ILD (Interstitial lung disease) New advances in 2020

1. Presenter:
Dr. Sai Krishna
Moderator:
Dr. Tabish Mohammad
Department Of Medicine
AIIMS, New Delhi
Preceptors:
Prof. Sanjeev Sinha,
Dr. Animesh Ray,
Department Of Medicine
Co-Preceptor:
Dr. Surabhi Vyas
Department of Radiodiagnosis
AIIMS, New Delhi
ILD- NEW
ADVANCES
1
26 Feb, 2020

2. At the end of seminar the listener will be able to
1. Understand definition of ILD
2. Classify different types of ILD
3. Know the most common types of ILD in India and across world
4. Know the HRCT and HPE patterns of common ILD’s
5. Anti-Fibrotic agents
6. Progressive fibrosing ILDs
7. Supportive care: i. Vaccination ii. LTOT iii. Pulmonary Rehabilitation
iv. Lung Transplantation
26 Feb, 2020 3

3. Interstitial Lung Disease(ILD) (or)
Diffuse Parenchymal Lung Disease(DPLD)
• Heterogeneous group of disorders
• Classified together because of similar clinical, radiographic and
pathological features.
• Begins in the “interstitium”
• “misleading to call interstitial lung disease”: leads to extensive alteration
of alveolar and airway architecture.
Am J Respir Crit Care Med 2013; 188:733.26 Feb, 2020 4

4. Classification of ILD
Interstitial Lung Diseases
Etiology known Etiology unknown
Inorganic exposure
• Asbestosis
• Silicosis
• Coal worker Pneumoconiosis
Organic exposure
• Bird-Fancier’s
• Farmer’s lung
• Mold
• Hot-tub HP
Smoking
• DIP
• RB-ILD
• LCH
Granulomatous
• Sarcoidosis
Idiopathic interstitial pneumonias
IPF Non-IPF
COP LIP AIPNSIP
Rare forms of
ILD
• LAM
Connective tissue disease
• Rheumatoid arthritis
•Polymyositis/dermatomyo
sitis
• Scleroderma
• Sjögren syndrome
Drugs/Radiation
• Nitrofurantoin
• Amiodarone
• Methotrexate
• Chemotherapy
• Radiotherapy
26 Feb, 2020 5AJRCCM, 2013;188(6):733–748.
DIP, desquamative interstitial pneumonia;
RB-ILD, respiratory bronchiolitis-ILD;
LCH, Langerhans cell histiocytosis;
LAM, lymph-angio-leiomyomatosis,
LIP, lymphocytic interstitial pneumonia;
AIP, acute interstitial pneumonia.

5. Epidemiology
i. ILD in India
ii. ILD-registry of India
iii. ILD Registries across the world
iv. ILD in western countries
26 Feb, 2020 6

6. 26 Feb, 2020 7
Sarcoidosis
40%
IPF
20%
CTD-ILD
12%
HP
10%
Non-IPF IIP
9%
Others
9%
PREVALENCE
(2018)
PLoSONE 13(2): e0191938
1. Sarcoidosis 40%,
2. IPF 20%
3. CTDs-ILD 12%
• Histologically confirmed
diagnosis in 40.6% patients

7. Epidemiology in Developed countries
26 Feb, 2020 8
ILDs of known causes
35%
Sarcoidosis
26%
IIP
24%
ILDs of unknown causes
10%
Particular ILDs
5%PREVALENCE
Eur Respir J 2017; 50:1602419
1. Sarcoidosis,
2. CTDs-ILD’s (n=145, 17%),
3. IPF (n=98, 11%),
4. Occupational ILD (n=42, 5%),

8. 26 Feb, 2020 9
i. History
ii. Examination
iii. Differentials
iv. Physiological
testing
v. Laboratory
evaluation
vi. CXR, HRCT
vii. Role of BAL
viii. Role of Lung Biopsy
ix. Latest Dx guidelines of IPF
Approach to ILD

9. Diagnostic Approach to ILD
Clinical
• History
• Examination
• Laboratory
• PFTs
Physicians Radiologists Pathologists
Multidimensional and multidisciplinary
Radiology
• Chest X-ray
• HRCT
Pathology
•Bronchoscopy:
1.BAL 2. TBLB
•Surgical lung biopsy
1.VATS 2. Open 3. TBLC
(MDD discussion is the ‘‘gold standard’’ for the diagnosis of the IIPs)
26 Feb,2020 10Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811
AIM: To differentiate IPF from other types

10. HISTORY
• Progressive Dyspnoea and DOE (70%)
• Dry cough (50%)
• Wheezing (HS, EP, Sarcoidosis)
• Chest pain (14%, Sarcoidosis, CTD’s, Cystic lung disease, complication)
• Haemoptysis (DAH)
• Pneumothorax (LAM)
26 Feb,2020 11Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811

