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INTERSTITIAL LUNG DISEASE
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1 Introduction
Synonyms: interstitial lung disease, diffuse parenchymal lung disease.
1.1
Description
Interstitial lung disorders (ILD) encompass a diverse range of diseases affecting
the gas exchanging regions of the lung, which may progress to diffuse lung
fibrosis.[1][2]
Some of these present acutely, whereas others have a sub-acute or chronic
course.
The overall prevalence in the United Kingdom is 1 in 3,000 – 4,000, and ILDs
account for 3,000 deaths per year.[3]
Aetiology and individual prevalence are described under the separate conditions
below. Sarcoidosis is also a cause of interstitial lung fibrosis (see Tuberculosis
and Sarcoidosis Protocol).
1.2
Diagnosis
Common features of ILD are a history of progressive dyspnoea and a dry cough,
associated with a chest radiograph (CXR) that shows widespread pulmonary
shadows.
The presence of finger clubbing is a variable sign in ILD. It occurs in 70% of
patients with cryptogenic fibrosing alveolitis and the interstitial alveolitis
associated with rheumatoid arthritis; however, it is almost never seen in the
fibrosing alveolitis associated with systemic sclerosis and extrinsic allergic
alveolitis.[4]
On auscultation, dry, fine end-inspiratory, basal ‘velcro’ crackles are commonly
heard.
1.3
Investigations
1.3.1
Lung Function Tests
Spirometry: a restrictive defect reduced total lung capacity and forced vital
capacity (FVC), with normal FEV1/FVC ratio of greater than 70% (FEV1 = forced
expiratory volume in 1 second).
Blood gases: hypoxaemia and hypocapnia. Impaired gas diffusion (reduced
transfer factor
1a).
Serial measurements over a period of time are often needed to assess slightly
low values and recognise excessive longitudinal decline.
1a Transfer factor is normally measured by the carbon monoxide absorption rate per unit volume of ventilated lung - DLCO –
the gas transfer coefficient.
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1.3.2
Radiography
CXR: -
lung size; distribution; size and nature of nodular and reticular
abnormalities; the presence of pleural disease; hilar lymphadenopathy and
confluent shadows allow the experienced eye to differentiate the types of
interstitial lung disorders. This has largely been superseded by computed
tomography scans for diagnosis, but CXR and physiology are the mainstays of
follow up.
High-resolution computed tomography (HRCT) allows detailed evaluation of the
lung parenchyma by using 1 - 2mm thick slices with a reconstruction algorithm
that maximises spatial resolution. This allows earlier diagnosis and narrows the
diagnosis based on HRCT pattern.
1.3.3
Biopsy
Small samples of lung parenchyma can be obtained by transbronchial biopsy
with a flexible bronchoscope; however, because of the small sample size it
should not be used to assess the degree of fibrosis.[5]
Larger samples can be obtained under GA by either thoracotomy or video-
assisted thoracoscopy. Surgical lung biopsy is recommended in patients without
contraindications to surgery.
The histology is often diagnostic in the early stages, but in advanced disease
may show non-specific lung fibrosis with no clue to aetiology.
1.3.4
Bronchoalveolar Lavage (BAL)
Performed during bronchoscopy; yields fluid for cytology and biochemical
analysis.
1.4
Differential Diagnosis
Other causes of diffuse lung infiltrates such as pulmonary oedema,
bronchiectasis, and alveolar cell carcinoma are usually distinguishable with the
above investigations, which also help to differentiate the following conditions.
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2
Idiopathic Pulmonary Fibrosis
Synonym: - Cryptogenic Fibrosing Alveolitis (CFA).
2.1
Definition
Historically, Idiopathic Pulmonary Fibrosis (IPF) was a family of idiopathic
pneumonias, sharing the clinical features of dyspnoea, radiological diffuse
pulmonary infiltrates and various findings of inflammation, fibrosis or both on biopsy.
(Appendix A: Table 1)
A consensus statement, published in 2000,[5] now limits IPF to patients with a
specific histological finding on biopsy, that of ‘usual interstitial pneumonia’ (UIP).
However, as few patients in the UK undergo open lung biopsy,[6] the group will retain
its heterogeneity, making prognosis more difficult.
