IPF

46. interim safety analysis
In October 2011, when approximately 50% of the data had
been collected, enrolment in triple therapy arm was stopped
Pred/Aza/
NAC
Placebo
Mortality 11% 1%
Hospitalization 29% 8%
Serious adverse
events (SAE)
31% 9%
PANTHER-IPF

47. Steroids
Azathioprine

48. PANTHER-IPF (part B)
• Prednisone, Azathioprine and N-acetylcysteine:
A Study That Evaluates
Response in IPF
NEJM 2012;366:1968
IPF
n=341
Placebo
n=131
NAC plus P/A
n=77
NAC alone
n=133
60 weeks
1”ry outcome:
FVC decline
2’ry outcome:
Acute
exacerbation,
disease
progression

49. part B
NAC arm completed at 52 weeks
PANTHER-IPF

50. N-Acetylcysteine

51. New era of anti-proliferative therapy
Pirfenidone
Nintedanib

52. Clinical Studies Assessing Pirfenidone in
Idiopathic Pulmonary Fibrosis: Research or
Efficacy and Safety Outcomes
Noble et al. Pirfenidone in patients with idiopathic pulmonary
fibrosis (CAPACITY): two randomized trials. Lancet 2011;377:1760
CAPACITY trials

53. CAPACITY
Enrolled patients with FVC ≥ 50%, DLCO ≥ 35%
• Randomized to pirfenidone or placebo for 72 weeks
• Primary endpoint: Change in FVC
IPF
n=779
Placebo
n=347
Pirfenidone (1197 mg)
n=87
Pirfenidone (2403 mg)
n=345
72 weeks
1”ry outcome:
FVC decline
2’ry outcome:
6-min walk,
progression free
survival
death

54. CAPACITY

55. Overall data of both studies show significant slowing in FVC decline
CAPACITY

56. Cochrane Review of Pirfenidone Studies
• First licensed treatment in EU in March 2011 for mild to
moderate IPF (FVC≥50%, TLCO≥35%, 6MWD ≥150m)
FDA did not approve the drug and demanded another trial

57. ASCEND
Assessment of Pirfenidone to Confirm Efficacy
and Safety in Idiopathic Pulmonary Fibrosis
Performed in response to an FDA request for an additional trial to support approval
King et al.
A phase 3 trial of pirfenidone in patients with idiopathic
pulmonary fibrosis
NEJM 2014;370:2083

58. ASCEND
IPF
n=555
Placebo
n=277
Pirfenidone (2403 mg )
n=278
52 weeks
1”ry outcome:
FVC decline
2’ry outcome:
6-min walk,
progression free
survival
dyspnea
death

59. ASCEND

60. – primary end pointASCEND

61. Secondary end pointsASCEND
(progression free survival)

62. Pooled analysis CAPACITY and ASCEND trials
Primary end-point

63. Pooled analysis CAPACIT and ASCEND trials
Subgroup analysis - Primary end-point

64. Pooled analysis CAPACIT and ASCEND trials
Secondary end-points

66. Pirfenidone summary

67. FDA approves Pirfenidone (Esbriet)
October 2014

68. RECAP (Research on Efficacy and Safety Outcomes) study)
SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2014; 31; 198-205

69. RECAP (Research on Efficacy and Safety Outcomes) study)
Kaplan-Meier estimates of overall survival

70. Vincent Cottin, and Toby Maher Eur Respir Rev 2015;24:58-64
duration of study follow-up for 345 patients randomised to pirfenidone in
the CAPACITY trial
RECAP (Research on Efficacy and Safety Outcomes) study
Long term tolerability and compliance