11. HISTORY
• Age and Gender
• Onset of symptoms
• Past Medical History
• Smoking History
26 Feb,2020 12
Acute (days to weeks)
Subacute (weeks to
mths)
Chronic (months to yrs)
Acute Hypersensitivity
Pneumonitis
Sarcoidosis IPF
Acute Eosinophilic
Pneumonia
Some Drug-Induced ILDs Sarcoidosis
Cryptogenic Organising
Pneumonia
Cryptogenic Organising
Pneumonia
Chronic Hypersensitivity
Pneumonitis
AIP (Hamman-Rich
syndrome)
Alveolar Haemorrhage
syndromes
PLCH
Exclusively in smokers
Increased risk in
smokers
Rare in active smokers
• Respiratory
Brochiolitis-ILD
IPF Sarcoidosis and HS
• Desquamative
interstitial pneumonia
DIP
Hypersensitivity
Pneumonitis
• Langerhans cell
histiocytosis (LCH)
Diffuse Alveolar
Haemorrhage
Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811
IPF usually presents at age >50 year and in
male gender
Majority of other ILD present below 50 years

12. HISTORY
• Age and Gender
• Onset of symptoms
• Past Medical History
• Smoking History
• Family History
• Prior Medication History and Irradiation
• Occupational and Environmental exposures
26 Feb,2020 13
• In IPF, mutations in the telomerase genes occur in 8%
to 15% of familial cases and 1% to 3% of sporadic
cases. (surfactant protein C and MUC5B)
• Familial clustering of sarcoidosis is present
Dyspepsia and regurgitation symptoms should
be enquired1
Fishman’s Pulmonary Diseases and Disorders, 5th ed. p808

13. Physical examination
• Tachypnoea, Clubbing, Cyanosis, Accessory respiratory
muscle use
• Decreased chest expansion, Fine, inspiratory, basilar “Velcro”
crackles, wheezing can indicate airway disease,
• Increased P2 component, a right ventricular heave, elevated
jugular venous pressure, and Pedal edema.
GPE Respiratory examination CVS examination
Tachypnoea Fine, inspiratory, basilar “Velcro”
crackles
Increased P2 component
Accessory respiratory muscle use Decreased chest expansion Right ventricular heave
SpO2 (RA), Clubbing, Cyanosis Wheezing indicate airway disease Elevated JVP
Systemic features of CTDs Pedal edema
26 Feb,2020 14Fishman’s Pulmonary Diseases and Disorders, 5th ed. p816
D/D’s

14. Evaluation
• CBC, RFT, LFT, URM
• ABG, SpO2
• PFT- FVC, FEV1/FVC (Restrictive/Obstructive/mixed)
• TLC, DLCo, 6MWT, IOS
• HIV antibodies
• CXR, HRCT, CECT chest(in select cases)
• Autoimmune Serology, Inflammatory markers
• Fundus, Serum ACE, Urine Calcium
• Complications- ECG, ECHO
26 Feb,2020 15Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811

15. PFT, DLco
26 Feb, 2020 16

16. Body Plethysmography
26 Feb, 2020 17

17. Question 1
26 Feb, 2020 18
• What if patient has poor effort
on PFT and DLCo?
• How to assess severity and
monitor progression?

18. Impulse Oscillometry
26 Feb, 2020 19
• IOS involves application of sine waves via a
mouthpiece, through which the subject
breathes normal TV.
• Higher frequencies(20Hz) reflect upper
airways and lower frequencies(5Hz) reflect
peripheral smaller airways.
• Measures respiratory system
i. Resistance/Impedance (Rrs) and
ii. Reactance (Xrs) at several frequencies
. (5Hz to 20Hz).

19. Radiological and
Histopathological evaluation
26 Feb, 2020 20

20. HRCT patterns in ILD
26 Feb, 2020 21https://www.uptodate.com/graphic 64841 Version 1.0
Peripheral Lung
zone
Central disease
(Broncho-vascular
thickening)
Upper zone predominance
Lower zone
predominance
IPF Sarcoidosis Sarcoidosis IPF
Asbestosis Chronic Hypersensitivity Pneumonitis RA-IPF
CTD Asbestosis
Eosinophilic
Pneumonia
Chronic Infectious diseases
(Tuberculosis, Histoplasmosis)
COP Pneumoconiosis
Pattern ILD-type
Fibrosis IPF
Chronic HP
Fibrotic NSIP
Cystic changes LAM
LCH
LIP
Consolidation COP
LCH
GGO NSIP
RB-ILD
HP
LIP
Nodules Silicosis
CAP
Sarcoidosis
Identification of dominant pattern and
lobes affected on HRCT are key to
radiological diagnosis

21. IPF
26 Feb, 2020 22Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811
• CXR: Bilateral, basal reticular
opacities with decreased lung
volumes
• HRCT: Bilateral, basal, peripheral,
subpleural honey combing(*)
with traction bronchiectasis (**)
• HPE: Heterogenous fibrosis,
fibroblastic foci (***)

22. 26 Feb, 2020 23
Latest Diagnostic Guidelines of IPF
Am J Respir Crit Care Med Vol 198, Iss 5, Sep 1, 2018
In view of increased diagnostic role of HRCT in ILD

