Hypersensitivity pneumonitis

Synonym: extrinsic allergic alveolitis

What is hypersensitivity pneumonitis?

Hypersensitivity pneumonitis (HP) - now the preferred term for extrinsic allergic alveolitis - is a condition in which there is diffuse, granulomatous inflammation of the lung parenchyma and airways in people who have been sensitised by repeated inhalation of organic antigens in dusts (eg, from dairy or grain products, animal dander and protein and water reservoir vapourisers).¹

There are acute, subacute and chronic forms. Acute and subacute forms cause a pneumonitis which can be recurrent. Chronic disease can cause fibrosis, emphysema and permanent lung damage.²

See also the separate Pneumonitis and Occupational asthma articles.

Pathogenesis and risk factors ¹

The pathogenesis is thought to involve both cell-mediated and immune complex-mediated hypersensitivity reactions. There may also be a genetic predisposition. It has been suggested that a possible viral trigger may initiate a flare. Radiology and pathology examinations of patients with COVID-19 virus infection revealed inflammatory reactions in the lung that resembled what is observed in hypersensitivity pneumonitis rather than in other viral pneumonia.³

Implicated antigens include avian antigens, mammalian proteins, fungi and fungal spores, bacterial antigens and small-molecular-weight chemicals. However, the provoking antigen can sometimes be difficult to identify with certainty.

It can be associated with many occupations and hobbies - the other risk factor is pre-existing lung disease. Examples are:

• Farmer's lung - one of the most common forms, due to exposure to mouldy hay. The major antigen is Saccharopolyspora rectivirgula.

• Bird-fancier's lung - one of the most common forms. Due to exposure to avian proteins - eg, pigeons, parakeets.

• Cheese-worker's lung - exposure to cheese mould, Penicillium casei.

• Malt worker's lung - exposure to Aspergillus clavatus in mouldy malt.

• Hot tub lung - exposure to Mycobacterium avium in poorly-maintained hot tubs.⁴

• Chemical worker's lung - trimellitic anhydride, diisocyanate and methylene diisocyanate act as the antigens during the manufacture of plastics, polyurethane foam and rubber.

• Mushroom worker's lung - exposure to thermophilic actinomycetes in mushroom compost.⁴

How common is hypersensitivity pneumonitis? (Epidemiology)¹

• There is a lack of international consensus on diagnostic criteria, which can affect prevalence figures. Population registry studies give an incidence of around 20 per 100,000 person-years.

• Diagnosis is usually in adulthood, unless there is a clear risk-factor in childhood (such as exposure to birds) - bird-fanciers lung is the commonest form of hypersensitivity pneumonitis in children, but is still a rare condition.⁵

Symptoms of hypersensitivity pneumonitis (presentation)¹

Acute form

• Symptoms usually start 4-8 hours after exposure to the sensitising antigen and resolve quickly, usually within 1-2 days .

• There is a flu-like illness with fever, chest tightness, dry cough and dyspnoea. Associated symptoms include malaise, chills, headache, generalised aches and pains, anorexia and tiredness.

• Symptoms are directly related to level of exposure, and low-level acute exposure may produce mild symptoms that last for just a few hours.

• Signs include fever, tachypnoea and bibasal fine inspiratory crackles. Wheeze is rare.

• In very severe cases, patients may develop life-threatening respiratory failure with cyanosis, respiratory distress at rest and high fever.

Subacute or intermittent form

• Symptoms tend to be less severe and more gradual in onset with a productive cough, dyspnoea, fatigue, anorexia and weight loss.

• There may be a history of repeated acute attacks.

• It can present as recurrent pneumonia.

• Signs are similar to above.

• Severe episodes can be life-threatening.

• After the exposure is removed it can take weeks or months for symptoms to resolve.⁶

Chronic form ¹

• In the chronic form there are often no systemic symptoms except weight loss and gradual diminution of exercise tolerance due to dyspnoea.

• If the source of the antigen is removed, there may only be partial improvement of symptoms.⁶

• Cyanosis and clubbing may develop.

• Tachypnoea, obvious respiratory distress and inspiratory crackles over the lower lung fields may be present.

• Eventually there may be chronic hypoxaemia and pulmonary hypertension with right heart failure.

• There may also be acute exacerbations in those with chronic disease.⁷

Differential diagnosis

• Infection (bacterial, fungal, viral including tuberculosis).

• Connective tissue disorders causing interstitial lung disease.

• Pulmonary fibrosis (including idiopathic).

• Asthma.

• Sarcoidosis.

• Histoplasmosis.

