Hypersensitivity pneumonia

HYPERSENSITIVITY PNEUMONIA JOHN BERNARDO, M.D. DAVID M. CENTER, M.D.

0011-5029/81/050001-0064-$06.00 9 1981, Year Book Medical Publishers, Inc.

SELF-ASSESSMENT QUESTIONS

1. Acute hypersensitivity pneumonia typically is characterized by which of the following symptoms? a. Wheezing. b. Chest pain. c. Dyspnea. d. Fever. e. Sputum production. 2. Which of the following sign(s) is (are) characteristic of acute hypersensitivity pneumonia? a. Hypertension. b. Wheezing. c. Rales. d. Hepatojugular reflux with hepatomegaly and peripheral edema. e. Cyanosis. 3. Acute hypersensitivity pneumonia is characterized by which of the following laboratory abnormalities? a. Eosinophilia. b. Elevated IgE. c. Leukocytosis with neutrophilia. d. Hypoxemia. e. Purulent sputum. 4. Hypersensitivity pneumonia commonly is confused with which of the following diseases? a. Acute bronchitis. b. Bacterial pneumonia. c. Viral pneumonia. d. Disseminated fungal disease. e. Chronic bronchitis. 5. Hypersensitivity pneumonia invariably is accompanied by: a. Arthus-type skin reactivity. b. Delayed-type skin reactivity. c. Immediate-type skin reactivity.

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d, Low complement levels. e. None of the above. f. All of the above. Antigens commonly associated with hypersensitivity pneumonia are: a. Thermoactinomyces vulgaris. b. Cotton fibers. c. Baker's yeast. d. Pigeon excreta. e. Ragweed pollen. Pulmonary function testing during a first acute attack of hypersensitivity pneumonia most probably would show: a. Decreased FEV1/FVC ratio, normal DLCO. b. Increased FEV1/FVC ratio, decreased DLCO. c. Decreased FEV1 and decreased FVC, increased DLCO. d. Decreased FEV~ and decreased FVC, decreased DLCO. e. None of the above. f. All of the above. The clinical symptoms of hypersensitivity pneumonia characteristically appear: a. Within 30 months of exposure to an antigen. b. 1 - 4 hours after exposure. c. 4 - 1 2 hours after exposure. d. 24-72 hours after exposure. e. On Monday mornings. Which of the following is (are) associated with chronic hypersensitivity pneumonia? a. Pulmonary fibrosis. b. Restrictive lung disease. c. Granulomas on lung biopsy. d. Lymphocytes in bronchoalveolar lavage. e. All of the above. f. None of the above. Pulmonary function testing in chronic hypersensitivity pneumonia characteristically would show: a. Decreased FEV 1, decreased FVC, decreased DLCO. b. Decreased FEV~, normal FVC, normal DLCO.

c. Decreased FEV1, normal FVC, decreased DLCO. d. Decreased FEV1, decreased FVC, normal DLCO. e. None of the above. f. All of the above. MATCHING (more than one answer may be applicable): 11. Farmer's lung. a. Thermoactinomyces vulgaris. 12. Bagassosis. b. Cotton fibers. 13. Asthma. c. Micropolyspora faenii. 14. Cheese-washer's d. Penicillium casei. lung. 15. Humidifier lung. e. Thermoactinomyces sacharii. MATCHING (more than one answer may be applicable): 16. Ragweed asthma, a. Type I hypersensitivity. b. Type II hypersensitivity. 17. Goodpasture's syndrome. c. Type III hypersensitiv18. Serum sickness. ity. 19. Lupus. d. Type IV hypersensitivity. e. Anergy. 20. Coccidioidomycoses. 21. Sarcoid. 22. Farmer's lung. 23. Allergic bronchopulmonary aspergillosis. TRUE-FALSE (in hypersensitivity pneumonia): 24. Prior exposure to an antigen is necessary for hypersensitivity pneumonia to occur. 25. Serum precipitins imply that clinical disease is present or will develop. 26. The presence of allergic asthma prevents the occurrence of hypersensitivity pneumonia. 27. Serum precipitins are protective in the disease. 28. The presence of delayed-type hypersensitivity implies that chronic disease will develop. 29. The development of chronic pulmonary fibrosis is connected most closely with the number of documented acute episodes. 30. The administration of corticosteroids is the treatment of choice.

31. Hypersensitivity pneumonia can present as an insidious chronic disease without prior acute episodes. 32. A positive reaction to bronchoprovocation proves the diagnosis. 33. There are some patients in whom Types I, III, and IV hypersensitivity can be demonstrated simultaneously. Answers are listed at the end of the article.

/.L is an Assistant Professor of Medicine at Boston University School of Medicine, where he is a member of the Pulmonary Division at Boston City Hospital and Boston University Medical Center. Dr. Bernardo's major research interests concern the effects of inflammatory and immune processes in the evolution of hypersensitivity pneumonia.

is an Assistant Professor of Medicine at Boston University School of Medicine. Dr. Center is the head of the allergy unit at University Hospital and a member of the Pulmonary Division of University Hospital and Boston University Medical Center. His research interests relate to inflammatory amplification systems in the lung and their role in chronic pulmonary interstitial injury and repair.

H YP ER S ENS I TI V I T Y P N E U M O N I A is a descriptive t e r m t h a t encompasses m a n y entities t h a t are similar in presentation and pathophysiology. The various disease entities included u n d er the um br e l l a of hypersensitivity pneumonia have engendered numerous synonyms, including allergic alveolitis, allergic pneumonitis, and hypersensitivity pneumonitis. Thus, it will be worthwhile to define hypersensitivity pneumonia in strict immunologic and pathologic t e r m s to help us u n d e r s t a n d the clinical presentation. The words hypersensitivity and allergy imply a complex sequence of events. First, implicit in these terms is the concept t h a t the individual (or animal) has been previously exposed to the offending etiologic agent (antigen). As a re-

sult of a single exposure or multiple exposures to the antigen in the past, none of which have resulted in the clinical expression of disease, the animal has become sensitized in a specific immunologic sense. Sensitization involves a complex sequence of events beyond the scope of this discussion; however, in general, it occurs with the help of macrophages that process antigen and present it in a usable form to lymphocytes. This antigen presentation can result in antibody production by B lymphocytes that have been transformed into plasma cells with the additional help and stimulation of ~'helper" T lymphocytes. The antibodies produced by exposure to this antigen can be of any class (IgA, IgE, IgG, or IgM), depending on the genetic predisposition of the animal, the temporal exposure to the antigen, the route of exposure and other poorly defined environmental factors. Thus, for example, under natural conditions, an appropriate host when exposed to airborne ragweed pollen via the respiratory tract will develop IgE antibodies, both locally in the lymphoid tissue in the lung and systemically in the spleen and other lymph nodes. Under therapeutic conditions, a similar or identical antigen administered subcutaneously in a preservative will stimulate the systemic production of IgG (or blocking antibodies) with similar specificity to the naturally occurring IgE, since these two antibody classes compete or block each other's binding and function. 1 Second, sensitization need not involve antibody formation that is measurable by traditional methods, but that may be restricted to special T or B lymphocytes with the capacity for memory. These cells have the ability to generate a unique type of inflammatory response when re-exposed to the antigen. The type of sensitization an individual experiences then dictates to a large extent the manifestations of ~hypersensitivity" disease that will occur. This concept is the basis for the Gell and Coombs classification for hypersensitivity reactions2 (Table 1). In this modification of their terms we find that Type I hypersensitivity occurs if IgE has been produced during sensitization. IgE has the capacity to bind avidly by its Fc portion to receptors on the surfaces of circulating basophilic polymorphonuclear

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leukocytes and tissue-bound mast cells. On subsequent reexposure, antigen interacts with two antibody-binding sites on the surface of these cells. This antigen-antibody reaction on the surface of mast cells or basophils results in the initiation of surface and intracellular events that ultimately lead to the generation and release of bioreactive mediators from these cells. 3 An example of such a mediator is histamine, which is present preformed in mast cell granules and is released into the surrounding milieu on antigen activation of the cells. 4 Histamine, of course, has the capacity to contract smooth muscle and to increase vascular permeability. Thus, if an antigen-antibody reaction occurs on the surface of the mast cells of the lung parenchyma or airways, bronchospasm and airway mucosal edema occur, as in asthma. If it occurs on the surface of skin mast cells, urticaria ensues; if in the nasal passages, rhinitis will follow. Therefore, the symptoms we observe in a hypersensitivity reaction are dependent not only on the antibody produced b u t on the location of the antigen-antibody interaction and the secondary events that occur as a result of that interaction. Since mast cells and basophils are present in the blood, the mucosal surface of the upper and lower respiratory tracts, and the skin and gastrointestinal tract, antigen-antibody reactions of the Type I or anaphylactic group can yield symptoms of cardiovascular collapse, conjunctivitis, wheezing, rhinitis, urticaria, and abdominal cramps. Symptoms and signs of nephritis, carditis, etc. characteristically would be absent, since geographically IgE antigenantibody reactions and their effector cells are not near TABLE 2.--CRITERIA FOR INDUCTIONOF HYPERSENSITIVITY Prior exposure to antigen Sensitization to antigen with induction of memory Re-exposure Antigen-specific reaction with the host memory system Initiation of an inflammatory response by the preceding reaction Amplification and progression of the inflammatory response (nonantigenspecific) in a permissive host Clinical presentation of symptoms and signs of disease depending on the location of antigen-specific reaction and type of inflammatory response 10