71. First author [ref.] Country Patients
Patient
characteristics
Efficacy outcome Adverse events
Treatment
discontinuation due
to adverse events %
GI Skin
WIJSENBEEK[13] Netherlands 52
Age: 63.4±7.7 years
Baseline FVC (%
pred): 68.3±18.4
Stable lung function in
17 out of 20 patients
treated for >6 months
(three out of 20
declined). In 11 out of
19 patients cough
score decreased
(unchanged: n=7;
increased: n=1)
NA NA 19
RAVAGLIA[14] Italy 81#
Age: 69 (41–81) years
Baseline FVC (%
pred): 70.8
Stable or significantly
improved lung function
in 40 (59%) out of 68
patients
NA NA 16
NIETOBARBERO[15] Spain 86
Age: NA Baseline FVC
(% pred): 70±19
Stable FVC
and DLCO in those who
had pulmonary function
testing (n=20)
35 (41) 11 (13)+ 14
BONELLA[16] Germany 45
Age: 69±7 years
Baseline FVC (%
pred): 61±15
Stable lung function in
28 (70%) out of 40
patients; subjective
improvement in cough
in 12 (33%) out of 36
patients
17 (38) 10 (22) 13
OKUDA [17] Japan 76
Age: 70.5±8.3 years
Baseline FVC (%
pred): 65.3±16.1
Reduction in FVC
and DLCO decline
18 (24)§ 19 (25)ƒ 18
ARAI [18] Japan 41
Age: 70 (65.5–75.5)
years Baseline FVC (%
pred): 66.7 (54.8–
77.8)¶
Significant reduction in
vital capacity decline in
patients with severity
grades I–II (Japanese
Respiratory Society
criteria)
24 (59)## 5 (12)+ 15
OLTMANNS[19] Germany 63
Age: 68±7 years
Baseline FVC (%
pred): 70±19
Stable lung function in
62% of patients
NA NA 13
CHAUDHURI[20] UK 40
Age: 65.8 (48–
80) years Baseline
FVC (% pred): 77.3
(46–146)
Reduction in FVC
and DLCO decline at
9 months
87 10+ 15
Real world experience with Pirfenidone

72. INPULSIS I and II Trials
NEJM 2014;370:2071
Randomized (3:2) to nintedanib/placebo for 52 wks
Nintedanib – An intracellular tyrosine kinase inhibitor
IPF
n=1066
Placebo
n=423
Nintedanib
n=638
52 weeks
1”ry outcome:
FVC decline
2’ry outcome:
Acute
exacerbation
Quality of life
Mortality
Nintedanib
300 mg daily

73. INPULSIS I and II Trials

74. INPULSIS - primary endpoint

75. INPULSIS 1
INPULSIS 2
INPULSIS - secondary endpoints

76. INPULSIS: Conclusions
In patients with idiopathic pulmonary fibrosis,
Nintedanib reduced the decline in FVC, which is
consistent with a slowing of disease progression.
Nintedanib slows disease progression by reducing the
decline in lung function by 50% in a broad range of IPF
patient types.
Nintedanib significantly reduced the risk of acute
exacerbations by 68%

77. FDA approves Nintedanib (Ofev)
October 2014

78. The overall results suggest that the treatment effect of nintedanib on slowing
disease progression persisted for 2 years
open-label extension of INPULSIS 1 & 11 trials. Interim results
734 (91%) were treated
in INPULSIS-ON
430 continuing
nintedanib treatment
304 initiating
nintedanib treatment
ERS 2015
INPULSIS-ON “TOMORROW TRIAL”

79. Combination therapy for IPF
Safety and pharmacokinetics of nintedanib and pirfenidone in
idiopathic pulmonary fibrosis
Ogura T et al. Safety and pharmacokinetics of nintedanib and pirfenidone in
idiopathic pulmonary fibrosis. European Respiratory Journal 2015 45: 1382-1392
• A randomised, double-blind, phase II, dose escalation trial
• 50 Japanese patients were randomized
• Adverse events = 9/17 (53%) nintedanib alone
10/21 (48%) nintedanib + pirfenidone
• Nintedanib had no effect on the pharmacokinetics of pirfenidone.

80. Safety and Tolerability Study of Pirfenidone in Combination With
Nintedanib in Participants With Idiopathic Pulmonary Fibrosis (IPF)
NCT02598193
Condition idiopathic pulmonary fibrosis
Treatments nintedanib, pirfenidone
Phase phase 4
Start date January 2016
End date May 2017
Trial size 80 participants

81. First Multinational Study Initiated to Evaluate OFEV®
(nintedanib) with Add-on of pirfenidone in the Treatment of
Idiopathic Pulmonary Fibrosis
NCT02579603
A 12-week, open-label, randomized, parallel-group study evaluating safety,
tolerability and pharmacokinetics (PK) of oral OFEV when taken in
combination with oral pirfenidone, compared to treatment with OFEV
alone, in people with IPF.
100 patients – multicenter – United States, Canada, Italy, Germany, France
and the Netherlands.
Ongoing

