Farmer's Lung

 

INTRODUCTION

Background: Farmer’s lung is the most common type of hypersensitivity pneumonitis. Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is an immunologically mediated inflammatory disease of the lung involving the terminal airways (see Hypersensitivity Pneumonitis). The condition is associated with intense or repeated exposure to inhaled biologic dusts. The classic presentation of farmer’s lung results from inhalational exposure to thermophilic Actinomyces species and occasionally from exposure to various Aspergillus species.

The effect of these antigens in farmers was described as early as 1713. In Britain in 1932, Campbell described a disorder of the lung due to inhalation of the dust from moldy hay. In 1964, Ramazzini and Wright described workers getting "diseases of the chest."

Thermophilic actinomycetes species include Saccharopolyspora rectivirgula (formerly Micropolyspora faeni), Thermoactinomyces vulgaris, Thermoactinomyces viridis, and Thermoactinomyces sacchari, among others. These organisms flourish in areas of high humidity and prefer temperatures of 40-60°C.

The thermophilic actinomycetes are ubiquitous organisms usually found in contaminated ventilation systems and in decaying compost, hay, and sugar cane (bagasse). Exposure to large quantities of contaminated hay is the most common source of inhalational exposure for farmers who develop farmer’s lung; therefore, grain farmers are not at risk for the development of the disease. Farmer’s lung is often a disease of dairy farmers who handle contaminated hay during the winter months. Most cases of farmer’s lung occur in cold, damp climates in late winter and early spring when farmers use stored hay to feed their livestock.

Exposure to the causative antigens depends on the type of farming, industry, and climate in the area. Note that farming practices are changing with time and that new antigens may be introduced or disappear from a region (eg, the disappearance of bagassosis in Louisiana sugar cane workers, the appearance of Pseudomonas fluorescens in machine operator’s lung). The dynamic nature of this disease and the changing environment may lead to new challenges for the clinician.

In addition to the inhalational exposure to the organic dusts responsible for the hypersensitivity reaction in farmer’s lung disease, allergens, chemicals, toxic gases, and infectious agents must also be considered as potential triggers of airway symptoms in symptomatic farmers. Farming is currently ranked as one of the top three most hazardous occupations, along with construction and mining.

 

Pathophysiology: The pathogenesis of farmer’s lung depends on the intensity, frequency, and duration of exposure and on host response to the causative antigen. Both humoral and cell-mediated immune responses seem to play a role in pathogenesis. During acute episodes, acute neutrophilic infiltration is followed by lymphocytic infiltration of the airways. Levels of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are increased. These cytokines have proinflammatory and chemotactic properties. They cause the recruitment of additional inflammatory mediators, resulting in direct cellular damage and changes in the complement pathway, which provide the necessary stimuli to increase vascular permeability and migration of leukocytes to the lung.

If the acute exposure is large, a dramatic increase in inflammation leads to increased vascular permeability, which can alter the alveolar capillary units, thus promoting hypoxemia and decreased lung compliance. If the exposure is prolonged and continuous, collagen deposition and destruction of the lung parenchyma occur with resultant decreased lung volumes.

Strong evidence suggests the involvement of immune complex–induced tissue injury (type III hypersensitivity). The timing of development of symptoms after exposure supports this conclusion. The presence of antigen-specific immunoglobulin and complement activation and deposition in the lung also supports immune-complex or type III hypersensitivity in the pathogenesis of farmer’s lung.

Cell-mediated, delayed-type hypersensitivity (type IV hypersensitivity) also plays a major role in the pathogenesis of this syndrome. The presence of lymphocytes, macrophages, and granulomas in the alveolar spaces and the interstitium supports this conclusion.

 

Frequency:

  • In the US: Farmer’s lung is one of the most frequent types of hypersensitivity pneumonitis.

     

    • Incidence is highly variable and depends on multiple factors, such as intensity, frequency, and duration of exposure, type of farming, and climate.

       

    • An incidence of 8-540 cases per 100,000 persons per year for farmers has been reported.

       

    • Hypersensitivity pneumonitis affects 0.4-7% of the farming population.
  • Internationally: The prevalence of farmer’s lung in the United Kingdom has been reported to be 420-3000 cases per 100,000 at-risk persons.

     

    • Epidemiologic surveys in France and Sweden show a cumulative prevalence of the disease in the range of 2.5-153 cases per 1000 farmers.

