Hypersensitivity Pneumonitis in the Workplace
Updated: September 2013
Originally Posted: 2002
Reviewed by Jonathan Bernstein, MD
Santiago Quirce, MD, PhD
Hospital Universitario La Paz
Servicio de Alergia
Universidad Autonoma de Madrid
Joaquín Sastre, MD, PhD
Fundación Jiménez Díaz
Servicio de Alergia
Universidad Autonoma de Madrid
Citation: Quirce S, Sastre J. Hypersensitivity pneumonitis in the workplace. (Disease Summary) Allergic Diseases Resource Center, World Allergy Organization, 2013.
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 with or without systemic manifestations [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. The report of the NHLBI/ORD workshop  stated that “hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is a complex health syndrome of varying intensity, clinical presentation, and natural history. HP is the result of an immunologically induced inflammation of the lung parenchyma in response to inhalation exposure to a large variety of antigens”. The HP Study Group  defined HP as “a pulmonary disease with symptoms of dyspnea and cough resulting from the inhalation of an antigen to which the patient has been previously sensitized”.
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.
The proportion of patients who develop HP for most antigens is unknown. It is estimated that 0.5% to 3% of farmers will develop HP . The general prevalence of the disease, however, seems to be lower than what had been reported 20 years ago .
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, metal working fluids, pharmaceutical agents), or others which are yet undefined [7-9].
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. 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 can be prevented. Occupations where there is exposure to moldy materials are particularly associated with the development of HP, such as 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.
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 [6,10]. 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 .
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. Antigens that cause HP also have adjuvant properties that enable them to activate complement and release cytokines directly which also may be relevant [6, 10]. In addition, exposure to airborne endotoxins, which is common in workplaces associated with HP, potentiates antigen-specific airway inflammation and allergen responses .
Figure 1 shows the natural history of hypersensitivity pneumonitis and the influence of host and environmental factors in disease expression and progression. (For more information about occupational agents responsible of HP see “Sensitizing Agents Inducers of Occupational Asthma, Hypersensitivity Pneumonitis and Eosinophilic Bronchitis” available here.)
Figure 1. Natural history of hypersensitivity pneumonitis.
A characteristic of HP is that only 5-15% of subjects exposed to a provoking antigen develop the disease [10, 12]. 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 .
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. 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).
There is no evidence of a clear genetic susceptibility to develop HP. Several studies have implicated links between HLA types and HP, with an increased occurrence of HLA DR7 in pigeon fancier’s lung , HLA B8 in pigeon fancier’s lung and farmer’s lung , and HLA-DQw3 in Japanese summer-type HP . Other studies, however, have found no association with HLA types .
Different studies have investigated other genetic susceptibilities in patients with HP, for example, increased frequencies of the alleles Gly-637 and the genotypes Asp-637/Gly-637 and Pro661/Pro661 on theTAP1 (transporters associated with antigen processing 1) gene , a polymorphism in the PSMB8gene  and polymorphisms of the IL-6 gene .
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 [1,2,6]. 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 [3, 10]. In fact, nonspecific interstitial pneumonitis, usual interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia (BOOP) may be the sole histologic expression of the disease.
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. Many patients have serum and/or BAL (bronchoalveolar lavage) 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.
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.
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. Presumably, like in idiopathic interstitial pneumonia, acute exacerbations of chronic HP may occur without further exposure to the offending antigen . It can be distinguished from bouts of acute HP related to continued exposure to antigen if patients present with: (1) prior diagnosis of chronic HP; (2) worsening of dyspnea within 1 to 2 months; (3) new radiographic opacities and; (4) absence of apparent infection, heart disease, and/or other identifiable cause. This type of acute exacerbation seems to predict a poor outcome .
HP is characterized by strong cellular and humoral responses to inhaled antigens. Lung cellular influx and inflammatory responses characteristic of HP are initiated by causative agents via immune cell receptors called Toll-Like Receptors (TLRs). In HP, when specific TLRs are activated, they react through an intracellular pathway, known as the MyD88 pathway, to release many proinflammatory cytokines and mediators . 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 . Th1 and Th17 cells are responsible for the production and release of tumor necrosis factor, interferon-α, IL-12, IL-17, IL-18, and IL-22-secreting Th17 cells in HP [22,23]. Increased T- regulatory cells may help to down regulate the disease and prevent the development of the disease .
The acute phase is dominated by macrophage-lymphocyte responses. An increased number of CD4+ Th1 cells appear in the BAL fluid shortly after exposure, but in most cases of HP CD8+ cells predominate later .
