Q3 2024 Earnings Conference Call and Webcast Slides
Diagnosis and Management of Interstitial Lung Diseases
1. The diagnosis and management of interstitial lung
diseases
Adam Wallis consultant thoracic radiologist, Katherine Spinks consultant respiratory physician
Queen Alexandra Hospital, Portsmouth PO6 3LY, UK
The interstitial lung diseases comprise a complex group of
pulmonary disorders principally affecting the pulmonary
interstitium. The group includes idiopathic pulmonary fibrosis,
hypersensitivity pneumonitis, sarcoidosis, and connective tissue
disease associated interstitial lung disease.
Recent years have witnessed an expansion of research studies,
large randomised controlled trials, and novel treatments in
interstitial lung diseases with the potential to change the
treatment landscape for patients. For some patients the aim will
be to control symptoms, whereas for others it may be possible
to stabilise disease or even achieve remission.
The aim of this review is to highlight the salient features in the
history and examination that can suggest a specific interstitial
lung disease, and suggest an approach to diagnosis and
management for the non-specialist.
How common are they?
Idiopathic pulmonary fibrosis is the commonest interstitial lung
disease, with an estimated incidence in the United Kingdom of
around 7.44 per 100 000 population1
and an estimated prevalence
varying from as many as 23.4 cases per 100 000 in Europe to
as many as 63 per 100 000 in the United States.2
Together with
idiopathic pulmonary fibrosis, hypersensitivity pneumonitis,
sarcoidosis, and connective tissue disease associated interstitial
lung disease constitute the majority of cases encountered in
everyday clinical practice. Other interstitial lung diseases such
as alveolar proteinosis are rare (estimated incidence around one
per two million population).3
How are they classified?
The interstitial lung diseases are a heterogeneous group of
conditions with varying prognoses and clinical behaviours.
Many are associated with major morbidity and mortality—for
example, the median survival of patients with idiopathic
pulmonary fibrosis is less than three years,4
whereas acute
interstitial pneumonia can be rapidly fatal. Others, such as
sarcoidosis, can regress without treatment.
Early referral to a specialist is important for accurate diagnosis,
prognosis, and appropriate management strategies. Despite this,
a cohort study of patients with idiopathic pulmonary fibrosis
identified a mean time from onset of dyspnoea to referral to a
specialist centre of 2.2 years.5
Delayed access was associated
with a higher risk of death, independent of disease severity.
Diagnosis and classification also affects the potential for entry
to the numerous drug trials currently underway.
The classification of interstitial lung diseases is complex (box
1), reflecting the various underlying causal factors and range
of histopathological findings. Although most of the disorders
are characterised by varying degrees of inflammation or fibrosis
of the pulmonary interstitium (the connective tissue scaffold
throughout the lung), a few, such as desquamative interstitial
pneumonitis and alveolar proteinosis, are characterised by
airspace filling. Some can be primarily inflammatory, such as
sarcoidosis, whereas others, such as idiopathic pulmonary
fibrosis, are primarily fibrotic and can be associated with
extensive distortion of the lung architecture and loss of volume.
The range of causal factors attributed to interstitial lung disease
include underlying connective tissue disease and occupational
or environmental exposures such as to asbestos, toxic drugs,
and radiation. Idiopathic pulmonary fibrosis is the most common
of the group of idiopathic interstitial pneumonias—that is,
interstitial lung diseases of unknown cause primarily classified
histologically and recently grouped together (see box 1).6
The
term cryptogenic fibrosing alveolitis is no longer used to
describe idiopathic pulmonary fibrosis.
Some cases of interstitial lung disease remain unclassifiable
despite a multidisciplinary approach. In a cohort study, 10% of
interstitial lung disease remained unclassified, and affected
patients had a prognosis better than those with idiopathic
pulmonary fibrosis and comparable to those with non-idiopathic
pulmonary fibrosis interstitial lung diseases.7
How are they assessed?