       

    • Incidence of farmer’s lung in Finland is 0.7%. This figure is calculated from death certificates.

Mortality/Morbidity: The mortality rate from farmer’s lung is reportedly 0-20%.

  • Death usually occurs 5 years after diagnosis.
  • Several factors have been shown to increase mortality rates in farmer’s lung, including clinical symptoms occurring more than 1 year before diagnosis, symptomatic recurrence, and pulmonary fibrosis at the time of diagnosis.
  • Comorbid factors: Although a history of smoking appears to decrease the overall risk for the development of hypersensitivity pneumonitis, a smoking history is the strongest predictor of increased respiratory symptoms once the diagnosis is made. Preexisting bronchial hyperreactivity with airway obstruction is also a factor.

CLINICAL

History: The clinical syndrome of farmer’s lung, as with other types of hypersensitivity pneumonitis, is categorized as acute, subacute, or chronic.

  • Acute farmer’s lung
    • Acute farmer’s lung develops after large exposure to moldy hay or contaminated compost. Symptoms often spontaneously resolve within 12 hours to days if antigen exposure is eliminated or avoided.
    • Acute farmer’s lung manifests as new onset of fever, chills, nonproductive cough, chest tightness, dyspnea, headache, and malaise.
    • If the inhalational exposure is large, patients may develop acute respiratory failure.
  • Subacute farmer’s lung
    • Subacute farmer’s lung manifests as chronic cough, dyspnea, anorexia, and weight loss.
    • Subacute disease is insidious in onset and may occur over weeks to months.
  • Chronic farmer’s lung
    • Chronic farmer’s lung results from prolonged and continuous exposure to the antigen.
    • Patients may have irreversible lung damage.
    • Patients may experience severe dyspnea at rest or with exertion.

Physical:

  • Acute farmer’s lung
    • Fever
    • Tachycardia
    • Nonproductive cough
    • Rales
    • Rales that persist after fever subsides
    • Wheezing (rare)
  • Subacute farmer’s lung
    • Normal examination findings between presentations
    • Anorexia
    • Weight loss
    • Chronic nonproductive cough
    • Generalized fatigue
  • Chronic farmer’s lung
    • Bibasilar rales
    • Clubbing - More often observed in patients with chronic farmer’s lung with long-standing hypoxemia and parenchymal damage
    • Anorexia
    • More severe dyspnea
    • Weight loss
    • Impaired exercise tolerance

Causes:

  • Thermophilic actinomycetes
    • S rectivirgula (formerly M faeni)
    • T vulgaris
    • T viridis
    • T sacchari
    • Aspergillus species

DIFFERENTIALS

Allergic and Environmental Asthma
Hypersensitivity Pneumonitis
Mycobacterium Avium-Intracellulare
Pneumocystis Carinii Pneumonia
Pneumonia, Bacterial
Pneumonia, Viral
Pulmonary Fibrosis, Idiopathic
Rhinitis, Allergic
Sarcoidosis


Other Problems to be Considered:

Differential diagnosis of farmer’s lung depends on the amount, intensity, duration, and frequency of exposure and on the stage of disease at clinical presentation.

  • Acute hypersensitivity pneumonitis due to farmer’s lung

  • Pulmonary edema

  • Bronchoalveolar cell carcinoma

  • Organic dust toxic syndrome

  • Chronic farmer’s lung

  • Congestive heart failure

  • Desquamative interstitial pneumonitis

  • Respiratory bronchiolitis - Interstitial lung diseases

  • Chemotherapeutic agents

  • Radiation

  • Inhaled toxins

  • Pneumoconioses

  • Toxic fume bronchiolitis (eg, caused by sulfur dioxide, nitrogen dioxide, ammonia, chlorine, phosgene, ozone)

  • Grain fever

  • Chronic bronchitis

WORKUP

Lab Studies:

  • No single diagnostic or clinical laboratory study is specific to the diagnosis of farmer’s lung. The most important diagnostic tool is a detailed environmental history.
    • Leukocytosis with neutrophilia (but not eosinophilia) and elevated erythrocyte sedimentation rate (ESR), C-reactive protein level, and quantitative immunoglobulin level are noted.
    • Precipitating immunoglobulin G (IgG) antibodies confirms past exposure but does not indicate active disease.
    • Precipitating antibodies are present in up to 50% of asymptomatic farmers exposed to the antigen.
    • In farmer’s lung, negative precipitin results have been reported because of a lack of appropriate antigen selection in serologic commercial testing.
    • Laboratories must select antigens based on knowledge of local climate and agricultural practices rather than reliance on commercially available antigen panels.

