5.16 - Restrictive lung diseases Flashcards
What are lung volumes like in restrictive lung disease?
Lung volumes are small - expansion is restricted
What are the two types of restrictive lung disease?
- intrinsic lung disease - alterations to lung parenchyma e.g. interstitial lung disease (ILD)
- extrinsic disorders - compress lungs or limit expansion
What are the different structures that can cause extrinsic disorders? (3)
- pleural
- chest wall
- neuromuscular (decrease ability of respiratory muscles to inflate/deflate the lungs)
What is the lung parenchyma?
The alveolar regions of the lung
What are the important cellular components of the lung parenchyma? (4)
- alveolar type 1 epithelial cell
- alveolar type 2 epithelial cell
- fibroblasts
- alveolar macrophages
What is the function of alveolar type 1 cells?
Gas exchange surface (approx. 70cm2)
What is the function of alveolar type 2 cells? (2)
Surfactant to reduce surface tension, stem cells for repair
What is the function of fibroblasts?
Produce extracellular matrix (ECM) e.g. collagen type 1
What is the function of alveolar macrophages? (2)
Phagocytose foreign material, surfactant
What is the interstitial space?
- space between alveolar epithelium and capillary epithelium
- contains lymphatic vessels, occasional fibroblasts and ECM
- structural support to lung
- very thin (few micrometres thick) to facilitate gas exchange
What are alveolar macrophages closely associated with?
The lung epithelium
What is found in interstitial lung diseases?
Inflammation or fibrosis in the interstitial space (ILD = umbrella term for disorders causing fibrosis and scarring of lungs, over 200 ILDs recognised)
What can we use to classify interstitial lung disease?
ATS/ERS International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias (2002, 2013)
How can interstitial lung disease be classified? (6)
- idiopathic - IPF (idiopathic pulmonary fibrosis), NSIP, DIP
- autoimmune-related - CTD associated (connective tissue disease associated) e.g. RA-ILD, SSc-ILD
- exposure related - hypersensitivity pneumonitis (HP), drug-induced
- with cysts or airspace filling
- sarcoidosis
- others - eosinophilic pneumonia etc
What kinds of interstitial lung disease (ILD) have better/worse prognoses?
- DIP/RBILD/cellular NSIP - 100% survival
- fibrotic NSIP ~ 30% survival
- UIP (usual interstitial pneumonia) - almost 0% survival, bad prognosis
How does interstitial lung disease present? (4)
- progressive breathlessness
- non-productive cough (dry)
- limitation in exercise tolerance
- symptoms of connective tissue disease
What do you ask about when taking a history for interstitial lung disease? (3)
- occupational and exposure history
- medication history (drug-induced ILD)
- family history (up to 20% idiopathic ILDs are familial)
What would you find on clinical examination of someone with interstitial lung disease? (4)
- low oxygen saturations (resting or exertion)
- fine bilateral inspiratory crackles
- digital clubbing
- +/- features of connective tissue disease - skin, joints, muscle
What investigations can be done to diagnose ILD? (5)
- blood tests e.g. anti-nuclear antibody (ANA), rheumatoid factor (RF), anti-citrullinated protein (CCP)
- pulmonary function tests
- 6-minute walk test (6MWT) - SpO2<88% associated with increased risk of death
- high-resolution CT scan (HRCT) - essential to diagnosis
- invasive testing: bronchoalveolar lavage (BAL), surgical lung biopsy (2-4% mortality)
What is the pathophysiology of interstitial lung disease (ILD)?
- scarring makes the lung stiff and reduces lung compliance
- reduced lung volumes (TLC, FRC, RV)
- reduced FVC
- reduced diffusing capacity of lung for carbon monoxide (DLCO)
- reduced arterial pO2 - particularly with exercise
- normal or increased FEV1/FVC ratio
What is essential for ILD diagnosis?
High-resolution CT (HRCT)
How does HRCT work?
- CT uses X-rays to obtain cross-sectional images
- rotating X-ray source and detectors spin around the patient gathering data
- HRCT - thin slices and high-frequency reconstruction - gives good resolution at level of secondary pulmonary lobule (smallest functioning lung unit identifiable on CT)
How do high and low density substances differ in X-rays?
- high-density substances e.g. bone absorb more X-rays and appear whiter
- low-density substances e.g. air absorb few X-rays and appear darker
What three planes are images viewed in?
- axial (perpendicular to long axis of body)
- coronal (parallel to long axis of body)
- sagittal
What HRCT pattern is seen in usual interstitial pneumonia (UIP)?