23. 26 Feb, 2020 24
Definite UIP Possible UIP Inconsistent for UIP
Distribution
Heterogenous Heterogenous • Peri BV
• Peri lymphatic
Location
B/L, Basal and Sub-Pleural
predominant
Sub-Pleural and Basal
predominant
Upper or midlung predominance
Honeycombing
Honey-combing ± Traction
bronchiectasis
Absent ± Traction
bronchiectasis
Absent
Cysts away from honeycombing
Nodules/Pleural plaques/
Consolidation/LAP may present
Reticular
pattern
Reticular abnormality Present Subtle
GGO
absence of any inconsistent
features
± Extensive GGO
HRCT in IPF
Am J Respir Crit Care Med Vol 198, Iss 5, Sep 1, 2018

24. IPF diagnosis based upon HRCT and biopsy patterns
26 Feb, 2020 25
IPF Suspected
Histopathology pattern
Definite UIP Possible UIP
Inconsistent with
UIP
Alternative Dx
HRCT
pattern
Definite UIP IPF IPF IPF Non-IPF dx
Possible UIP IPF IPF IPF (Likely) Non-IPF dx
Inconsistent
with UIP
IPF IPF (Likely) Indeterminate Non-IPF dx
Alternative Dx IPF (Likely) Non-IPF dx Non-IPF dx Non-IPF dx
Am J Respir Crit Care Med Vol 198, Iss 5, Sep 1, 2018

25. Cellular NSIP
26 Feb, 2020 26Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811
• CXR: Bilateral, basal reticular
opacities with decreased lung
volumes
• HRCT: Bilateral, basal, peripheral
GOO with sub-pleural sparing
and no honeycombing.
• HPE: Temporally uniform septal
thickening and inflammation

26. Sarcoidosis
26 Feb, 2020 27Fishman’s Pulmonary Diseases and Disorders, 5th ed. p823
 CXR: Bilateral hilar LAP and
reticulonodular infiltrates.
 HRCT: Bilateral hilar lymphadenopathy
and micronodules with a perilymphatic
distribution including spreading along
the fissures
 HPE: Heterogenous fibrosis,
fibroblastic foci (***)

27. Hypersensitivity Pneumonitis
26 Feb, 2020 28Fishman’s Pulmonary Diseases and Disorders, 5th ed. p840
• CXR: Bilateral lower lobe 2- to 3-mm
nodules.
• HRCT: Diffuse nodular radiodensities
in the lower lobes, with areas of
ground-glass densities posteriorly.
• HPE: Interstitial mononuclear
inflammation and loosely formed
granulomatous lesions

28. Organising Pneumonia
26 Feb, 2020 29Fishman’s Pulmonary Diseases and Disorders, 5th ed. p878
 CXR:unilateral or bilateral patchy
areas often migratory usually
peribronchovascular, peripheral,
subpleural
 HRCT: Multifocal, peripheral areas
of consolidation
 HPE: Patchy organizing pneumonia
pattern of exudates, fibroblasts,
and inflammatory cells

29. Lung Biopsy
• Definitive diagnosis of pattern of ILD.
• Methods:
1. Bronchoscopy:
BAL, TBLB, TLCB
2. SLB:
VATS, Open procedure
• Cryobiopsy is safe and has lower complication and mortality
rates compared to SLB with good diagnostic agreement
26 Feb, 2020 30
Respiration 2016;91:215–227
Eur Respir J 2016; 48: 1274–1277

30. Further Evaluation
2018 ATS
recommendations
for further
evaluation of
1. Probable UIP
2. Indeterminate
for UIP and
3. Alternative
Diagnosis
26 Feb, 2020 31
Evaluation Definite UIP pattern Possible, Inconsistent for UIP
History of medication and
environmental exposures
Motherhood statement
Serological testing for CTD Motherhood statement
BAL NOT recommended
(conditional)
Conditional recommendation
SLB NOT recommended Conditional recommendation
TBLB NOT recommended Conditional recommendation
TLCB NOT recommended Conditional recommendation
Am J Respir Crit Care Med Vol 198, Iss 5, Sep 1, 2018
UIP pattern on HRCT is diagnostic of IPF
Decision of Lung biopsy should be
based on a careful risk–benefit analysis

31. Q. Match the following HPE features with appropriate ILD
26 Feb, 2020 32
ILD-type HPE features
1. UIP A. Hyaline membrane formation
2. AIP B. Non-caseating granuloma
3. RB-ILD C. Paucity of interstitial Inflammation
4. Hypersensitivity Pneumonitis D. Foamy macrophages
5. Pulmonary alveolar proteinosis E. Pigmented alveolar macrophages
Question 2

32. Quick recap..
• ILD of known causes should be differentiated from idiopathic causes.
Sarcoid, IPF, CTD-ILD most common ILDs
• MDD is the recommended approach. IPF should be differentiated from
other ILDs. IOS is can be used in patients with poor effort.
• Definite UIP pattern on HRCT does not require further evaluation.
UIP pattern on HRCT≠ IPF
26 Feb, 2020 33