The subacute phase is characterized by granuloma formation. After recruitment and activation, macrophages develop into epitheliod and multinucleated giant cells . Lymphoid follicles containing plasma cells also develop in the lesions during this phase. In the chronic phase pulmonary fibrosis takes place as the result of collagen formation by myofibroblasts and activation of alveolar macrophages which produce TGF-b1, 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 also contribute to the fibrosis of HP, along with macrophage, lymphocyte, plasma cell, and neutrophil effector cells.
The histologic expression of HP may be similar to other interstitial lung diseases such as interstitial pneumonitis (NSIP), usual interstitial pneumonia, and BOOP [26-30]. Therefore, the diagnosis of HP should be based not only on histopathologic findings but also by demonstration of an immune response to an antigen (i.e., lymphocytic proliferation or production of specific serum antibodies) together with a detailed environmental exposure history.
- Clinical history. A number of diagnostic criteria recommendations for HP have been published [31-34]. In its acute form, the diagnosis of HP can be quite straightforward, based 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, though it can be normal as well. However, the variability in HP’s clinical presentation (particularly in subacute and chronic forms) may lead to under diagnosis unless it is considered as a diagnostic possibility. Once the diagnosis of HP is suspected, a thorough occupational and environmental history is essential. Potential causative antigenic exposures should be investigated, as well as the temporal relationship between environmental exposures and clinical manifestations. If the suspected exposure is in the workplace, one should obtain material safety data sheets (MSDS) which may help identify the specific agent(s). 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 .
- Lung function tests typically show a reduction in lung volumes manifested as an FEV1/FVC >1 (restrictive pattern). Impairment of diffusing lung capacity for carbon monoxide (Dlco) and hypoxemia may be present but are not always seen. Superimposed airway obstruction may be present, particularly with chronic HP which can confuse the diagnosis.
- Chest radiography shows a range of abnormalities from an alveolar filling pattern to reticulonodular shadowing, depending on the degree of alveolitis and fibrosis. Bilateral micronodular infiltrates or patchy-ground glass opacities are better demonstrated with high-resolution computed tomography with contrast. 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 .
- High-Resolution CT Scan (HRCT). Abnormal HRCT scan in HP is almost always abnormal in acute HP [49,50]. However, in the acute phase, the abnormalities present are often difficult to distinguish between HP and IPF (ground-glass infiltrates, nodular opacities) whereas chronic HP images are identical to those of usual interstitial pneumonia [36-38]. CT scan features that best differentiate chronic HP from other interstitial diseases are lower areas of the lung with decreased attenuation and vascularity, centrilobular nodules, and absence of lower-zone predominance of abnormalities . Mediastinal lymphadenopathy on HRCT scan is a common occurrence in HP .
- Laboratory tests. Specific serum precipitating antibodies are found in many, but not all, patients with HP [3,6]. The sensitivity may be increased by performing IgG ELISA tests, which should be ordered selectively, but unfortunately, even the ELISA technique lacks standardization. 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 by gel diffusion with serum concentration is reasonably sensitive, but its specificity is low. Skin prick testing also show a low specificity and are not helpful in the diagnosis of HP .
- 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 [42, 43].
The most characteristic cell profile in BAL fluid is of a lymphocytic alveolitis (≥ 30% for nonsmokers and ex-smokers, and ≥ 20% for current smokers) with a predominance of CD8+ T cells. However, the cell profile is dependent upon the interval from last antigenic exposure. A neutrophil alveolitis is seen immediately after antigen challenge and the number of CD8+ T cells falls after cessation of antigenic contact . A lymphocytic alveolitis is also found in asymptomatic subjects exposed to an antigen and in patients with organic dust toxic syndrome. Lymphocyte subsets, especially the CD4/CD8 ratio and activation, were previously believed to be helpful in differentiating HP from sarcoidosis. This is now challenged, since the CD4/CD8 ratio can be increased in HP to levels as high as those seen in sarcoidosis [44, 45] .The usefulness of induced sputum in the investigation of HP, is currently unclear .
- Pulmonary inhalation challenge (PIC). In some instances, when a new etiological agent is being investigated, or there are conflictive diagnostic tests, a PIC in the workplace or in the laboratory with the suspected agent may be the only way to establish its causative role [47,48]. Provocative testing by specific inhalation challenge, however, is rarely required to make the diagnosis of HP. Body temperature, FVC, and diffusion indices (DLco and Kco) should be assessed during PIC in order to identify hypersensitivity pneumonitis reactions. An increase in body temperature > 0.5 ºC during PIC showed a sensitivity of 100% and a specificity of 82% in the diagnosis of patients with suspected HP . Changes in body temperature and FVC are predictive values for chronic HP .