those organs. This theme is one that we will stress repeatedly throughout this monograph. It is, that a complex sequence of events is necessary for hypersensitivity reactions to occur; this sequence ultimately dictates the nature of the clinicalpresentation (Table 2). Type II hypersensitivity reactions (see Table 1) are characterized by the production of IgG or IgM antibodies against an antigen that either subsequently becomes bound to a specific organ-cell type or is similar or identical to an antigen expressed on the surface of that cell. Once circulating antibody finds its way to these cells, an antigen-antibody reaction on the cell surface occurs. This antigen-antibody reaction can generate a cytolytic event that results in cell death (e.g., immune hemolytic anemia). ~ An organ-specific example of this reaction is Goodpasture's syndrome, where antibody is directed against the basement membrane of lung and kidney. 6 As a result of this antigenantibody interaction involving a class of antibodies capable of fixing or activating the complement system, tissue destruction ensues. This can be caused directly by cell lysis after activation of terminal complement components, or indirectly by cell lysis secondary to an inflammatory reaction that can follow. Therefore, Type II hypersensitivity reactions are dependent on sensitization either to an autologous antigen (i.e., lung basement membrane) by presentation of that antigen to the immune system in a way that stimulates antibody production or by development of an antibody to an antigen that resembles, is bound to, or crossreacts with normal tissue antigens. In the example of Goodpasture's syndrome, pulmonary hemorrhage and nephritis occur whereas in immune hemolytic anemia red blood cell lysis is the prominent feature. Again, the symptoms observed are dependent on the type of sensitization (that is, the production of IgG or IgM), the site where antigen and antibody interact, and the secondary reactions with activation of amplification systems that occur as a result of that interaction. Type III hypersensitivity reactions (see Table 1) occur as a result of sensitization with subsequent production of IgG antibody. On re-exposure to large amounts of antigen, an11

tigen-antibody complexes precipitate and deposit themselves intravascularly or in those tissues first encountered.7 In the case of the deposition intravascularly of antigen-antibody complex, this commonly occurs at branching points and in tortuous blood vessels; the symptoms or signs of disease are dependent on the organ receiving blood from the affected vessel. Classically, deposition of antigen-antibody complex occurs in the small arteries, arterioles, and venules of the skin and the kidney, resulting in rashes and nephritis, respectively. Examples of these phenomena include serum sickness, where the antigen(s) traditionally is (are) horse serum protein, and systemic lupus erythematosus, where the antigen may be endogenous nucleic acids. There exists in addition some evidence that antigens without access to the systemic circulation can produce localized Type III reactions if the antigen-antibody complex present is sufficient to precipitate. This is what probably occurs in the skin with intradermal injection of the appropriate antigen (the "late" skin reaction) and perhaps this is what occurs in the pulmonary interstitium or alveolar wall after inhalation of some antigens. The basic and most important aspect of Type III reactions, however, is the secondary inflammatory response that occurs at the site of deposition of antigen-antibody complex, s The antibody must be of the type that, when complexed with antigen, will activate complement via the classic pathway. The activation in situ of complement then is responsible for the ensuing reaction, which includes a neutrophilic polymorphonuclear leukocytic infiltration and the activation and release of phagolysosomal enzymes that damage normal tissue. In the case of blood vessel walls, local hemorrhage with activation of coagulation factors occurs, effectively occluding the lumen. Activation of the complement system leads to the generation of the vasoactive proteins, the anaphylatoxins, C3a and C5a, which enhance vascular permeability, and the chemotactic factor C5a, which attracts neutrophils. Complement activation can damage antibody-coated target cells directly via its terminal components or indirectly by creating an intense inflammatory reaction at the site of activation. In a classic systemic antigen-antibody complex Type 12

III reaction, arthritis, dermatitis, and glomerulonephritis are the cardinal clinical features, because the physical conditions in the blood vessels of these organs are most suitable to deposition of antigen-antibody complex. Other organs are also involved with varying frequency, including the brain, the meninges, pleura, pericardium, and occasionally the lung parenchyma. The damage that results from Type III hypersensitivity has been termed the phenomenon of the ~innocent bystander," since the organ involved is not primary to the pathogenic process. Type IV or delayed hypersensitivity reactions (see Table 1) are different from the other three types just described. The sensitizing and memory step is not dependent on immunoglobulin production, but rather on the T lymphocyte. For sensitization to occur, the antigen needs to be processed and presented to T cells by macrophages. The memory mechanism of the T cell is as yet undefined. However, on re-exposure, the memory cells undergo blast transformation, during which time they proliferate, and produce factors with diverse biologic activities, termed lymphokines. 9 The functions of the many lymphokines include the attraction of leukocytes, their immobilization at the sites of the activated lymphocytes, and the subsequent activation of these leukocytes. In addition, the monocyte/macrophage seems to be capable of specific sensitization, and on re-exposure to antigen will secrete mediators similar to lymphokines, termed monokines. Macrophages, in addition, can be '~activated" to secrete these bioreactive mediators by lymphokines, thereby generating another positive amplification stimulus to the inflammatory process. Of importance for this discussion is the fact that when a sensitized T lymphocyte is re-exposed to antigen, it proliferates and produces lymphokines that attract, immobilize and activate monocytes, eosinophils, neutrophils, and other leukocytes. This collection of inflammatory cells can organize into a granuloma if antigen is present for a prolonged period. The inflammatory process then can cause secondary tissue damage because of the release of the destructive contents of infiltrating cells at the same time that it is serving the positive function of isolating, destroying, and disposing 13

of foreign antigen. In the lung, tuberculosis or fungal diseases are classic examples of Type IV hypersensitivity whereas in other organs contact dermatitis and organtransplant rejection may be cited as examples. The various types of hypersensitivity reactions have some characteristic features that have been used in the past to differentiate among them, bearing in mind, of course, that sensitization and initiation of one type of hypersensitivity reaction does not preclude another. Thus, Type I reactions are associated with higher than normal levels of IgE, peripheral or tissue eosinophilia, symptoms that begin within 20 minutes after exposure to the antigen and a characteristic pruritic wheal-and-flare skin reaction that occurs 1 5 - 2 0 minutes after intradermal injection of appropriate antigen. 1~The time course for the development of symptoms is rapid because mast cell and basophil mediators are released within minutes after exposure to the antigen, and because the end-organ response occurs rapidly after interaction with these mediators. For example, bronchial smooth muscle contracts and vascular endothelium becomes permeable within seconds after stimulation by histamine. It should be noted that immediate hypersensitivity reactions can also manifest a "late" phase. 1~ In the lung, this is seen as a second diminution in respiratory function four to 12 hours after initial exposure whereas in the skin an indurated, painful erythematous lesion is noted. Biopsies of the late phase of immediate skin reactions demonstrate the presence of a mixture of inflammatory cells of all types (neutrophils, eosinophils, monocytes, and lymphocytes), suggesting that the original mast cell activation resulted in the release of chemotactic factors for these cell types. The delay in symptoms is explained by the time it would take for these cells to migrate to the appropriate area. Type III reactions (see below) have been ruled out as a secondary cause of some of these reactions to antigens such as grass pollen by utilizing antibody to IgE as the eliciting agent and demonstrating by immunofluorescent techniques that complement had not been activated. In other circumstances, particularly with allergic bronchopulmonary aspergillosis, there is some evidence that both 14

Type I and Type III reactions occur simultaneously, since IgE and IgG antibodies are present. Type III reactions are associated with complement-fixing, precipitating, or hemagglutinating antibodies to the antigen, blood and tissue neutrophilia, and symptoms that begin four to 12 hours after exposure. The skin test reaction also occurs four to 12 hours after intradermal injection of antigen. It is erythematous, indurated, and painful and usually is associated with a neutrophilic infiltration with the deposition of C3 and immunoglobulin just as is seen in the tissues of affected organs. It takes four to 12 hours for these symptoms to begin because they result from the presence of inflammatory cells. Even though antigen-antibody interaction and subsequent complement activation occur within minutes following the introduction of antigen, several hours are necessary for neutrophils to traverse the distance required from the intravascular space to accumulate in sufficient numbers to induce an inflammatory reaction. These reactions are dependent on complement activation and neutrophilic infiltration, and can be prevented by depleting the sensitized host of either component. TM These reactions can persist for as long as the neutrophils remain, and thus their duration is dependent on continual complement activation with subsequent generation of chemotactic activity. TM Type IV reactions rarely begin less than 2 4 - 4 8 hours after exposure to antigen and are associated with granulomas or mononuclear cell infiltrations. Skin test responses in these sensitive individuals are delayed for from 48 to 72 hours after intradermal injection of the antigen, and are erythematous and indurated, with mononuclear cells predominant histopathologically. The slow time course for the development of skin reactivity when Type IV sensitization has occurred is dependent on two major factors. First, antigen-macrophage-T lymphocyte interaction results in the stimulation of these cells to generate and release mediators that are not preformed or the result of rapid enzymatic action. These lymphokines and monokines are, in general, proteins and glycoproteins that require RNA-dependent synthetic mechanisms. These events take hours (or longer) 15

to occur. Second, the inflammatory reaction that we see clinically is dependent on the cellular infiltrate. Since this is predominantly mononuclear, a significant length of time (once again probably hours to days) is required for sufficient cells to accumulate to produce symptoms. Furthermore, the duration of the reaction will depend on the duration of presence of the inciting agent. Thus, soluble tuberculoprotein generates a positive delayed-type skin reaction in a sensitive host in 2 4 - 4 8 hours, which usually subsides in three to six days TM whereas reactions to foreign bodies can remain for the life of the individual if the antigen is insoluble. 1~ Type II reactions are organ-directed, and therefore the temporal features of presentation and skin test reactivity are difficult to characterize and will not be discussed further. By these definitions, hypersensitivity reactions really should be termed sensitivity reactions. However, as we will discuss in greater detail below, the clinical presentation of symptoms does not always correlate with the laboratory evidence of sensitization. Thus, the last essential element in the development of a disease state must be a permissive host; one that when sensitized and re-exposed allows the activation of the inflammatory response to occur unchecked. The presentation and characteristic features of the various types of hypersensitivity are important to consider because, as we will discuss later, hypersensitivity pneumonia has features that are common to several of these classes of hypersensitivity. Finally, to complete our discussion of definitions, the terms pneumonia, pneumonitis, and alveolitis imply an inflammatory reaction in the lung parenchyma and alveoli. By exclusion, this means that the predominant reaction is not in the airways or blood vessels but in the alveolar walls and pulmonary interstitium. Since inflammatory reactions are characterized by edema, transudation, and exudation of serum contents into tissues and infiltration of leukocytes, in the case of pneumonia or alveolitis, we should see edematous alveolar walls and a widened interstitium packed 16

with inflammatory cells, some of which have reached the alveolar spaces themselves. Thus, the geographic location of this inflammatory response should dictate the clinical presentation of symptoms and signs. Furthermore, the location of the response implies some physical properties of the antigen, such as its size and distribution in the airways following inhalation. The time course of development of disease and the histopathology should also give us some clues to the type of sensitization, and thus perhaps to some logical ways to treat the disease. Hypersensitivity pneumonia remains a descriptive term only. Missing is the differentiation between acute and chronic disease and their interrelationships. Most of our ability to discriminate among the various types of hypersensitivity rests with acute challenge and subsequent observation. The signs, symptoms, pathology, and immunology associated with chronic persistent or chronic intermittent exposure to the antigen (regardless of the type of sensitization) are less well defined and tend not to be so clear cut as those outlined in Table 1. Moreover, in the case of hypersensitivity pneumonia in the human, there are few pathologic data available in the acute disease, and chronic disease is associated with pulmonary fibrosis, a complicating factor whose relationship to the acute and/or persistent inflammation of hypersensitivity is not known. The following sections of this monograph will discuss the clinical and laboratory aspects of both acute and chronic hypersensitivity pneumonia. An attempt will be made at the end to define the pathophysiology of h u m a n hypersensitivity pneumonia utilizing this information as well as some data from animal models to fill in the gaps in our understanding. CLINICAL PRESENTATION