Although dyspnoea is typical, a high index of clinical suspicion
is necessary to facilitate early diagnosis as patients often present
with non-specific signs and symptoms. In some cases interstitial
lung disease may only be suspected after an incidental finding
on a chest radiograph. It is not uncommon for patients to have
been treated for infection or oedema before referral to specialist
care. A lack of response to treatments for infection or pulmonary
Correspondence to: A Wallis adam.wallis@porthosp.nhs.uk
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Clinical Review
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2. The bottom line
• The interstitial lung diseases are a complex group of disorders, but idiopathic pulmonary fibrosis, hypersensitivity pneumonitis,
connective tissue disease associated interstitial lung disease, and sarcoidosis make up the majority seen in clinical practice
• Patients present with non-specific signs and symptoms and so a high index of suspicion is required
• Typical findings of bi-basal crepitations can be mistaken for pulmonary oedema, but patients usually lack other features of this; a lack
of response to treatment for oedema or infection should raise suspicion of interstitial lung disease
• Early referral to specialist services enables prompt diagnosis and management to optimise outcome, and this process can be facilitated
by investigations in the community, including chest radiography and some serology
• Symptom control, occupational therapy, and palliative care are also important aspects of managing patients with interstitial lung
disease, requiring input from multiple agencies and specialists
Sources and selection criteria
We carried out an electronic search of Medline and Embase for relevant original papers and systematic reviews using the search terms
“pulmonary fibrosis”, “interstitial lung disease”, and “diffuse parenchymal lung disease”, prioritising those published from 2010. Relevant
articles from the Cochrane databases and personal references were also included.
Box 1 Simplified classification of interstitial lung disease
Interstitial pneumonias (often idiopathic)
Chronic fibrosing—idiopathic pulmonary fibrosis, idiopathic non-specific interstitial pneumonia
Acute or subacute—organising pneumonia, acute interstitial pneumonia
Smoking related—respiratory bronchiolitis associated interstitial lung disease, desquamative interstitial pneumonia
Unclassifiable
Connective tissue disease associated
Rheumatoid arthritis, scleroderma, dermatomyositis, polymyositis
Drug associated
Methotrexate, bleomycin
Inhalational exposures
Asbestosis, hypersensitivity pneumonitis, pneumoconioses
Granulomatous
Sarcoidosis, hypersensitivity pneumonitis
Familial and other inherited syndromes
Others and rare conditions
Lymphangioleiomyomatosis, Langerhans cell histiocytosis
oedema should prompt consideration of a diagnosis of interstitial
lung disease.
Symptoms
As well as suggesting a diagnosis of interstitial lung disease, a
detailed history can in some cases provide sufficient information
to indicate a specific form or cause of the disease. Box 2 lists
the key points to cover in the history.
Patients most typically present with dyspnoea. The time course
over which symptoms develop can help to differentiate the types
of disease. Some interstitial lung diseases, such as organising
pneumonia or acute interstitial pneumonia, can present rapidly,
whereas the more usual time course for many forms such as
idiopathic pulmonary fibrosis is insidious, with breathlessness
often present for more than a year. Age is also important. Some
interstitial lung diseases, including hypersensitivity pneumonitis
and connective tissue disease associated interstitial lung disease,
more typically present in patients aged less than 50 years. Most
patients with sarcoidosis present at ages 25-40 years, but the
disease is not uncommon in older people, and a Japanese study
found a bimodal distribution, with 30% of cases occurring after
the age of 50 years.8
Idiopathic pulmonary fibrosis typically
presents in patients in their 60s or 70s.
Cough is commonly encountered in interstitial lung disease and
is often dry and exacerbated by reflux (itself implicated as a
causative factor in interstitial lung disease). Patients may feel
general malaise and constitutional upset, particularly those with
underlying connective tissue disease, vasculitis, and some cases
of sarcoidosis. Pertinent questions concerning connective tissue
diseases relate to symptoms of Raynaud’s phenomenon, sicca
symptoms (dry eyes and difficulty swallowing), sclerodactyly,
and arthralgia. Haemoptysis is unusual and may suggest a
complication such as infection, pulmonary embolism,
malignancy, or a pulmonary vasculitis. Patients with known
connective tissue disease and increasing respiratory symptoms
should be referred to a respiratory specialist. It is also possible
for lung disease to prevent de novo in patients with no previous
clinical features of connective tissue disease (for example,
rheumatoid arthritis) so this needs to be actively looked for,
especially in patients with a usual interstitial pneumonia
morphology on computed tomography; joint symptoms may
develop later.
