16th January 2024

Hypersensitivity pneumonitis

Background

Hypersensitivity Pneumonitis (HP), also known as Extrinsic Allergic Alveolitis (EAA), is an interstitial lung disease (ILD) characterised by alveolar and bronchiolar inflammation triggered by a non-IgE immunological response secondary to repeated inhalation of an antigen.

Pathophysiology

HP is a result of complex genetic predisposition and environmental factors. Differences in susceptibility to HP are related to polymorphisms of the major histocompatibility complex (MHC) class II molecules (mainly HLA-DR and DQ). These are responsible for presentation of processed exogenous antigens to T-lymphocytes, which initiate the antigen-specific immune response.

A combination of type III (immune complex-mediated) and type IV (delayed) hypersensitivity reactions are implicated in HP. Exposure to the causative agent triggers a type III reaction after initial sensitisation. Repetitive exposure leads to a delayed hypersensitivity (Type IV) reaction, triggering activation of CD8 cytotoxic T cells. This leads to macrophage activation and granuloma formation. Disease progression, such as in fibrotic HP, is linked to an exaggerated T-cell immune response, specifically the TH2 response, which is believed to promote collagen deposition and fibrosis of the lung.

Aetiology

There are a vast range of implicated antigens in HP. The most common include the following:

Bacteria/Fungi

• Thermophilic actinomycetes-this includes Micropolyspora faeni and Thermoactinomyces vulgaris
  • Farmer’s lung
    • Occurs following exposure to mouldy crop
    • Micropolyspora faeni is the most common antigen
• Mycobacterium avium complex (MAC)- Found in poorly maintained hot tubs
• Aspergillus clavatus– malt worker’s lung (found in mouldy malt)
• Penicillium casei– cheese-worker’s lung (found in mouldy cheese)

Animal proteins

• Avian proteins– Bird fancier’s lung
  • Found in bird droppings or feathers of birds
  • Includes pigeons, chickens, turkeys, parakeets, and ducks

Reactive chemicals

• Acid anhydrides
• Isocyanates- these include varnishes and chemical foams
• Metalworking fluids

In addition, colonisation of various atypical mycobacteria and moulds in wind instruments can be implicated in the development of HP amongst wind instrument players.

Presentation

Traditionally, the clinical presentation of HP has been classified as acute, subacute, and chronic. Recent classification systems now consider separate phenotypes dependent on the presence or absence of fibrosis, thus categorising HP as fibrotic and non-fibrotic.

HP presents heterogeneously; common symptoms of both fibrotic and non-fibrotic disease include dyspnoea and chronic cough. Less common symptoms include constitutional symptoms such as fever, weight loss and malaise.

Acute presentations are more in keeping with non-fibrotic HP, whereas progressive symptoms are more consistent with fibrotic disease. Smoking is found to be a protective factor in developing HP.

Non-fibrotic HP features:

• Acute presentations typically occur 6 to 18 hours following high-level exposure to a causative agent
  • Symptoms may include fever, malaise, cough, and dyspnoea
• Patients may also present sub-acutely with similar progressive symptoms. This occurs over a period of weeks to months
• Physical examination may be normal- but inspiratory crackles and squeaks can be heard due to small airways inflammation

Fibrotic HP features:

• Insidious onset of dyspnoea, cough, anorexia, and weight loss
• Occurs secondary to chronic exposure to the sensitised antigen
• On examination, digital clubbing, focal or diffuse inspiratory crackles, and inspiratory squeaks may also be present. Wheezing is rare.

Diagnosis 

There is no single gold standard diagnostic test for HP. Diagnosis is based on detailed exposure history, clinical presentation, and a combination of investigations.

Laboratory tests

• Serum IgG (precipitins) against causative antigens
  • Only indicates exposure to specific antigens rather than diagnosis of HP
  • High false negative rate
  • The specific causative antigen may not be represented in the testing panel due to the vast range of causative agents.

Pulmonary function tests

• Non-fibrotic HP demonstrates a restrictive pattern
• Fibrotic HP- demonstrates both an obstructive and restrictive features

Imaging

Chest radiography

• Chest x-rays may be normal
• Where changes are present (more common in fibrotic HP), there are predominantly upper zone reticular interstitial changes with lung volume loss

High-resolution CT scan (HRCT)

• Typical findings in HP include:
  • Centrilobular ground-glass nodules due to bronchiolar inflammation
  • Air trapping occurs following inflammation of small airways, leading to retained air
  • Ground glass changes– interstitial inflammation leads to increased lung density

In HP, HRCT typically demonstrates a “three density pattern” which describes varying areas of attenuation- ground glass changes, decreased lung density (due to air trapping) and also areas of normal lung parenchyma. This is highly specific for HP. Such changes overlap with other forms of ILD. Sparing of bases and air trapping favours a diagnosis of HP.

Bronchoalveolar lavage (BAL)

• Flexible bronchoscopy with BAL typically displays lymphocytosis >30% in HP
• This helps to exclude other lung diseases which may present similarly to HP
• A low CD4+/CD8 + lymphocytosis is suggestive of HP
• Sarcoidosis presents with a high CD4+/CD8+ ratio of >3.5

Lung biopsy

• This should only be considered if a definitive diagnosis cannot be reached despite the above investigations.
• Lung biopsy histology shows a mixture of lung fibrosis, alveolitis and non-caseating granuloma formation.

Management 

Non- pharmacological management

Antigen avoidance

• Identifying and eliminating the causative antigen is the most crucial step in management.

Pharmacological management

Glucocorticoids

• HP may respond to steroids initially and is used in both fibrotic and non-fibrotic disease. However, there is little evidence regarding long-term outcomes or progression of disease.

Non-steroid therapies

• In fibrotic HP, anti-fibrotic agents have been suggested for treatment
• Nintedanib (a tyrosine kinase inhibitor) is licensed for use in chronic progressive fibrosing ILDs in several countries

References

• Chandra, D. and Cherian, S. V. (2021) Hypersensitivity Pneumonitis. StatPearls Publishing.
• “Erratum: Diagnosis of hypersensitivity pneumonitis in adults: An official ATS/JRS/ALAT clinical practice guideline” (2021) American Journal of Respiratory and Critical Care Medicine, 203(1), pp. 150–151. doi: 10.1164/rccm.v203erratum1.
• Hamblin, M., Prosch, H. and Vašáková, M. (2022) “Diagnosis, course and management of hypersensitivity pneumonitis,” European Respiratory Review: an official journal of the European Respiratory Society, 31(163), p. 210169. doi: 10.1183/16000617.0169-2021.
• Holling, T. M., Schooten, E. and van Den Elsen, P. J. (2004) “Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men,” Human immunology, 65(4), pp. 282–290. doi: 10.1016/j.humimm.2004.01.005.
• Karr, R. M. et al. (1978) “Occupational asthma,” The Journal of allergy and Clinical Immunology, 61(1), pp. 54–65. doi: 10.1016/0091-6749(78)90474-8.
• Reid, P. A. and Reid, P. T. (2013) “Occupational lung disease,” The Journal of the Royal College of Physicians of Edinburgh, 43(1), pp. 44–48. doi: 10.4997/JRCPE.2013.111.