11th January 2024

Background

The term ‘interstitial lung disease’ (ILD), synonymous with ‘diffuse parenchymal lung disease’ (DPLD), is used to describe a large number of lung disorders sharing similar clinical, radiological and pathological features. They are all characterised by a degree of fibrosis and/or inflammation of parenchymal interstitium, which results in impaired gas exchange. There are more than 200 different subtypes of ILDs, the commonest being idiopathic pulmonary fibrosis (IPF), sarcoidosis, and extrinsic allergic alveolitis (EAA), also known as hypersensitivity pneumonitis (HP).

Classification

Classification of ILDs has been a subject of much debate. This is hardly surprising, given the sheer amount of disorders covered by the term. However, classifying ILD is clinically important, as management and prognosis often depend on its specific subtype.

The most widely used classification model is based on ILD aetiology. It can be established in approximately 35% of cases. Up to 65% fall under the ‘unknown aetiology’ category, which is then further subdivided into idiopathic interstitial pneumonias (IIPs) and ‘rare’/’ others’ (see below)

Adjusted from ‘Approach to the adult with interstitial lung disease: Clinical evaluation’. Talmadge E King, Jr, MD, ed. By Kevin R Flaherty, MD, MS. UpToDate.com [Internet]. https://www.uptodate.com/contents/approach-to-the-adult-with-interstitial-lung-disease-clinical-evaluation  

CTD-ILD: connective tissue disease-ILD; IIP: idiopathic interstitial pneumonia; IPF: idiopathic pulmonary fibrosis

Another way to classify ILDs has been proposed:

Native parenchymal disorders

• IPF
• Non-specific interstitial pneumonia (NSIP)
• Acute interstitial pneumonia (AIP)
• Cryptogenic organising pneumonia (COP)

Systemic disease-related ILD

• Connective tissue-related ILD (CTD-ILD), e.g. myositis, rheumatoid arthritis (RA), scleroderma, systemic lupus erythematosus (SLE)
• Vasculitides, e.g. granulomatosis with polyangiitis (GPA), Churg-Strauss syndrome (EGPA), anti-glomerular basement membrane (anti-GBM) disease

Exposure related CTD

• Drug-related
• Radiation related
• Hypersensitivity pneumonitis
• Post infective

Vascular disorders

• Diffuse pulmonary haemorrhage

Epidemiology

Registries of various ILDs have been initiated in many countries, yet it remains challenging to determine incidence accurately due to differences in diagnostic criteria used and rarity of many of these conditions. In England alone, between 2,000 and 4,000 individuals are diagnosed with ILD every year. The most common subtypes are sarcoidosis, HP and IPF, accounting for 50-75% of all cases. Sarcoidosis incidence is estimated to be between 3 to 5 cases per 100,000 people per year in the UK, and it seems to be more common in patients of Afro-Caribbean descent.

The majority of ILDs are more common in older individuals, but sarcoidosis, connective tissue disease-associated ILD, pulmonary Langerhans cell histiocytosis, and inherited forms of ILD typically present between the ages of 20 and 40. Pneumoconiosis and IPF occur more frequently in men, while CTD-ILD is more common in women.

Pathophysiology

ILD subtypes all share similar pathophysiological mechanisms, and all primarily affect the same part of the lung: its interstitium. Lung interstitium contains a complex mixture of connective tissue elements, which together create a matrix supporting the respiratory tree and alveoli. It can be subdivided into parenchymal, axial and peripheral compartments. Axial interstitium surrounds primary bronchi and pulmonary arteries and is continuous with interlobular septa. The peripheral compartment contains strong supportive fibres between the visceral pleura and the lung parenchyma. In ILDs, it is the parenchymal interstitium that is mainly affected. It represents the ‘interface’ between alveolar epithelial cells and capillary endothelium, thus supporting the intralobular, gas-exchanging part of the lung.

The two key mechanisms by which the parenchymal interstitium is damaged in ILD are fibrosis and inflammation. Initial insult, be it by an environmental agent, drug, or an autoimmune process, leads to an influx of inflammatory cells; fibroblasts and type II pneumocytes get activated in order to repair the damage. Both processes result in accumulation of extracellular matrix components, which distort the alveolar/capillary interface and impair the gas exchange. As the disease progresses, the architecture of alveolar lumens and bronchi gets distorted as well. Mechanisms at play include alveolar infiltration with proliferating fibroblasts, traction bronchiectasis due to the scarred tissue ‘pulling’ the airways apart, and alveolar haemorrhage due to damaged capillary walls.

It is worth noting that some ILDs are predominantly fibrotic (e.g. IPF), while others are mainly inflammatory (e.g. ILDs in vasculitis), although many demonstrate some combination of the two. Diseases on each end of the spectrum share certain characteristics. For example, fibrotic ILDs tend to have a slower onset, poor response to therapy, and progressive course. In contrast, inflammatory ILDs tend to present acutely or sub-acutely, are mostly treated with immunosuppressive medications, and can be reversible. This distinction is clinically important, as knowing where the disease lies on the fibrosis-inflammation spectrum allows us to predict disease behaviour and response to therapy, even when specific diagnosis is challenging to establish.