Smoking is associated not just with idiopathic pulmonary
fibrosis but with respiratory bronchiolitis interstitial lung disease
and the rarer interstitial lung diseases Langerhans cell
histiocytosis and desquamative interstitial pneumonitis, as well
as accounting for coexisting emphysema.51
Retrospective trials
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3. Box 2 Key points in the history of suspected interstitial lung disease
• Symptoms of interstitial lung disease: dyspnoea, cough (often dry)
• Non-specific symptoms: fever, fatigue, weight loss
• Symptoms of reflux disease
• Dysphagia (connective tissue disease associated interstitial lung disease)
• Joint pains, morning stiffness, dry eyes or mouth, skin changes, Raynaud’s phenomenon, photosensitivity (connective tissue disease
associated interstitial lung disease)
• Neurological, rashes (sarcoidosis, connective tissue disease associated interstitial lung disease)
• Ocular symptoms (connective tissue disease associated interstitial lung disease, sarcoidosis)
• Family history
• Medical history—for example, autoimmune disorders, inflammatory bowel disease, and renal disorders such as granulomatous
polyangitis
• Exposures, including drugs (for example, nitrofurantoin, bleomycin, methotrexate), occupation (for example, metal, wood, or asbestos
workers), and environmental (for example, birds)
• Personal characteristics of patients, including age, sex, and smoking status
suggest that gastro-oesophageal reflux disease contributes to
the pathogenesis of fibrosis.9
Patients should be specifically
questioned about symptoms relating to gastro-oesophageal reflux
disease, including non-acid reflux, which may cause or
exacerbate interstitial lung disease by means of recurrent
episodes of aspiration.
Drugs and exposures
Obtaining a detailed drug, occupational, and exposure history
is necessary. Box 3 lists several important occupational and
environmental factors implicated in hypersensitivity
pneumonitis.
Pulmonary toxicity has been attributed to a wide variety of
prescription and over the counter medicines as well as illicit
drugs (box 4). Patients starting new implicated drugs or
established on them should be warned about and assessed for
the development of respiratory symptoms. Mechanisms include
alveolar damage progressing to fibrosis (for example,
amiodarone, bleomycin), hypersensitivity (for example,
methotrexate), or organising pneumonia (for example,
nitrofurantoin). In some patients, withdrawing the offending
drug (and suitable replacement of an alternative if indicated)
can result in complete resolution and so prompt referral is
advised when suspected.
Family history
The pathogenesis of interstitial lung diseases is complex but
there is evidence of a strong interplay between environmental
and genetic factors. Some rare genetic syndromes are implicated
(such as Hermansky-Pudlak syndrome), some interstitial lung
diseases are more common in particular racial groups (for
example sarcoidosis is more common in black people than in
white ethnic groups), and interstitial lung disease can also be
familial. Familial interstitial pneumonia is defined as two or
more family members with an idiopathic interstitial pneumonia.
In over 40% of these families there is more than one type of
fibrosis in affected members, suggesting a shared genetic
susceptibility. A familial component is seen in at least 20% of
cases of idiopathic pulmonary fibrosis.10
The clinical implications of increased understanding of the
genetic foundation to the interstitial lung diseases, particularly
idiopathic pulmonary fibrosis, include possibilities for clinical
genetic testing and prospective screening.
Examination
Bilateral fine end inspiratory crepitations are classic on
pulmonary examination, but other auscultatory findings are also
associated with interstitial lung diseases. For example, the
bronchiolitis found in hypersensitivity pneumonitis is suggested
by high pitch end inspiratory squeaks and squawks. Patients
with cystic lung diseases such as Langerhans cell histiocytosis
and lymphangioleiomyomatosis may present with findings of
a pneumothorax, and pleural effusion in those with connective
tissue disease associated interstitial lung disease,
lymphangioleiomyomatosis, or, less commonly, sarcoidosis. A
pleural rub may be present in patients with rheumatoid arthritis
or systemic lupus erythematosus. Despite severe disease, patients
with sarcoidosis often have a relative paucity of chest findings.
A multitude of extrapulmonary findings exist. Finger clubbing
is said to occur in over half of patients with idiopathic
pulmonary fibrosis and is associated with a worse outcome,52
but it can also be seen in other interstitial lung diseases such as
desquamative interstitial pneumonitis as well as with
development of complications such as lung cancer. Clubbing
typically suggests progressive severe pulmonary fibrosis in
patients with sarcoidosis. A meta-analysis of white patients with
connective tissue disease associated interstitial lung disease
found a high prevalence of pulmonary hypertension,11
signs of
which include prominent a and v waves, a loud second heart
sound, and the murmurs of mitral and tricuspid regurgitation.
Patients may have peripheral oedema. Some of the interstitial
lung diseases are associated with a greater risk of cardiac
involvement, including sarcoidosis (cardiomyopathy and
conduction disorders) and connective tissue disease associated
interstitial lung disease (myocarditis, pericarditis, pericardial
effusion).
Numerous cutaneous findings are associated with connective
tissue disease and rheumatological conditions known to cause
fibrosis. Erythema nodosum is typically associated with
sarcoidosis, a heliotrope rash with dermatomyositis, and
calcinosis with scleroderma. Box 5 lists other clinical
manifestations. Examination allows for assessment of severity,
with features including cyanosis.