33. Management of ILD
26 Feb, 2020 34
i. Management of IPF
ii. Management of other ILD’s
iii. AE-ILD
iv. Prognosis of ILD
v. Follow-up of ILD

34. MANAGEMENT
OF IPF
26 Feb, 2020 35
Role of Immunosuppresants and NAC
Anti-Fibrotic agents
Smoking cessation
Oxygen therapy
Vaccination
Pulmonary rehabilitation
• Early diagnosis is key in
management

35. IMMUNOSUPPRESSANTS
26 Feb, 2020 36
• Increased oxidant burden in the
epithelial-lining fluid of lung.
• The PANTHER-IPF trial
ANTI-OXIDANTS
• Historically suppressing the
inflammatory processes of IPF
• The PANTHER-IPF trial (halted
early)
N Engl J Med 2012;366:1968-77

36.  Anti-Fibrotic agents
26 Feb, 2020 37
1. Pirfenidone 2. Nintedanib

37. Pirfenidone
26 Feb, 2020 38
• Multiple MOA
• CAPACITY trial2
• ASCEND trial3
• Pooled analysis of
. both
POOLED ANALYSIS
• To determine mortality outcomes at 52, 72 and 120 weeks
• At 52 weeks
• Reduced all cause mortality in Pirfenidone group (all-cause mortality hazard ratio
[HR] 0·52 [95% CI 0·31-0·87; p=0·0107])
• At 120 weeks
• Reduced mortality in Pirfenidone group: treatment-emergent all-cause mortality
(p=0·0420), IPF-related mortality (0·0237)

38. • TOMORROW trial
• INPULSIS-1 and INPULSIS-2
26 Feb, 2020 39
Nintedanib

39. 26 Feb, 2020 40
Nintedanib Perfinidone
MOA Triple TK inhibitor (FGF, VEGF, PDGF) Anti-inflammatory(TGF-b), Antioxidant, and
Antifibrotic(inhibit collagen synthesis)
Dose 200-300mg per day 1800-2400mg per day
Hepatic & Renal
Modification
Child-Pugh class B or C: Use is not recommended.
Renal adjustments not required.
ESRD requiring dialysis and Child-Pugh class C : Use
is not recommended
ADR NVD(50%), Anorexia, Photosensitivity, Hepatotoxicity
(14%). Avoid in pregnancy and Breast feeding.
Diarrhoea, Hepatotoxicity
Avoid in pregnancy and breast feeding
Cautions Risks of bleeding and arterial thrombosis: Risk of GI
perforation(rare); anticoagulant and prothrombotic
drugs to be avoided
CYPA12 inhibitors (eg: fluvoxamine and
ciprofloxacin) can raise pirfenidone levels;
CYP1A2 inducers(eg: omeprazole, smoking) can
lower pirfenidone levels
Strategies to
minimise ADR
• Use anti-diarrhoeal agents, temporary dose
reduction to 100mg BD
• Monitor LFT
• Slow increase over 14 day period, take with
food, use antacids, antiemetics, sun avoidance
• Monitor LFT
T. Ofev 150mg, Rs. 98,000 for 30 days T. Perfinex 200mg, Rs. 5280 for 30 days
Anti-Fibrotic agents slow down the progression of disease
but do not modify the disease course.
Should be started early in course of IPF provide greater
benefits.

40. • Thalidomide: Thalidomide improved cough and respiratory quality of
life in patients with IPF.
• GERD: High prevalence in IPF. Increased length of survival and reduced
radiographic evidence of fibrosis with treatment.
• Lung Transplantation: For advanced stages of IPF. 5-year survival data
approach 50%(most important complication- BOS )
• Supplemental Oxygen: Patients with hypoxemia (PaO2 <55 mm Hg or
SpO2 <88%) at rest or during exercise.
• Pulmonary Rehabilitation: Quadriceps strengthening exercises.
26 Feb, 2020 41Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811

41. •Which anti-fibrotic agent to choose?
26 Feb, 2020 42
Nintedanib
(vs)
Pirfenidone

42. Dual Anti-Fibrotic
26 Feb, 2020 43

43. 26 Feb, 2020 44
• Which among the following statements about
the drug Nintedanib is not true?
1. Blocks both PDGFR alpha and beta
2. Inhibits PDE-5 and increases cGMP in the lungs
3. Used in the treatment of IPF
4. A 2nd line drug for Non-small cell lung Carcinoma
Question 3

44. Non specific interstitial pneumonia
• It is second most common morphological and pathological pattern of the ILD.
• Middle aged woman
• Differential diagnosis:
• Connective tissue disorders (70%)
• HIV
• Hypersensitivity Pneumonitis
• Drug Induced pneumonitis - amiodarone, methotrexate, nitrofurantoin, Chlorambucil
• Treatment - Steroids(1mg/kg) alone/with mycophenolate or azathioprine, cyclophosphamide,
rituximab, Calcineurin inhibitors(rarely), Pulmonary Rehabilitation, Lung transplantation
26 Feb, 2020 45