Imaging Studies:

  • Chest radiography
    • Findings are normal between acute attacks.
    • Findings are abnormal during acute and subacute stages of disease.
    • Diffuse air-space consolidation is typical of acute farmer’s lung (with acute antigen exposure).
    • Nodular or reticulonodular pattern is characteristic of the subacute phase.
    • Linear radiodensities may be discovered and indicate areas of fibrosis from previous attacks.
    • Pulmonary apices are often spared on plain chest radiography.
  • High-resolution computed tomography
    • High resolution CT scanning is a superior diagnostic modality compared with plain radiography.

       

    • Pulmonary fibrosis with honeycombing is observed in chronic disease.

       

    • Peri-bronchovascular distribution of nodules with ground-glass attenuation may be observed.

       

    • A normal finding on high-resolution CT scans eliminates the possibility of active acute or chronic farmer’s lung.

Other Tests:

  • Pulmonary function tests
    • Spirometry findings may be normal between attacks and before the development of chronic disease.
    • Acute, subacute, and chronic forms of farmer’s lung have a restrictive ventilatory pattern with reduced forced vital capacity (FVC), reduced total lung capacity (TLC), and preserved airflow.
    • Mild-to-severe hypoxemia at rest or during minimal exercise may be present with active disease.
    • Decreased diffusion capacity is present with active disease.

Procedures:

  • Bronchoscopy
    • Bronchoscopy is useful to exclude other disease processes in the acute setting and to obtain bronchoalveolar lavage (BAL) fluid samples for cell counts.
    • Transbronchial biopsy may show evidence of peri-bronchovascular granuloma formation supporting the diagnosis, but its yield is limited because of sampling size.
  • Open lung biopsy
    • Consider this procedure if noninvasive tests are equivocal or inconclusive.
    • Consider this procedure if the patient’s presentation is atypical in the presence of significant clinical evidence for the disease.
Histologic Findings: Chronic interstitial inflammation is present with infiltration of plasma cells, mast cells, histiocytes, and lymphocytes. Small and poorly organized nonnecrotizing granulomas are present, usually adjacent to bronchioles. Interstitial fibrosis is often present in chronic disease. Changes consistent with bronchiolitis obliterans may be evident. Guidelines for diagnosis of farmer’s lung are as follows:

 

  • Major criteria

     

    • Symptoms compatible with hypersensitivity pneumonitis

       

    • Evidence of exposure to appropriate antigen by history or detection of antigen-specific antibody in serum and/or BAL fluid

       

    • Characteristic radiographic changes on plain radiographs or high-resolution CT scans

       

    • Bronchoalveolar lymphocytes (if BAL was performed)

       

    • Pulmonary histological changes compatible with hypersensitivity pneumonitis (if lung biopsy was performed)

       

    • Positive natural challenge findings (reproduction of symptoms and laboratory abnormalities after exposure to the probable environment)

     

  • Minor criteria

     

    • Presence of bibasilar rales

       

    • Decreased diffusion capacity

       

    • Arterial hypoxemia either at rest or during exercise

 

TREATMENT

Medical Care: Systemic corticosteroid administration and avoidance measures constitute the primary treatment for farmer’s lung.

Diet: No dietary restrictions are needed.

Activity: Patients may decrease activity because of cough and dyspnea on exertion. In a patient with acute farmer’s lung, pulmonary function improves once antigen exposure is eliminated. Between episodes of acute disease, activity may be unlimited.

MEDICATION

Systemic corticosteroids (combined with avoidance measures) are the primary agents used to treat farmer’s lung.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, cromolyn, nedocromil) or systemic immune modulators are not indicated for treatment at this time.