How are they investigated?
Initial investigations
Patients with suspected interstitial lung disease should be
referred promptly to specialist services. Several investigations
can be requested in the community to facilitate a more rapid
diagnosis and to assess for complications before referral. Routine
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4. Box 3 Occupational and environmental factors implicated in hypersensitivity pneumonitis
Occupational
• Numerous, including “farmers lung” (commonly thermophilic actinomycetes or Aspergillus species) and “bird fanciers lung” (check for
precipitating antigens to pigeons, budgerigars, or parrots)
• Other high risk occupations include those with exposure to animals (for example, veterinary medicine, farming); bakers or those who
mill grains; those who work with or manufacture wood or paper, including MDF; textile workers; those involved in the plastics, painting,
or electronics industry, or with exposure to any aerosolised organic chemicals; and metal workers
• Asbestos—high risk occupations include plumbers, electricians, and construction, dockyard, and railway (exposure may have occurred
many years ago) workers
Environmental
• Inhaled allergens aerosolised in water from, for example, swimming pools, hot tubs, air conditioning units, humidifiers. Allergens
include thermoactinomycetes and Aspergillus, Klebsiella, and Acanthamoeba species
• Feather bedding; the acquisition of feather duvets or pillows should be queried
• High levels of damp mould in the home or frequent contact with compost in the garden (Aspergillus species)
Box 4 Drugs known to cause pulmonary toxicity
• Antirheumatoid agents—methotrexate (can occur after dose or formulation change even in long term users), gold, leflunamide,
sulphasalazine, penicillamine
• Chemotherapeutic agents—bleomycin, chlorambucil, tyrosine kinase inhibitors (for example, imatinib), cyclophosphamide
• Biological agents—antitumour necrosis factor (etanercept, infliximab)
• Selective serotonin reuptake inhibitors—citalopram, fluoxetine
• Antibiotics—nitrofurantoin, cephalosporins
• Cardiac agents—amiodarone, angiotensin converting enzyme inhibitors, statins
• Others—talc, illicit drugs (including cocaine and talc used to cut many drugs), azothioprine, interferons
Any drug can potentially cause pulmonary toxicity. If in doubt see www.pneumotox.com
Box 5 Key features in the clinical examination of interstitial lung disease
• Bi-basal end inspiratory crepitations (fibrosis)
• Inspiratory squeaks (hypersensitivity pneumonitis)
• Finger clubbing
• Pleural effusion (connective tissue diseases, lymphangioleiomyomatosis, sarcoidosis)
• Pulmonary hypertension (particularly connective diseases)—a and v waves, murmurs of tricuspid regurgitation or pulmonic regurgitation,
peripheral oedema
• Arthritis (connective tissue disease or sarcoidosis)
• Skin—erythema nodosum (sarcoidosis), Raynaud’s phenomenon/sclerodactyly/telangiectasia (systemic sclerosis)
• Lymphadenopathy and hepatosplenomegaly (sarcoidosis)
• Neurological findings (sarcoidosis, vasculitis, and connective tissue diseases)
• Ocular signs (sarcoidosis, connective tissue diseases)
blood tests can give supporting evidence of inflammation or
complicating factors, such as hypercalcaemia in sarcoidosis.
Guidance from the British Thoracic Society suggests a full blood
count, urea and electrolytes, liver function tests, calcium,
erythrocyte sedimentation rate, and C reactive protein as initial
tests. Other tests depend on the clinical context and will typically
be arranged by the interstitial lung disease clinic.12
Urinalysis is helpful in suspected vasculitis. Community
spirometry may demonstrate a restrictive lung defect. However,
many patients with emphysema also develop fibrosis, and
because of the contrasting physiologies, spirometry may be
normal or obstructive and so this alone should not detract from
a suspected diagnosis. These patients with combined emphysema
and fibrosis are more likely to develop pulmonary
hypertension.13
Radiological investigation
Chest radiography—Chest radiography is typically the first
radiological investigation requested. Although neither sensitive
nor specific,14
radiography should not be overlooked as a simple
tool to identify clues as to the underlying condition. Reviewing
serial radiographs can help determine whether changes are acute
or chronic. Patterns of disease such as upper or lower lung
predominance can suggest particular conditions, and underlying
causal factors may be found such as asbestos pleural plaques.
Chest radiography may help exclude oedema or infection and
can screen for complications, including malignancy. Typical
findings in idiopathic pulmonary fibrosis include reticulations
and reduced lung volumes (fig 1⇓).
