Clinical Review

The diagnosis and management of interstitial lung diseases

BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h2072 (Published 07 May 2015) Cite this as: BMJ 2015;350:h2072
  1. Adam Wallis, consultant thoracic radiologist,
  2. Katherine Spinks, consultant respiratory physician
  1. 1Queen Alexandra Hospital, Portsmouth PO6 3LY, UK
  1. Correspondence to: A Wallis adam.wallis{at}porthosp.nhs.uk

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

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.

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.

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.

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

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 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.

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

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 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.

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)

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.

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

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.

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)

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 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).

Figure1

Fig 1 Chest radiograph showing reduced lung volumes and reticulations (*) in a patient with idiopathic pulmonary fibrosis

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 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.

Figure2

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)

Figure3

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)

Figure4

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

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.

Further serological tests

View this table:

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).

Figure5

Fig 5 Flow diagram of an approach to interstitial lung disease diagnosis

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.

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 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.

Additional educational resources

Resources for healthcare professionals
  • Sounds of IPF (www.soundsofipf.co.uk)—auscultatory recordings of various pulmonary conditions

  • National Institute for Health and Care Excellence. Idiopathic pulmonary fibrosis: the diagnosis and management of suspected idiopathic pulmonary fibrosis (www.nice.org.uk/Guidance/cg163)

  • British Thoracic Societies (www.brit-thoracic.org.uk)—standards of care for patients with respiratory disease; clinical guidelines; and research

  • Map of Medicine ILD pathway (http://mapofmedicine.com)—evidence based guidance and decision making pathways for interstitial lung diseases

  • NICE quality standard. Idiopathic pulmonary fibrosis (www.nice.org.uk/guidance/qs79)—areas for quality improvement covering the diagnosis and management of idiopathic pulmonary fibrosis

Resources for patients
  • British Lung Foundation (www.blf.org.uk)—excellent resource for patients and carers, with links to self help publications and local events, research information, and fundraising

  • Pulmonary Fibrosis Trust (www.pulmonaryfibrosistrust.org)—useful support website for patients and carers

  • Action for Pulmonary Fibrosis (www.actionpulmonaryfibrosis.org)—further support information for patients and carers with pulmonary fibrosis, also with webinars and further links to charitable fundraising

A patient’s story

At 71 I was fit for my age, when I noticed increasing shortness of breath on exertion. I thought I should do something about it when I became breathless after a surface swim before doing a wreck dive in the Red Sea, and I also had to stop to recover after rallies when playing racquet-ball. I was referred to a respiratory consultant with an interest in interstitial lung disease. As a retired GP, I had a pretty good idea that pulmonary fibrosis might be a possibility, and this was confirmed by lung biopsy—a necessary but rather uncomfortable procedure. It was difficult to come to terms with the diagnosis and its poor prognosis, as my wife and I had been looking forward to an active and lengthy old age spent together travelling and watching our grandchildren grow up. However we have been supported by an excellent team, and I am grateful for having been prescribed pirfenidone. Although it has its side effects, it has changed our outlook, as after 10 months of treatment my respiratory function tests have not declined further. I keep exercising as much as I can, and am now optimistic about staying around for longer than I first anticipated.

Notes

Cite this as: BMJ 2015;350:h2072

Footnotes

  • 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.

References

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