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ILDs for CMTs
1. Interstitial Lung Diseases
for CMTs
Dr Laura-Jane Smith
Respiratory Registrar, Whittington Hospital
Honorary Clinical Lecturer in Medical Education, UCL
@drlaurajane
http://www.slideshare.net/_elljay_
June 2015
2. Objectives
• Describe what ILDs are
• Explain the basis of the classification of ILDs
• List the steps in diagnosis of ILDs
• Update evidence for treatment of IPF
• List the specific features of some interesting
ILDs
9. Dear colleague,
I’d be grateful if you would see this 76 year
old actor who has a 7 month history of
breathlessness and cough.
Heart sounds are normal and he has no
peripheral oedema. Chest expansion equal.
There are bibasal crackles. Sats 95% on air.
PMH: HTN
Meds: amlodipine 5mg OD
Lives with husband. Smokes occasional
cigar but no cigarettes.
Best wishes,
Dr GP
12. Interstitial lung diseases
Sarcoidosis
Idiopathic
(IPF)
Associated
with
connective
tissue
disease
Radiotherapy
Drugs Post-ARDS
Pulmonary fibrosis Hypersensitivity
pneumonitis Rare / infiltrations
RB-ILD
Eosinophilic
pneumonias
Organising
pneumonia
LAM
Histiocytosis X
Pneumoconiosis
Alveolar
proteinosis
ILD: classification
60% ILDs
LIP
10-20% ILDs
Usually UIP Usually NSIP
Asbestosis
End stage of many ILDs is fibrosis
5-15% RTX pts
within 1-3/12,
progresses over
6-12/12
Lymphangitis
carcinomatosis
Other
Eosinophilic
pneumonias
Chronic
aspiration
Organising
pneumonia
LAM
Histiocytosis X
amyloid
Alveolar
proteinosis
DIP
13. Idiopathic Pulmonary Fibrosis
• Incidence 14-43/100000 worldwide
• 2000 new cases/yr in UK
• Median age of presentation 70yrs
• Progressive breathlessness over months-yrs
• Dry cough
• Finger clubbing 15-20%
• Fine, late inspiratory ‘Velcro’ crackles
14. Idiopathic Pulmonary Fibrosis
Activation of coagulation
Adapted from: Camelo, Ana, et al. "The
epithelium in idiopathic pulmonary
fibrosis: breaking the barrier." Frontiers
in pharmacology 4 (2013).
15. Investigations
Bloods: exclude specific causes
Lung function tests: restrictive defect, small lung
volumes, reduced transfer factor
Imaging: thickened interlobular septa, ground glass
infiltration, and honeycombing in a sub-pleural and
basal distribution
Bronchoscopy: BAL/EBUS helps exclude other
diagnoses and infection
Lung biopsy: Surgical/VATS biopsy is considered only
if the diagnosis is unclear and will change
management
17. Prognosis
• Insidious disease progression
– Rate of decline in FVC ~150-200mL/yr
– Periods of acute deterioration, unpredictable
• Prognosis very poor
– Most die within 5-10 years
– 20-30% alive at 5 years after diagnosis
20. Treatment
• 1999 ATS/ERS statement recommended ‘standard
therapy’ for IPF based on expert opinion and several
small cohort studies – Azathioprine and Prednisolone
• IFIGENIA – Idiopathic Pulmonary Fibrosis
International Group exploring N-acetylcysteine I
Annual
– 3 Drug Regimen (PAN) preserved Pulmonary
Function > 2 Drug Regimen (PN)
N Engl J Med 2005;353:2229-42.
21. Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary
Fibrosis. (2012). New England Journal of Medicine, 366(21), 1968–
1977. doi:10.1056/NEJMoa1113354
22. RCT of NAC
Martinez, Fernando J., et al. "Randomized Trial of N-acetylcysteine in Idiopathic Pulmonary
Fibrosis." The New England journal of medicine 370.22 (2014): 2093.
23. Recent trials
• The ASCEND trial: A Phase 3 Trial of Pirfenidone in Patients with
Idiopathic Pulmonary Fibrosis; N Engl J Med 2014;370:2083-92.