High resolution computed tomography—High resolution
computed tomography is now a standard investigation in patients
with suspected interstitial lung disease. In some cases where
history is compatible it may be diagnostic, precluding the need
for bronchoscopy or surgical biopsy.15
Idiopathic pulmonary
fibrosis causes a “usual interstitial pneumonia” pattern of fibrosis
associated with honeycombing (cystic dilation of distal
bronchioles secondary to fibrotic destruction of adjacent
airspaces16
). Usual interstitial pneumonia is not specific to
idiopathic pulmonary fibrosis and can be seen in other interstitial
lung diseases, including connective tissue disease associated
interstitial lung disease, asbestosis, and sarcoidosis. The clinical
features and associated radiological findings, such as pleural
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5. plaques in asbestosis or oesophageal dilation in scleroderma,
may help to differentiate the underlying causes.
Radiologists are able to describe a pattern on high resolution
computed tomography as being typical of usual interstitial
pneumonia, possible usual interstitial pneumonia, or atypical
of usual interstitial pneumonia, which can help with decision
making.15
Figure 2⇓ gives a representation of the typical
appearance on high resolution computed tomography of the
most commonly encountered interstitial lung diseases. Figures
3⇓ and 4⇓ are examples of the appearance of typical usual
interstitial pneumonia and non-specific interstitial pneumonia
on computed tomograms.
Other specialist investigations
Patients should undergo full pulmonary function tests including
gas transfer measurement, the serial results of which are useful
in assessing response to treatment or deterioration. These are
usually more illuminating than static lung volume assessment.
The typical pattern of pulmonary function tests in interstitial
lung disease is a restrictive one, but several smokers may have
coexistent airways disease and in these patients restrictive
patterns are uncommon. Patients with sarcoidosis may have an
obstructive pattern owing to endobronchial involvement. A low
gas transfer measurement at baseline indicates those with worst
prognosis in idiopathic pulmonary fibrosis.17
The six minute walk test gives a useful baseline for pulmonary
rehabilitation18
and correlates with disease severity and long
term outcome in idiopathic pulmonary fibrosis.19
Other
investigations are tailored to the suspected diagnosis. Serological
testing can determine allergen responses in hypersensitivity
pneumonitis or underlying or emergent connective tissue disease
(table⇓). Provocation tests for hypersensitivity pneumonitis are
not standardised and generally not needed.
How is the diagnosis confirmed?
A multidisciplinary team, composed of respiratory physicians,
thoracic radiologists, pathologists, and specialist nurses, is the
current standard in the diagnosis of interstitial lung disease.20
The typical diagnostic strategy is to confirm the presence of
interstitial lung disease, establish a diagnosis where possible
(with emphasis on excluding underlying causes), stage the
disease, and discuss treatment objectives (fig 5⇓).
Some patients’ conditions are more complex, and despite
pooling knowledge the multidisciplinary team cannot always
reach a confident diagnosis. In this case the risks and benefits
of further sampling with bronchoscopy or surgical lung biopsy
will be considered. It may be necessary for the team to come
up with a working diagnosis of the form of interstitial lung
disease present to facilitate treatment strategies. Not all cases
require histological confirmation; particularly where clinical
and radiological opinion is in agreement.20
Increasing age is
associated with an increased likelihood of idiopathic pulmonary
fibrosis.21
Bronchoscopy
Bronchoscopy allows samples to be taken to exclude infection,
for cell differentials, and to enable small volume endobronchial
or transbronchial biopsies to be examined histologically.
Bronchoscopy is generally safe, with the major complications
being pneumothorax or bleeding after transbronchial biopsy.
Bronchoalveolar lavage yields cell differentials that are generally
not diagnostic alone but can support a diagnosis of
hypersensitivity pneumonitis or sarcoidosis if lymphocytosis is
present, and they can be screened for malignant cells. The
American Thoracic Society suggests using high resolution
computed tomography to select an appropriate location for
biopsy.22
Endobronchial or transbronchial biopsies are useful
in establishing a diagnosis of sarcoidosis. These samples are
too small to allow histological classification of other interstitial
lung diseases and are of limited value in the presence of
established fibrosis. Transbronchial biopsies are not indicated
in suspected idiopathic pulmonary fibrosis. However in some
cases of suspected idiopathic pulmonary fibrosis a differential
diagnosis is chronic hypersensitivity pneumonitis and in these
circumstances bronchoalveolar lavage can be an important
diagnostic discriminator.