Measurement of an increase in body temperature is a better parameter to measure than the absolute value . A sensitivity of 92% and a specificity of 100% for the diagnosis of HP are observed when any of the following responses were elicited during PIC in patients with suspected HP:
- FVC decrease >15% or DLCO decrease >20% compared to baseline values;
- 10%–15% FVC decrease plus at least 1 of the following criteria with respect to clinical status and basal analytic values:
- white blood cell increase of 20%,
- O2 saturation decrease by 3%,
- significant radiologic changes,
- rise in body temperature > 0.5 ºC, and
- presence of clinical symptoms (for example, cough, dyspnea);
- FVC decrease <10% but with evidence of 3 or more of the previously mentioned clinical or analytic criteria .
In the HP study by Dalphin and colleagues the most significant predictors of HP were exposure to a known offending antigen (odds ratio OR 38.8), symptoms 4-8 h after exposure (OR 7.2), positive precipitating antibodies (OR 5.3), inspiratory crackles (OR 4.5), recurrent episodes of symptoms (OR3.3), and weight loss (OR 2.0) . The probability of HP ranged from 98% when all six predictors were present to 0% when none of the predictors were identified. The HP Study emphasized that a thorough clinical history is of the utmost importance in the diagnosis of HP.
A study by Lacasse and colleagues , which included 168 patients, revealed two-clusters of patients. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills, body aches) and normal chest radiographs compared to those in cluster 2 (127 patients), who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests, and fibrosis on HRCT scan. No differences in nodular opacities were observed on HRCT scan between clusters 1 and 2 groups. There has been considerable disagreement between the current classification of HP and the results of this previous analysis, and subacute HP has particularly remained difficult to define. It is clear that no single clinical feature, radiological or laboratory test is diagnostic of HP and that the diagnosis of this disease is made by a constellation of clinical features in conjunction with radiographic, lung function and immunological test abnormalities (See Table 1, modified from ref. 10).
Table 1. Differential diagnosis of presenting symptoms; exclude other causes.
(modified from Bourke et al, ref. 10)
- Identify exposure to an occupational provoking antigen
- Demonstrate an immune response to the antigen
- Precipitating antibodies by agar gel immunodiffusion
- IgG ELISA
- Specific sensitized T cells
- Establish the relationship of symptoms to antigen exposure
- Temporal relationship
- Information from MSDS
- Assess the degree of impairment of lung function
- Spirometry, lung volumes (plethysmography)
- Diffusing capacity (DLCO)
- Determine the extent of radiographic abnormality
- Consider the need for lung biopsy or bronchoalveolar lavage
- Consider the usefulness of a workplace or laboratory-based challenge study
- Exclude alternative diagnoses (e.g. sarcoidosis, inhalational fevers)
Lung infection is by far the most common confounding condition in the differential diagnosis of patients with acute HP. In the chronic form of the disease, the differential diagnosis of HP includes a spectrum of diffuse parenchymal diseases including idiopathic interstitial pneumonias and sarcoidosis.
The cornerstones for treatment of HP are early diagnosis, identification of the causative agent, and avoidance of the antigen. Thus, the recognition of the offending agent(s) is crucial but often difficult. The identification of a specific agent in the workplace may require procedural changes such as modification of work processes and wearing of personal protective equipment. Education of physicians and other healthcare professionals and populations at risk may be helpful in the early recognition of symptoms and facilitate implementation of preventive strategies . In some occupations associated with HP, complete cessation of antigen exposure may be particularly difficult such as farmers. The effectiveness of protective equipment, such as HEPA-filtered helmets, has not been proven . 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 . One study suggested that inhaled steroids could be effective (54). Pentoxifylline has also been reported to be of some benefit .
The long-term outcome of subjects with HP is highly variable. Factors that are important in determining the outcome include duration and intensity of the type of antigen exposure, CT scan findings, lung pathologic changes, and possibly genetic background [56-58]. With appropriate treatment, most cases of HP have a favorable outcome, with improvement or normalization of lung function [58,59]. Farmers with chronic HP more often develop emphysema  whereas pigeon breeders usually evolve toward lung fibrosis, with a poor 5-year prognosis similar to subjects with IPF [60,61].
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