Specific conditions

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis (CFA), is a chronic, progressive fibrosis of the lungs with an unknown cause. It is currently thought that an unknown antigen, e.g. a virus, tobacco or environmental pollution, causes activation of mesenchymal cells and subsequent secretion of extracellular matrix. Genetic factors are important in pathogenesis; predisposing mutations described so far include mucin 5B (MUC5B; present in up to 35% of IPF cases), surfactant protein C (SPC), surfactant protein A (SPA), and telomerase (TERT, TERC). Fibrosis in IPF is always progressive and has been compared to cancer in this regard. Indeed, it has been observed that, in contrast to what happens in normal healing process, fibroblasts in IPF acquire resistance to apoptosis and an ability to invade surrounding tissues – features usually associated with malignant processes. Eventually, progressive fibrosis leads to respiratory failure.

Extrinsic allergic alveolitis

Extrinsic allergic alveolitis (EAA), or hypersensitivity pneumonitis (HP), is a term for a subset of ILD disorders caused by an abnormal immunological reaction to an organic antigen. It is not an atopic disease and is not characterised by a rise in tissue eosinophils or IgE.

HP can be acute, subacute and chronic. Acute HP is an example of type III hypersensitivity reaction, in which antigen-antibody complexes deposit in lung interstitium, causing influx of inflammatory cells. Between flares, patients are asymptomatic, and their imaging is usually clear.

The chronic form of HP is a type IV, delayed hypersensitivity reaction in which T cells play a key role. It is also called ‘fibrotic’ HP, as persistent inflammation leads to progressive scarring of the lung. It is not clear why some individuals develop fibrotic HP. Notably, it can persist even after removal of causative antigen exposure. It can present and look similar to IPF, which is why histology is often required to distinguish the two. The most common triggers are outlined in Table 1.

Table 1: Antigen causes of hypersensitivity pneumonitis (not exhaustive). Adapted from Mudawi et al. (2021). An update on interstitial lung disease. British Journal of Hospital Medicine.

Pneumoconiosis

Pneumoconiosis is a group of diseases caused by inhalation of inorganic dust, usually in occupational context. Particles of <5 microns in size are small enough to reach terminal bronchioles and alveoli. Inflammation is triggered by a combination of direct toxicity to pneumocytes and alveolar macrophages (in particular asbestos, silica) and cell-mediated hypersensitivity reaction (e.g. berylliosis) in genetically predisposed individuals. Repeated exposure leads to a variety of clinical manifestations (Table 2).

Table 2: common types of pneumoconiosis. Adapted from Chapman, S.J. Oxford Handbook of Respiratory Medicine, 4th ed, 2021

Sarcoidosis

Sarcoidosis is a multisystem condition which involves lungs in 90% of all cases. It is believed to be caused by an abnormal immunological response to a benign antigen in a genetically predisposed host. The antigen triggers T-cell mediated response, which includes macrophage activation and production of interferon-γ. As a consequence, non-caseating granulomas are formed, and raised angiotensin converting enzyme (ACE) levels can often be detected in these patients, secondary to high macrophage activity. Macrophages also contain 1α-hydroxylase, the enzyme that catalyses the conversion from inactive to active vitamin D. As a result, sarcoidosis is often associated with hypercalcemia, which is occasionally significant enough to cause symptoms. In up to 60% of cases, sarcoidosis resolves in 2-5 years, often requiring no treatment. Some patients, however, progress to developing progressive lung fibrosis.

Connective tissue disease-related ILD

Connective tissue diseases (CTDs) can cause a variety of pulmonary complications, and ILD is one of the most serious ones. It is common for both conditions to be diagnosed simultaneously or for patients to develop ILD years after their CTD diagnosis. However, occasionally, the opposite occurs, and CTD patients present with pulmonary symptoms alone. Thus, it is important to consider systemic disease in any patient with new diagnosis of ILD (see ‘presentation’).

Pathophysiology of CTDs is beyond the scope of this section. The most common conditions leading to ILD are SLE, RA, Sjogren’s, systemic sclerosis, myositis and dermatomyositis.

Drug-induced ILD

Drug-related ILD can present either acutely (e.g. with certain antibiotics) or years after discontinuing the causative agent (e.g. cytotoxics). Full list of drugs which have been reported to cause pulmonary toxicity is available on ‘Pneumotox’ database: https://www.pneumotox.com/drug/index/. However, it is useful to be familiar with the most common examples (Table 3).

Radiation-related ILD can present as an acute radiation pneumonitis (weeks to months after exposure), fibrotic radiation pneumonitis (6 to 12 months) or radiation recall pneumonitis (years).

Table 3: common medications linked to pulmonary toxicity. Adapted from Chapman, S.J. Oxford Handbook of Respiratory Medicine, 4th ed. 

References

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• Marvin I. Schwarz & Talmadge E. King. Interstitial Lung Disease, fifth edition. Published by PMPH-USA, 2011. IBSN 1607950243
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• Chapman, S.J. Oxford Handbook of Respiratory Medicine, 4th ed. Oxford Medical Handbooks, 2021, ISBN: 9780198837114
• Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157-79. doi: 10.1146/annurev-pathol-012513-104706. Epub 2013 Sep 13. PMID: 24050627; PMCID: PMC4116429.
• Talmadge E King, Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention. uptodate.com, accessed on 10/01/2023.
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• Mudawi, Dalia & Heyes, K & Hastings, R & Rivera Ortega, Pilar & Chaudhuri, Nazia. (2021). An update on interstitial lung disease. British Journal of Hospital Medicine. 82. 1-14. 10.12968/hmed.2020.0556.