– Oral Anti-fibrotic Therapy
– Reduced Disease Progression (Lung Function, Exercise
Tolerance, Progression Free Survival)
– Fewer Deaths
• Efficacy & Safety of Nintedanib in Idiopathic Pulmonary Fibrosis; N
Engl J Med 2014;370:2071-82.
– Intracellular Inhibitor of Multiple Tyrosine Kinases
– Reduced Decline in FVC – Slowing of Disease Progression
– Associated with Diarrhoea, < 5% Drop Out
24. From: Adamali, Huzaifa I., and Toby M. Maher. "Current and
novel drug therapies for idiopathic pulmonary fibrosis." Drug
design, development and therapy 6 (2012): 261.
39. Key points
• Interstitial lung diseases are a heterogenous
group of diseases featuring non-infective
infiltrations of the interstitium and alveoli
• Patients present with breathlessness and cough
• Patients have a restrictive deficit on spirometry
and reduced transfer factor
• Some patterns on HRCT are characteristic
• The key to diagnosis is clinical, radiological and
histological correlation
• IPF is a distinct disease which is incurable and
often has a poor prognosis, but new treatments
are emerging
Heterogeneous group of non-neoplastic disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis.
The interstitium includes the space between the epithelial and endothelial basement membranes and it is the primary site of injury in the IIPs.
Frequently affect not only the interstitium, but also the airspaces, peripheral airways, and vessels along with their respective epithelial and endothelial linings.
Over last 7 months has found it difficult to keep up with friends when walking on holiday in Capri/New Zealand. His breathlessness has slowly worsened. He now finds himself breathless after climbing 1 flight of stairs. He walks slowly on level ground which is frustrating when he is with his younger husband. He is not breathless at rest or lying flat. He sometimes coughs but does not produce sputum. No swelling of legs. No malaise, weight loss, fevers. No rashes, skin thickening or muscle or joint pain. Takes amlodipine for HTN but no other medications. No history of rheumatological diseases or cancer. He works as an actor and is not aware of any exposure to asbestos or other dusts/chemicals. He does not keep pigeons or other birds.
He is not breathless at rest. He has finger clubbing, but his joints are normal. He has no rashes or peripheral oedema. JVP is not raised. Heart sounds are normal. Trachea is central. Lung expansion is equal but slightly reduced, and percussion note is normal. On auscultation there are bibasal fine inspiratory crepitations. Oxygen saturations are 95% on air, but fall to 91% after walking 50m.
CXR and CT Chest
Other investigations:
ECHO: mild LVH, otherwise normal
Bloods normal including CK, ESR, CRP normal. RF and ANA negative.
Connective tissue disease: 80% have RA, 14% systemic sclerosis, 6% other diseases eg dermatomyositis.
Pneumoconioses and sarcoidosis also lead to fibrosis
All 4 major and 3 minor criteria required.
Task 2: treatment options – brainstorm in groups
PANTHER-IPF recruited patients with mild-moderate impairment in pulmonary function and randomly assigned to:
3 drug regime (PAN)
NAC alone
Matched placebos for pred & NAC or matched for each of the active therapies
Increased mortality and trial forced to be abandoned in 2011
Increased rate of death in combination-therapy group (8 vs 1, p=0.01) & hospitalisation (23 vs 7, p<0.001)
No Evidence of Physiological Benefit
Terminated
New drugs on the horizon??
You may get patietns with ILDs in PACES. What should you expect? How do they mark?
Physical signs may include; cyanosis, on oxygen, finger clubbing, tachypnoea, reduced chest expansion, fine late inspiratory crepitations bilaterally.
Look for complication of cor pulonale.
Look for asociated conditions eg RA, scleroderma
Died June 2015
Connective tissue disease: 80% have RA, 14% systemic sclerosis, 6% other diseases eg dermatomyositis.
Pneumoconioses and sarcoidosis also lead to fibrosis
Task 3: name some drugs which cause pulmonary fibrosis
Type 4 hypersensitivity reaction to multiple exposures to antigen
Pulmonary fibrosis, predominantly upper lobes
CD4+ helper T cells recognize antigen in a complex with Class II major histocompatibility complex. The antigen-presenting cells in this case are macrophages that secrete IL-12, which stimulates the proliferation of further CD4+ Th1 cells. CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Th1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.