2.1.1
Aetiology of IPF
The cause of IPF is unknown, but it is probably an inflammatory and immune
response to lung damage in genetically predisposed individuals.[4] Reports have
described familial cases of IPF with an autosomal dominant pattern of
inheritance.[7] Some cases may be associated with previous exposure to dusts
(e.g. metal or wood), and about 30% have auto-antibodies such as rheumatoid
or anti-nuclear factor. Cigarette smoking may be an independent risk factor,
75% of cases of IPF are current or former smokers.[8] Latent viral infections have
also been implicated, but to date no candidate virus has been shown to cause
IPF.[8]
2.1.2
Prevalence of IPF
The precise prevalence of IPF is unknown but is estimated at between 3 - 6
cases per 100,000 in the general population[5] and it is slightly more common in
males than females.[8]
The incidence of IPF increases with age. Patients become symptomatic in the
fifth and sixth decade and approximately 2/3 of patients are over the age of 60 at
the time of diagnosis.[5] In the age group 35 - 44 years the prevalence is
2.7/100,000.[5]
2.2
Diagnosis
Insidious onset of non-productive cough and progressive dyspnoea.
Dyspnoea most prominent and disabling symptom.
Clubbing
in
70%.
Dry, end-inspiratory, ‘velcro’ basal crackles in 80%. With disease progression
these become pan-inspiratory and extend to the upper zones.
Cyanosis, cor pulmonale, an accentuated pulmonary second sound, right
ventricular heave and peripheral oedema may be observed in the late phases of
the disease.
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2.3
Investigation
2.3.1
Pulmonary Function Testing in IPF
Reduced total lung capacity (TLC), functional residual capacity (FRC) and
residual volume (RV).
Smokers and patients with superimposed COPD may have normal volumes
early in the disease.
Patients are tachypnoeic, taking rapid shallow breaths.
FEV1 and FVC are reduced. But FEV1/FVC ratio is normal or raised (> 70%).
The gas transfer factor DLCO is reduced because of a reduction in capillary
volumes as well as ventilation and perfusion abnormalities.
Formal cardiopulmonary exercise testing is more sensitive in the detection of
abnormalities of oxygen transfer. Exercise gas exchange is a sensitive
parameter to monitor the clinical course, but is not often performed in UK
practice.
2.3.2
CXR in IPF
Most have abnormal CXR at time of presentation and basal reticular shadowing
may be present for years before the development of symptoms. A normal CXR
does not exclude the histological finding of usual interstitial pneumonia (UIP) on
biopsy.
Peripheral reticular opacities at lung bases, with reduced lung volumes are
common findings. Patients with co-existing emphysema may have preserved or
increased lung volumes.
2.3.3
High Resolution Computed Tomography in IPF
Pattern in IPF of patchy, predominantly peripheral, sub-pleural, bibasal reticular
abnormalities.[5] A normal HRCT scan cannot exclude infiltrative disease. One
third of cases will be missed if HRCT scans alone are used for diagnosis.[5]
Patients with predominant reticular opacity or honeycombing usually progress
despite treatment.
The extent of lung fibrosis on HRCT is an important predictor of survival.[5]
2.3.4
Bronchoalveolar Lavage in IPF
Despite its value as a research tool, the diagnostic use of BAL in IPF is limited.[5]
2.3.5
Lung Biopsy
UIP is the histological pattern that identifies patients with IPF.[5] However, a
review of 200 patients in the UK showed that transbronchial or open lung
biopsies were performed in only 33% and 7.5% of patients respectively: the
diagnosis of IPF was made on clinical grounds in most cases.[6]
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2.4
Treatment
Conventional treatment options include corticosteroids, immunosuppressives
(e.g. azathioprine), cytotoxic agents (e.g. cyclophosphamide) and antifibrotic
agents (colchicines or d-penicillamine) either alone or in combination.
Given that there is no clinical evidence that treatment improves survival or
quality of life, (and that treatment is associated with risk of complications)
therapy may not be indicated for all patients.[5]
2.4.1
Corticosteroids
Used ubiquitously, but no randomised controlled trial data: 10-30% objective
improvement; 40% report subjective improvement.[3]
High doses used 40-100mg for 2-4 months and then dose reduced.
If improvement occurs, it happens in the first 3 months of treatment, and
responsive patients are maintained on corticosteroid therapy.
Relapses or deterioration whilst on steroids warrant escalation of dose or
addition of an immunosuppressive agent.
2.4.2
Cytotoxic Treatment (Azathioprine/Cyclophosphamide)
Used for steroid non-responders or those with side effects on steroids.[3][5]
Favourable responses in a few small treatment trials.
2.4.3
Lung Transplantation
Patients <55 years old, without complicating medical illnesses should be referred
early to regional transplantation centres.[8] Patients up to 65 years old may be
considered for transplantation.