82. Effectiveness of combined therapy with pirfenidone and inhaled
N‐acetylcysteine for advanced idiopathic pulmonary fibrosis:
A case–control study
34 patients
12-month follow-up
Treatment was considered ineffective if the decline in FVC was ≥10% and effective if the
decline was <10%.
Inhaled NAC plus pirfenidone (n = 24)
Pirfenidone alone (control; n = 10).
Results:
Annual rate of change in FVC in NAC plus pirfenidone group = −610 mL
pirfenidone group = −1320 mL (P < 0.01)
Progression free survival (PFS ) in NAC plus pirfenidone group = 304 days
Pirfenidone group = 168 days (P = 0.016)
Conclusion: Combination treatment with inhaled NAC and oral pirfenidone reduced the
rate of annual FVC decline and improved PFS in patients with advanced IPF.
Respirology, April, 2015. 10.1111/resp.12477

83. Thalidomide for the treatment of cough in
idiopathic pulmonary fibrosis. a randomized trial
Ann Intern Med. 2012 Sep 18;157(6):398-406
• 98 participants were screened
24 were randomly assigned
23 received treatment
20 completed treatment period
• Cough Quality of Life Questionnaire (CQLQ) scores significantly
improved with thalidomide
(mean difference vs. placebo, -11.4 [95% CI, -15.7 to -7.0]
P < 0.001
• Thalidomide also significantly improved scores on the visual
analogue scale of cough
(mean difference vs. placebo, -31.2 [CI, -45.2 to -17.2]
P < 0.001

84. Strong recommendation Conditional recommendation
Level of recommendations as per IPF guidelines
Strong
recommendation
against use
Conditional
recommendation
against use
Conditional
recommendation
for use
Issue not
addressed or
deferred for
future discussion
2015 vs. 2011 treatment guidelines for IPF

85. 2015 vs. 2011 treatment guidelines for IPF
Strong
recommendation
against use
Conditional
recommendation
for use
Not
addressed
or deferred
Conditional
recommendation
against use

86. 2015 vs. 2011 treatment guidelines for IPF
Conditional
recommendation
for use
Conditional
recommendation
against use
Not
addressed
or deferred

87. Current Clinical Trials in IPF
116 studies in IPF
22 therapeutic trials
• BIBF 1120
• QAX576
• Plasma exchange, rithuximab
and steroids for acute exacerbations
• Sirolimus
• Losartan
• Phase I
– AB0024
– PRM-151
– STX-100
– CC930
– IW001

88. Proposed IPF pharmacological management
Pirfenidone Nintedanib Clinical trials
Assess in 6-12 months
Stabilization or Improvement
Decrease in FVC<10% DLCO<15%
Continue treatment
Severe disease
FVC <50% DLCO < 35%
Worse
Decrease in FVC>10% DLCO>15%
Lung Transplant
Mild – Moderate disease
FVC>50% and DLCO >35%

89. Lung transplantation in
idiopathic pulmonary fibrosis
Single vs Bilateral Transplant trends
2014 Lung transplant referral
guidelines for IPF patients
Kistler et al. BMC Pulmonary Medicine 2014, 14:139
• Age limits
• Histopathologic or radiographic evidence of
usual interstitial pneumonitis (UIP)
• Abnormal lung function: FVC <80%
predicted
or DLCO <40% predicted
• Any dyspnea or functional limitation
attributable to lung disease
• Any oxygen requirement, even if only
during exertion
Weill D, et al. J Heart Lung Transplant. 2014 Jun 26.

90. Post transplant survival of patients with IPF
Source Yr of
transplant
No. of IPF
patients
%age of patients alive
ISLT
Annual
report
3 months 1 yr 3 yr 5 yr 10 yr
1900-2011 8528 85 75 59 47 34
Source Yr of
transplant
No. of IPF
patients %age of patients alive
ISLT
Annual
report
SLT/BLT 1 yr 3 yr 5 yr 10 yr
1900-2011 8528 SLT 75 57 43 20
BLT 74 63 49 35
Total
Single vs Bilateral transplant
Kistler et al. BMC Pulmonary Medicine 2014, 14:139

91. Pre-transplant mortality on wait list

92. Kaplan-Meier survival analysis for lung
transplants by etiology of end-stage lung disease
Arch Surg. 2011;146(10):1204-1209

93. Acute exacerbation of IPF (AEx-IPF)
Diagnostic criteria for AEx-IPF
1. Previous or concurrent diagnosis of IPF
2. Unexplained worsening or development of dyspnea within
30 days
3. HRCT with new bilateral ground-glass abnormality and/or
consolidation superimposed on a background reticular or
honeycomb pattern consistent with UIP pattern
4. No evidence of pulmonary infection by endotracheal
aspirate or BAL
5. Exclusion of alternative causes, including:
• Left heart failure
• Pulmonary embolism
• Identifiable cause of acute lung injury (sepsis, aspiration, trauma,
reperfusion pulmonary edema, pulmonary contusion, fat embolization,
inhalational injury, cardiopulmonary bypass, drug toxicity, acute
pancreatitis, transfusion of blood products, and stem cell transplantation)
Am J Respir Crit Care Med 2007