Surgical biopsy
Surgical lung biopsy can be expected to provide a specimen
that is diagnostic of specific types of interstitial lung disease,
although there are issues with interobserver and intraobserver
variability,53
even between expert pathologists, and this must
be taken into account when considering patient selection.
Benefits must be assessed against risks, particularly as these
patients are prone to respiratory compromise, exacerbations,
pulmonary hypertension, and other comorbidities. A
meta-analysis showed mortality rates of 4.3% at 30 days for
open lung biopsy and 2.1% for video assisted thoracoscopic
surgery biopsy.23
This means that careful deliberation is needed
before recommending surgical lung biopsy. Mortality increases
with age. However, confirming a diagnosis in some forms of
interstitial lung disease may not be possible without surgical
lung biopsy.
How are they treated?
Treatment objectives vary depending on the clinical behaviour
of the interstitial lung disease.15
In many interstitial lung diseases
such as idiopathic pulmonary fibrosis the aim will be to slow
or stabilise disease progression. Other interstitial lung diseases,
such as respiratory bronchiolitis associated interstitial lung
disease, are self limiting and potentially reversible. In patients
with unclassifiable disease, representing around 10% of the
interstitial lung disease cohort7
the multidisciplinary team will
have to reach a working diagnosis and use this to determine a
pragmatic approach to treatment and monitoring. Treatment
plans should also include supportive therapies, including
pulmonary rehabilitation, symptomatic relief (for example,
cough, anxiety), and supplementary oxygen.
Therapeutics
Specific interstitial lung diseases are discussed with brief
information about their management.
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis constitutes over half of the cases
of interstitial lung disease encountered in clinical practice24
and
carries a prognosis worse than many malignancies.
Previous treatment strategies including steroids,
cyclophosphamide, triple treatment (prednisolone, azathioprine
and N-acetyl cysteine), or N-acetyl cysteine alone have been
shown to be ineffective or harmful.25
A randomised controlled
trial of N-acetyl cysteine showed no benefit compared with
placebo in the treatment of idiopathic pulmonary fibrosis.26
These are no longer recommended options. However, N-acetyl
cysteine and other mucolytics are sometimes used as expectorant
adjuncts.
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6. Certain patients may benefit from entry onto drug trials for
emerging new treatment options, which can help slow down
the inexorable rate of decline in idiopathic pulmonary fibrosis.
Pirfenidone is the only licensed treatment currently approved
by the National Institute for Health and Care Excellence for
idiopathic pulmonary fibrosis in the UK. NICE recommends
its use in patients with a forced vital capacity of 50-80%
predicted.27
It is expensive, requires monitoring of lung function
tests, and side effects include nausea, dyspepsia, fatigue, and
photosensitivity. Randomised controlled trials have shown that
it does not reverse established fibrosis but slows the rate of
decline in pulmonary function tests otherwise seen and modestly
reduces all cause mortality28
supported by evidence from recent
clinical trials.29
According to NICE guidelines in the UK and
widely adopted elsewhere, treatment is to be discontinued if
lung function declines by 10% from baseline or more in a year.27
Nintedanib, an intracellular tyrosine kinase inhibitor with
antifibrotic and anti-inflammatory properties, is newly licensed
but not yet approved by NICE and in clinical trials also slows
the rate of decline of pulmonary function tests similar to
pirfenidone.30
The main side effect is diarrhoea, anticoagulants
are contraindicated, and monitoring using lung function tests is
also required. Other drugs are in phase 2b trials (simtuzimab,
lebrikizumab), and the future of clinical treatment for idiopathic
pulmonary fibrosis is looking more promising.
Connective tissue disorder associated interstitial
lung disease
Lung involvement in connective tissue diseases ranges from
fibrosis to pulmonary vascular disease, vasculitis, and pleural
complications.
Despite the considerable burden of pulmonary complications
in connective tissue disease, the treatment of associated
interstitial lung disease is not supported by much robust
evidence. The only randomised controlled trials relate to the
use of cyclophosphamide in scleroderma. One showed a
significant modest effect on lung function and health related
quality of life.31
Although in the second there was no significant
improvement, there was a trend towards improvement in forced
vital capacity, and treatment was well tolerated.32
Immunosuppressants are the treatment agents of choice. Despite
their risks, the evidence base for their use is minimal with little
data to guide optimal initiation and duration of treatment.