2.5
Prognosis
IPF kills about 1500 people p.a. in the UK[3] and the mortality is increasing. The
highest rates of mortality in the UK occur in the industrialised central areas of
England and Wales. The mean length of survival from the time of diagnosis
varies between 3.2 and 5 years.[5
The cause of death is respiratory failure in 40%. In the majority death is
triggered by a complicating illness, mainly coronary artery disease and
infections. Bronchogenic carcinoma occurs in 10-15% of patients.
Spontaneous remissions do not occur.
Some patients follow an indolent course over many years, and these are thought
to represent other disorders misdiagnosed as IPF.[7]
Indicators of longer survival include: younger age at onset (< 50), female sex,
beneficial response or stable disease 3 - 6 months after initial corticosteroid
treatment.[5]
Following lung transplantation a 5-year survival rate of 50 - 60% is quoted.[5]
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3
Connective Tissue Diseases
3.1
Description
In about 35% of cases the typical features of IPF occur as part of a connective
tissue disease, which often has various other lung complications.[9]
3.2
Rheumatoid Disease
Interstitial lung disease is clinically detected in less than 5% of patients with
rheumatoid arthritis, although studies have shown a much higher prevalence of
interstitial changes using HRCT scans.[10][11]
The natural history of interstitial lung disease in rheumatoid arthritis has not been
well studied, and there are no data on prognostic factors. The radiological
changes on HRCT scanning were more peripherally distributed in RA compared
to IPF.[12] Rheumatoid factor may prove to be protective against progressive
fibrosis. Drugs such as methotrexate, gold or penicillamine may cause lung
fibrosis.
3.3
Systemic Sclerosis (Scleroderma)
Progressive systemic sclerosis and the CREST variant: (
Calcinosis;
Raynaud’s
phenomenon; o
esophageal dysfunction/dysmotility;
Sclerodactyly; and
Telangiectasia) have interstitial lung involvement that is indistinguishable from
idiopathic fibrosing alveolitis.[13]
3.4
Systemic Lupus Erythematosus
Acute lupus pneumonitis occurs in only 0.9% of cases and generally develops
during a generalised flare of SLE with multi-system involvement. This presents
clinically as severe dyspnoea of recent onset, tachypnoea, fever, basal crackles
and hypoxaemia. CXR shows diffuse basal alveolar infiltrates and pleural
effusions. The mortality is high (50%) and survivors have evidence of a
restrictive ventilatory defect with hypoxaemia.[9][14]
Chronic diffuse interstitial lung disease. Symptomatic interstitial lung disease
has a prevalence of 3%. All patients present with dyspnoea and half have
pleuritic pain. Restrictive defects are present on pulmonary function testing and
diffusion capacity is reduced.[9][14]
Shrinking lungs syndrome (SLS) is characterised by unexplained dyspnoea,
small lung volume with restrictive physiology and an elevated diaphragm that is
thought to be due to a myopathy. Corticosteroids are the mainstay of treatment
with most patients returning to their previous pulmonary function.[15]
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3.5
Polymyositis and Dermatomyositis
Interstitial lung disease is detected in 5 - 40% of patients and may present
clinically as three types[16]:
1. Acute/sub-acute: with severe rapidly progressive dyspnoea and
hypoxaemia.
2. Chronic: with slowly progressive dyspnoea.
3. Asymptomatic.
The onset of respiratory symptoms may precede, coincide or follow the onset of
the myositis. Corticosteroids are the mainstay of treatment.
Immunosuppressant and cytotoxic agents are used second-line. The decision to
treat is usually based on clinical, (rather than radiological), activity.
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4
Extrinsic Allergic Alveolitis
Synonym: - hypersensitivity pneumonitis.
4.1
Description
Extrinsic allergic alveolitis (EAA) is an immunologically induced inflammatory lung
disease resulting from repeated inhalations of any one of a variety of causative
agents, including organic dusts and active chemicals. This response involves
antibody reactions, immune complex formation, complement activation and cellular
responses, causing inflammation of the lung parenchyma, alveolar walls and
terminal airways.[17]
4.1.1
Aetiology
Farmer’s and mushroom/malt/sewage-worker’s lung – inhalation of spores from
various fungi which grow in warm damp hay/straw/grain; vegetable/mushroom
compost; whisky maltings and sewage. Occupational exposure to cheese
mould, mouldy corks and sugar cane mould are also implicated in EAA.
Bird-fancier’s lung – inhalation of avian antigens by keepers of racing pigeons
and pet birds.
Rodent-handler’s lung – inhalation of rodent urinary protein.
Humidifier lung/ventilation pneumonitis – inhalation of bacteria/fungi/moebae/
nematode debris from water in air conditioners/humidifiers.