The first recorded description of what most likely was hypersensitivity pneumonia appeared in 1713, when Ramazzini 16 detailed the symptoms of workers who developed a disabling respiratory illness following inhalation exposure to the dust of overheated cereal grains that had not been 17

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properly dried prior to storage. Despite occasional reports in subsequent years, lung diseases resulting from the inhalation of organic dusts generated little interest until 1932, when Campbell iv described in detail the variable course of an acute and chronic respiratory illness that occurred in farm workers during and following exposure to moldy hay. Since Campbell's classic description of farmer's lung, the list of organic agents responsible for similar diseases has been expanding (Table 3) as more potential offenders are identified and occupations or avocations labeled as potential risks. Yet, undoubtedly many cases of hypersensitivity pneumonia go unrecognized or misdiagnosed as any one of several similarly appearing lung diseases. Conversely, several diseases with different pathophysiologies have been confused with hypersensitivity pneumonia; the most important ones are listed in Table 3. Acute symptoms most commonly are confused with viral or bacterial pneumonia, tracheobronchitis, or pleuritis. The reason for this most likely is explained by the variable presentation and course of hypersensitivity pneumonia, as well as the lack of a comprehensive history of exposure. As can be seen in Table 3, the list of agents that have been implicated in the pathogenesis of hypersensitivity pneumonia is not restricted to exotic occupationally encountered organic dusts. Thus, failure to clean a home humidifier system properly ~s might lead to the development of disease in a susceptible individual. ANTIGENIC CHARACTERISTICS

Typically, the antigen is an organic particulate, usually a dust, small enough to reach the alveolar units following inhalation. TM Thus, size may range from 0.5 to 6 ~m in diameter. The nature of the antigenic determinants for any given antigen is extremely complex and beyond the scope of this discussion. However, several general characteristics of antigens capable of inducing hypersensitivity pneumonia have been described (Table 4). The implications of the size characteristics are that these antigens reach the alveoli and do not lodge in the larger airways. Therefore, 20

TABLE 4.--ANTIGENIC CRITERIA FOR SENSITIZATION IN HYPERSENSITIVITYPNEUMONIA

Major Characteristics Particulate organic m a t t e r less t h a n 6 ~m in size Nondigestibility by lysosomal enzymes W a t e r insoluble

Minor Characteristics Complement activation via the alternative pathway Adjuvant effect

both the initial event in sensitization and the site of pathology occur in the alveolar walls. With respect to elicitation of chronic hypersensitivity pneumonia associated with granuloma formation (see below), it seems that antigens need to be selectively resistant to digestion by lysosomal enzymes.~~ Theoretically, this would enhance the possibility that a foreign body (localized Type IV) reaction would occur and allow for prolonged persistence and presentation of antigen to macrophages. Along these same lines, antigens therefore usually are particulate. ~9 The particulate nature potentially has some clinical immunologic significance for two reasons. First, in animal studies in which sensitization to ovalbumin has occurred, the form of the antigen administered on re-exposure can dictate which type of clinical hypersensitivity predominates. For example, in guinea pigs sensitized with soluble ovalbumin in complete Freund's adjuvant, re-exposure to intratracheal soluble ovalbumin results in anaphylaxis whereas identical re-exposure with particulate antigen gives a syndrome similar to acute hypersensitivity pneumonia. 21 Second, the type of sensitization created may also be determined by the physical nature of the antigen, with soluble antigens favoring the formation of precipitating, complement-fixing antibodies whereas particulate antigens produce T cell sensitivity. This division is not invariable by any means and numerous exceptions occur, depending on the species and many other factors. Next, many antigens associated with hypersensitivity pneumonia are capable of directly activating the complement system via the alternative pathway. 22 This implies that sensitization need not be a necessary step in all forms 21

of the disease, particularly in acute forms if complement activation is a sufficient prerequisite. Specifically, Micropolyspora faenii, Thermoactinomyces vulgaris, and various Aspergillus species have been shown to activate the alternative complement sequence in h u m a n serum in vitro. Finally, in a manner descriptively similar to mycobacteria although immunologically dissimilar, the cell walls of Micropolyspora faenii can act as adjuvants for cell-mediated immunity. 23 Their role in enhancing antibody formation is not known. For further information concerning antigens in hypersensitivity pneumonia, the reader is referred to a recent review on the subject. 24 SYMPTOMS The classic acute clinical presentation of hypersensitivity pneumonia is that of fever, malaise, cough, and shortness of breath that begins within several hours after exposure and lasts until the exposure ceases. Less well appreciated is an insidious presentation, in which the patient complains of progressive shortness of breath over months or years and has a chest x-ray compatible with a diffuse interstitial process. Without a clear index of suspicion in this latter group, the disease m a y well be misdiagnosed by the unwary physician as one of the many interstitial pneumonias and the patient's management becomes compromised. Hypersensitivity pneumonia can present in acute or chronic form (Table 5). In the acute disease, patients become symptomatic with fever, malaise, shortness of breath, and cough, usually developing within four to 12 hours of exposure to the offending antigen. The relationship between antigenic exposure and the onset of symptoms in many of these patients is fairly clear, and the diagnosis is established easily. In those with no recognized history of exposure, relief from symptoms following removal from a suspected environment can provide an important diagnostic clue; symptoms usually resolve within days to weeks following cessation of exposure with little, if any, residua. Symptoms of airway obstruction are noted rarely, occur in a small percentage (5%-10%) of patients with the acute

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form of the disease, and then usually only if they have coexisting asthma. The chronic form of hypersensitivity pneumonia is associated with repeated or continuous exposure to antigen. In such cases, the symptoms of acute disease may become more severe, presenting as recurrent acute episodes and accompanied by severe malaise and loss of weight. Alternatively, the onset can be insidious, with progressive shortness of breath on exertion as the sole complaint. Once again, in the former type of chronic presentation, the clinical diagnosis may be obvious whereas in the latter it is established only by thorough history-taking and with a high index of suspicion. Despite the fact that a large number of individuals may become exposed to a given antigen, and a significant proportion develop precipitating antibodies to that antigen, only a small percentage actually develop symptoms. The development of disease thus depends on several additional factors, including host susceptibility (which may be in part genetically determined) as well as environmental factors, such as the dose of antigen inhaled. The relationship between the nature of the exposure to the antigen and the development of disease is not clear. For example, while the inhalation of spores by a farmer m a y be massive (it has been estimated that a farmer working with moldy hay can inhale and retain 750,000 fungal spores per minute within the lung25), severe disease can be produced on exposure to a single bird and cage at home. Such low-grade persistent exposure may be significant in developing many of the known and perhaps as yet unknown hypersensitivity pneumonias, and offers a particularly difficult diagnostic puzzle to the physician presented with a case of unknown lung disease. SIGNS The physical findings in both the acute and chronic forms of hypersensitivity pneumonia generally follow the symptoms (see Table 5). Most notably in the acute disease, symptoms usually begin four to 12 hours following expo24

sure; tachypnea, occasionally accompanied by cyanosis, usually predominates. With minimal exertion, the patient becomes extremely short of breath. Fever m a y be lowgrade, but can range to 40 C, and sinus tachycardia usually is present. Auscultation of the chest may reveal bilateral rales, most often at the bases, whereas wheezing is distinctly unusual. Cough, when present, usually is nonproductive; sputum usually is not available for analysis. Complete blood count often reveals a mild neutrophilic leukocytosis. In chronic hypersensitivity pneumonia, breathlessness with exertion, or even at rest, is the most notable finding, and m a y be associated with cyanosis. At later stages there may be clear evidence of debilitation as evidenced by significant weight loss. Chest auscultation usually discloses widespread rales; again, ronchi and wheezing are unusual. Peripheral blood count reveals normal numbers of leukocytes and a normal differential count. Although sputum is not produced, bronchoalveolar lavage reveals a lymphocytosis among recovered cells. Patients with end-stage disease develop respiratory failure, and changes of cor pulmonale are seen in patients with late pulmonary fibrosis. OCCUPATIONAL HISTORY