Corticosteroids and steroid sparing agents, including
azathioprine and mycophenolate, are generally used in mild
disease, with cyclophosphamide for more severe or refractory
cases. Drug induced interstitial lung disease is a problem in the
connective tissue disease associated interstitial lung diseases as
almost every drug used to treat the underlying connective tissue
disease can potentially cause interstitial lung disease. Reactions
can range from infiltrates, worsening of underlying fibrosis, to
acute alveolar damage, which may be life threatening. A high
index of suspicion and close monitoring are required.
Sarcoidosis
Sarcoidosis is a multisystem, granulomatous, inflammatory
condition that typically presents in younger adults, not unusually
with extrathoracic symptoms such as erythema nodosum.
Sarcoidosis has a predilection for the respiratory system—in a
large American cohort the chest was involved in over 90% of
cases.33
Patients can progress from stage 1 disease (bihilar
lymphadenopathy only) to stage 2 or more (parenchymal lung
involvement) without being aware that they have sarcoidosis.
As many as 10% may progress to fibrosis.
Stage 1 sarcoidosis manifests typically as bihilar and right
paratracheal lymphadenopathy (Garland’s triad). Granulomatous
infiltration of the lung results in perilymphatic nodularity in
stage 2 and 3 disease. As many as 10% of cases progress to
fibrosis (stage 4), the extent and type of which are more variable
than idiopathic pulmonary fibrosis.
British Thoracic Society guidelines suggest that treatment is
not required for asymptomatic stage 1 sarcoidosis, nor
asymptomatic stage 2 and 3 disease with only mild pulmonary
function test abnormalities. Steroids have been used since the
1950s as first line treatment for progression or symptoms in
sarcoidosis.34
Inability to minimise the dose, side effects, or
failure to respond may require alternative immunosuppressive
agents, but evidence is lacking. Methotrexate is the most
commonly used steroid sparing agent,35
with response rates of
up to 60%.36
Others include azathioprine,37
hydroxychloroquine,38
or tumour necrosis factor alpha inhibitors such as infliximab
for recalcitrant disease.39
Inhaled corticosteroids may help
control troubling cough or associated airways disease and avoid
some side effects associated with higher dose oral steroids. A
systematic review of their use showed that effects are small and
results generally inconclusive.40
Hypersensitivity pneumonitis
Hypersensitivity pneumonitis (extrinsic allergic alveolitis) can
occur at any age owing to exaggerated immune response to
inhalation of antigens. It can present in acute, subacute, and
chronic forms—as many as 20% of interstitial lung disease is
due to chronic hypersensitivity pneumonitis.41
Management involves identifying and removing the sensitising
agent. This can be obvious but it is often difficult to identify
and still more difficult to remove allergens, especially ubiquitous
environmental agents. Steroids are often used to abate symptoms
when removal of the offending agent fails to help or is not
possible, and when there is functional impairment. There are
no controlled trials of the management of chronic
hypersensitivity pneumonitis. Intravenous cyclophosphamide
may be successful and there are case reports of success using
biologicals in refractory cases.42
Pulmonary rehabilitation
There is good evidence that pulmonary rehabilitation helps
breathless patients. A meta-analysis has confirmed the benefit
of pulmonary rehabilitation in patients with interstitial lung
disease.43
Patients in randomised controlled trials showed
meaningful improvements in distances achieved in six minute
walk tests.44 45
Unfortunately pulmonary rehabilitation is not
universally available and in many regions is restricted to patients
with chronic obstructive pulmonary disease in whom effects
are better known and documented. The benefits are in improving
non-respiratory muscle strength and fitness, which contribute
to improved walking distances. Psychosocial support, nutritional
advice, and advice on smoking cessation may also be offered
during classes.
Lung transplantation
Lung transplantation offers survival benefits in carefully selected
patients. It aims to improve survival and quality of life; the
prognosis without transplant should be less than 50% survival
at five years. Twenty three per cent of lung transplants
worldwide are performed on patients with idiopathic pulmonary
fibrosis.46
Connective tissue diseases account for less than 4%
of indications, and other interstitial lung diseases even fewer.
