Hypersensitivity Pneumonitis in the Workplace

Santiago Quirce, MD, PhD
Joaquín Sastre, MD, PhD

Select One Definition Causative agents and environmental factors Host risk factors Clinical features Immunopathogenesis Diagnosis Treatment References Printer-friendly version

Definition

Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is an allergic lung disease that occurs as the result of an immunologic inflammatory reaction to the inhalation of any of a variety of organic dusts or low molecular weight chemicals (1, 2). The disease is a diffuse, predominantly mononuclear inflammation of the lung parenchyma, particularly the terminal bronchioles, interstitium, and alveoli. The inflammation often organizes into granulomas and may progress to fibrosis. There is a wide variety of agents that can cause the disease, most of which are present in the workplace (3-5). Thus, HP usually presents itself as an occupational respiratory disease.

Causative agents and environmental factors

HP develops as a result of the immunologically mediated events and the physiologic consequences that occur in the lung after inhalation of the responsible antigen in a sensitized individual. The offending agents may be bacterial (e.g. thermophilic actinomycetes), fungal (e.g. Alternaria, Aspergillus, Trichosporon), animal proteins (e.g. serum avian proteins), plant or insect proteins, low molecular weight chemicals (e.g. acid anhydrides, isocyanates), or others which are yet undefined (1-9).

Because of the great variety and ubiquity of the potential causative agents of HP, many individuals are exposed to them as part of their occupational, domestic or recreational environments. The prevalence of the disease, however, seems to be lower than 20 years ago (4). Most of the causative antigens have been recognized in a wide variety of occupations; thus, once the offending agent has been identified, it can be avoided and the disease prevented. Occupations in which there is exposure to moldy materials are particularly associated with the development of HP, for example, farmers, mushroom and tobacco workers. Other workers at particular risk include woodworkers, maple bark strippers, stucco workers, malt workers, bird fanciers, pigeon breeders, machine operators and foundry workers (1-9).

In general, there appears to be a direct relationship between the intensity of antigen exposure and the development of HP. Intensity (concentration) and duration of exposure to the antigen, frequency of exposure, particle size, and antigen solubility may influence disease latency, prevalence, severity and course (4,5). It is believed that acute HP usually results from intense intermittent exposure to inhaled antigens and that subacute HP results from a less intense but more persistent exposure. Chronic HP usually develops from acute or subacute forms of the disease. There may be an exposure threshold that has to be exceeded before acute and perhaps subacute forms of HP develop. The risk of HP is low under this exposure threshold and high beyond it, with a dose/effect relationship (5). Concurrent environmental factors may influence the development of HP, for example, HP occurs more frequently in nonsmokers than in smokers (possibly by impairment of macrophage function). In some circumstances, the onset of HP in sensitized asymptomatic subjects may be precipitated by additional lung inflammation, for example after viral or bacterial infection. The fact that many of the antigens of HP also have adjuvant properties that enable them to activate complement and release cytokines directly may also be relevant (4,5). In addition, exposure to airborne endotoxins, which is common in the workplaces associated with HP, potentiates antigen-specific airway inflammation and allergen responses (10).

Figure 1 shows the natural history of hypersensitivity pneumonitis and the influence of host and environmental factors in disease expression and progression.

Figure 1. Natural history of hypersensitivity pneumonitis.

Host risk factors

A characteristic of HP is that only 5-15% of subjects exposed to a provoking antigen develop the disease (5, 11). A much larger number of subjects exposed to the antigen develop sensitization in the form of a humoral or cellular immune response, but do not progress from sensitization to expression of disease (5).

Host risk factors are poorly characterized, with the exception of those linked to exposure factors. HP is more common in males than in females, predominating in middle-aged individuals, which is likely to reflect the characteristics of the exposed working population. As happens with other immune-mediated lung diseases, there is some evidence of a genetic predisposition, which, acting together with a specific environmental factor, leads to disease expression.

Several studies have implicated links between HLA types and HP, with an increased occurrence of HLA DR7 in pigeon fancier's lung (12), HLA B8 in pigeon fancier's lung and farmer's lung (13), and HLA-DQw3 in Japanese summer-type HP (14). Other studies, however, have found no association with HLA types (5).

Different results between studies may reflect inconsistent associations, the diversity of the clinical syndrome, the complexity of genetic factors, or the influence of additional environmental factors. Genetic factors are known to affect various components of the immune response. In HP there are preliminary reports suggesting that gene polymorphisms may play an important role. For instance, high responders to TNF-a are at greater risk for developing farmer's lung and pigeon fancier's lung (15). Polymorphisms of the Fc-receptor may also be relevant in determining the antibody response to a specific antigen (8).