Pituitary snuff-taker’s lung – inhalation of cattle or pig pituitary extracts.
Plastic/laboratory workers and paint/vineyard-sprayers – inhalation of solvents,
isocyanates, fungicides and other chemicals.[17] Isocyanates cause occupational
asthma in the majority of cases, with hypersensitivity pneumonitis accounting for
1-4.7%.[18]
4.1.2
Prevalence
Estimated to contribute less than 1% to occupational lung disease.[19]
Approximately 50% of cases affect farm workers, and 15% affect workers in
material, metal or electrical processing trades.[17] Smokers are less likely to
develop all types of EAA.
In the UK bird-fancier’s lung is the most prevalent at present, since 12% of the
population keep birds and of these 0.5 to 7.5% will develop bird-fancier’s lung.
In areas of high rainfall, where ‘traditional’ farming methods are used, the
prevalence of farmer’s lung may reach 10%. However, where modern farming
methods are used, the prevalence is 2 - 3% or less and the farming population
represents only 1 - 2% of the total population.
In developed countries humidifier lung is being recognised with increasing
frequency, both at work and at home.
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4.2
Diagnosis
There is no diagnostic test that is pathognomonic for EAA. The clinical
presentation can be acute, sub-acute or chronic, as summarised in Table 2
(Appendix A).
EAA should be distinguished from the effects of toxins (e.g. paraquat) and dusts
(e.g. asbestos).
4.3
Treatment
The acute exacerbation of EAA may be treated with corticosteroids, which produces
a rapid clinical improvement. There is some debate as to whether this rapid
improvement increases the likelihood of further exposure, by decreasing antigen
avoidance.[20]
The mainstay is complete avoidance of exposure to the provoking antigen. Those
unable or unwilling to change their causative occupation can use industrial
respirators, which filter out 98% of respirable dust from the ambient air.[17]
Continuing exposure should be accompanied by surveillance (with regular CXRs
and lung function tests). When there is progressive disease exposure should cease.
4.4
Prognosis
If exposure to the antigen ceases: The risk of continuing symptoms on cessation of
the exposure increases with the duration of exposure. Following acute EAA,
continuing inflammation and membrane leakiness was found for 2 - 15 years, even
when patients were asymptomatic.
Continuation of antigen exposure: The risk of continued exposure is progressive
fibrosis; however this only occurs in a minority of affected subjects.[17] A follow-up
study of farmers with acute farmer’s lung showed that, whilst the majority continued
to live on farms, only 39% developed radiological changes of fibrosis and only 30%
developed an impairment of gas transfer.[21]
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5
Main Disabling Effects
The chronic interstitial lung disorders cause a restrictive pattern of ventilatory
impairment, which leads to an overall reduction in lung volume and impaired gas
diffusion across the alveolar-capillary membrane. As lung function deteriorates,
progressive dyspnoea will restrict exertional activities.
Corticosteroids are the mainstay of treatment in IPF and other forms of diffuse
lung disease. These are used at high doses and for long periods of time,
increasing the risk of side-effects, which may be disabling (Table 3).
Problems may occur with reduced atmospheric pressure. Commercial air travel
usually involves depressurisation to a cabin altitude of 6,000ft (1,830m). The
reduced partial pressure of oxygen has little effect on healthy travellers, but with
pulmonary disease may cause symptoms or subtle signs of hypoxia.
5.1
Assessing The Claimant
Clinical respiratory examination findings do not correlate well with functional
ability and the assessment is best made from the:
1. The History of Activities of Daily Living (Typical Day), taking variation into
account.
2. Informal Observation of the claimant’s activities at examination.
In the IB-PCA, the functional areas first affected are ‘walking up/down stairs’,
and ‘walking’. Other physical functional areas may be affected by the musculo-
skeletal side effects of high-dose steroid therapy, namely proximal myopathy
and osteoporotic fracture. Vision may be affected by the development of
cataracts and glaucoma. Mental health may also be affected by high-dose
steroid therapy and psychological side effects are more common with increasing
age.[5] Euphoria may cause patients to underestimate their level of disability.
Exemption from the IB-PCA should be considered if the limitation of effort
tolerance is severe and progressive, causing significant limitation of normal daily
activities that require more than minimal exertion (e.g. climbing stairs/washing/
dressing). Clinical examination in these cases may show clinical signs of cor
pulmonale.
5.2
Occupational and Legislative Issues
Assessment of fitness for work in the presence of chronic lung disease depends
essentially on whether the various elements of pulmonary function are adequate
and whether there is any restriction, through breathlessness, of capacity to
undertake the level of physical exertion required by the job in its particular
environment. Rarely, cough alone may be sufficiently distressing to the worker
(or fellow workers) to limit effective work capacity.