45. CTD-ILD
26 Feb, 2020 46
Connective tissue disorders Frequency of ILD
Scleroderma 45%
PM/DM 20-50%
MCTD 20-60%
Rheumatoid arthritis (MC) 20%
Sjogren’s syndrome <25%
SLE 2-8%
Rheumatic
disease
Frequency of
ILD (%)
Characteristic
pattern
Comment
Systemic Sclerosis
45 (clinically
significant)
NSIP
UIP
More common in diffuse disease;
topoisomerase-1 antibodies
Rheumatoid
Arthritis
20 to 30 UIP
NSIP
Increased risk with cigarette smoking
Polymyositis/Derma
tomyositis
20 to 50 NSIP
UIP
COP
More common with anti-synthetase antibodies
Sjogren syndrome
Up to 25 NSIP
LIP
-
SLE 2 to 8 AIP Usually in patients with multisystem disease
MCTD 20 to 60 NSIP -
Castelino and Varga Arthritis Research & Therapy 2010, 12:213
CTD-ILD with AI features: Clinical and serologic features
suggestive, but do not meet criteria for a specific CTD.

46. 26 Feb, 2020 47
• Scleroderma Lung Study I
(2006)
• Scleroderma Lung Study II
(2016)
Management of
SSc-ILD

47. Management of
SSc-ILD
• Scleroderma Lung Study I (2006)
• Scleroderma Lung Study II (2016)
HRCT: NSIP(MC) or UIP(1/3 rd)
• Scleroderma Lung Study III
• SENSCIS
• Autologous HSCT: ASTIS, SCOT,
ASSIST trials
26 Feb, 2020 48
SLS-III (ongoing)
• Double-blind Phase-II randomised trial
• (Recruiting) SSc-ILD patients (MMF+placebo
vs MMF+pirfenidone.

48. Management of other ILD’s
• COP: Corticosteroids (3-6 months), Management of secondary causes, favourable
prognosis. Cyclophosphamide has been tried in AFOP1
• RB-ILD: Smoking cessation, Prednisolone 40 to 60 mg/d for 6 weeks maintenance for
6-9 months.
• AIP: High/pulse-dose glucocorticoid therapy, azathioprine, cyclosporine,118
Cyclophosphamide.
• LIP: Immunosuppression in Idiopathic LIP and CTD-related ILD, HAART in HIV-related
LIP.
• HP: Avoidance of antigen exposure, Glucocorticoids(oral/inhaled) for persistent
symptoms
26 Feb, 2020 49Fishman’s Pulmonary Diseases and Disorders, 5th ed. p811

49. Role of Rituximab
• Clinical benefits with rituximab is seen in patients with progressive
ILD a/w Antisynthetase syndrome.
• Rituximab had an acceptable safety profile in refractory pulmonary
sarcoidosis, but efficacy is inconsistent.
• Rituximab is wisely used in rapidly progressive RA-ILD unresponsive
to corticosteroids and methotrexate.
• Currently not approved in management of ILDs.
26 Feb, 2020 50
Biologics have risk of ILD exacerbation. Importantly, TNFa
induced ILD could be rapidly progressive and even fatal.

50. 1. False regarding UIP pattern on HRCT chest?
a) Honeycombing is most characteristic feature of UIP
b) Traction Bronchiectasis is most characteristic feature of UIP
c) Seen exclusively in IPF patients
d) NSIP pattern is usually associated with CTD-LD
26 Feb, 2020 51
Question 4

51. 1. Most common CTD-ILD associated with UIP pattern?
a. Systemic sclerosis
b. Rheumatoid Arthritis
c. Dermatomyositis
d. Anti-synthetase syndrome
26 Feb, 2020 52
The first randomized trial of antifibrotics in
RA-ILD (TRAIL trial) is currently under investigation
Question 5

52. Quick recap..
• Early diagnosis and early management is key in management of ILDs.
Immunosuppressants antioxidants are not indicated in IPF.
• Nintedanib and Pirfenidone has similar efficacy, hepatotoxicity should be
monitored on treatment.
• Management of Non-IPF patterns is mainly by immunosuppressants.
MMF is first line therapy in SSc ILD, Nintedanib is approved for SSc ILD.
• Rituximab can be used as rescue therapy, nevertheless with caution.
26 Feb, 2020 53

53. 26 Feb, 2020 54
i. Progressive fibrosing ILD’s
ii. Role of dual Anti-fibrotics in Progressive fibrosing ILD’s
iii. Biologics and Investigational drugs
iv. Role of r-Pentraxin-2 in IPF
Future Directives in ILD

54. Progressive Fibrosing ILD
26 Feb, 2020 55
Progressive
Fibrosing ILDs
Autoimmune
ILDs
HP
Non-IPF IIPs
Exposure-
related
IPF
Other ILDs
Sarcoidosis
ILDs
• IPF is the “prototype” progressive
fibrosing ILD and has no known
cause
• The chronic fibrosing ILD that have
similar biological and clinical
behaviors are clubbed to
Progressive fibrosing ILD
Eur Respir Rev 2019; 28: 180100