Honeycomb changes - bottom and edges of lungs (found in IPF etc)
What HRCT pattern is seen in organising pneumonia?
Ground-glass change and areas of inflammation
Why is multidisciplinary diagnosis important in ILD?
Integration of clinical, radiological +/- pathological information is needed to make a diagnosis
Which members of the MDT are involved in diagnosis and managing ILD? (7)
- physiotherapist and occupational therapist
- clinical nurse specialist
- radiologist
- pulmonologist
- respiratory physiologist
- pathologist
- rheumatologist
How is ILD managed in early stages? (7)
- pharmacological therapy - immunosuppressive drugs, antifibrotics
- clinical trials
- patient education
- vaccination
- smoking cessation
- treatment of comorbidities - gastroesophageal reflux, obstructive sleep apnoea, pulmonary hypertension
- pulmonary rehabilitation
How is ILD managed in late/end stages? (3)
- supplemental oxygen
- lung transplantation
- palliative care - symptom management, end-of-life care
What is idiopathic pulmonary fibrosis? (IPF)
- progressive, scarring lung disease of unknown cause
- average decline in forced vital capacity (FVC) = 150-200mls per year
What is the epidemiology of idiopathic pulmonary fibrosis like?
- 6000 new cases diagnosed each year
- 1% of all deaths in the UK
- incidence increases with age - most >60 years
- more common in men
What is the clinical trajectory like in IPF like?
- variable clinical trajectory - not everyone affected in the same way
- differences in sub-clinical period, pre-diagnosis period and post-diagnosis period
- differences in onset of disease, onset of symptoms, diagnosis and death
What are acute exacerbations of IPF?
- occur in 5-15% of patients
- median survival 3-4 months
- in-hospital mortality ~50%
What kind of prognosis is IPF associated with?
IPF associated with a poor prognosis - median untreated survival 3-5 years
What are the proposed predisposing factors for IPF? (3)
- genetic susceptibility - MUC5B, DSP
- environmental triggers - smoke, viruses, pollutants, dusts
- cellular ageing - telomere attrition (short telomeres), senescence
What is the proposed mechanism of IPF?
- injury
- alveolar epithelial cell dysfunction
- profibrotic macrophages
- aberrant fibroblast activity
- excess accumulation of ECM –> thickens interstitium and makes it harder to get air in and out of alveoli
- alveolar remodelling and honeycomb cyst formation (reduced gas exchange)
What is IPF initiated by?
- alveolar epithelial injury
- denuded alveolar epithelium seen by electron microscopy
- targeted injury to AECIIs (alveolar epithelial type 2 cells) in mouse model - increased collagen deposition
- re-epithelialisation disturbed in IPF
What is the histopathology of IPF like?
- usual interstitial pneumonia (UIP) pattern
- microscopic honeycomb cyst
- fibroblastic foci = proliferating fibroblasts/myofibroblasts - active disease
- spatial and temporal heterogeneity
What are the characteristic features of IPF on a CT scan?
- subpleural honeycombing (at edges)
- traction bronchiectasis (widened bronchi due to pulling by damaged lungs)
- basal predominance
- textbook finding on CT: bilateral interstitial shadowing (typically small, irregular, peripheral opacities - ground-glass, later progressing to honeycombing)
Is immunosuppression used for IPF?
Immunosuppression is harmful in IPF
What did the PANTHER-IPF trial show with regard to immunosuppression?
- immunosuppression is harmful in IPF
- randomised, double-blind, placebo-controlled trial
- combination treatment with prednisolone + azathioprine + N-acetylcysteine –> increased risk of death and hospitalisation
- led to a change in the conventional treatment for IPF
How can antifibrotics be used in IPF?
Antifibrotics slow disease progression in IPF but do not cure
Nintedanib: tyrosine kinase inhibitor
Pirfenidone: pyridine compound
How can clinical trials be used to treat IPF?
Different clinical trials/drugs target different parts of the fibrotic pathways - alveolar space, epithelium, mesenchyme, endothelium, vascular space
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 can hypersensitivity pneumonitis (HP) be classified?
- acute HP: intermittent, high-level exposure
- abrupt symptom onset, flu-like syndrome 4-12h after exposure
- chronic HP: long-term, low-level exposure
- nonfibrotic - purely inflammatory
- fibrotic - associated with higher mortality
What is an example of acute HP? (4)
- going on holiday and contacting animal faeces
- rat faeces
- bird droppings
- hot tubs/metals/foods
What is the epidemiology of hypersensitivity pneumonitis (HP)? (6)
- rare: incidence in UK ~1 per 100k
- mean age onset 50-60 years
- M = F
- less frequent in smokers
- worldwide prevalence varies due to differences in antigen exposure, agricultural, industrial practices etc
- 3-fold increased risk of death compared to general population
What is hypersensitivity pneumonitis driven by?
