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BEST OF ILD: EARLY DIAGNOSIS, BIOMARKERS, TREATMENTS AND DELIVERY
1. Dr. Raja Dhar
• Director and Head of Dept, Pulmonology, C K group of Hospitals, Kolkata.
• Director Research and Education, National Allergy Asthma Bronchitis Institute, Kolkata.
• Chair- Training and Education Initiatives, Indian Chest Society
• Director, HERMES exams Asia (European Diploma in Respiratory Medicine)
• Director, Asia Pacific Alliance for Control of Influenza (APACI)
• Lead author for EMBARC India. 128 Publications in indexed journals and Abstracts in
International Conferences
• Associate Editor for Respirology and on Editorial Board for multiple other journals
• Dronocharya Award for Excellence in Continuing Medical Education in India (IHW),
Indira Gandhi Gold Medal for Outstanding Individual achievement in Medicine (GEPRA)
2. .
Raja Dhar
MD, MRCP (UK), MSc (EBM, UK), CCT (UK), FCCP (US)
Director and Head of Department, Deptt of Pulmonology
CK Birla Hospitals
Director, Education and Research
NAABI Kolkata
BEST OF: INTERSTITIAL LUNG DISEASE
3. BEST OF ILD
• Literature search from Jan 2019- May 2022
• 4 areas identified. 322 relevant papers on PubMed. Shortlisted 62
papers which are relevant to areas discussed. Some discussed in
detail. Some are a mere mention.
• Early Diagnosis and Screening, Biomarkers in ILD, Treatment of
Fibrotic Interstitial Lung disease- present and future, alternative route
of drug administration
4. Screening: Reality or a pipe-dream?
EARLY DIAGNOSIS OF FIBROTIC INTERSTITIAL LUNG
DISEASE: CHALLENGES AND OPPORTUNITIES
5. Cosgrove GP et al. BMC Pulm Med 2018;18:9
BACKGROUND
• Diagnostic delay is a common problem in patients with
fibrotic ILD (including IPF)
• Many patients are misdiagnosed and given ineffective
treatments
• A timely diagnosis reduces unnecessary investigations and
may improve outcomes
6. Lamas DJ et al. Am J Respir Crit Care Med 2011;184:842-7
WHAT ARE THE EFFECTS OF DIAGNOSTIC DELAY?
7. Spagnolo P et, Lancet Respir Med 2021. Published Online July 28, 2021 https://doi.org/10.1016/ S2213-2600(21)00017-5
WHY ARE PATIENTS WITH FIBROTIC ILD DIAGNOSED LATE?
• Insidious onset
• Non-specific symptoms
• Minimal symptom burden
• Scarce knowledge of fibrotic ILD among primary care
physicians and non-ILD experts
• Long waiting times at specialist centres
8. Greater awareness of clinical manifestations of
fibrotic ILD
Finger clubbing
Incidental identification of ILD on imaging
Interstitial lung abnormalities (ILA)
Thickett D et al. BMJ Open 2020;10:e034428
POTENTIAL SOLUTIONS TO DIAGNOSTIC DELAYS
• Greater awareness of clinical manifestations of fibrotic ILD
• Finger clubbing
• Incidental identification of ILD on imaging
• Interstitial lung abnormalities (ILA)
9. Eur Respir J 2021;40:519-21
“It is time that the stethoscope […] be also the (presently
only) genuine tool for an earlier diagnosis of IPF, the
prerequisite for earlier treatment, and maybe for
improvement of the long-term clinical outcome of this
dreadful disease.”
10. Sgalla G et al. BMC Pulm Med 2019;18:103
DIGITALLY RECORDED LUNG SOUNDS
11. DIGITALLY RECORDED LUNG SOUNDS
Sgalla G et al. BMC Pulm Med 2018;18:103
HRCT pattern Bilateral “Velcro-type” crackles
Unilateral “Velcro-type”
crackles
OR (CI 95%) p OR (CI 95%) p
FILD* 13.46 (5.71–29.182) < 0.001 0.58 (0.29–1.16) 0.12
Definite UIP 19.8 (5.28–74.25) < 0.001 0.49 (0.14–1.66) 0.25
Possible UIP 13.09 (4.87–35.2) < 0.001 0.55 (0.23–1.34) 0.19
Inconsistent with UIP 10.8 (3.85–32.85) < 0.001 0.75 (0.26–2) 0.53
12. Spagnolo P et, Lancet Respir Med 2021. Published Online July 28, 2021 https://doi.org/10.1016/ S2213-2600(21)00017-5
INCIDENTAL IDENTIFICATION OF ILD
13. Sverzellati N et al. Eur Respir J 2011;38:392-400
PREVALENCE OF ILD IN A LUNG CANCER SCREENING PROGRAM
14. Hatabu H et al. Lancet Respir Med 2020;8:726-37
INTERSTITIAL LUNG ABNORMALITIES
The term interstitial lung abnormalities (ILAs) refers to the presence of CT
findings compatible with ILD but without previous suspicion of ILD
When associated with respiratory signs, symptoms, or functional
impairment, ILAs are likely to represent mild ILD rather than subclinical
abnormalities
ILAs are often associated with respiratory symptoms, functional
impairment, risk of progression and increased all-cause mortality, hence
their clinical relevance
15. Spagnolo P et, Lancet Respir Med 2021. Published Online July 28, 2021 https://doi.org/10.1016/ S2213-2600(21)00017-5
INTERSTITIAL LUNG ABNORMALITIES
16. Hatabu H et al. Lancet Respir Med 2020;8:726-37
PREDISPOSING RISK FACTORS
Advanced age
Male sex
Tobacco smoke exposure
Occupational/environmental exposures
Carriage of the MUC5b rs35705950 mutant (T) allele
17. SCREENING FOR FIBROTIC ILD – WHO TO SCREEN