Clinical features

HP is a complex dynamic clinical disorder that varies in its initial presentation and clinical course. The disease can present as an acute, subacute or chronic form (1-4). This traditional classification, although still clinically useful, may cause some confusion as it is often assumed that there is a progression from acute to chronic disease if antigen exposure continues. In fact, the interaction of antigen exposure and host response in the initiation and progression of the disease is considerably more complex than this, and the clinical course of the disease is unpredictable (5).

Acute form

Patients exhibit dyspnea, fever, tachypnea, myalgia and often cough 2 to 9 hours after exposure to the antigen. Bibasilar rales and occasionally cyanosis are found at physical examination. Hypoxemia and diffuse chest radiological nodulations are often present. The symptoms peak between 6 and 24 hours and resolve without specific treatment in 1 to 3 days, except for fever, which remits in a few hours. This clinical picture relapses after exposure to an environment that contains the responsible agent. Most patients have serum and/or BAL fluid precipitating antibodies against the causative antigen at presentation. Between acute episodes, chest radiographs typically revert to normal, although changes suggestive of fibrosis may be present.

Subacute form

This stage is similar to the chronic form in that dyspnea develops insidiously, but these patients also have discrete episodes of acute symptoms after antigen exposure.

Chronic form

The symptoms are not clearly related to a particular exposure and may consist predominantly of constitutional symptoms of weight loss, fever, and fatigue. End stage pulmonary fibrosis is frequently seen at presentation. Serum antibodies tend to wane after cessation of exposure, complicating the diagnosis.

Immunopathogenesis

HP is characterized by strong cellular and humoral responses to inhaled antigens. There is proliferation of cytotoxic lymphocytes (CD8+) and a striking production of IgG antibodies, presumably from proliferation of plasma cells stimulated by CD4+ Th1 lymphocytes (4). Inhaled antigen-carrying particles are ingested by pulmonary macrophages. The interaction between antigens, IgG antibodies and cytotoxic lymphocytes causes the cascade of events that is responsible for the activation of inflammatory cells and for the synthesis and release of a wide variety of mediators that trigger the inflammatory reaction in the peripheral airways and surrounding interstitial tissue. Many of the details of this inflammatory process, however, are still obscure.

The acute phase is dominated by macrophage-lymphocyte responses. After inhalation, soluble antigens bind IgG antibody, the immune complexes initiate the complement cascade, and the resulting C5 activates macrophages (16). Subsequently, macrophages secrete chemokines (IL-8, MIP-1 , RANTES) and cytokines (IL-1, TNF- , IL-6, IL-12) that first attract neutrophils and after several hours attract and activate circulating T lymphocytes and monocytes. MIP-1 and IL-12 promote the differentiation of CD4+ Th0 cells to Th1 cells. Increased numbers of CD4+ Th1 cells appear in the BAL fluid shortly after exposure, but in most cases of HP CD8+ cells predominate later (4).

The subacute phase is characterized by granuloma formation. After recruitment and activation, macrophages develop into epitheliod cells and multinucleated giant cells (17). Lymphoid follicles containing plasma cells also develop in the lesions during this phase.

In the chronic phase pulmonary fibrosis takes place. Collagen formation by myofibroblasts occurs. Activated alveolar macrophages produced TGF- 1, a potent stimulator of fibrosis and angiogenesis. Increased numbers of mast cells (of the connective tissue type) are present in BAL fluid, which correlate with procollagen III levels, and may contribute to the fibrosis of HP, along with macrophages, lymphocytes, plasma cells, and neutrophils (3-5).

Diagnosis

In its acute form, the diagnosis of HP can be quite straightforward, relying on the information obtained from a careful history and physical examination. The patients should have documented contact with the appropriate environmental antigen and have inspiratory crackles at physical examination. The variability in its clinical presentation (particularly in subacute and chronic forms), however, may lead to underdiagnosis of the condition unless it is considered as a diagnostic possibility. Once the diagnosis of HP is suspected, a thorough occupational and environmental history is necessary. Potential causative antigenic exposures should be investigated, as well as the temporal relationship between environmental exposures and clinical manifestations. In some circumstances it may be difficult to differentiate HP from other lung diseases, such as asthma or chronic obstructive pulmonary disease, which may be aggravated by the irritant effect of inhaled particulate matter, and from non-immunologically mediated syndromes associated with the inhalation of organic dusts, such as occurs in organic dust toxic syndrome and inhalational fevers (5).

No single clinical feature, radiological or laboratory test is diagnostic of the disease and the diagnosis is made by a combination of clinical features, radiographic abnormalities, lung function and immunological tests (Table 1, modified from ref. 5).