- 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 triggers hypersensitivity pneumonitis?
Environmental allergens: bacteria, mycobacteria, fungi, animal proteins, plant proteins, enzymes, chemicals, metals
How do you do a diagnostic work-up of hypersensitivity pneumonitis? (5)
- detailed exposure history - antigen not identified in ~50%
- inspiratory ‘squeaks’ on auscultation - caused by coexisting bronchiolitis
- specific circulating IgG antibodies (serum precipitins) to potential antigens
- HRCT (ground-glass changes, air-trapping)
- bronchoalveolar lavage (BAL) lymphocyte count >30%
What HRCT changes are seen in hypersensitivity pneumonitis? (5)
- centrilobular ground-glass nodule (bronchiolocentric inflammation)
- air-trapping (narrowing of small airways)
- ground glass (interstitial inflammation)
- mosaic attenuation pattern
- three-density pattern
How is hypersensitivity pneumonitis treated? (4)
- complete antigen removal/avoidance is crucial
- corticosteroids often used
- immunosuppressants e.g. mycophenolate mofetil (MML) and azathioprine used but poor evidence base
- progressive, fibrotic HP - Nintedanib (antifibrotic)
What is systemic sclerosis associated (SSc) ILD?
SSc is an autoimmune connective tissue disease characterised by immune dysregulation and progressive fibrosis that affects skin, with variable internal organ involvement
What is the epidemiology of systemic sclerosis associated ILD like?
- rare: 10-50 cases per 1million per year
- affects young, middle-aged women
- ILD develops in 30-40% and is most common cause of death - 10-year mortality of 40%
- slow indolent course vs rapid progression
What factors can worsen survival in SSc-associated ILD? (5)
- male
- older age
- smoker
- > 20% extent on HRCT
- FVC<70%
What are the clinical features of systemic sclerosis (SSc)? (5)
- sclerodactyly
- Raynaud’s
- telangiectasias
- abnormal nailfold capillaroscopy
- digital ulcer
What is CREST syndrome (SSc)?
- Calcinosis (white calcium deposits in skin)
- Raynaud’s phenomenon (spasm of blood vessels in response to cold/stress)
- Esophageal dysfunction (acid reflux and decreased oesophagus motility)
- Sclerodactyly (thickening and tightening of the skin on the fingers and hands)
- Telangiectasias (dilation of capillaries causing red marks on surfaces of skin)
How can SSc be classified based on skin involvement? (2)
- limited cutaneous SSc - pulmonary hypertension more common
- diffuse cutaneous SSc - ILD more common
High levels of what antibodies can indicate SSc? (2)
- anti-centromere (limited cutaneous)
- anti-Scl-70 (diffuse cutaneous, associated with increased ILD)
What is the pathogenesis of SSc-ILD?
- tissue injury, vascular injury and autoimmunity trigger fibrosis
- fibrosis: fibrocytes recruited and resident fibroblasts activated, myofibroblasts express alphaSMA and produce collagen –> ECM deposition
- this triggers inflammation (Treg, Th17, Th2 –> IL4, IL5, IL13)
What can trigger tissue injury in SSc-ILD? (4)
- genetic predisposition
- gastro-oesophageal reflux
- oxidative stress
- environmental stimuli:
- organic solvents
- silica
- viruses
What can trigger vascular injury in SSc-ILD? (3)
- endothelial cell injury
- tissue hypoxia
- ineffective angiogenesis
What are HRCT patterns in SSc-ILD?
Non-specific interstitial pneumonia (NSIP) pattern is the most common pattern (can also get UIP pattern)
How is SSc-ILD managed?
- 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)
- progressive fibrotic phenotype - Nintedanib (antifibrotic)
Summary slide on restrictive lung disease.
- interstitial lung disease (ILD) is an important cause of restrictive lung disease
- characterised by inflammation or fibrosis in the interstitium which causes impaired gas exchange
- pathogenesis, disease trajectory and treatment varies according to type of ILD
- most common type is IPF which is associated with poor prognosis
- other causes of restrictive lung disease include extrinsic disorders which compress lungs or limit expansion
- diseases of pleura, chest wall and neuromuscular disease
