1B restrictive lung disease Flashcards
What is a restrictive lung disease?
- Lung volumes are small
- Expansion of lung is restricted
What is lung expansion restricted by in restrictive lung disease?
- Intrinsic lung disease (alterations to lung parenchyma)
- Interstitial lung disease (ILD)
- Extrinsic disorders (compress lungs or limit expansion)
- Pleural
- Chest wall
- Neuromuscular (decrease ability of respiratory muscles to inflate/delate the lungs)
What is the lung parenchyma?
The alveolar regions of the lung
What is the interstitial space?
Space between alveolar epithelium and capillary endothelium
What are the important cellular components of the lung parenchyma?
- Alveolar type 1 epithelial cell
- Alveolar type 2 epithelial cell
- Fibroblasts
- Alveolar macrophages
What do alveolar type 1 epithelial cells do?
Gas exchange surface (approx. 70m2)
What do alveolar type 2 epithelial cells do?
Surfactant to reduce surface tension, stem cell for repair
What do fibroblasts in the lung parenchyma do?
Produce extracellular matrix (ECM) e.g. collagen type 1
What do alveolar macrophages do?
Phagocytose foreign material, surfactant
What are the functions of the interstitial space?
- Contains lymphatic vessels, occasional fibroblasts and ECM
- Structural support to lung
- very thin (few micrometres thick) to facilitate gas exchange
Which immune cells are closely associated with the lung epithelium?
Macrophages
What are interstitial lung diseases?
Inflammation or fibrosis in the interstitial space
What subsets of ILDs are there?
- Idiopathic
- Autoimmune
- Exposure related
- With cysts or airspace filling
- Sarcoidosis
- Others
What are the clinical presentations of ILD?
- Progressive breathlessness
- Non-productive cough
- Limitation in exercise tolerance
- Symptoms of CTD
- Occupational and exposure history
- Medication history (drug induced?)
- Family history (up to 20% are familial)
What clinical examination findings are there for ILD?
- Low O2 sats (resting or exertion)
- Fine bilateral inspiratory crackles
- Digital clubbing
+/- features of connective tissue disease- skin, joints, muscles
What investigations are done for ILD?
- Blood tests (e.g. ANA, RhF, CCP)
- Pulmonary function tests
- 6-minute walk test (6MWT)
- SpO2 ≤ 88% associated with increased risk of death
- High-resolution CT scan (HRCT)
- Invasive testing:
- Bronchoalveolar lavage (BAL)
- Surgical lung biopsy (2-4% mortality)
Describe the physiology of ILD in the lungs
- Scarring makes the lung stiff so ↓ lung compliance
- ↓ Lung volumes (TLC, FRC, RV)
- ↓ FVC
- ↓ diffusing capacity of lung for carbon monoxide (DLCO)
- ↓ arterial PO2 – particularly with exercise
- Normal or ↑ FEV1/ FVC ratio
Describe the pattern of forced expiration
FEV1/FVC ratio = 100% → normally 100- a restrictive ratio doesn’t always mean disease, since small sporty people with large airways and little lungs can empty their lungs quickly
What is HRCT?
High-resolution CT: essential for ILD diagnosis
- thin slices and high-frequency reconstruction – gives good resolution at level of secondary pulmonary lobule (smallest functional lung unit identifiable on CT)
What does this HRCT pattern show?
Usual interstitial pneumonia
What does this HRCT pattern show?
Non-specific interstitial pneumonia
What does this HRCT pattern show?
Organising pneumonia
Why is MDT diagnosis important in ILD?
Integration of clinical, radiological +/- pathological information to make a diagnosis
How is early ILD managed?
- Pharmacological therapy
- immunosuppressive drugs, antifibrotics
- Clinical trials
- Patient education
- Vaccination
- Smoking cessation
- Treatment of co-morbidities (GORD, obstructive sleep apnoea, pulmonary HTN)
- Pulmonary rehab
How is late ILD managed?
- Supplemental oxygen
- Lung transplantation
- Palliative care (symptom management, end-of-life care)
What are some key examples of ILD?
- Idiopathic pulmonary fibrosis
- Hypersensitivity pneumonitis (HP)
- Systemic sclerosis (SSc); associated ILD
What is idiopathic pulmonary fibrosis (IPF)?
- Progressive, scarring lung disease of unknown cause
- 6,000 new cases diagnosed each year
- 1% of all deaths in UK
- Incidence increases with age - most >60yrs
- More common in men
- Average decline in forced vital capacity (FVC) = 150 – 200mls / year
What is AE-IPF?
Acute exacerbations of IPF
- Occur in 5-15% of patients
- Median survival 3-4 months
- In-hospital mortality ~50%
What is the prognosis like for IPF?
