Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is an inflammatory disease of the lungs and airways that develops in response to repeated inhalation of a wide range of aerosol antigens. The clinical picture and course of HP are highly variable and depend on such factors as the nature of the antigen, the intensity and duration of exposure to the antigen, as well as on the characteristics of the patient's immune response. The annual incidence of HAP is 1.28 -1.94 cases per 100 000. Currently, the diagnosis of HP is usually based on the characteristic clinical picture, high-resolution computed tomography (HRCT) data, bronchoscopy, lung biopsy, and evidence on the antigen. HRCT plays a central role in the diagnosis of HP. The most common finding on HRCT in HP is ground-glass opacities, which can be associated with centrilobular nodules and air trapping. In some cases, the fibrotic HP signs are very similar to those of idiopathic pulmonary fibrosis (IPF), and most changes are found in the lower regions and subpleurally. Therapy for HP usually includes avoiding exposure to the antigen, considering corticosteroids (CS) and/or immunosuppressive therapy to suppress the active inflammatory/immune response, and treating comorbidities. Nintedanib therapy in patients with progressive fibrotic HP results in a slower decline of lung function compared to placebo.

Hypersensitivity pneumonitis is an inflammatory disorder of the lung parenchyma that develops in response to prolonged inhalation of antigen. The disease is initially characterized by a granulomatous pneumonitis and some reversibility after termination of antigen exposure, but long-term exposure to antigen can culminate in interstitial fibrosis and irreversible damage to lung tissue. Alternative terms for hypersensitivity pneumonitis include "extrinsic allergic alveolitis" as well as terms related to specific occupations, such as "farmer's lung," "bird breeder's lung," and "bagassosis." Hypersensitivity pneumonitis is a relatively uncommon occurrence, even among individuals heavily exposed to antigen. Epidemiologic surveys of farming populations in Europe and the United States have found prevalence rates ranging from 4 to 85 cases per thousand exposed. 1 The variability in reported prevalence likely reflects differences in annual rainfall, farming practices, and clinical criteria used to establish a diagnosis of hypersensitivity pneumonitis. There is limited data on the prevalence of hypersensitivity pneumonitis among bird breeders, but it may be estimated as 5 to 15 cases per hundred exposed. 1 This review will cover causative agents, pathogenesis, clinical presentations, laboratory features, diagnosis, and therapy of hypersensitivity pneumonitis, with an emphasis on data from recent studies in both animals and human subjects.

CAUSATIVE AGENTS
A variety of organic antigens have been demonstrated to cause hypersensitivity pneumonitis 2 ( Table 1). Hypersensitivity pneumonitis was first described in 1932 as a disease of farmers who developed symptoms after exposure to moldy hay. 3 Subsequent investigation identified the etiologic agents as thermophilic bacteria (most commonly Micropolyspora faeni and Thermoactinomyces vulgaris) that proliferated in warm, moist hay. 4 Thermophilic bacteria remain the most common cause of hypersensitivity pneumonitis and are responsible for cases of hypersensitivity pneumonitis in grain handlers, mushroom workers, sugar cane workers, and in individuals exposed to contaminated humidifiers and air conditioners. Inhaled fungi (such as Aspergillus clavatus, Penicillium frequentans) have been shown to cause hypersensitivity pneumonitis in workers exposed to moldy malt, redwood dust, and cork dust. Inhaled animal proteins can also cause hypersensitivity pneumonitis, the prototype being "bird breeder's lung" following the inhalation of avian proteins in bird excreta or feathers. Insect proteins and amebae may also precipitate hypersensitivity pneumonitis in exposed workers. Some exposures to drugs or inorganic chemicals may result in pulmonary syndromes similar to hypersensitivity pneumonitis. In most such cases, however, there is evidence for an immunoglobulin E (IgE)-mediated immune reaction with eosinophilia. These features are not characteristic for hypersensitivity pneumonitis related to inhaled antigen (vide infra). An exception to this may be pulmonary toxicity associated with amiodarone therapy, which can include the histologic changes of hypersensitivity pneumonitis, including a lymphocytic alveolitis. 5 Some pulmonary reactions to toluene diisocyanate 6 and to trimellitic anhydride 7 also have features compatible with hypersensitivity pneumonitis (fever, pulmonary infiltrates, and a lymphocytic alveolitis), but the precise pathogenesis of these reactions has not been clarified.