55. Percentage of patients with non-IPF ILDs who
develop a progressive fibrosing phenotype
26%
31%
24%
32%
29%
21%
20%
18%
0%
5%
10%
15%
20%
25%
30%
35%
RA-ILD SSc-ILD Other CTD-ILDs iNSIP Unclassifiable IIP HP Sarcoidosis-ILD Other non-IPF ILDs
Progressive fibrosis was defined as fibrosis detected by HRCT (reticular abnormality with traction bronchiectasis with or without honeycombing) that was
progressive in terms of worsening of lung function (FVC and/or DLCO) and/or respiratory symptoms and/or chest images. Based on online physician survey
Eur Respir Rev 2019; 28: 180100

56. Ongoing Trials of Pirfenidone in non IPF ILDs
Progressive
fibrosing ILD
RA-ILD
Chronic HP
Chronic HP
Chronic fibrosing
ILD
ILD with CADM
Eur Respir Rev 2018; 27: 18007426 Feb, 2020 57

57. Ongoing trials of Nintedanib in non IPF ILDs
SSc
Progressively
fibrotic ILD
Post lung Tx
BOOP
26 Feb, 2020 58Eur Respir Rev 2018; 27: 180074

58. Pathobiology
of ILD
• Impaired muco-
ciliary clearance
• Altered micro-
biome and
bacterial burden
• Innate immunity
(alveolar
macrophages)
• Premature aging
of alveolar
epithelial cells
• Aberrant repair to
subclinical injury
with fibroblast
proliferation
26 Feb, 2020
59
The
Antifibrotics
doi: 10.3389/fmed.2019.00041

59. Potential Future Therapies for IPF
26 Feb, 2020 60
doi: 10.3389/fmed.2019.00041

60. • Fibrocytes, usually inactive fibroblast-like cells are derived from peripheral
blood monocytes
• Purified serum amyloid P, also known as pentraxin2, inhibits monocyte
differentiation into profibrotic fibrocytes
26 Feb, 2020 61
Recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung
function over 28 weeks
JAMA. doi:10.1001/jama.2018.6129

61. Biomarkers in ILD
26 Feb, 2020 62
• CTD-ILD and IPF share common biomarkers suggesting common
pathways.
• KL-6 and SP-D are sensitive but not specific to diagnose lung
fibrosis in
IPF and SSc-ILD diagnosis
• KL-6 is the most sensitive circulating biomarker for diagnosis.
• KL-6 and CCL18 can predict worsening in IPF and SSc-ILD.
• Serum S100A12 levels for assessing clinical severity and prognosis of DM-ILD.

62. Further Reading on ILD
• The pulmonary microbiota in sarcoidosis: observational study: Respir
Res 20, 46 (2019)
• Thalidomide for the Treatment of Cough in IPF: Ann Intern Med , 157 (6), 398-406
(RCT)
• Long-term macrolides in diffuse ILDs: Eur Respir Rev 2017; 26: 170082
• Drug induced ILD: J. Clin. Med. 2018, 7, 356
• Infliximab related ILD: PMCID: PMC3752574
• HP Caused by Cephalosporins: Allergy Asthma Immunol Res. 2015;7(5):518–522
• The Lung microbiome in ILD: Curr Opin Pulm Med. 2017 September ; 23(5): 404–410
26 Feb, 2020 63

63. Case Vignette
• A 58-year-old male, teacher by occupation, presented to medicine OPD with
shortness of breath, dry cough, fatigue and weight loss for ten months. He was a
former smoker. He had no history of exposure to organic or inorganic dust. H/O
inhaler use was present without any significant improvement.
• Physical examination-
• SpO2- 88% at rest, RR- 26/min, use of accessory muscle noted
• Bilateral basal Velcro rales present.
• No features of heart failure.No signs of CTD
• Rest of the systemic examination was normal.
• Routine investigation were normal except for raised HCT-56%
• ESR ,CRP, ANA, RF, anti CCP negative
26 Feb, 2020 64

64. 26 Feb, 2020 65

65. PFT interpretation
26 Feb, 2020 66

66. 26 Feb, 2020 67
Further evaluation
• CXR: Bilateral, basal reticular
opacities with decreased lung
volumes
• HRCT: Bilateral, basal, peripheral,
subpleural honey combing(*)
with traction bronchiectasis (**)
No nodule or cyst
S/o UIP pattern
Diagnosis: IPF with type 1 RF
Management:
Pharmacological- As already discussed
Supportive Therapy

67.  Supportive management
in ILD
26 Feb, 2020 68

68. Supportive Care
• Smoking cessation
• Vaccination
• Long term oxygen therapy
• Pulmonary rehabilitation
• Treatment of gastro oesophageal
reflux disease (GERD)
• Lung transplantation
ATS/ERS 201526 Feb, 2020 69

69. Vaccination
• PPSV-23
first dose 19-64 year
2nd dose after 65 years
5 year apart
1 year gap from PCV
• PCV 13-
• After 65 years of age
26 Feb, 2020 70