Poor
Median untreated survival is 3-5 years
What are the proposed mechanisms of IPF?
Predisposing factors:
- Genetic susceptibility
- MUC5B, DSP
- Environmental triggers
- Smoke, viruses, pollutants, dusts
- Cellular ageing
- Telomere attrition, senescence
How is IPF initiated?
Alveolar epithelial injury
- Denuded alveolar epithelium seen by electron microscopy1,2
- Targeted injury to AECIIs in mouse model – ↑ collagen deposition3
- Re-epithelialization disturbed in IPF4
Describe the histopathology of IPF
- honeycomb cyst
- fibroblastic
What are characteristic features of IPF on CT scan?
Why was there a change in the conventional treatment for IPF?
Immunosuppression is harmful in IPF
PANTHER-IPF trial
- Randomized, double-blind, placebo-controlled trial
- Combination treatment with prednisone + azathioprine +N-acetylcysteine –> increased risk of death and hospitalisation
- Led to a change in the conventional treatment for IPF
Give examples of antifibrotics and their effect on IPF
- Nintedanib (tyrosine kinase inhibitor)
- Pirfenidone (pyridine compound)
Antifibrotics slow disease progression in IPF but do not cure
What treatment for IPF is in clinical trials?
Drugs targeting fibrotic pathways
What is hypersensitivity pneumonitis (HP)?
- ILD caused by immune- mediated response in susceptible and sensitised individuals to inhaled environmental antigens
- Genetic and host factors may explain why only few exposed individuals get HP
- Involves small airways and parenchyma
How is HP classified?
-
Acute HP
- Intermittent, high-level exposure
- Abrupt symptom onset, flu-like syndrome 4-12 hours after exposure
-
Chronic HP
- Long-term, low-level exposure
- Nonfibrotic (purely inflammatory)
- Fibrotic (associated with high mortality)
What is the epidemiology of HP?
- Rare - incidence in UK ~ 1 per 100,0001
- Mean age onset 50 – 60 yrs
- M = F
- Less frequent in smokers
- Worldwide prevalence varies due to differences in antigen exposure, agricultural, industrial practices etc.
- 3- fold ↑ risk of death compared to general population1
What is HP driven by?
Immunological dysregulation
- Antigen exposure and processing by the innate immune system
- Inflammatory response mediated by T-helper cells and antigen-specific immunoglobulin (Ig) G antibodies
- Accumulation of lymphocytes and formation of granulomas
What are some environmental antigens for HP?
- African Grey Parrots (exposure to droppings)
- (Mouldy) Hay
What is the diagnosis of HP like?
- Detailed exposure history – antigen not identified in ~50%1
- Inspiratory ‘squeaks’ on auscultation - caused by the coexisting bronchiolitis
- Specific circulating IgG antibodies (serum precipitins) to potential antigens
- HRCT
- Bronchoalveolar lavage (BAL) lymphocyte count >30%2
What is the treatment for HP?
- Complete antigen removal/avoidance is crucial
- Corticosteroids often used
- Immunosuppressants e.g. mycophenolate mofetil (MMF) and azathioprine used but poor evidence base
- Progressive, fibrotic HP – Nintedanib (antifibrotic)1
What is systemic sclerosis associated (SSc) ILD?
Autoimmune connective tissue disease characterised by immune dysregulation and progressive fibrosis that affects skin, with variable internal organ involvement
- Slow indolent course vs. rapid progression
What is the epidemiology of SSc ILD?
- Rare: 10-50 cases per 1mill per year
- Affects young, middle-aged women
- Develops in 30-40% and is most common cause of death- 10year mortality of 40%
- Male, older age, smoker, >20% extent on HRCT, FVC <70% –> worse survival
What are the clinical features of SSC?
How are SSc clinical features classified?
Based on skin involvement
- Limited cutaneous SSc (pulmonary HTN more common)
- Diffuse cutaneous SSc (ILD more common)
What autoantibodies are in SSc?
- Anti-centromere
- Anti-Scl-70: associated with increased with ILD
Describe the pathogenesis of SSc-ILD
What are HRCT patterns in SSc-ILD?
Non-specific interstitial pneumonia (NSIP) pattern is the most common pattern
What is the management of SSc-ILD?
- Determined by disease extent on HRCT and lung function trajectory (monitor every 3 – 6 months)
- Corticosteroid use is controversial and risk of renal crisis with high doses (>10mg/day)
- Immunosuppressives – cyclophosphamide, mycophenolate mofetil (MMF)1
- Progressive fibrotic phenotype– Nintedanib (antifibrotic)2