PATHOGENESIS
The pathogenesis of hypersensitivity pneumonitis involves the following features: (1) repetitive exposure to particulate antigen, (2) immunologic sensitization of the host to antigen, and (3) host susceptibility to immune-mediated damage of lung tissue.
Hypersensitivity pneumonitis is seen only in individuals who are exposed to inhaled antigens frequently (often daily) over a prolonged period of time. The clinical syndrome does not result from single or sporadic exposures to antigen. This requirement for prolonged exposure means that hypersensitivity pneumonitis is most often recognized in relationship to an occupational exposure. To cause hypersensitivity pneumonitis, inhaled antigen must be small enough to reach the alveolar space (1 to 3 µm diameter) and must be in particulate form. Experimental studies indicate that inhalation of soluble organic antigens does not result in the histologic lesions characteristic of hypersensitivity pneumonitis. 8 Resistance to degradation by lysosomal enzymes is probably also important, so that the antigen can persist long enough in lung tissue to sensitize the host. 9 An immune response of the host to inhaled antigen is critical for the development of hypersensitivity pneumonitis, although the specific im-mune reactions responsible for tissue damage are poorly characterized. In contrast to asthma, the pathogenesis of hypersensitivity pneumonitis is not dependent on immediate or IgE-mediated hypersensitivity, but appears to involve a combination of immune complex-mediated and cell-mediated immune reactions to inhaled antigen. 10 In support of immune complex-mediated tissue injury, precipitating antibodies can be demonstrated in serum from affected individuals 11 and in bronchoalveolar lavage fluid. 12 Immunofluorescent analysis has also demonstrated antibody and complement in lung tissue from patients with hypersensitivity pneumonitis. 13 In addition, the delayed onset of symptoms after antigen exposure (generally 4 to 6 hours) matches that of an immune complex-mediated or Arthus response. On the other hand, the histopathology of hypersensitivity pneumonitis does not demonstrate the vasculitis typical of immune complex-mediated tissue injury and is more compatible with a cell-mediated reaction, showing mononuclear cell infiltrates and granulomas. 14 Peripheral blood and lavage lymphocytes from patients with hypersensitivity pneumonitis also proliferate in response to antigen in vitro, 15 which is characteristic for a cell-mediated immune reaction.
Recent data from animal and human studies suggest that immune reactions to inhaled antigen may vary during the evolution of the hypersensi-197 tivity pneumonitis syndrome. 16 In animals exposed to intratracheal antigen, there is often an early hemorrhagic alveolitis and influx of neutrophils into the alveolar space, findings compatible with immune-complex lung injury. 1718 With continued exposure, this pattern of inflammation resolves and is replaced by a granulomatous response more compatible with a cell-mediated immune reaction. 19 Studies of lavage fluid from patients with acute hypersensitivity pneumonitis also support an initial immune-complex form of lung injury, showing increased numbers of neutrophils, activated complement components, and chemotactic factors for neutrophils. 20 In humans challenged with aerosolized antigen, bronchoalveolar lavage demonstrates a transient neutrophil alveolitis, which resolves completely by 8 days after exposure. 21 This body of evidence suggests that the pulmonary inflammatory response to inhaled antigen evolves from early immune complex-mediated lung injury, mediated in part by neutrophils, to later cellmediated lung injury, dominated by lymphocytes. Because patients generally come to medical attention after prolonged exposure to antigen, human lung tissue most commonly shows the later pattern of a cell-mediated immune process in the lung parenchyma with patchy mononuclear cell infiltrates and granulomas. 14,22 A critical unanswered question concerns what host factors predispose an individual to develop hypersensitivity pneumonitis after exposure to an appropriate antigen. Epidemiologic studies have shown that only a small percentage of those who are occupationally exposed to antigen develop pulmonary symptoms or disease. 1,23 Although the risk for disease may be somewhat dependent on intensity or duration of exposure to antigen, emerging data suggest that host factors are important in the pathogenesis of hypersensitivity pneumonitis. For example, attempts to develop animal models of hypersensitivity pneumonitis have revealed significant differences among strains of mice with regard to susceptibility for a pulmonary granulomatous response to antigen. 24 In mice, these genetic differences in susceptibility to disease correlate with both H-2 and non-H-2 genes. 25 The consequence of these genetic differences may be an altered capacity to produce suppressor T lymphocytes and macrophages, which are necessary to down-regulate immune reactions to inhaled antigen. 26 ' 27 In humans, genetic studies have so far failed to reveal a consistent association between hypersensitivity pneumonitis and a specific histocompatibility locus. 28,29 Interestingly, tobacco smoking may alter an individual's propensity for hypersensitivity pneumonitis. Hypersensitivity pneumonitis is less common in pigeon fanciers 30 and farmers 31 who also smoke than in similarly exposed nonsmokers. The mechanism for this putative protective effect of tobacco smoke has not been elucidated.
Examination of cells retrieved by bronchoalveolar lavage has provided some insights into host responsiveness to inhaled antigen. For example, Keller and coworkers 32 found that lavaged lymphocytes from antigen-exposed but asymptomatic pigeon breeders had suppressor cell function in vitro, whereas lavage lymphocytes from patients with pigeon breeder's disease showed no suppressor function. This suggested that patients with hypersensitivity pneumonitis may have defective generation of suppressor cells. However, a study by Semanzato and colleagues 33 found identical in vitro suppressor cell function in lymphocytes from farmers with hypersensitivity pneumonitis and from asymptomatic, antigen-exposed controls. On the other hand, these investigators also found cytotoxic activity in lung lymphocytes from patients with disease that was not apparent in cells from asymptomatic controls. This cytotoxic activity was later shown to result from both natural killer cells and cells analogous to lymphokine-activated killer cells. 34 Lavaged alveolar macrophages from patients with hypersensitivity pneumonitis have also been shown to display markers of cellular activation, specifically increased surface expression of class I and II major histocompatibility determinants and decreased receptors for transferrin. 35 All of these findings indicate that cells recovered by lavage from individuals with hypersensitivity pneumonitis have functional abnormalities compatible with an ongoing immune response, but it is not yet clear which of these functions are involved in the pathogenesis of lung injury and which represent a normal response of the host to prevent tissue injury in the presence of continued antigen exposure.
In summary, the pathogenesis of hypersensitivity pneumonitis involves a combination of both immune complex and cell-mediated lung injury in response to inhaled antigen. Antigen-exposed individuals who go on to develop hypersensitivity pneumonitis may have a genetically determined susceptibility for the disease, possibly relating to defective suppressor cell function. In susceptible individuals, it is likely that immune reactions are not appropriately suppressed and progress unimpeded to cause tissue injury.