Familiar Interstitial Lung Disease
Connective tissue disease
Rheumatoid arthritis: male gender, older age, cigarette smoking, RF and anti-CCP positivity,
MUC5B genotype
Systemic sclerosis: anti-Scl70 antibodies
Polymyositis/dermatomyositis: anti-synthetase, anti-PM-Scl and anti-MDA-5 antibodies
Occupational exposure (i.e., metal and wood dusts and asbestos)
18. Spagnolo P et, Lancet Respir Med 2021. Published Online July 28, 2021
https://doi.org/10.1016/ S2213-2600(21)00017-5
SCREENING FOR
FIBROTIC ILD – HOW
TO SCREEN
19. Key Messages
• Early identification of individuals with fibrotic ILD poses a number of
challenges
• Many occupational/environmental exposures as well as a family
history of the disease are associated with increased risk of preclinical
and overt fibrotic ILD
• Screening programmes are currently realistic only in selected
populations at high risk of developing the disease
22. Jenkins et al Lancet Respir Med 2015
Matrix derived
markers
distinguish
progressive
from stable IPF
23. Jenkins et al Lancet Respir Med 2019
Patients with
rising matrix
neoepitopes have
increased risk of
mortality
24. Patients with rising C1M, C3M, C6M and CRPM have
increased risk of mortality
Organ et al Respir Res 2019
25. . MMP7
SpD CA19-9
CA-125
Maher et al Lancet Respir Med 2021
Disease versus Healthy Progression versus Stable
Rising levels and Mortality
Unbiased Proteomic Analysis Identified Four Candidate
Biomarkers for Assessment in IPF
27. Time (Days)
Survival
Fraction
A) CA-125 B) CA19-9
C) SP-D D) MMP-7
HR 2.54 P<0.001 HR 1.71 P=0.057
Rising Levels of CA-125 Predicts Increased Mortality
Maher et al Lancet Respir Med 2017
34. Jenkins et al ERS 2020
Nintedanib reduces CA-125 levels in the INMARK study
35. Summary
• CT remains the ‘gold standard’ diagnostic biomarker for
established disease but serum biomarkers may help in early
or complex cases.
• MMP7 either alone or in a panel of different biomarkers
adds granularity to baseline prognostic assessment.
• Nordic and epithelial biomarkers identify different disease
compartments and may be useful as endotypic biomarkers
• CA-125 is a standardised assay and may have value as a
theranostic biomarker.
36. Conclusion
• MMP7 and CA-125 are almost ready for ‘prime time’ use in
the management of IPF.
37. TREATMENT OF FIBROTIC INTERSTITIAL LUNG DISEASE:
CURRENT APPROACH AND FUTURE DIRECTIONS
49. A phase 3a study of Galectin 3 inhibition in IPF
• 24 patients in 3 dose groups
• 5 active, 3 placebo
• Doses: 0.3, 3 and 10 mg per day
• Primary endpoint: Safety
• Secondary endpoints: PK and Markers of efficacy
• Four centers in the UK (RBH Lead centre)
• Last Patient, Last Visit Nov 1, 2016
Day
0
Day
14
Examinations,
Including lung lavage
Examinations,
Including lung lavage
Daily inhalation of TD139
0.3-10 mg
Hirani N…….Maher TM presented at ATS 2017
Galectin-3
TD139
50. TD139 Induces
Profound Reduction
in Galectin-3 in
Alveolar
Macrophages
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-40000
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-10000
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Gal3 GM aa macs
***
Hirani N…….Maher TM presented ATS 2019
51. Some Plasma Inflammation Biomarkers Show
Trends to reduction
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YKL-40
Dose Group
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Hirani N…….Maher TM presented ATS 2017
53. Conclusions
• Early diagnosis of ILD is a must for better results. Screening might be a
reality in the not too distant future.
• Biomarkers would increasingly be used for prognostication and for
prediction of mortality. MMP 7 and CA 125 ready for ‘prime time’ use
• Drugs divided as immuno-modulatory and fibro-modulatory. Long
pipeline in both IPF and non IPF ILD
• Newer modalities of drug delivery mainly in patients with central
disease as opposed to peripheral/sub-pleural disease.
53
11/27/2022
Editor's Notes
148 subjects were enrolled: bilateral “Velcro-type” crackles predicted the presence of FILD at HRCT (OR 13.46, 95% CI 5.85–30.96, p < 0.001) and most strongly the UIP pattern (OR 19.8, 95% CI 5.28–74.25, p < 0.001).
The definition of ILAs is purely radiological and is based on the incidental identification of CT abnormality. Differentiation between ILAs and clinical and subclinical ILD must be on the basis of clinical evaluation.
The prevalence of ILAs in older individuals (>60 years) is 4-9% in smokers and 2-7% in non-smokers.
ILAs capture the entire continuum of ILD from early morphologic changes to clinically relevant disease.
The prevalence of hiatus hernia in ILA is similar to that of the general population and that the presence of hiatus hernia is not associated with an increased risk of ILA or ILA progression.