94. Baseline IPF Exacerbation

95. Histopathological features
• The most common finding is
diffuse alveolar damage
superimposed on the
underlying UIP. Organizing
pneumonia and extensive
fibroblastic foci have also
been reported.
Am J Respir Crit Care Med 2007, 176:636–643.
Am J Surg Pathol 2007, 31:277–284.

96. Incidence of AEx-IPF
Study IPF Patient Population
Reported
Incidence
Collard et al 461 patients – retrospective review
14.2% at I yr
20.2% at 3 yr
Kim et al
147 biopsy-proven cases followed up for
2 yr
8.5% at 1 yr
Martinez et al
168 placebo patients in whom IPF was
diagnosed clinically or by biopsy followed
up for at least 48 wk
4.8% overall with
median of 76 wk
of follow-up
Azuma et al
35 placebo patients in whom IPF was
diagnosed clinically or by biopsy followed
up for 9 mo
14.3% at 9 mo
Taniguchi et al 74 patients – retrospective review
8.6 % at I yr
23.9 % at 3 yr

97. Mortality in AEx-IPF
• Systemic review of 8 studies:
pooled mortality rate: 1 month 60%
3 months 67%
• Other studies:
mortality as high as 85%
mean survival 3-13 days
Eur J Intern Med 2008;19:227-3
Eur J Intern Med 2008;19:227-3
Intensive Care Med 2001;27:1868-74

98. Risk factors for AEx-IPF
• lower FVC and/or lower DLCO
• Higher degree of dyspnea (score>2 on mMRC)
• Presence of pulmonary hypertension
• Co-existence of emphysema
• Invasive procedures – bronchoscopy and
thoracoscopic biopsy.
• GERD – pepsin presence in BAL
• Extent of fibrotic changes on CT scan
• Smoking
• ?virus infections (a well-controlled study by Wootton et al.found evidence of
viral respiratory infection in only 4 of 34 patients who presented with AE-IPF)

99. International consensus, the American Thoracic Society, the European
Respiratory Society, the Japanese Respiratory Society, and the Latin American
Thoracic Association (ATS/ERS/JRS/ALAT) guidelines
• supportive care – main treatment
• corticosteroids
“corticosteroids should be used in the majority of patients
with AE-IPF, but not using corticosteroids may be a
reasonable choice in a minority”
recommendation is weak and based on very low quality
evidence
No specific recommendations regarding the dose, route,
and duration of corticosteroid therapy are made
Management of AEx-IPF

100. Use of immunosuppressant drugs and other
modalities in AEx-IPF
• Treatment of AE-IPF with Direct hemoperfusion with a
polymyxin B-immobilized fiber column (PMX-DHP)
improved 12-month survival. (31 patients)
BMC Pulm Med. 2015 )Feb 22;15:15
• Plasma exchange + rituximab + corticosteroids (6 patients)
Am J Respir Crit Care Med 2013;187:A5712
• Cyclophosphamide + corticosteroids (small case series)
Eur Respir J 2011;38:1487-9
• Tacrolimus + Corticosteroids (5 patients)
Intern Med 2011;50:189-95

101. Summary
• IPF is a rare disease with high mortality.
• Median survival is worse than most cancers
• Diagnosis is based on HRCT and/or histological
evidence of UIP while known causes are ruled out.
• Early and accurate diagnosis is important as available
treatments are tested on mild to moderate IPF
• New evidence suggest efficacy of Pirfenidone and
Nintedanib in delaying the decline in lung function and
reducing exacerbations.

102. • There is evidence against the use of steroids and
immunosuppressive agents in IPF
• Acute exacerbation of IPF should be treated with supportive
care and steroid use in this clinical setting may be beneficial.
• Non-pharmacological treatment include long term oxygen
therapy , pulmonary rehabilitation and supportive care.
• Eligible Patients should be referred for lung transplant
evaluation as soon as possible.
• Screening should be done for pulmonary hypertension,
obstructive sleep apnea, gastroesophageal reflux disease,
and coronary artery disease.
• End-of-life care and palliative care services
Summary – cont..

103. Thank you