CLINICAL PRESENTATIONS
There is a wide spectrum of symptoms and signs in hypersensitivity pneumonitis, but most 198 patients can be classified as having either an acute or chronic presentation. In acute hypersensitivity pneumonitis, patients experience cough, fever, chills, and dyspnea in relation to antigen exposure, and these symptoms resolve with cessation of exposure. Typically, there is a 4-to 12-hour latent interval between exposure and symptoms, so that affected individuals may experience nocturnal fever and cough as a response to antigen exposure during the day. Many patients are aware that their job or hobby is making them ill, and may give a history of repetitive episodes over months or years. However, patients with milder symptoms may not recognize such a relationship, and it may be helpful to ask whether symptoms improve on the weekends away from work and then recur with return to work on Mondays. Physical examination of patients with acute hypersensitivity pneumonitis may show tachypnea, cyanosis, and bibasilar crackles. Wheezing is uncommon.
The chronic presentation is characterized by insidious and progressive symptoms of dyspnea and fatigue. In these cases, the intensity of antigen exposure is relatively low, and patients typically do not experience repetitive episodes of acute dyspnea or cough. Affected individuals often do not connect their symptoms with an adverse exposure during their work or hobby. There may be a history of chronic productive cough, and patients with chronic hypersensitivity pneumonitis can be mistakenly diagnosed as having chronic bronchitis. 36 Weight loss may be a prominent symptom, but fever is relatively uncommon. Physical examination may reveal bibasilar crackles. Clubbing of the extremities is unusual. With prolonged antigen exposure, patients with chronic hypersensitivity pneumonitis may experience cor pulmonale.
Another clinical presentation involves hypersensitivity pneumonitis related to inhalation of microorganisms from a contaminated humidifier or air conditioning system. 37 This presentation has been called "humidifier lung." Clinically, affected patients may show features of either acute or chronic hypersensitivity pneumonitis, and there are often other affected individuals in the work environment. Such cases of hypersensitivity pneumonitis may occur in an epidemic fashion as a cluster of atypical pneumonias. Patients may be aware of some relationship between their symptoms and the workplace and may note improvement on the weekends. Diagnosis can be challenging because the symptoms may be confused with other pulmonary or systemic illnesses. In addition, workers are often unaware of a workplace humidification system and may attribute their symptoms to second-hand tobacco smoke or other possible toxic exposures.

GENERAL
Leukocytosis is common in cases of hypersensitivity pneumonitis, with white blood cells counts in the 20,000 to 30,000 cells/mm 3 range. 2 The differential white cell count shows an excess of polymorphonuclear leukocytes, predominantly neutrophils. It should be emphasized that eosinophilia is relatively uncommon, and a normal eosinophil count does not exclude the possibility of hypersensitivity pneumonitis. Serum immunoglobulins are increased in a polyclonal fashion except for IgE, which is usually normal.