70.  Role of LTOT
in ILD
26 Feb, 2020 71

71. Indications for Long-Term Oxygen Therapy
(LTOT) in COPD and ILD
Oxygen therapy in COPD and interstitial lung
disease ERJ Open Res J. 2019
• PaO2 ≤55 mmHg or SpO2 ≤88 percent
• PaO2 ≤59 mmHg or SpO2 ≤89 percent with
• cor pulmonale, or
• Hematocrit > 55%, or
• Peripheral edema (right heart failure)
26 Feb, 2020 72

72. Available options
26 Feb, 2020 73
Oxygen concentrator on rent-
4000 Rs/month
security money 4000Rs
Appolohomes- 9121326363
Non government NGOs-
http://dnipcare.blogspot.com/

73. How to prescribe LTOT ?
26 Feb, 2020 74
• Oxygen flow to maintain
transcutaneous SpO2 to 90-92%

74.  Role of Pulmonary
Rehabilitation in ILD
26 Feb, 2020 75

75. Objectives:
• To determine whether pulmonary rehabilitation in patients with ILD has beneficial effects on exercise
capacity, symptoms, quality of life and survival compared with no pulmonary rehabilitation in patients
with ILD.
• To assess the safety of pulmonary rehabilitation in patients with ILD.
Main Results
• 9 studies included, 6 were abstracts
• 5 included in meta-analysis
• (86 participants who undertook pulmonary rehabilitation and 82 control participants).
• Pulmonary rehab improved:
• 6 minute walk distance by 44.34 m (95% CI - 26.04 to 62.64 m)
• Oxygen consumption (VO2 peak) by 1.24 mL/kg/min−1 (95% CI 0.46 to 2.03 mL/kg/min−1
• Dyspnea
• Quality of life
26 Feb, 2020 76

76. 26 Feb, 2020 77

77. 26 Feb, 2020 78

78. 26 Feb, 2020 79

79. Thus Pulmonary Rehabilitation is associated with immediate improvements
in functional exercise capacity, dyspnea and quality of life.
But what about long term effects?
26 Feb, 2020 80

80. Recent trial – long
term effects of
Pulmonary
Rehabilitation
• Evaluated effects of PR at 6 months and 1 year on
• exercise capacity (6-Minute Walking Distance, 6MWD; Peak Work Rate,
Wmax)
• quality of life (St George’s Respiratory Questionnaire, SGRQ)
• quadriceps force (QF) and
• objectively measured physical activity in ILD
Result:
Exercise capacity, quality of life and muscle force increased significantly after the program as compared
to control at 1 year. Physical activity did not change.26 Feb, 2020 81

81. • 60 patients with COPD were randomly divided into 2 groups
• (group 1) was taught yoga exercises including asanas , pranayam , meditation and
relaxation technique
• (group 2) underwent pulmonary rehabilitation
• one hour of training twice a week for the first 4 weeks
Chest. 2015;148(4_MeetingAbstracts26 Feb, 2020 82

82. 26 Feb, 2020 83
Exercise training
Pathophysiological abnormality Benefits of exercise training
Decrease in lean body mass Increase in fat free mass
Decreased TY1 fibres Normalizes proportion
Decreased cross-sectional area of muscle fibres Increases
Decreased capillary contacts to muscle fibres Increases
Decreased capacity of oxidative enzymes Increases
Increased inflammation No effect
Increased apoptotic markers No effect
Reduced glutathione levels Increases
Lower Intracellular pH, increased lactate levels and
rapid fall in pH on exercise
Normalization of decline in pH

83. Types of exercises
Clin Chest Med 35 (2014) 313–322
26 Feb, 2020 84

84. Lower-extremity training
• Leg ergometer
• Walking
• Stationary
cycling
• Bicycling
• Stair climbing
• Swimming
26 Feb, 2020 85

85. Upper Limb Training
• Typical muscles targeted are the
biceps, triceps, deltoids, latissimus
dorsi, and the Pectorals
• Cycle ergometry
• Free weights/lifting a
dowel/throwing a ball
26 Feb, 2020 86

86. • Pursed Lip Breathing – shifts breathing pattern and inhibits dynamic airway collapse.
• Posture techniques – forward leaning reduces respiratory effort, elevating depressed diaphragm by
shifting abdominal contents.
• Diaphragm Breathing – Some patients with extreme air trapping and hyperinflation have increased
WOB with this technique
• Yoga: timed breathing techniques
Chest Physical Therapy & Breathing
Retraining
Cochrane Database Syst Rev. 2012 Oct 17;10:CD008250.Holland, et al,2012
26 Feb, 2020 87

87. Home based breathing exercise for ILD
• Step 1- breath in via nose + slow active movement
• Step 2- breath out - pursed lip
• Step 3- breath in via nose + slow active movement
• Step 4- breath out- pursed lip
*Movement during inspiration in ILD
*Movement during expiration in COPD
26 Feb, 2020 88

