Interstitial Lung Disease


Introduction

Interstitial lung disease (ILD) is an umbrella term for a broad spectrum of conditions affecting the lung interstitium, which is the space between an alveolus and its surrounding capillaries.1

In the UK, the prevalence of ILD is 50 per 100,000. The commonest type of ILD is idiopathic pulmonary fibrosis, which has an incidence of 6,000 new cases per year.2

Mortality varies across the different ILDs as they are a heterogeneous range of conditions. Mortality is particularly high in idiopathic pulmonary fibrosis, with a median survival of 4 years, which is worse than most types of cancer.3


Aetiology

Pathophysiology

In ILD, there is inflammation and fibrosis (scarring) in the lung interstitium (figure 1).5

Some ILDs (such as sarcoidosis) are predominantly inflammatory, with little fibrosis. This inflammation is mediated by innate and adaptive immune cells and may resolve.6

Other ILDs (such as idiopathic pulmonary fibrosis) are characterised by fibrosis in the lung interstitium, which is irreversible. Fibrosis is triggered by repeated injury to the lung tissue (e.g. from inhaled toxins).

Usually, fibroblasts respond to this lung injury by secreting extracellular matrix, which repairs the injuries. In ILD, genetic mutations lead to excess secretion of extracellular matrix, which accumulates in the lung interstitium, leading to fibrosis.7

The lung interstitium becomes thicker, increasing the diffusion distance for oxygen to travel from the air in the alveoli to the blood in the surrounding capillaries. Hence, gas exchange in the lungs is compromised.

Lung Interstitial Space Diagram
Figure 1. Location of the interstitial space in the lungs.8

Classification4

Primary (unknown cause)

  • Idiopathic pulmonary fibrosis
  • Acute interstitial pneumonia (can be acute or subacute)
  • Desquamative interstitial pneumonia (associated with smoking)

Secondary (known cause)

Connective tissue and autoimmune disease:

  • Sarcoidosis
  • Rheumatoid arthritis
  • Systemic lupus erythematosus (SLE)

Infective:

  • Mycoplasma pneumonia
  • Pneumocystis pneumonia

Environmental:

  • Asbestosis
  • Silicosis

Drugs:

  • Methotrexate
  • Amiodarone
  • Bleomycin

Risk Factors

Risk factors for ILD include:

  • Male sex
  • Cigarette smoking
  • Regular dust exposure (could be occupational)

Clinical features

History

Typical symptoms of ILD include:

  • Progressive exertional dyspnoea (usually presents slowly, over many weeks and months)
  • Dry cough
  • Connective tissue disease symptoms, such as arthralgia, difficulty swallowing and dry eyes
  • General malaise and fatigue (due to underlying connective tissue disease or vasculitis)9

Other important areas to cover in the history include:

  • Drug history: ask about any exposure to medications which cause ILD (see “Classification” section).
  • Smoking history: quantify in pack-years (1 pack-year = smoking 20 cigarettes a day for a year). Also ask about e-cigarettes and illicit inhaled substances, such as “crack” cocaine.10,11
  • Occupation: may be exposed to inhaled toxins. Susceptible occupations include farmers (hay dust and Aspergillus mould), bakers (flour dust and additive enzymes) and plumbers/construction workers (asbestos).12
  • Social history: ask about the presence of mould and pets at home, and if the patient has any hobbies which increase exposure to inhaled toxins (such as bird-keeping, which exposes the patient to avian proteins).

Clinical examination

A full respiratory examination should be performed in suspected cases of ILD. Also perform a brief examination of the patient’s joints, to assess for the presence of connective tissue disease.

Typical clinical findings in ILD include:

  • Bilateral fine end-inspiratory crepitations (may sound like Velcro): due to the sudden opening of small airways during inspiration, which were held closed during the previous expiration.13
  • Dullness to percussion: due to pleural effusion, which can occur in sarcoidosis and some connective tissue diseases.14
  • Finger clubbing (figure 2): may be due to increased secretion of growth factors, leading to increased growth of extracellular matrix in the nails.15
  • Skin signs: includes Raynaud’s phenomenon in systemic sclerosis (figure 3), erythema nodosum in sarcoidosis (figure 4).
  • Arthritis: due to connective tissue disease.

Differential Diagnoses

Exertional dyspnoea and cough have important differential diagnoses. Table 1 outlines these differential diagnoses, and the features which differentiate them from ILD.

Table 1. Differential diagnoses of ILD.

