Hypersensitivity pneumonitis

Hypersensitivity pneumonitis, previously known as extrinsic allergic alveolitis, represents a group of immune-mediated pulmonary disorders characterised by an inflammatory and/or fibrotic reaction affecting the lung parenchyma and small airways.

Its diagnosis relies on a constellation of findings: exposure to an offending antigen, characteristic signs and symptoms, abnormal chest findings on physical examination, and abnormalities on pulmonary function tests and radiographic evaluation. 

Terminology

Hypersensitivity pneumonitis can be categorised into two subtypes ^13,14:

• non-fibrotic hypersensitivity pneumonitis
• fibrotic hypersensitivity pneumonitis

In patients where an inhaled antigen exposure has not been identified the terms cryptogenic hypersensitivity pneumonitis or hypersensitivity pneumonitis of undetermined cause have been used ¹⁴.

Previously, hypersensitivity pneumonitis had been categorised into ⁵

• acute hypersensitivity pneumonitis
• subacute hypersensitivity pneumonitis
• chronic hypersensitivity pneumonitis

although this is no longer in favour given the difficulty in delineating between these particular subtypes ¹⁴.

Epidemiology

Incidence varies widely based on climate, geography, and occupational or environmental exposures although is estimated at ~0.6 (range 0.3-0.9) per 100,000 population ¹⁴.

Clinical presentation

The onset of symptoms may be acute (weeks-months) or can be insidious (month-to-years of gradually worsening symptoms) ¹⁴. Common symptoms include dyspnoea and cough with less common symptoms being weight loss, fever/chills, malaise, chest tightness and wheezing ¹⁴.

Clinical examination may demonstrate mid-inspiratory squeaks and finger clubbing. There is a restriction pattern with decreased diffusing capacity on pulmonary function tests ^3,14. 

Pathology

Aetiology

More than 200 different antigens have been associated with the development of hypersensitivity pneumonitis. Antigen exposure may be domestic, industrial and/or recreational and there may be more than one antigen exposure ¹⁴:

• microbes
  • fungi/moulds, e.g. mushrooms, Aspergillus, Cryptococcus
  • yeasts, e.g. candida
  • bacteria, e.g. Pseudomonas
  • protozoa, e.g. Amoebae
  • nematodes
  • mites, e.g. Acarus siro
• proteins
  • animal proteins, e.g. animal fur dust, avian droppings/feathers
  • plant proteins, e.g. wood particles, grain flour
• inorganic particular matter
  • chemicals, e.g. isocyanate found in paint hardener
  • pharmaceuticals, e.g. antibiotics such as penicillin, immunosuppressants such as sirolimus/everolimus ⁸
  • metals, e.g. cobalt, zinc

The triggering particles are usually in the range of 1-5 micrometres in size ⁵. In ~40% (range 30-50%) the inciting agent may not be identified ¹⁴.

Depending on the type of precipitant, numerous other more precipitant-specific clinical terms have been used such as:

• bird fancier's lung (a.k.a. pigeon fancier's lung)
• farmer's lung
• cheese workers' lung
• bagassosis
• mushroom worker’s lung
• malt worker’s lung
• maple bark disease
• hot tub lung
• wine maker’s lung
• woodsman’s disease
• thatched roof lung
• tobacco grower’s lung
• potato riddler’s lung
• summer-type pneumonitis
• dry rot lung
• machine operator’s lung
• humidifier lung
• shower curtain disease
• furrier’s lung
• miller’s lung
• lycoperdonosis
• saxophone lung

Microscopic appearance

The histopathologic process consists of chronic inflammation of the bronchi and peribronchiolar tissue, often with poorly defined granulomas and giant cells in the interstitium or alveoli. Fibrosis and emphysema may develop later on.

Most cases of hypersensitivity pneumonitis, whether acute or insidious, include the following four histologic features in variable amounts and combinations ³.