Historical information is indispensable in establishing the diagnosis. Most often, the occupational history leads the physician to the correct diagnosis, but it must be remembered that any organic particulate of appropriate antigenicity and particle size may cause disease in a susceptible individual, and may be found anywhere in the patient's environment. Because of the importance of the history in making the diagnosis, we shall describe the usual presentations of the more widely encountered varieties of hypersensitivity pneumonia. The reader is once again referred to Table 3. FARMER'S LUNG.--Aside from being the subject of Campbell's classic paper, 17 farmer's lung perhaps is the most 25

widely recognized of the hypersensitivity pneumonias. The antigen is found in moldy hay that has self-heated during storage; the rise in temperature results mainly from the growth and proliferation of microorganisms. TM Hay with less t h a n 16% moisture has been shown to develop little spontaneous heating. However, if not dried properly prior to storage, the moisture content can reach or exceed 40%, with resulting temperatures of 60-65 C providing an ideal environment for the proliferation of thermophilic organisms. Of these, as already noted (see Table 3), Micropolyspora faenii and Thermoactinomyces vulgaris are the most important. When the moldy hay is forked or raked, large numbers of spores are released into the air, often creating a dense white cloud. Unfortunately, this often is done in the closed confines of a barn or silo, where the farmer is exposed to an enormous concentration of respirable antigen. 19 In Campbell's description of farmer's lung, all patients presented with symptoms in the spring following a summer of unusually heavy rainfall when hay had been harvested and stored in a damp state. Indeed, even today, the disease appears to be more prevalent in the late winter and spring as lower layers of silage, containing the highest concentration of spores, are removed to be used for food or bedding. Hay stored in silos or stacks has a greater propensity to support the growth of thermophilic organisms than hay stored in bales, most likely because of the better aeration of the hay contained in the smaller units. In some instances, grains (oats, barley, corn) stored improperly before drying have undergone similar fermentations and have been responsible for outbreaks of hypersensitivity pneumonia. Typically, as described above, symptoms begin hours following an exposure to moldy compost. The patient begins to feel ill with fever, chills, and shortness of breath. Removed from the environment, his symptoms usually improve, and he returns to work only to experience a recurrence. Such a cycle of repeated episodes, varying widely in intensity, m a y persist for years before the diagnosis is established. 26

On the other hand, the farmer may present with insidious, relentlessly progressive shortness of breath, with or without a history of recurrent respiratory illness. In such cases, the clinical history should be investigated thoroughly, with the diagnosis of hypersensitivity pneumonia as a major consideration. The exact prevalence of the disease is not certain, and likely varies with geographic location for several reasons (see below). In a survey of farmers in Scotland, Grant and colleagues 26 estimated a case rate of 86 per 1,000. More recently, Chmelik and colleagues 27 estimated an incidence of 100 new cases per year in Wisconsin. Complicating the issue is the fact that many cases go unrecognized, probably resulting in underestimations of actual incidence and prevalence rates. The presence of serum precipitins is not diagnostic, although most farmers with active disease have precipitins to thermophilic Actinomyces (70%-90%) (Table 6); approximately 20% of asymptomatic-exposed farmers also have similar levels of precipitating antibody in their sera. That such data are nonspecific is further highlighted by a recent study of 1,072 asymptomatic office workers, 5% of whom had serum precipitins against thermophilic Actinomyces (see Table 6). Farmer's lung is not to be confused with silo-filler's disease or the more recently described mycotoxicosis. 2s Silofiller's disease results from the inhalation of nitrogen dioxide produced by the interaction with air of the nitric oxide generated by freshly stored silage. The oxidized gas is heavier than air, and remains suspended over the silage as a brown-yellow cloud, which is inhaled by anyone working in the immediate vicinity. The disease itself begins as a bronchitis and bronchiolitis caused by the toxic effects of the gas, which is distinctly different from the pathophysiology of hypersensitivity pneumonia. Mycotoxicosis is characterized by acute respiratory symptoms in patients who are not specifically sensitized. The symptoms follow inhalation of massive numbers of fungal spores. The clinical course of this disease is similar to that seen early in acute hypersensitivity pneumonia and may well be a result of activation of the alternative complement pathway 22 by the 27

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spores within the alveolar spaces, resulting in an acute airspace pneumonia similar to the alveolar consolidation of lobar pneumonia. Its course is self-limited, and recovery is the rule. LUNG (BIRD-FANCIER'S DISEASE).--In 1965, Reed and colleagues 29 described three patients with recurrent acute episodes of pneumonia associated with exposure to pigeons, with symptoms and Signs similar to those previously reported in farmer's lung. Subsequent reports have incriminated other birds (parakeets [budgerigars], turkeys, chickens) in the pathogenesis of the disease. Symptoms follow inhalation of proteins found in bird excreta, which on drying become easily dispersed as a fine dust. The patient usually has regular contact with birds and notes the onset of fever, malaise, and shortness of breath several hours following exposure to dried excreta, usually in a caging or roosting area. Alternatively, the onset of symptoms m a y be insidious in nature, as can be seen with patients who experience mild recurrent exposure to these droppings, as, for example, from a parakeet kept at home. Carefully elicited historical information m a y reveal the etiology in either instance. Precipitating antibodies against feathers and serum, in addition to pigeon-dropping extracts, have been demonstrated in high proportions of patients with active bird-fancier's disease. In fact, in this disease in particular it has been argued that a negative serology places the diagnosis in question. However, the presence of precipitating antibodies m a y not be sufficient to cause the disease, since they can be found in significant numbers of exposed-asymptomatic pigeon breeders (see Table 6). Attempts to define associations between pigeon-breeder's disease and various HLA haplotypes have met with varying results. Several reports have associated the disease with HLA antigens (HLA-B8 and HLB-BW40) 3~ 31 whereas a more recent study failed to demonstrate any relationship between HLA antigens and the development of pigeonbreeder's lung. 32 Clearly more work will be necessary to define the likely contribution of genetic factors to the development of hypersensitivity pneumonia. PIGEON-BREEDER'S

29

BAGASSOSIS.--Bagasse is the fibrous material that remains after the sugar-containing liquid is expressed from sugar cane. It is used in the manufacture of insulating and acoustic materials, paper, and cardboard. It is bundled into bales and subjected to similar conditions as hay, especially if stored indoors, in that fermentation may proceed during storage, favoring the growth and proliferation of thermophilic actinomycetes, most notably Thermoactinomyces sacharii. Although extensive production of bagasse began in the early 1920s in Louisiana, the first recognized case characterized by symptoms similar to acute farmer's lung was not reported until 1941. 3~ Following that report, additional cases were discovered at the same factory where the originally reported patient received his exposure, and, subsequently, most early cases were derived from bagasse that originated in Louisiana and was shipped elsewhere. It should be emphasized, therefore, that this is not a disease of sugar cane workers; it affects susceptible factory workers, stevedores, or anyone else who works with the moldy fiber after it has been stored. HUMIDIFIER LUNG.--Exposure to agents that have been implicated in the development of hypersensitivity pneumonia can occur in the home or office from contamination of heating, humidifying, or air-cooling equipment by microorganisms. T vulgaris and T candidus (as well as some protozoa) have been cultured in suspected cases from the environments served by these systems. TM Involved heating systems are typically of the forced-air type, where organisms can proliferate within the ductwork. The water-containing reservoirs of humidifiers or the reservoirs and filter systems of some types of air-cooling units likewise may harbor organisms that have been implicated in the disease. Since the disease is not acquired in a typically "dusty" setting, the environmental association may be overlooked initially and the diagnosis missed, especially if the onset of symptoms has been insidious. In such cases, only if sufficient suspicion is raised by supporting clinical and laboratory data can the proper diagnosis be made. This carries

30

with it a great deal of concern, since considerable numbers of people are exposed daily to such environments. In a study by do Pico and colleagues, 51 5% of 1,072 asymptomatic office workers had positive precipitins to thermophilic Actinomyces on screening, attesting to the ubiquitous nature of the antigen. Likewise, in their report of four patients with hypersensitivity pneumonia, Banaszak et al. 34 noted that eight of 23 asymptomatic office workers (35%) exposed to the same environment had precipitins to a thermophilic organism cultured from an air conditioner serving the area. Typically, symptoms occur or worsen with increased use of the contaminated system, as occurs with changes of seasons. Support for the diagnosis can be obtained by evaluating the patient for precipitins to organisms cultured from the system, or by bronchial provocation with the suspected antigen. Treatment beyond the acute stage involves the removal or thorough cleaning of the contaminated appliance. The disease itself is similar in its clinical presentation to other forms of hypersensitivity pneumonia, and should not be confused with IgE-mediated mold-induced asthma. MALT-WORKER'S LUNG.--A small percentage of malt workers exposed to high concentrations of spores of Aspergillus clavatus develop symptoms and findings of hypersensitivity pneumonia. In the production of malt, fresh barley is dried and then stored in silos for several months. It then is rehydrated and sprayed with hypochlorite to kill any fungi that might remain. It then is placed into a heated, humid atmosphere, where it is agitated frequently while germination occurs. It is during this last step that fungal spores are dispersed into the environment, and sensitization, and subsequently disease, occurs in susceptible individuals. Among 711 Scottish workers with exposure recently evaluated, 5% were found to have had clinical disease; 81% of these demonstrated precipitins to A. clavatus on serologic testing. 35 MAPLE BARK-STRIPPER'SDISEASE.--This disease has been described in lumber workers, 36 and is related to the inhalation of the spores of Cryptostroma corticale, which grows 31

beneath the bark of maple trees. In the processing of the logs, stripping of the bark liberates large numbers of spores into the air, and often the concentration is intensified by poor ventilation in the working area. Steps taken by the lumber industry to minimize dispersion of spores to protect the workers at risk (such as isolation of workers from the logs during the stripping process) have resulted in a decline in the incidence of this disease. Of additional interest, in this disease, spores have been identified in lung biopsy specimens, a finding restricted to relatively few of the hypersensitivity pneumonias. LYCOPERDONOSIS.--Inhalation of the spores of the genus Lycoperdon 37 (puffball) has been described as a folk remedy

for curing nosebleeds. Several cases of clinical disease resembling acute hypersensitivity pneumonia have been described in individuals following such inhalation, and although further documentation was not attempted in these patients, presumptive evidence was strong enough to include this disorder among the hypersensitivity pneumonias. SUBEROSIS.--This disorder has been described as a disease of cork workers. 3s The inhalation of moldy cork dust presumed to contain spores of P e n i c i l l i u m species most likely is responsible for sensitization and induction of disease. Symptomatic workers have precipitins in their sera against the suspected antigen. As can be seen, the list of disorders is diverse and extensive. In some cases, the cause will be obvious with the etiology clearly related to the patient's current occupation. In others it m a y be necessary to question the patient about hobbies that might involve exposure to suspected antigens, exposure to water reservoir systems that might harbor organisms responsible for hypersensitivity pneumonia, or even the occupation of a spouse, who might bring home antigens on his or her clothing. Where the index of suspicion is sufficiently high, prior occupational history must be explored, especially in the patient presenting with the symptoms of chronic disease whose current occupation may have 32

no relation to an ongoing fibrotic process. The importance of the clinical history in establishing the diagnosis cannot be overemphasized; besides possibly saving the patient from an open lung biopsy, an accurate diagnosis with identification of the etiologic environmental agent forms the cornerstone of therapy (see below). LABORATORY DATA