Differential diagnosisFeatures differentiating from ILD
COPDCough is more productive of sputum

Lung function tests: obstructive pattern (FEV1/FVC < 70%)

Examination and chest X-Ray: chest hyperinflation

AsthmaDiurnal variation in symptoms and peak flow

History of atopy

Lung function tests: bronchodilator reversibility

Congestive cardiac failureOrthopnoea (dyspnoea while lying down)

Paroxysmal nocturnal dyspnoea (sudden dyspnoea which wakes the patient up from sleep)

Blood tests: elevated BNP

Echocardiogram: reduced ejection fraction

Lung cancerSignificant weight loss

Haemoptysis

Imaging: visible tumour

BronchiectasisCough is more productive of sputum

More frequent lower respiratory tract infections, often starting in childhood

Lung function tests: obstructive pattern (FEV1/FVC < 70%)


Investigations

Bedside investigations

  • Pulse oximetry: aim for 94-98% initially, but the target saturations may be reduced in progressive disease (this is a decision made by a senior clinician).
  • Urine dipstick: haematuria and proteinuria may suggest underlying vasculitis.19
  • Lung function tests: typically show a restrictive pattern (reduced FVC and normal FEV1), but may also be normal.

Laboratory investigations

  • FBC: may show anaemia of chronic disease.
  • CRP and ESR: may be elevated.
  • U&Es: may be deranged if there is an underlying vasculitis.
  • Autoimmune antibodies: anti-CCP suggests rheumatoid arthritis, ANA suggests SLE. Autoimmune antibodies may also be raised in idiopathic pulmonary fibrosis.20

Imaging

  • Chest X-ray (figure 5): typically shows reticular (fine) opacities. The location of fibrosis may suggest particular causes (table 2).
  • High-resolution CT (HRCT) (figure 6): HRCT is preferred to volume CT as it provides higher quality images of the lung parenchyma, which is the area affected in ILD. Some ILDs, especially idiopathic pulmonary fibrosis, show a “usual interstitial pneumonia” pattern, which includes:
    • Honeycombing (clusters of cystic airspaces)
    • Traction bronchiectasis (dilated airways, which are pulled apart by areas of surrounding fibrosis)
    • Reticular opacities (thickening of the lung interstitium)

Table 2. The causes of upper zone and lower zone fibrosis.

Upper zone fibrosis = CHARTSLower zone fibrosis = RASIO
Coal-worker pneumoconiosis

Histiocytosis-X

Ankylosing spondylitis

Radiation (e.g. for breast cancer)

Tuberculosis

Sarcoidosis and silicosis

Rheumatoid arthritis

Asbestosis

SLE, scleroderma and Sjogren’s syndrome

Idiopathic pulmonary fibrosis

Others (including drugs)

Invasive investigations

  • Bronchoalveolar lavage (BAL) (figure 7): a bronchoscope (small camera) is inserted into the airways, and sterile saline is injected through the bronchoscope into the airways. The saline is then collected via suction and analysed. This helps to diagnose the underlying cause of the ILD, and to also exclude infection or malignancy.23
  • Trans-bronchial biopsy/surgical lung biopsy: a small sample of lung is collected and then analysed by a pathologist. This may be needed if previous tests are inconclusive, or if a tissue sample is needed to make the diagnosis.
Bronchoscopy diagram
Figure 7. Bronchoscopy. Bronchoalveolar lavage is performed during bronchoscopy.24

Management

Conservative management

  • Avoid any underlying causes (e.g. drug or inhaled toxin)
  • Smoking cessation
  • Pulmonary rehabilitation
  • Annual influenza vaccine and one-off pneumococcal vaccine

Medical management

Medical management varies for each type of ILD. Some important examples include:

  • Idiopathic pulmonary fibrosis: antifibrotics (nintedanib or pirfenidone).
  • Sarcoidosis: corticosteroids (prednisolone).
  • Connective tissue disease: corticosteroids and steroid-sparing agents (azathioprine or mycophenolate).
  • Extrinsic allergic alveolitis: corticosteroids.
Long-term oxygen therapy (LTOT)

Some patients with ILD may benefit from LTOT. Indications for LTOT are one of the following:

  • SpO2 <88%
  • PaO2 <7.3kPa

LTOT is contraindicated in current smokers due to the risk of burns.

Surgical management

  • Lung transplantation: for patients with severely impacted quality-of-life, despite optimum medical management.25

Complications

Disease-related complications

  • Respiratory failure: due to failure of gas exchange in the lungs.
  • Pulmonary hypertension: due to chronic hypoxic pulmonary vasoconstriction (constriction of blood vessels supplying fibrotic areas of the lung, to direct blood to healthier areas of the lung).26
  • Anxiety and depression: due to impaired quality-of-life.

Treatment-related complications

  • Due to long-term steroid use: osteoporosis, hypertension, Cushing’s syndrome.
  • Due to antifibrotics: diarrhoea, nausea, anorexia.

Key points

  • ILD is an umbrella term for a broad spectrum of conditions which affect the lung interstitium.
  • ILD can be classified based on whether it has an unknown cause (primary) or a known cause (secondary).
  • ILD typically presents with exertional dyspnoea and dry cough, but it may present with non-specific symptoms (such as malaise).
  • A diagnosis is based on laboratory results (which may suggest an underlying autoimmune cause) and imaging.
  • Management of ILD varies according to the underlying cause – steroids and antifibrotics are potential options.
  • The main complications of ILD are respiratory failure and pulmonary hypertension.

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Reviewer

Dr Neeraj Shah

Respiratory Medicine Registrar


Editor

Dr Chris Jefferies


References

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