Table 1. Steps in the diagnosis of work-related hypersensitivity pneumonitis (modified from Bourke et al, ref. 5)

1. Identify exposure to an occupational provoking antigen
2. Demonstrate an immune response to the antigen
   • Precipitating antibodies, IgG ELISA
   • Specific sensitized T cells
3. Establish the relationship of symptoms to antigen exposure
   • Temporal relationship
   • Work-related
4. Assess the degree of impairment of lung function
   • Spirometry, lung volumes (plethysmography)
   • Diffusing capacity (DLCO)
5. Determine the extent of radiographic abnormality
6. Consider the need for lung biopsy or bronchoalveolar lavage
7. Consider the usefulness of a workplace or laboratory-based challenge study
8. Exclude alternative diagnoses (e.g. sarcoidosis, inhalational fevers)

• Lung function tests typically show a reduction in lung volumes (restrictive pattern), impairment of gas diffusion and hypoxemia. Superimposed airway obstruction may be seen, particularly with chronic HP.
• Chest radiography shows a range of abnormalities from an alveolar filling pattern to reticulonodular shadowing, depending on the combination of alveolitis and fibrosis. Bilateral micronodular infiltrates or patchy-ground glass opacities are better demonstrated with high-resolution computed tomography. In the subacute stage, a reticulonodular pattern is observed. In chronic disease, chest radiography demonstrates loss of volume and reticulonodular infiltrates suggestive of interstitial fibrosis or honeycombing. Nevertheless, a meta-analysis of available reports showed that only 80% of subjects with acute HP had abnormal chest radiographs (18).
• Laboratory tests: Specific serum precipitating antibodies are found in many, though not all, patients with HP (4). The sensitivity may be increased by performing IgG ELISA tests, which should be ordered selectively. However, as many as 40-50% of asymptomatic individuals exposed to the same antigens also have IgG antibodies in their serum. Thus, for the diagnosis of HP, the presence of serum precipitins is reasonably sensitive, but its specificity is low. Skin tests also show a low specificity and are not helpful in the diagnosis of HP (19).
• Bronchoscopy, to obtain diagnostic lung tissue and BAL fluid, may be necessary to confirm the diagnosis. Not withstanding, the histopathologic features of HP are distinctive but not pathognomonic. These include a diffuse interstitial infiltrate, scattered noncaseating granulomas, and cellular inflammation of the bronchioles (20). In advanced disease, where fibrotic changes predominate, the pathologic features may be indistinguishable from other causes of lung fibrosis, such as idiopathic pulmonary fibrosis.
  The most characteristic cell profile in BAL fluid is of a lymphocytic alveolitis with a predominance of CD8+ T cells. However, the cell profile is dependent upon the interval from last antigenic exposure and a neutrophil alveolitis is seen immediately after antigen challenge, and the number of CD8+ T cells falls after cessation of antigenic contact (5). A lymphocytic alveolitis is also found in asymptomatic subjects exposed to an antigen and in patients with organic dust toxic syndrome.
• In some instances, when a new etiological agent is being investigated, a pulmonary inhalation challenge in the workplace or in the laboratory with the suspected agent may be the only way to establish its causative role (21,22). Provocative testing by specific inhalation challenge, however, is rarely required to make the diagnosis of HP.

Schuyler and Cormier (23) have proposed diagnostic criteria for HP (Table 2). The diagnosis is confirmed if the patient fulfills 4 of the major criteria and at least 2 of the minor criteria and if other diseases with similar symptoms are ruled out.

Table 2. Diagnostic criteria for HP (Adapted from Schuyler and Cormier, ref. 23).

Major criteria

1. Symptoms compatible with HP
2. Historical evidence of exposure to an appropriate antigen or detection in the serum and/or BAL fluid of precipitating antibodies (IgG)
3. Findings compatible with HP on chest radiograph or high resolution CT scan (usually small centrilobular nodules, but there may be areas of hyperlucency or emphysema)
4. BAL fluid lymphocytosis
5. Pulmonary pathologic changes compatible with HP
6. Positive "natural" or controlled inhalation challenge: reproduction of symptoms and laboratory abnormalities after exposure to the suspected antigen

Minor criteria

1. Bibasilar rales
2. Decreased diffusing capacity
3. Arterial hypoxemia, either at rest or during exercise

Treatment

The cornerstones of treatment of HP are early diagnosis, identification of the causative agent and the avoidance of further exposure to this antigen. The prognosis is very good if the disease is detected early and exposure to the offending agent ceases. Thus, the recognition of the offending agent(s) is crucial, but often difficult. The identification of a specific agent may lead to changes in the occupational environment. Education of physicians and other healthcare professionals and populations at risk may be helpful in the early recognition of symptoms and encourage them to adopt preventive strategies. In some occupations associated with HP, complete cessation of antigen exposure may be particularly difficult, e.g. farming. The effectiveness of protective equipment, such as HEPA-filtered helmets, has not been proven (4). Supportive management and a short trial of systemic corticosteroids (e.g. prednisone 0.5-1 mg/kg/day for 2-4 weeks) is adequate in acute HP. Subacute forms of HP may require higher doses of corticosteroids for several months. The long-term beneficial effects of corticosteroids on arresting disease progression in subacute or chronic HP remains to be established (4).

References

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