88. 2
26 Feb, 2020 89

89. 2
26 Feb, 2020 90

90. 26 Feb, 2020 91

91.  Role of GERD
treatment in ILD
26 Feb, 2020 92

92. • Investigated whether antacid medication modified natural course of
disease or affected Nintedanib therapy
• Post-hoc analysis of two phase-3 RCT’s of Nintedanib in IPF (n = 406)
• adjusted annual rate of decline in FVC was:
• Antacid group: − 252.9 mL/year
• placebo group: − 205.4 mL/year
• (difference of − 47.5 mL/year [95% CI: –105.1, 10.1]; p = 0.1057)
Anti-acid medication use was not associated with a more favorable course of disease, and
did not impact the treatment effect of nintedanib
26 Feb, 2020 93

93. Role of Antacid Therapy in IPF
• In two previous observational studies, antacid use was associated
with a slower decline in lung function and a lower mortality rate (1),
(2)
• Current guidelines recommend the use of antacid therapy to treat IPF
• However recent data suggest contradictory findings
• One recent study also found increased risk of respiratory infections
with antacid therapy (3)
(1) Lancet Respir Med 2013; 1: 369-76.
(2) Am J Respir Crit Care Med 2011; 184: 1390-4
(3) Stat Med 1983; 2: 267-71.
26 Feb, 2020 94

94.  Role of Lung
Transplantation in ILD
26 Feb, 2020 95

95. Adult Lung Transplants
Major Indications by Year (Number)
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
NumberofTransplants
Transplant Year
COPD A1ATD CF IIP ILD-not IIP Retransplant
2017
JHLT. 2017 Oct; 36(10): 1037-1079
DPLD is 2nd
most
common
indication
(28.2%)
J Heart Lung Transplant. 2015;34(10):1264
LUNG TRANSPLANTATION
26 Feb, 2020 96

96. Referral criteria
97
ILD
• Histopathologic or radiographic UIP or
NSIP
•FVC < 80% or DLCO < 40% predicted
• Any dyspnea or functional limitation
• Any oxygen requirement,
• For inflammatory ILD, failure to improve
dyspnea, oxygen requirement, and/or lung
function after trial of medical therapy
• Decline in FVC 10%/ DLCO 15% in 6 months of
follow-up
• Desaturation to < 88% or distance < 250 m or >
50 m decline in 6MWD over 6-month
• Pulmonary hypertension
• Hospitalization because of respiratory decline,
pneumothorax, or acute exacerbation
Listing criteria
Consideration for referral for transplantation at time of diagnosis as evaluation and
waiting list periods may span from months to years
26 Feb, 2020

97. Outcomes:
• Lung transplantation can prolong survival and improve quality of life
for highly selected candidates
• 66% of transplant recipients with IPF survive for > 3 years
• 53% survive for more than 5 years
• Common complications
• primary graft dysfunction
• acute and chronic forms of allograft rejection
• Cytomegaloviral and other infections
• Cancer
• IPF does not recur in the allograft
26 Feb, 2020 98

98. Take Home Message
• High index of suspicion and early diagnosis impacts prognosis
• Multi Dimensional diagnosis is gold standard
• Immunosuppressants and Anti-oxidants are not recommended in IPF
• The acceleration observed last years in the research in the field of IPF
pathogenesis led to a better understanding of the cellular and molecular
mechanisms involved
• This has resulted in the approval of two new antifibrotic drugs for IPF
patients that halt disease progression.
• There is a significant increase in the number of clinical trials exploring new
molecules which may provide new therapeutic approached in IPF
• Anti-Fibrotic agents have proven safety and efficacy in IPF.
• Early initiation of Pulmonary Rehab and timely referral to Lung transplant.
26 Feb, 2020 99

99. 26 Feb, 2020 100
Thank you.!
the
Struggle
you’re in
today
is the developing
Strength
you need for
tomorrow

100.  HRCT findings in ILD
26 Feb, 2020 101

101. Hypersensitivity Pneumonitis
26 Feb, 2020 102Fishman’s Pulmonary Diseases and Disorders, 5th ed. p840
 HRCT Lung:
Head cheese sign

102. Organising Pneumonia
26 Feb, 2020 103Fishman’s Pulmonary Diseases and Disorders, 5th ed. p878
 HRCT: Multifocal, peripheral
areas of consolidation

103. Respiratory Bronchiolitis
26 Feb, 2020 104
High-resolution CT images through the upper (A) and mid (B) thorax show diffuse,
centrilobular ground-glass nodules (arrows).

104. Lymphocytic Interstitial Pneumonia
26 Feb, 2020 105
Axial CT images through the upper (A) and mid (B) thorax show multiple thin-walled
cysts of varying sizes bilaterally involving the upper and lower lobes. Note the
presence of normal lung parenchyma between the cysts

105. Hypersensitivity Pneumonitis
26 Feb, 2020 106
 40 year old male patient with
exposure to both birds and shells
who presented with progressive
dyspnea and weight loss and had
hypoxemia and a restrictive
ventilatory defect.
 Note the diffuse nodular
radiodensities in the lower lobes,
with areas of ground-glass
densities posteriorly.