ROENTGENOGRAPHICFINDINGS The roentgenographic changes seen in hypersensitivity pneumonia are variable and depend on the stage and severity of the disease. 39 Acute disease is associated with two roentgenographic patterns. The first is a diffuse, poorly defined, nodular mottling that tends to involve the midlung zones while sparing the apices and bases. The nodules are small, up to several millimeters in diameter, with indistinct borders unlike the sharp, distinct nodularity seen in miliary tuberculosis or in silicosis. Second, either accompanying the first pattern, or distinct from it, soft linear or patchy infiltrates may be noted,~9, 40 again usually involving the midlung zones. Acute exacerbations may be characterized by the appearance of superimposed, diffuse acinar shadows that resolve as symptoms clear. The reversibility of the nodular or linear shadows usually relates to the continuation of the exposure; if exposure to the antigen ceases, the chest roentgenogram m a y return to normal in a matter of days to weeks 39 (Figs 1 and 2). Pleural effusion or pleural thickening is seen very rarely in acute or chronic hypersensitivity pneumonia and the presence of either should alert the clinician to other possible diagnoses. 4~ Likewise, hilar adenopathy is rare, although cases of acute hypersensitivity pneumonia with hilar node enlargement on chest roentgenogram have been reported. The roentgenographic patterns in the acute disease result from involvement of the alveolar units in the acute inflammatory response. With chronic disease, changes of 33

Fig 1,--A 20-year-old white male with a six-year history of pigeon breeding, His major complaints were progressive dyspnea for four months and 34

diffuse interstitial fibrosis become evident. Linear shadows become more distinct as a reticular pattern emerges. There is loss of lung volume with an unusual predilection for the upper lobes, accompanied by compensatory overinflation of less-involved areas. Fibrotic changes m a y involve primarily the periphery of the lung, giving the appearance of a "white wall." In the end-stage lung, honeycombing may be seen as well as cardiac enlargement because of the development of cor pulmonale (Fig 3). An abnormal chest roentgenogram need not accompany other manifestations of active hypersensitivity pneumonia. In a study of pigeon breeders, Unger and colleagues 41 noted five of 12 patients with overt clinical symptoms and normal chest films. Similarly, in a study by Stolz and colleagues 42 of 26 mushroom workers with active disease, normal chest roentgenograms were described in 18. Thus, in the presence of clinical symptoms, a normal chest roentgenogram does not rule out active disease. PHYSIOLOGY Pulmonary function abnormalities in hypersensitivity pneumonia can be divided into those seen in acute and chronic (or persistent) disease. Classically in the acute disease there are reductions in lung volumes and arterial oxygen saturation. Usually the forced expiratory volume in one second (FEV 1) and forced vital capacity (FVC) are similarly reduced, with a reduction in total lung capacity (TLC). Diffusing capacity for carbon monoxide (DLCO) m a y be reduced. This is the picture of restrictive, not obstructive, lung disease, most likely reflecting the inflammatory response within the interstitium rather than the airways.27, 43 In the experimental setting, these findings deweight loss. Chest roentgenogram (A) illustrates diffuse bilateral nodules and linear shadows, involving primarily the mid and upper lung zones. After removal of the pigeons and corticosteroid therapy, he was asymptomatic when examined five months later. Chest roentgenogram at that time (B) had returned to normal.

35

36

velop following bronchoprovocation in h u m a n s within four to 12 hours, paralleling clinical findings. These abnormalities can last as long as 24-36 hours after a single acute exposure.19, 29 With recurrent intermittent exposure or with chronic low-grade exposure, these abnormalities can progressively worsen. 44 At later stages, a reduction in the diffusing capacity of the lung for carbon monoxide and arterial oxygen desaturation with exercise become more prominent features. With time, evidence of airflow obstruction develops (as reflected by an abnormal ratio of FEV1 to FVC and maximal midexpiratory flow rate [MMEFR]), indicating late involvement of the small airwaysJ ~ Persons with a history of five or more symptomatic recurrences are at a significantly greater risk for developing progressive nonreversible functional abnormalities as measured by diminutions in vital capacity, total lung capacity (TLC), and DLCOJ 5 Persistent abnormalities of this n a t u r e invariably are seen in patients who develop pulmonary fibrosis. SPECIAL LABORATORYSTUDIES SEROLOGY (ANTIBODY LEVELS).--The role of circulating antibodies in the pathogenesis of hypersensitivity pneumonia is not well understood. While most patients with ac-

Fig 2 . - - A 57-year-old white male draftsman was referred with a history of two years of progressive dyspnea and weight loss. Chest roentgenogram (A), which previously had been normal despite symptoms, now showed diffuse, ill-defined nodular densities, involving both upper and lower zones. Lung biopsy (see Fig 4) revealed an interstitial mononuclear infiltrate with clusters of lymphocytes and granulomas. He was treated with prednisone with good clinical response, although no specific diagnosis had been made. As the corticosteroids were tapered, a relapse occurred. On detailed questioning at this time, it was learned that his symptoms were worse in the fall and winter and were related to the use of a humidified forced-air heating system. His serum contained precipitating antibody to thermophilic organisms cultured from the humidifier reservoir. Following removal of the humidifier, prednisone was successfully discontinued with no recurrence of symptoms. Chest roentgenogram two years later (B) was normal. 37

Fig 3.--A 75-year-old stenographer presented ten years earlier with a twoyear history of progressive dyspnea. The history for environmental exposure to agents known to induce interstitial lung disease was negative. Lung biopsy revealed an interstitial mononuclear cell inflammatory process with occasional granulomas and fibrosis. Despite initial therapy with corticosteroids, symptoms continued to progress, At time of follow-up (i.e., 12 years following onset of symptoms) she had grade IV dyspnea. On physical examination there were tales bilaterally. Chest roentgenogram reveals fibrotic changes bilaterally. A specific etiology never was identified.

tive pigeon-breeder's disease or farmer's lung have specific precipitating antibodies of the IgG type in their serum detectable by immunoelectrophoresis, similar levels of antibody can be detected in the serum of m a n y exposed but asymptomatic individuals. Thus, as noted in Table 6, while as many as 100% of symptomatic pigeon breeders m a y demonstrate precipitating antibody to pigeon antigens in their sera, 48 40% of asymptomatic pigeon breeders can have precipitins. In fact, in one study, Kawai and colleagues 55 noted precipitins against Thermoactinomyces sacchari and 38

bagasse dust in 62% and 59% respectively of normal asymptomatic volunteers. Antibodies are primarily of the IgG class, with subtypes IgG1, IgG2, and IgG3 being common. Likewise, specific IgM and IgA also have been detected. Among these groups are antigen-specific antibodies capable of fixing complement, which might play a significant role in the development of the initial lesion within the lung. This will be discussed in greater detail in the last section. Total serum IgE levels are normal in patients with active disease. Since some patients with hypersensitivity pneumonia can be shown to have positive immediate wheal-and-flare skin tests to the responsible antigen, it can be inferred that specific IgE levels occasionally are elevated. However, similar skin test results can be demonstrated in asymptomatic-exposed persons, and since patients with active disease usually do not display rhinitis, bronchospasm, or urticaria as seen with classic IgE-mediated reactions, IgE seems to be of little importance. The issue is further confused by the fact that antigenic preparations used in skin testing and determination of serum precipitins are not pure. Circulating antibody levels among similar population groups tend to vary from report to report (see Table 6). This probably is a result of several factors, including differences between individual exposures, the antigenic preparations used for serologic testing, and the techniques involving the serologic studies themselves. Either differences in genetic predisposition to sensitization and precipitating antibody formation or prevalence of antigens in various environments might account for the variability noted in studies performed in different geographic locations. It seems logical to assume that farmers are exposed to the antigen to a greater extent than are city dwellers. This is supported by the percentage of clerical workers with precipitins to thermophilic actinomycetes (5%) 51 as compared to asymptomatic farmers (22%). 5o In addition, in a recent study by Scribner et al., 56 sera from different groups of symptomatic patients submitted for precipitin studies demonstrated con39

siderable differences in specific antigen reactivity, suggesting at least that environmental influences are important. The implications of possible genetic factors will be discussed in greater detail later. Furthermore, it should be remembered that the agents responsible for hypersensitivity pneumonia are a heterogenous, complex group, each with multiple antigenic determinants. 24 The antigenic preparations used to test for circulating antibody are crude mixtures containing up to 50 of these antigenic substances extracted from cultures or other preparations, and may contain other unrelated antigens. The lack of standardization of antigenic preparations further complicates the picture, with interlaboratory variations dependent on the mixture of antigen used, among other factors. Thus, although an individual might be sensitized to a specific antigenic determinant or group of determinants, these may not be represented sufficiently in the testing material. Thus, both false negative and false positive results may occur. Last, although the performance of identical tests, such as immunoelectrophoresis, may vary among laboratories, the use of newer assays, such as radioimmunoassays,~4 adds considerable sensitivity to the study of populations at risk. Increased numbers of patients and asymptomatic-exposed individuals thus are being found to have circulating antibody to the relevant antigen(s) because of improved sensitivity of the assays used. To date, however, these assays have been of no use in defining subgroups within exposed populations who have or are susceptible to active disease. Although it is noted that patients with symptomatic hypersensitivity pneumonia develop precipitating, complement-fixing antibody, there is no evidence for systemic immune-complex deposition in diseased individuals. This may be explained by the lack of sufficient antibody to form immune complexes in the circulating compartment. Or, more likely, there is a lack of availability of antigen in the circulation, localizing the immune response to the lung. Along these lines it has been noted that there are normal circulating complement levels in experimentally induced human disease. 40