SEROLOGY
Precipitating antibodies to the offending antigen are present in the serum of most patients with hypersensitivity pneumonitis. 11 Unfortunately, the prevalence of serum antibodies in antigen-exposed populations is much higher than the prevalence of hypersensitivity pneumonitis. For example, antibodies have been reported in up to 10% of farmers 38 and in up to 40% of pigeon breeders. 39 This means that the presence of serum antibodies to antigens related to hypersensitivity pneumonitis must be considered evidence for antigen exposure rather than for disease. The titer of serum antibodies has also been shown not to correlate with the presence of disease. 39 In addition, cases of hypersensitivity pneumonitis have also been reported in which no serum antibodies were detectable. 40 Recent studies have identified specific antibodies in the serum of patients with bird breeder's lung, which are not present in asymptomatic but antigenexposed subjects. These antibodies are reactive to pigeon IgA and to a component of pigeon dropping extract. 42 The value of these antibodies in the evaluation of workers suspected of having hypersensitivity pneumonitis awaits confirmation.

RADIOLOGY
The chest radiograph may be normal in acute hypersensitivity pneumonitis, but more typically shows nodular interstitial disease with a predilection for the lung bases. During an acute episode, coalescent alveolar infiltrates may be present, which can be confused with an infectious pneumonitis. With prolonged antigen exposure and chronic hypersensitivity pneumonitis, there are radiographic changes of diffuse interstitial fibrosis and honeycombing, most prominent in the upper lung fields. Hilar and mediastinal adenopathy is uncommon, as is a pleural effusion. 199

PULMONARY FUNCTION TESTING
Symptomatic patients with acute hypersensitivity pneumonitis will often have restrictive abnormalities on pulmonary function testing, but the likelihood of an abnormal test is dependent on the time since last exposure to antigen. Typically, the vital capacity, total lung capacity, and diffusing capacity are decreased 4 to 6 hours after antigen exposure, and then return slowly toward normal. If a prolonged interval has elapsed since antigen exposure, pulmonary function may be normal. In cases of chronic hypersensitivity pneumonitis, abnormalities on pulmonary function testing tend to be fixed and show little reversibility. Arterial blood gases may show hypoxemia, which is further aggravated with exercise.
Because pulmonary function testing may be normal in patients with hypersensitivity pneumonitis, some laboratories have challenged patients suspected of having the disease with inhaled antigen. This may be done by recreating the work experience (and antigen exposure) in the laboratory or by exposing a patient to graded concentrations of aerosolized antigen. The value of challenge testing has been reviewed by Hendrick and coworkers. 43 Patients with hypersensitivity pneumonitis will respond adversely to the offending antigen and experience fever and dyspnea 4 to 6 hours after exposure. Along with systemic symptoms, there is usually a decrease in the vital capacity and diffusing capacity as well as hypoxemia and leukocytosis. These abnormalities resolve slowly over the 24 hours following exposure. Antigens used in inhalation challenge are usually extracts of bird droppings and molds and so are poorly standardized. Considerable confusion also exists as to what constitutes a positive response to inhaled antigen, and reproducibility between laboratories has not been demonstrated. Finally, because challenge testing may precipitate high fever and hypoxemia, it is not without potential risk. For all of these reasons, inhalation testing with aerosolized antigens is reserved for laboratories experienced with the technique.