• cellular bronchiolitis: chronic inflammatory cells lining the small airways, sometimes with resultant epithelial ulceration
• diffuse chronic interstitial inflammatory infiltrates: primarily consisting of lymphocytes and plasma cells but often including eosinophils, neutrophils, and mast cells
• poorly circumscribed interstitial non-necrotising (non-caseating) granulomas: consisting of lymphocytes, plasma cells, and epithelioid histiocytes, with or without giant cells
• individual giant cells in the alveoli or interstitium

Smoking is protective against hypersensitivity pneumonitis, presumably by the inhibitory action of nicotine on macrophage activation and lymphocyte proliferation and function ⁹. However, when smokers do develop hypersensitivity pneumonitis, it is more commonly fibrosing disease with a worse prognosis ¹⁰.

Subtypes

Hypersensitivity pneumonitis can be categorised into two subtypes based on the absence/presence of fibrosis given this is a determining factor in prognosis ^13,14:

• non-fibrotic hypersensitivity pneumonitis: purely inflammatory
• fibrotic hypersensitivity pneumonitis: mixed inflammatory/fibrotic or purely fibrotic

Radiographic features

HRCT chest is the main imaging technique for hypersensitivity pneumonitis with the various features for each subtype being able to be described as ¹⁴:

• typical hypersensitivity pneumonitis
• compatible with hypersensitivity pneumonitis
• indeterminate for hypersensitivity pneumonitis when features of the above two are absent

Plain radiograph

In population-based studies, the sensitivity of chest radiography for detection of this disease is relatively low ¹. Many patients may indeed have normal radiographs ³. 

Abnormal plain radiographic findings may be observed in some patients can include ³

• numerous poorly defined small (<5 mm) opacities throughout both lungs, sometimes with sparing of the apices and bases
• airspace disease: usually seen as ground-glass opacities (can be patchy or diffuse, resembling pulmonary oedema) or, more rarely, as consolidation
• a pattern of fine reticulation may also occur
• zonal distribution is variable from patient to patient and may even show temporal variation within the same patient

Later stages

• when fibrosis develops: there may be a reticular pattern and honeycombing, which sometimes are more severe in the upper lobes than in the lower ones
• volume loss may occur: particularly in the upper lungs, and peribronchial thickening may be visible
• cardiomegaly may develop as a result of cor pulmonale

CT

Non-fibrosing hypersensitivity pneumonitis

• typical: at least one abnormality of the parenchyma and small airways
  • parenchyma: ground-glass opacity (GGO), mosaic attenuation
  • small airways: ill-defined centrilobular nodules, air trapping
  • diffuse distribution +/- basal sparing
• compatible: non-specific changes reported in hypersensitivity pneumonitis
  • parenchyma: uniform and subtle GGOs, airspace consolidation, pulmonary cysts
  • diffuse distribution (although variant distributions of basal predominant or peribronchovascular) ¹⁴

Fibrosing hypersensitivity pneumonitis

• typical
  • coarse reticulations with lung distortion +/- non-predominate traction bronchiectasis and honeycombing
  • distribution may be
    • random
    • mid-zone predominant
    • relative lower zone sparing
  • small airways disease
    • ill-defined centrilobular nodules and/or GGOs
    • mosaic attenuation, three-density pattern (head cheese sign) and/or air trapping
• compatible
  • usual interstitial pneumonia (UIP) pattern
  • extensive GGOs with subtle lung fibrotic changes
  • variant distribution of lung fibrosis
    • peribronchovascular
    • subpleural
    • upper zones
  • small airways disease
    • ill-defined centrilobular nodules
    • three-density pattern and/or air trapping
• indeterminate
  • UIP pattern alone (i.e. no variant distribution or small airways disease)
  • indeterminate or probable UIP pattern
  • fibrotic non-specific interstitial pneumonia (NSIP) pattern
  • organising pneumonia ¹⁴

Other associated features of both subtypes include ^ref:

• small volume mediastinal lymphadenopathy (generally 10-20 mm in short-axis diameter) 
• occasional pulmonary arterial enlargement
• centrilobular emphysema
• with developing fibrosis, there can be reticulation, mainly in the middle portion of the lungs or fairly evenly throughout the lungs but with relative sparing of the extreme apices and bases

Treatment and prognosis

Removal of the precipitant is often the key to management.

Differential diagnosis

Due to a variable radiographic presentation, it may not be meaningful to give a differential diagnosis for hypersensitivity pneumonitis per se. It is better to refer to the differential for a particular radiographic feature:

• differential for centrilobular nodular opacities
• differential for ground-glass opacities