SKIN TESTING

Because of the inherent ability of many organic antigen extracts to elicit a nonspecific inflammatory response even in unexposed, normal individuals, skin testing has largely been restricted to patients in whom animal protein antigens are the suspected responsible agents, as in pigeonbreeder's disease. 19 Typically, a late (Type III) reaction is seen in these patients. Reactions occur four to 12 hours following antigenic administration and are similar histologically to the classic Arthus reactions, with an early polymorphonuclear perivascular infiltration with immune-complex deposition that evolves into a mononuclear cell response. 19 The interpretation of true delayed responses typical of Type IV hypersensitivity reactions is difficult because frequently inflammatory reactions that begin at four to 12 hours persist beyond 48 hours. This m a y reflect both Type III and Type IV sensitization or m a y be consistent with either alone. Likewise, as noted previously, immediate (Type I) hypersensitivity reactions m a y be seen in patients with hypersensitivity pneumonia as well as in asymptomatic-exposed individuals. Thus, skin testing tends to provide corroborative rather than diagnostic information, and has not afforded much insight into the pathophysiology of the disease. Because serology and skin testing are not always helpful, bronchial challenge with specific antigen has been utilized to confirm diagnostic impressions in some cases. Early studies by Williams 57 in 1963 using aerosolized aqueous extracts of moldy hay resulted in a response typical of acute farmer's lung in 12 of 15 patients with disease whereas no response was noted in any of 20 controls. Similar studies have been repeated with many of the agents suspected of causing hypersensitivity pneumonia, and a positive result is generally accepted as proof of cause and effect. 19 As an alternative to the use of aerosolized extracts, the patient might provide a sample of the materials suspected of harboring the responsible antigen. After the patient has undergone a thorough physical examination, chest x-ray, and pulmonary function studies, the material is agitated 41

while the patient breathes the dust thus created for a predetermined period (20-30 minutes). Physical examination and pulmonary function studies are repeated every two hours for ten hours; a chest roentgenogram is repeated at eight hours. A positive result, consisting of a rise in temperature, a mild leukocytosis, an increase in minute ventilation, and a decrease in lung volumes usually is first seen four to six hours following challenge. Signs of airway obstruction generally are not seen. If no reaction develops, a repeat challenge might be attempted the next day using a more prolonged exposure to dust or a more concentrated antigen extract. The use of bronchoprovocation should be restricted to cases in which the specific diagnosis is not certain or in which skin tests or precipitin studies cannot be done or do not correlate with historical information. There is absolutely no need to expose a patient with a clearly defined association between exposure and symptoms supported by specific in vitro studies, to the risks of bronchial challenge. Likewise, patients with impaired pulmonary function should not undergo provocation. These studies, needless to say, require a significant commitment of time by both physician and patient. They should be performed by experienced personnel, in a laboratory containing resuscitation equipment and people familiar with its use. Corticosteroids should be available for parenteral administration if a severe reaction develops. Unlike similar testing in asthmatics, bronchoprovocation in suspected cases of hypersensitivity pneumonia is not well standardized, either in terms of dose of the antigen administered or the specific end points (i.e., temperature elevation, etc.), although reproduction of disease is sufficient to define a positive response. Still, it can provide valuable information in selected cases and is an important experimental tool. Studies in vitro of the immune response have demonstrated that circulating lymphocytes from most diseased as well as a smaller percentage of asymptomatic-exposed individuals are capable of generating macrophage migration inhibition factor (MIF) activity on exposure to specific an42

tigen (see Table 6). As with the previously noted immunoglobulin-dependent reactions, these studies, which assess the cellular immune responses, fail to discriminate between symptomatic and asymptomatic-exposed individuals. This may reflect compartmentalization of the relevant immune response to the lung or may indicate that systemic cellular immunity is not the only important route of sensitization. BRONCHOALVEOLARLAVAGE An interesting approach to examining the inflammatory response within the lung has been bronchoalveolar lavage, 58 assuming that the components of the lavage fluid and the cell populations recovered by lavage reflect the status of disease in alveolar structures. Such reported access to an ongoing parenchymal inflammatory process such as hypersensitivity pneumonia without resorting to lung biopsy might provide enormous insight into the pathogenesis of that process, especially since peripheral blood antibody and cellular responses do not always correlate with disease activity. In the future, it might also replace the need for open lung biopsy in confusing or obscure cases. In patients with active hypersensitivity pneumonia, Reynolds et al. ~9 found bronchoalveolar lavage to contain an increased proportion of lymphocytes with an increase in the ratio of T and B cells as compared to peripheral blood. Likewise, increases in IgG and IgM relative to albumin have been noted in the lavage fluid of patients with hypersensitivity pneumonia whereas IgA, IgE, C4, and C6 are at normal levels. More recently, Moore and colleagues6~ have demonstrated both nonspecific responsiveness to mitogen as well as specific antigen reactivity in lymphocytes recovered by bronchoalveolar lavage from patients with pigeon-breeder's disease. Unfortunately, we have not yet reached the point where the information that can be obtained by bronchoalveolar lavage is sufficiently diagnostic to eliminate the necessity for obtaining tissue in unclear cases. Although such studies 43

potentially m a y provide useful diagnostic information, their use should be restricted at present to investigative protocols. PATHOLOGY The histopathologic findings in hypersensitivity pneumonia vary with the stage of the disease. Abnormalities are confined to the lung, which suggests that antigen does not gain access to the circulation but usually is deposited in the alveolar walls. In the acute stage, the most likely lesion is that of an inflammatory alveolitis characterized by intra-alveolar hemorrhage accompanied by alveolar and interstitial accumulations of neutrophilic polymorphonuclear leukocytes and interstitial edema. 61' 82 Our understanding of the acute disease process in humans unfortunately is limited by the few cases actually recognized as such and biopsied at this stage, but these findings generally are supported by the animal models of hypersensitivity pneumonia used to study the disease, as well as our current concepts concerning its pathogenesis83, 84 (see below). Most lung biopsies in patients suspected of having active hypersensitivity pneumonia are performed during the subacute or chronic stages of the disease when the antigen has not been identified or improvement has not followed removal of the offending agent from the patient's environment. There is, however, a significant amount of biopsy data available from patients evaluated over the past 20 years. Here, the most characteristic lesion is a mononuclear cell interstitial and intra-alveolar inflammatory reaction accompanied by noncaseating granulomas 81 in up to 70% of cases. Bronchiolitis obliterans and terminal bronchiolitis is present in up to 50%. 8~ Cell aggregates are composed of macrophages, monocytes, lymphocytes, and plasma cells, and occupy widened interalveolar septae as well as alveolar spaces in a focal fashion, favoring peribronchiolar areas. Foam cells, derived from macrophages or Type II pneumocytes, also are typically present in large 44

numbers in both the interstitium and the alveoli. Giant cells, of the foreign body type, are variably present. The intense mononuclear cellularity distinguishes the lesion of hypersensitivity pneumonia from that of sarcoidosis, where granulomas generally predominate. Similarly, the presence of Schaumann bodies, common in sarcoidosis, is seen rarely in hypersensitivity pneumonia. Figure 4 is a lung biopsy from the patient with humidifier lung whose roentgenogram appears in Figure 2. Figure 4, A is a low-power view showing striking diffuse and patchy interstitial cellularity and granulomas. Higherpower view (Fig 4, B) is a granuloma typical of this disease surrounded by lymphocytes. Figure 4, C illustrates an interstitial nodular collection of lymphocytes resembling a lymphoid nodule. A biopsy such as this is diagnostic of hypersensitivity pneumonia caused by any antigen. At this point, the lesion may be reversible or may progress to interstitial pulmonary fibrosis. The conditions favoring resolution in some individuals and progression in others are not known (see below). In a recent study of 141 patients with farmer's lung, it is suggested that the number of symptomatic recurrences rather than merely continued exposure might determine the likelihood of development of fibrosis. 45 As fibrosis develops, granulomas become a less prominent feature. Here, the lesion is characterized by diffuse interstitial fibrosis that may be impossible to differentiate from that of any etiology. Infiltration of the collagen-thickened interalveolar septae by mononuclear cells is variable and focal, and may relate to the persistence of exposure to antigen during the fibrotic phase. End-stage irreversible fibrosis with "honeycombing" and cor pulmonale is seen commonly in patients with far-advanced chronic hypersensitivity pneumonia. Generally, the pathologic findings are independent of the etiologic agent involved. There are several notable exceptions, however. In bagassosis, vegetable (sugar cane) fibers consisting of plant carbohydrates and cellulose have been identified within the alveolar structures in some biopsy specimens. Likewise, in patients with suberosis, cork dust 45

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m a y be noted within the lung. However, for the great majority of patients, histopathologic findings are useful only to establish or support a specific diagnosis made on clinical grounds. Patients who present with classic symptoms, signs, and laboratory findings of hypersensitivity pneumonia with a compatible history need not undergo biopsy. Since removal of the offending agent from the environment is essential, observation for improvement in clinical status, roentgenogram, and pulmonary function tests for several weeks to months in a controlled environment frequently is sufficient to establish the diagnosis. Chronic cases with fibrosis generally are more difficult to assess because they may not improve with therapy. Under such circumstances, bronchoscopy (with bronchoalveolar lavage if appropriate laboratory facilities are available) and transbronchial lung biopsy m a y provide sufficient tissue to make the diagnosis. If not, open lung biopsy is the procedure of choice. As noted above, a positive response to bronchoprovocation is an alternative diagnostic procedure to open lung biopsy. As stated earlier, it should be performed only if proper testing facilities are available. COURSE

ACUTE DISEASE For the patient who presents with an episode of acute symptoms, the outcome usually is that of complete resolution, although rare deaths following acute exposure to antigen have been reported. 62 The patient's illness usually excludes him from the offending environment by virtue of hospitalization or bed rest or just absence from work, and, without continued exposure, symptoms subside over several days. On re-exposure following recovery from the illness, the course may repeat itself and may be attributed by the unknowing patient or physician to recurrent respiratory infections. It is somewhat uncertain what the eventual outcome for these individuals might be, although patients with no further exposure most likely will return to normal lung function accompanied by a return of lung architecture 47

to the premorbid state. The patient with recurrent acute symptoms who does not recognize the cause of his illness might become chronically ill. As noted previously, multiple episodes of recurrent symptomatic exposure place the patient at risk to develop pulmonary fibrosis. Lung function may show the characteristics of chronic hypersensitivity pneumonia, with a restrictive ventilatory pattern, arterial hypoxemia, and a reduced DLCO, as symptom-free periods become less frequent and chronic symptoms develop. CHRONIC DISEASE