Patient selection is important, and guidelines47
suggest referring
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7. patients with idiopathic pulmonary fibrosis for consideration
of transplant when they demonstrate a 10% or greater reduction
in forced vital capacity over six months and a decrease in oxygen
saturations to below 89% or the need for oxygen at rest. A single
centre retrospective study of 105 patients showed that patients
with idiopathic pulmonary fibrosis who desaturate to this extent
have a five year survival of 20% compared with 60% in those
who do not desaturate.48
In patients without idiopathic pulmonary
fibrosis, transplant should be considered in those with forced
vital capacities less than 50% or hypoxaemia (partial pressure
of oxygen <55 mm Hg).49
The International Society of Heart
and Lung Transplantation suggests an upper age limit of 65
years, although an American registry report of results from 1988
to 2011 shows improving graft and patient survival in those
over this age limit.50
Contraindications also include
mycobacterial infection, tobacco and substance misuse without
prolonged abstinence, recent malignancy, untreatable major
non-respiratory organ damage, and obesity. Half of patients
with idiopathic pulmonary fibrosis receive bilateral lung
transplants. Unadjusted three month mortality in patients with
idiopathic pulmonary fibrosis is 15% and in those who survive
one year the five year survival is 60%.46
Patients will typically
gain considerable functional improvement in activities of daily
living. One in six patients on the waiting list dies before a
suitable donor organ is identified.
What are the considerations for end of life
care?
Managing patients with interstitial lung disease (particularly
idiopathic pulmonary fibrosis) very much encompasses end of
life care. Some patients present too late for antifibrotic treatment,
and supportive care with symptom based management is all that
is available. Managing patient expectations from the outset is
important, even in those in whom specific treatment is indicated,
as effects of treatments remain modest in most. Patients face
having to cope with increasing limitation as a result of
breathlessness and many are well aware of the prognosis. Careful
explanations, provision of condition specific literature, and
expert support are necessary. Specialist nursing support is
paramount for these patients and disease specific patient support
groups are increasingly being formed, such as the British Lung
Foundation and charities such as Action for Pulmonary Fibrosis
in the UK.
Early involvement of teams such as occupational therapists to
assist with practical problems surrounding the maintenance of
independence (for example, installing stair lifts and hand rails),
community nursing teams, and palliative care specialists is vital.
Mobility support—for example, scooters and disabled parking
badges—is also important. Admission to a hospice and support
are available in many areas to those without cancer diagnoses,
and expert input regarding palliative care can be invaluable in
managing end stage disease. Patients should have time to
consider their wishes for end of life care, including making
decisions about hospital admission and resuscitation status in
the same way as those with other life limiting conditions.
Contributors: AW conceived the review, carried out the literature search,
drafted and revised the manuscript, organised the figures, and prepared
the manuscript for publication. He is the guarantor. KS helped draft and
revise the manuscript.
Competing interests: We have read and understood the BMJ policy on
declaration of interests and declare the following interests: KS has
received consultancy fees from Intermune/Roche.
Provenance and peer review: Not commissioned; externally peer
reviewed.
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9. Table
Table 1| Further serological tests
Indication
Serological marker
Connective tissue disease
Rheumatoid factor, antinuclear antibodies Jo-1 and Scl-70
Hypersensitivity pneumonitis
Specific serum IgG antibodies
Myositis
Creatine kinase, myoglobin
Immunodeficiency
Immunoglobulin’s
Vasculitis
Cytoplasmic ANCA, perinuclear ANCA, anti-glomerular basement membrane
ANCA=antineutrophil cytoplasmic antibodies.
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10. Figures
Fig 1 Chest radiograph showing reduced lung volumes and reticulations (*) in a patient with idiopathic pulmonary fibrosis
Fig 2 Simplified diagram of typical high resolution computed tomography appearance of the most commonly encountered
interstitial lung diseases. Idiopathic pulmonary fibrosis (usual interstitial pneumonia pattern; lower lung predominant subpleural
reticulations, traction bronchiectasis, and honeycombing with paucity of ground glass opacification). Non-specific interstitial
pneumonia (lower lung predominant subpleural ground glass opacification and fine reticulations, with traction bronchiectasis
in the fibrotic stage and typically an absence of honeycombing). Hypersensitivity pneumonitis: acute: centrilobular or
geographical ground glass opacification and air trapping (mosaic attenuation), chronic: fibrosis with reticulation, traction
bronchiectasis, and possibly honeycombing. Sarcoidosis (mediastinal and bihilar lymphadenopathy, perilymphatic nodularity;
when fibrotic often perihilar, mass-like, or honeycombing). Organising pneumonia (nodules or consolidation, often a perilobular
pattern, fluctuation)
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11. Fig 3 Axial computed tomography in a patient with idiopathic pulmonary fibrosis showing a typical usual interstitial pneumonia
pattern of fibrosis with subpleural honeycombing (A) and with traction bronchiectasis (B)
Fig 4 Axial computed tomography in a patient with fibrosing non-specific interstitial pneumonia showing ground glass
opacification (A) and traction bronchiectasis (B) without honeycombing
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12. Fig 5 Flow diagram of an approach to interstitial lung disease diagnosis
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