BRONCHOALVEOLAR LAVAGE
The technique of bronchoalveolar lavage has been used to recover cellular and soluble materials from the lungs of patients with hypersensitivity pneumonitis, 44 and there is increasing interest in the role bronchoalveolar lavage may have in the evaluation and clinical management of patients exposed to inhaled antigen. Bronchoalveolar lavage in hypersensitivity pneumonitis typically shows excess numbers of lymphocytes, accounting for up to 80% of lavaged cells. 12 Most of these lymphocytes are of the cytotoxic/suppressor (CD8+) rather than the helper/inducer (CD4+) phenotype, so that the CD4/CD8 ratio in lavaged cells is decreased. 33,45,46 These findings contrast with T lymphocytes in lavage fluid from patients with sarcoidosis and berylliosis, which are predominantly of the helper/inducer (CD4+) phenotype. The number of alveolar macrophages in hypersensitivity pneumonitis is not different from controls, although macrophages account for a smaller percentage of lavaged cells because of the high numbers of lymphocytes. 44 Neutrophils are also present in normal numbers in samples of lavage fluid from patients with chronic hypersensitivity pneumonitis. 44 However, excess lavage neutrophils have been demonstrated in patients with acute hypersensitivity pneumonitis 20 and after antigen challenge, 21 suggesting that neutrophil influx into the alveolar space may be an early event in the inflammatory response to inhaled antigen. Mast cells have also been reported to be present in increased numbers in symptomatic patients with hypersensitivity pneumonitis. 47 Examination of the noncellular components of lavage fluid also reveals abnormalities in patients with hypersensitivity pneumonitis. Total protein and albumin are increased in lavage fluid, perhaps reflecting a vascular permeability defect. 12 Such a permeability defect might contribute to gas exchange and compliance abnormalities in hypersensitivity pneumonitis and facilitate penetration of inhaled antigen to the pulmonary interstitium, where granuloma formation occurs. The concentrations if IgG, IgM, and IgA antibodies are increased in lavage fluid, and the IgA concentration exceeds the serum concentration, suggesting local synthesis. 48 Specific antibodies to the offending antigen have also been demonstrated in lavage fluid, 12 ' 48 along with activated components of complement. 20 A fundamental problem with the analysis of lavaged material is that many of the abnormalities observed in patients with hypersensitivity pneumonitis are also found in antigen-exposed patients without symptoms or clinical evidence of lung disease. Thus, increased numbers of lymphocytes are present among lavaged cells from asymptomatic pigeon breeders 49 and dairy farmers, 15 especially in individuals with precipitating serum antibodies. Furthermore, when patients with hypersensitivity pneumonitis are studied after cessation of exposure, increased numbers of lavage lymphocytes persist for years after clinical recovery. 47,50 The decreased CD4/CD8 ratio in lavaged lymphocytes may increase toward the normal range during the resolution phase of hypersensitivity pneumo-200 nitis, 50,51 but this is not an invariable finding. 44 Clearly, a lymphocytic alveolitis appears to be a common finding in antigen-exposed individuals, and the presence of excess lymphocytes alone in lavage fluid cannot be used as a diagnostic marker for hypersensitivity pneumonitis.

DIAGNOSIS
Because there is no single diagnostic test for hypersensitivity pneumonitis, establishing a diagnosis in an individual patient is often difficult. In acute hypersensitivity pneumonitis, differential diagnosis includes toxic fume exposure and viral and atypical pneumonias. In chronic hypersensitivity pneumonitis, the differential diagnosis may include sarcoidosis, idiopathic pulmonary fibrosis, and other forms of interstitial lung disease. The first clue should be an occupational history indicating prolonged exposure to antigen. Pulmonary function testing showing restriction may be helpful, as may serum antibodies to an appropriate antigen, but neither test will firmly establish a diagnosis of hypersensitivity pneumonitis. At that point, demonstrating a recurrence of symptoms when the patient returns to work may be sufficient to make a clinical diagnosis of hypersensitivity pneumonitis. However, physicians should be wary of attributing a patient's symptoms to hypersensitivity pneumonitis, if making that diagnosis could result in loss of employment. In such cases the diagnosis of hypersensitivity pneumonitis must be conclusive, and inhalation challenge testing with aerosolized antigen may be indicated. At the present time, there is no documented utility for bronchoalveolar lavage in the evaluation of patients suspected of having hypersensitivity pneumonitis. Lung biopsy is usually not necessary to establish a diagnosis of hypersensitivity pneumonitis. However, in selected cases lung biopsy may be useful to exclude other causes of interstitial lung disease. A large tissue sample is required to exclude sarcoidosis and idiopathic pulmonary fibrosis, so that open lung biopsy is preferable to transbronchial biopsy.

PROGNOSIS AND THERAPY
With continued antigen exposure, symptomatic patients with hypersensitivity pneumonitis show an accelerated decline in pulmonary function. This has been demonstrated for both pigeon breeder's lung 52 and for farmer's lung. 53 Because chronic hypersensitivity pneumonitis can culmi-nate in irreversible interstitial fibrosis, 54 early diagnosis and cessation of antigen exposure are imperative. If possible, work practices should be altered to eliminate the production of aerosolized antigen or the patient should be moved to a new position that does not entail antigen exposure. Respiratory protection devices have been shown to decrease symptoms during antigen challenge, 55 but their efficacy in preventing chronic disease with long-term exposure to antigen is unknown. If the work environment cannot be altered, symptomatic patients should be advised to change their job or hobby to eliminate further exposure to the offending antigen. Other than antigen avoidance, treatment of patients with hypersensitivity pneumonitis is mainly supportive. Corticosteroids are probably justified during an acute attack of hypersensitivity pneumonitis, 56 but there is no evidence that long-term use of corticosteroids will alter the natural history of the disease. Hyposensitization with injected antigens is contraindicated, because of the possibility of aggravating immune complex lung injury. Antifungal agents are of no conceivable benefit.