In patients with prolonged exposure to antigen who develop insidious symptoms of hypersensitivity pneumonia, the course usually is one of progressive functional deterioration, with structural changes within the lung that are consistent with the chronic pathology as described above. The course can be inexorable despite removal from the offending agent as well as pharmacologic manipulations, and in these cases is characterized by progressively restrictive physiology with reductions in DLCO, progressive arterial hypoxemia, which worsens with exercise, and reduced lung compliance--findings consistent with progressive interstitial pulmonary fibrosis. The final outcome usually is that of development of respiratory insufficiency and cor pulmonale, coinciding with the development of end-stage honeycombing. Again, this end stage is indistinguishable from that of any cause of pulmonary fibrosis. THERAPY

Appropriate therapy of these disorders ideally should include both treatment of the inflammatory pneumonia as well as removal of the patient from the antigen-containing environment. 19 The patient with acute or subacute symptoms usually is placed at bed rest, away from the offending environment, and supplemental oxygen is administered to relieve hypoxemia. Antipyretics are used as necessary. The rationale for the use of corticosteroids is not entirely clear. Although their use has been advocated in a number of im43

munologically mediated lung diseases, their mechanisms of action as related to the pathogenesis of hypersensitivity pneumonia and their long-term beneficial effects have yet to be established. Nevertheless, administration of corticosteroids (prednisone, 1 mg/kg/day) to severely ill patients at early stages of the disease often results in a dramatic relief from symptoms. This high-dose therapy usually can be tapered rapidly over four weeks' time. In patients with more chronic disease, the role of corticosteroids is even less clear. Once pulmonary fibrosis becomes established, the involved lung will not revert to normal; steroids are given in the hope of reducing the intensity of any accompanying inflammation, presuming that such inflammation not only augments the symptoms in the face of coexisting fibrosis but also precedes the development of additional fibrotic changes. Again, high-dose therapy is recommended for four to six weeks, with slower tapering depending on the patient's clinical, roentgenographic, and physiologic responses over several months. The key to any therapeutic regimen, however, is preventing further antigenic stimulation by removing the patient from the offending environment. There is little justification for administering long-term corticosteroids to an ill patient merely to relieve symptoms in order to permit a return to the area responsible for the exposure except in extraordinary social circumstances. It is possible that such therapy could suppress symptoms while at the same time allowing the disease process to progress to the chronic stage. Furthermore, since the response to antigen is not dose dependent and inhalation of only a small number of antigenic particles may be sufficient to trigger a symptomatic response, eradication ~" the antigen from the environment must be complete. Once the diagnosis is established and the etiologic agent and its source identified, appropriate steps can be taken to avoid re-exposure. Humidifier lung and air conditioner lung can be prevented by frequent cleaning of equipment. Face masks are available but must be tight-fitting and capable of filtering particles in the vicinity of one micrometer in size, thus offering too much resistance to airflow to be practical in most work set49

tings. In several industries, methods have been devised to prevent growth of fungi and dissemination of fungal spores. For example, in sugar cane processing, proliferation of fungal organisms m a y be suppressed by spraying the bagasse with dilute propionic acid; indeed, merely wetting the fibers before handling is sufficient to reduce drastically spore dissemination. The latter may be useful in the processing of hay as well, although thorough drying of hay or grain prior to storage is equally effective. Automated devices used to physically separate workers from spore-containing environments are expensive but effective, as has been shown by the lumber industry's efforts to control antigenic exposure. In some instances, the patient m a y be forced to change jobs, to find a new hobby, or to move to a different home if other attempts to control exposure fail. It is not certain who might comprise this final group of individuals, since it is not known in whom the disease is likely to progress with chronic exposure. PROGNOSIS

The prognosis in an individual case of hypersensitivity pneumonia is difficult to determine. Although the initial episode usually results in complete recovery in the absence of further exposure, progression to subacute or chronic disease m a y occur. 66 Likewise, it is difficult to predict the outlook for the patient who presents with chronic symptoms. Thirty percent to 60% of patients with farmer's lung who have continued exposure are disabled by pulmonary symptoms within five years. In these patients, a mortality of from 10% to 15% can be expected directly resulting from their lung disease. 45 In many cases it may be difficult to accurately advise a patient, especially since such advice m a y have drastic economic and social consequences. Although it is not clear which of these patients will progress to irreversible lung disease, in patients with farmer's lung who continue to farm, symptomatic recurrences seem to be the most important indicator of the likelihood of progression to pulmonary fibrosis. These patients should leave the 50

farm. Others m a y continue farming if they avoid antigencontaining environments. Further studies are necessary to answer this important question. PATHOGENESIS

Alveolar lung disease associated with exposure to environmental or occupational antigens such as the thermophilic fungi or avian proteins presents an unusual and interesting pathogenetic problem. Although we have entitled this monograph Hypersensitivity Pneumonia, we must determine whether the diseases we have discussed actually are caused by exaggerated inflammatory reactions occurring in susceptible individuals as a result of specific sensitization (see Tables 1 and 2). Since many of the antigens associated with this syndrome are potent activators of the alternative complement system in vitro, could all of the clinical and laboratory phenomena we observe be the result of nonspecific complement activation in the alveolar walls? 22 There is a lot of good evidence that in fact these patients are sensitized. Antibodies of some type almost universally are found, which at least demonstrates that these patients must have been exposed previously to the offending agent. 5~ Second, bronchoprovocation with the offending antigen results in a reproduction of symptoms, which does not occur with other unrelated antigens also capable of activating the alternative complement pathway. 19 Third, evidence of other types of sensitization also are present frequently, such as delayed-type skin reactivity, blastogenesis, or lymphokine production in vitro by lymphocytes from affected individuals incubated in the presence of appropriate antigen. 44 Since the inflammatory response of these patients on exposure to antigen is exaggerated and actually results in the development of a disease process, we are justified in calling the pneumonia sensitized farmers develop on exposure to Thermoactinomyces vulgaris, for example, a ~'hypersensitivity" reaction. Clinically, roentgenographically, and histopathologically, it is clear that the disease is primarily pneumonic rather than vascular or bronchocentric. We have chosen 51

t h e t e r m p n e u m o n i a r a t h e r t h a n p n e u m o n i t i s or alveolitis to e m p h a s i z e t h e point t h a t t h e location of t h e i n f l a m m a t o r y i n f i l t r a t e is s i m i l a r to t h a t of o t h e r p n e u m o n i a s (i.e., v i r a l or eosinophilic). T h e issue of w h a t t y p e of h y p e r s e n s i t i v i t y r e a c t i o n is responsible for t h e s u b s e q u e n t disease process is not so e a s y to discern. To begin, we should not forget t h a t in t h e h u m a n disease c o m p l e x t h e ~antigens" are b y no m e a n s pure; and, e v e n if t h e y were, t h i s would not p r e v e n t m u l t i p l e f o r m s of i m m u n e s e n s i t i z a t i o n to a single a n t i g e n , n o r w o u l d it t a k e into account in a n o n i m m u n o l o g i c sense t h e direct effect of t h e a n t i g e n on t h e individual. TM I t can be said, h o w e v e r , w i t h some confidence t h a t T y p e I h y p e r s e n s i t i v i t y p l a y s little or no role in t h e d e v e l o p m e n t of t h e classic a c u t e a n d chronic s y m p t o m s discussed a b o v e (Table 7). T h e r a r i t y of a i r w a y disease, p e r s i s t e n t a s t h m a , a n d t h e u n u s u a l p r e s e n c e of i m m e d i a t e s k i n r e a c t i v i t y m a k e I g E m a s t c e l l - d e p e n d e n t r e a c t i o n s q u i t e u n l i k e l y . I n addition, t h e lack of p a t h o l o g i c s i m i l a r i t i e s b e t w e e n chronic atopic a s t h m a a n d chronic h y p e r s e n s i t i v i t y p n e u m o n i a also strongly militates against Type I hypersensitivity playing a n i m p o r t a n t role in t h e chronic disease. T A B L E 7.--MAJOR EVIDENCE FOR AND AGAINST TYPE I HYPERSENSITIVITY FOR

AGAINST

Human: 1. Presence of immediate skin test reactivity in some patients 2. Ability of Type I reactions to elicit late responses

1. 2. 3. 4.

Experimental: 1. Coincident anaphylactic and late symptoms in some animal models 2. Rare observations of passive transfer of acute disease reactivity with serum

1. Rare presence of immediate skin test reactivity in animals 2. No evidence for mast cell or basophil-mediator release 3. Absence of immediate symptoms in most animal models

52

Normal IgE levels Lack of airways obstruction Lack of upper airway symptoms Rarity of late Type I reactions to occur without prior immediate symptoms 5. Lack of similar chronic pathology in recurrent asthma

Similarly, there is no evidence at all that a cytotoxic event directed against any particular lung cell or component occurs either in acute or chronic hypersensitivity pneumonia. Thus, Type II hypersensitivity seems also to provide, at this time, no explanation for the pathologic features observed in any phase of the disease. Great attention has been paid over the years to the theory that hypersensitivity pneumonia is a disease caused by deposition of antigen-antibody complex in alveolar walls 19'4s, 50.~ (Table 8). The aspects of hypersensitivity pneumonia that lend support to this theory include the time course of development of the acute symptoms, the presence of fever, chills, neutrophilic leukocytosis, the presence of precipitating, complement-fixing antibodies, and the early neutrophilic parenchymal lung infiltrates seen in the rare patient biopsied during the acute phase. Unfortunately, however, this is not the whole story. Patients with acute disease do not demonstrate systemic complement activation, and biopsies of patients ~ith chronic disease do not reveal C3 or IgG by immunofluorescent techniques. Perhaps most damning, the chronic disease resembles pathologically a delayed-type hypersensitivity reaction with granuloma formation (see Table 1) and a preponderance of mononuclear cells as the infiltrating inflammatory components. Experimentally, sensitivity is transferable by mononuclear cells. Sensitization with pure antigens, which elicits complement-fixing antibody production, and re-exposure to those antigens results in an acute syndrome that resembles acute hypersensitivity pneumonia. 21 Yet, repeated exposure, at least in the rabbit and guinea pig models thus far reported, does not result in the development of a reproducible model of chronic hypersensitivity pneumonia. In addition, of course, it is well known that the majority of exposed individuals who develop precipitating antibodies do not develop clinical disease, and likewise do not always develop symptoms on bronchial provocation. This has led to a hypothesis that the initiating event in hypersensitivity pneumonia may be the direct activation of complement through the alternative pathway (without the need for specific antibody) in susceptible individuals. 22'67 53

