11th January 2024

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.