• Drug-induced interstitial lung disease.

Diagnosis

History and examination

• Good history-taking is essential to aid diagnosis. A high index of suspicion is needed.

• Sensitisation can occur after a period of exposure to the antigen, varying from weeks to years.

• Be alert to occupation, pets, hobbies and environmental factors in those who present with chronic cough and respiratory symptoms or acute symptoms with no obvious infectious trigger.

• Also remember that water damage to the patient's home or school may precipitate symptoms as well as the use of a hot tub, sauna or swimming pool.

• Examination may be normal, or may reveal inspiratory crackles or clubbing.

Investigations

• Blood tests: inflammatory markers may be raised but are nonspecific. There may be serum antibodies detectable in some patients but there are no detectable antibodies in many. The presence of antibodies is nonspecific, as they may also occur in those who have been exposed but have no disease. Despite the pitfalls of false positives and false negatives, analysis of antigen-specific IgG antibodies can be useful as supportive evidence for diagnosis. The antibody titre level may also be helpful.⁸

• CXR: in the acute form this may be normal (which does not exclude the diagnosis) in some or show diffuse micronodular interstitial shadowing. In the subacute form, there may be micronodular or reticular opacities in the mid/upper lung fields. In the chronic form, there may be features of fibrosis with loss of lung volume.⁹

• CT scanning: high-resolution CT is a good way to evaluate the stage of disease and usually shows typical changes.⁹

• Lung function testing: this can be normal but can sometimes help to determine the degree of respiratory impairment. Spirometry shows a restrictive defect in acute and subacute forms but there may be a mixed restrictive/obstructive picture in the chronic form. Oxygen saturation may be reduced with further desaturation on exercise. There may also be reduced capacity of the lungs to diffuse carbon monoxide.¹⁰

• Inhalation challenge test (provocation testing): temperature, circulating neutrophil and lymphocytes, lung function and exercise tests are performed after inhaling the suspected allergen. This can produce symptoms and should only be performed in specialised centres. ¹

• Bronchoalveolar lavage: analysis of the lymphocyte count and CD4/CD8 cell ratio in bronchoalveolar lavage fluid may aid diagnosis. There is usually a lymphocytosis and the CD4/CD8 ratio is reduced to less than 1. This adds to the evidence favouring hypersensitivity pneumonitis, but is not diagnostic. ⁹

• Transbronchial or open lung biopsy: this may show characteristic histopathological features.

Management of hypersensitivity pneumonitis ¹⁰¹

• In acute severe cases with significant respiratory distress and/or the presence of cyanosis, consider immediate referral to hospital for further assessment.

• Supplemental oxygen should be given to treat hypoxaemia.

• In the acute form, simply avoiding further exposure will usually result in recovery without medication.

• Once the diagnosis is made it is important to avoid allergen exposure. This may require a change of job. Before such a drastic step, consultation with a respiratory consultant or specialist in occupational medicine may be prudent. Respiratory protective equipment used at work reduces antibody counts but does not improve the clinical features of chronic hypersensitivity pneumonitis.

• Corticosteroids may be indicated for the treatment of severe acute and subacute forms and for chronic forms that are severe or progressive . However, steroids don't seem to alter the long-term outcome. Inhaled steroids are not beneficial.

• In advanced chronic disease, pulmonary fibrosis can still progress and death can occur despite aggressive corticosteroid therapy .

• Azathioprine and mycophenolate mofetil have been used as steroid-sparing agents and also in resistant cases.

• Other treatments tried are rituximab and leflunomide have also been reported in small studies to be of benefit.

• In chronic HP with progressive fibrosis, antifibrotic agents have been suggested.

• Lung transplantation has also improved medium-term survival rates in chronic HP, with five year survival of up to 70%.¹¹

Complications of hypersensitivity pneumonitis

These can include:

• Spontaneous pneumothorax.

• Pulmonary fibrosis.

• Emphysema.

• Respiratory insufficiency or failure.

• Cor pulmonale.

Prognosis

• Early recognition and control of exposure are key to outcome.

• In acute and subacute forms, most patients recover lung function completely when exposure to the antigen stops. However, this may take several years for subacute forms.

• The chronic form may be progressive and irreversible and result in debilitating fibrotic lung disease with high mortality rates.

Preventing hypersensitivity pneumonitis

• Health and Safety measures at work, including wearing appropriate protective equipment and having adequate air filters and ventilation.

• Avoiding pastimes which provoke the illness.

• Adequate maintenance of hot tubs/indoor swimming pools, humidifiers, heating, ventilation and air-conditioning equipment.