With mild degrees of impairment (e.g. FEV1 > 60% predicted) the results of lung
function tests correlate poorly with symptoms and the results of exercise tests.
However, most subjects with FEV1 in the range 40 - 60% of predicted have
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symptoms on strenuous exertion, and with FEV1 < 40% of predicted heavy
manual work becomes very difficult to sustain.[22]
The degree of impairment of lung function is only one of a number of factors that
determine work capacity, psychological factors such as motivation and mood are
also important.
Most occupational respiratory hazards are controlled by the Control of
Substances Hazardous to Health (COSHH) Regulations 1994 and/or the
management of Health and Safety at Work Regulations 1992.
These regulations place a duty on employers to assess whether the use of any
substance constitutes a risk to the health of employees. Where a risk of ill
health exists and medical tests can identify pathological change at an early
stage (when remedial action can be taken), such tests must be provided.
The risk must also be controlled by appropriate means, such as elimination of
the harmful agent, enclosure of the process, exhaust ventilation or the provision
of respiratory protection. Workers exposed to respiratory sensitisers giving a
risk of EAA should be subject to periodic assessment by questionnaire and
measurements of ventilatory function. EAA is a prescribed disease (B6) under
the Social Security Contributions and Benefits Act (1982), so affected workers in
the relevant occupations are eligible to claim Industrial Injuries Scheme Benefit
which, if awarded, is usually payable for life.
Most occupational causes of EAA are associated with the handling of mouldy
vegetable produce; drying vegetable material before storage could prevent most
cases.
5.3
Rehabilitation
Pulmonary rehabilitation programmes use a supportive environment in which to
restore muscle strength and endurance, maximise functional level and improve
quality of life.
Objective measures are necessary to assess functional improvement, such as
the 6-minute walking test or the shuttle walk test. It has been claimed that a 6-
minute walking distance of 150 feet represents the minimum distance necessary
to maintain independent living in an apartment setting.
There is little published data on exercise reconditioning and ILD. One study
showed an improvement in 6-minute walking distance from 213 to 506 feet after
the training programme, despite no substantial improvement in pulmonary
function tests. Although the improvement appeared substantial, the
investigators did not assess the impact on quality of life scores.[23]
Patients with end-stage interstitial lung disease may not be referred to
rehabilitative programmes as they may be considered beyond rehabilitation.
Referral early in the course of the disease may improve functional capacity.[23]
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Appendix A - Tables
Table 1: Historical Classification
IDIOPATHIC INTERSTITIAL PNEUMONIAS
Clinical Terminology
Pathological Findings
Idiopathic Pulmonary Fibrosis
Usual interstitial pneumonia
Desquamative interstitial Desquamative interstitial
pneumonia or
pneumonia or
Respiratory bronchiolitis interstitial
Respiratory bronchiolitis interstitial
lung disease
lung disease
Acute interstitial Pneumonia
Diffuse Alveolar Damage
Non specific interstitial pneumonia
Non specific interstitial pneumonia
Cryptogenic organising pneumonia
Organising pneumonia,
Bronchiolitis obliterans organising
peribronchiolar inflammation
pneumonia
Table 2: Presentation of Extrinsic Allergic Alveolitis
PRESENTATION
Features Acute
Sub-acute
Chronic
Fever Chills
+ -
-
Dyspnoea
+ +
+
Pr
Produc
od
Cough
Non-productive
tive
uct
ive
Malaise
+ +
+
Weight loss
- +
+
Dif
Crackles
Bibasal Diffuse
fus
e
Nodula
Fib
r
CXR
Nodular infiltrates
ros
infiltrat
is
es
Pulmonary Function
Restrictive Mixed
Mi
xe
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Tests
d
De
Decrea
cre
DLCO
Decreased
sed
as
ed
Adapted from Grammer 1999[24]
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Table 3: Potential Side Effects of High Dose Steroids
SIDE
EFFECT
Osteoporosis
Vertebral compression fracture
Musculo-skeletal
Aseptic necrosis of femoral or
humeral head
Myopathy
Depression
Psychological
Euphoria
Psychosis
Cardiovascular
Hypertension
Truncal obesity
Hyperglycaemia/diabetes
Endocrine and Metabolic
Metabolic alkalosis
Secondary adrenal insufficiency
Posterior capsular cataracts
Ophthalmic
Raised intra-ocular pressure
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6
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EBM – Interstitial Lung Disease
Version: 2 a (draft)
MED/S2/CMEP~0053(n)
Page 18
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