Drug Category: Corticosteroids -- Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Drug Name
 Prednisone (Deltasone, Orasone, Meticorten) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prescribed for severe symptoms or significant lung dysfunction despite antigen avoidance.
Adult Dose 0.5 mg/kg/d PO for 4-8 wk, then taper
Pediatric Dose 4-5 mg/m2/d PO; alternatively, 0.05 -2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; bacterial, fungal, or tubercular systemic infections
Interactions Coadministration with estrogens may decrease clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, and increased incidence of infection may occur with glucocorticoid use

FOLLOW-UP

Further Inpatient Care:

  • Systemic corticosteroids
  • Serum precipitins
  • Flexible bronchoscopy to exclude other etiologies
  • Transbronchial biopsy may be of limited benefit in patients with acute farmer’s lung.
  • Open lung biopsy may be indicated to confirm the diagnosis if other diagnostic criteria are not met.

Further Outpatient Care:

  • Routine spirometry with lung volumes and diffusion capacity
  • Arterial PO2 and arterial-alveolar gradient: Recommend exercise (6-min walk or by ergometer) if the room air PO2 level is normal.
  • Monitor chest radiographs and consider high-resolution CT scans of the chest to seek resolution of infiltrates or presence of ground-glass opacities that may indicate a need for further treatment with corticosteroids and/or continued insult to the lungs by antigen exposure.

Deterrence/Prevention:

  • Complete avoidance of the antigen is indicated.
  • Protective devices (eg, masks) may reduce the amount of antigen; however, again, complete avoidance is recommended.
  • Maintaining humidity at less than 60% may discourage microbial growth.
  • Keeping hay on farms dry and well protected may discourage growth of bacteria and molds.

Complications:

  • Cor pulmonale
  • Hypoxemic respiratory failure
  • Pulmonary fibrosis
  • Death

Prognosis:

  • The long-term prognosis of farmer’s lung varies and depends on the extent of fibrosis and the amount of irreversible damage to the lung parenchyma.
  • In some patients, the disease may progress even after the antigen exposure has been eliminated.
  • If the diagnosis of farmer’s lung is confirmed before irreversible changes have developed, most patients recover with minimal functional abnormalities and few become disabled.
  • In the acute stages, restriction with decreased static compliance and diffusing capacity that reverses over several weeks (with antigen avoidance) may occur.
  • In subacute disease, bronchiolitis and granuloma formation might be slower to resolve even with corticosteroid therapy.
  • Individuals with a ground-glass appearance on high-resolution CT scans of the chest have higher response rates to systemic corticosteroids.
  • Patients with honeycombing or pulmonary fibrosis may have less than a 20% response to corticosteroids and a mortality rate greater than 90% at 5 years after diagnosis.
  • Predictors of long-term decline in farmer’s lung
    • Recurrent acute episodes
    • Allergy to mites, organic dust, and fungal elements

       

    • Smoking, which promotes deterioration of lung function in patients diagnosed with farmer’s lung

Patient Education:

  • Environmental control and complete avoidance of the antigen should be the goal.
  • Complete avoidance of the environment or farm may be required to ensure prevention of chronic disease and survival.

MISCELLANEOUS

Medical/Legal Pitfalls:

  • Failure to diagnose farmer’s lung in children living on farms
  • Failure to review a patient’s work and occupational history with emphasis on progression or improvement of symptoms when the patient is away from the farm
  • Failure to recognize farmer’s lung when pulmonary function test and radiographic findings are normal between exacerbations
  • Failure to recognize the limits of transbronchial biopsy and serum precipitins: Interpretation of these tests is dependent on the size of the sample and proper testing with the correct antigen, respectively.
  • Making the common mistake of misdiagnosing acute farmer’s lung as viral/bacterial pneumonia or acute infection

Special Concerns:

  • History of recurrent pneumonia should prompt consideration of hypersensitivity pneumonitis.
  • A complete environmental and occupational history is the key to prompt diagnosis of farmer’s lung.
  • Periodic episodes of acute respiratory symptoms without obvious triggers should also clue the clinician to evaluate for farmer’s lung.
  • Consider recommending the wear of filtration masks. This practice is not the criterion standard and should be considered only as the last resort with the understanding that it may not provide complete protection from the antigen.
  • Encourage smoking cessation measures.
  • Krebs von den Lungen-6 (KL-6) has been recognized as a marker for the activity of diffuse interstitial lung diseases, and levels may be elevated in patients with farmer’s lung.
  • Consider Penicillium species and subspecies in Canada and Europe. Fatalities from farmer’s lung have been associated with Penicillium brevicompactum and Penicillium polivicolor.