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By-products of complement activation thus would recruit and stimulate neutrophils and macrophages to release cytoplasmic and lysosomal components, perpetuating and amplifying the inflammatory reaction. This is a difficult theory to support, since no study of sequential tissue and cellular events in humans is available. Moreover, correlation between phenomena in vitro and pathophysiology in vivo is lacking also. For example, the studies correlating the ability of thermophilic actinomycetes to activate the alternative pathway of complement in patients' serum with and without expression of disease has not been pursued adequately. Second, we have no idea where "geographically" the complement activation occurs in the lung. Third, the precise manner by which the macrophages and neutrophils may continue to perpetuate inflammatory reactions when initiated by an appropriate agent also is not clear. There are, however, data accumulating from animal models of hypersensitivity pneumonia that do implicate the alveolar macrophage as a participant in the inflammatory reaction. For example, guinea pigs systemically sensitized with ovalbumin and then subsequently re-exposed by intratracheal instillation of particulate antigen experience an acute neutrophilic alveolitis several hours after the challenge. 21 Interestingly, alveolar macrophages from these challenged animals spontaneously secrete a chemotactic factor for neutrophils. Alveolar macrophages obtained from similarly sensitized but unchallenged animals can also be stimulated to release chemotactic activity for neutrophils in vitro on exposure to antigen (ovalbumin) whereas those from unsensitized normal control animals do not. Although this chemotactic activity is not complement-derived, the presence of serum in the in vitro setting greatly augments the chemoattractant activity for neutrophils. It is clear now that there is more than one population of macrophages (although the previously mentioned studies have not separated macrophages into subpopulations). Some of these macrophages bear Ia antigens,* which presumably are *Serologicallyderived cell surface antigens codedby the immune response (I) regionof the majorhistocompatibilitycomplex(HLA). 55

present in cells involved in antigen processing. These cells could themselves become specifically sensitized. Others, which are Ia antigen negative, seem to be more active phagocytic cells. One then could speculate that sensitization involves not only B cell production of antibody but also the sensitization of resident alveolar macrophages as well (in addition to T lymphocytes). On re-exposure to antigen, the acute phase might be secondary to interaction of antigen-alveolar macrophages, with subsequent generation and release of chemotactic activity for neutrophils. These cells would participate in the early inflammatory events in a manner similar to classic Type III reactions. This could explain the lack of systemic complement activation in humans and the lack of correlation of symptoms with the presence of antibody. Perhaps symptoms would correlate better with evidence of sensitization of the alveolar macrophages. Although the alveolar macrophage provides the basis for an attractive hypothesis, it is an unproved theory that does not explain the entire picture. It does not explain the delayed-type skin reactivity in some patients, 52 nor the release of lymphokines by peripheral blood mononuclear cells of sensitized individuals in vitro, nor the presence of granulomas in association with pulmonary fibrosis in the chronic disease, nor the increased numbers of (T) lymphocytes obtained by bronchoalveolar lavage in patients with chronic disease. 58' 59 All of these findings are best explained by T lymphocyte sensitization with subsequent development of delayed-type hypersensitivity (Table 9). This type of sensitization, of course, cannot account for the acute events that occur in the first 24 hours after exposure (or bronchopr0vocation) to antigen, but gives us an acceptable explanation for passive transfer of sensitization by mononuclear cells, the presence of granulomas, etc. Bronchoalveolar lavage studies have strengthened the concept that delayed-type sensitivity is responsible in some way, since lymphocytes obtained by lavage from patients with pigeonbreeder's disease will produce lymphokines in vitro whereas peripheral blood lymphocytes from the same pa56

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tients do n o t . 52 Patients with hypersensitivity pneumonia have also been found to have higher proportions of lymphocytes in lavage fluid than normal controls. 58 Thus, local sensitization may play a much greater part in the development of disease than previously expected. Some recent studies emerging from populations of pigeon breeders and farm workers have suggested that another pathophysiologic and immunologic mechanism may be important in the development of clinical symptoms.68 It has been noted that peripheral blood lymphocytes from symptomatic pigeon breeders will produce lymphokines in vitro in response to antigen whereas the cells from asymptomatic but similarly exposed individuals do not. These observations were carried further, pursuing the theory that the expression of disease might occur as a result of a lack of inhibition (or suppression) of the immunologic response in a manner similar to the mechanisms that permit autoantibody production in systemic lupus erythematosus. It was postulated that almost all exposed individuals will become sensitized, but of those sensitized individuals, only those who have insufficient suppressor activity (for the specific immunologic responses) would go on unchecked to develop symptoms caused by an inflammatory reaction. In some preliminary studies it has been shown that the peripheral blood cells of individuals with symptoms lack the ability to generate suppression of a blastogenic response in vitro when stimulated with a nonspecific inducer of suppressor cells, concanavalin A. 8s Although no information is yet available on antigen-specific suppressor activity in ,symptomatic versus nonsymptomatic individuals, these early observations provide a good explanation as to why similarly exposed individuals with comparable levels of precipitating antibodies can develop no disease at all, or overt severe disease. The defect in suppressor (cell) activity could be either genetic, waiting for the appropriate clinical setting to express itself, or acquired through unknown means. In a purely speculative exercise, one could invoke again a central role for the alveolar macrophage if delayed-type hypersensitivity and suppressor cell activity were respon58

sible for the clinical expression of chronic hypersensitivity pneumonia. First, macrophages play an essential role in antigen processing and presentation for T lymphocyte sensitization. Second, they are a component necessary for granuloma formation. Third, they can participate in suppressor cell systems through the production of monokines; and, last, they have been implicated in the production of chemoattractant activity for lymphocytes, in addition to neutrophils. Thus, specific macrophage sensitization could occur on exposure to antigen with subsequent T lymphocyte sensitization. Re-exposure would result acutely in the activation of alveolar macrophages to initiate an acute inflammatory reaction consisting first of the influx of neutrophils and then of the release of neutrophil and alveolar macrophage lysosomal enzymes, which could do damage to tissues. The initiating step may be accompanied by local complement activation. The influx of neutrophils is followed by the influx of lymphocytes,89 which, in the presence of insoluble persisting antigen, would become activated and initiate granuloma formation. This in turn would attract still more macrophages and lymphocytes to the lung. The entire reaction could be aborted if antigen in addition to activating an inflammatory response also activated a negative control system (suppressor activity) from alveolar macrophages, which dampened the acute process and prevented the chronic reaction from occurring. Delayed-type hypersensitivity would be a necessary component in this series of events whereas Type III hypersensitivity need not play an essential role. This is a speculative scheme only. Extensive study of various patient populations and animal models, characterization and purification of antigens responsible for human disease, determination of the constituents of local lung sensitivity, and further information on the relationship between inflammation and the interstitial pulmonary fibrosis seen in chronic disease pose equally intriguing questions beyond the scope of this monograph. The answers are necessary before we have a complete understanding of the mechanisms behind development of hypersensitivity pneumonia. 59

SUMMARY

Acute hypersensitivity pneumonia is characterized by the onset of fever, malaise, dyspnea, and dry, hacking cough four to 12 hours following exposure to an appropriate antigen to which the individual has been sensitized. It is associated with leukocytosis (neutrophilia), infiltrates on chest roentgenogram, and spirometry suggestive of restrictive lung disease. Usually, serum precipitins for the offending antigen are present. A history of exposure is of primary importance in making the diagnosis, which can be confirmed by bronchoprovocation with the suspected antigen. The acute disease usually is self-limited but can be treated with corticosteroids. It need not progress to chronic disease, and thus lung biopsy or bronchoalveolar lavage rarely are indicated to help make the diagnosis. Chronic hypersensitivity pneumonia can present as slowly progressive breathlessness or less insidiously, following recurrent acute attacks. Findings consistent with interstitial fibrosis on chest roentgenogram and pulmonary function (restrictive pattern with a diminished diffusing capacity) are present. Serum precipitins and/or measures of delayed-type hypersensitivity usually are present, as is late or delayed-type skin test reactivity. Bronchoalveolar lavage reveals an increased number of T lymphocytes whereas lung biopsy demonstrates granulomas with lymphocytes early and fibrosis late in the disease. The chronic disease is only variably reversible with corticosteroids and removal of the antigen from the environment. The mechanisms behind the pathogenesis of both acute and chronic processes remain speculative and need not be the same. It seems most clear that in chronic hypersensitivity pneumonia, Type IV hypersensitivity is present. The acute disease can be explained either by local Type III reactions or by stimulation of alveolar macrophages. Suppressor activity may play a part in the development of symptoms in sensitized individuals.

60

ACKNOWLEDG MENTS W e w o u l d l i k e t o t h a n k D r s . O. E p l e r a n d E. A. O a e n s l e r for p r o v i d i n g t h e c a s e m a t e r i a l s u s e d i n t h e f i g u r e s . W e would also like to thank Sharon Davignon, Laurie B e a r d s l e y , a n d K a r l a i B r o w n e for e x p e r t t e c h n i c a l a s s i s tance. REFERENCES 1. Lichtenstein L.M., Holtzman A., Burnett L.S." A quantitative in vitro study of the chromatographic distribution and immunoglobulin characteristics of human blocking antibody. J. Immunol. 101:317, 1968. 2. Gell P.G.H., Coombs R.R.A.: Clinical Aspects of Immunology, ed. 2. Philadelphia, F. A. Davis Co., 1969. 3. Ishizaka K., Ishizaka T., Hornbrook M.M.: Biologic function of the Fc fragment of E myeloma protein. Immunochemistry 7:687, 1970. 4. Riley J.F., West G.B.: The presence of histamine in tissue mast cells. J. Physiol. (Lond.) 120:528, 1953. 5. Leddy J.P.: Immunological aspects of red cell injury in man. Semin. Hematol. 3:48, 1966. 6. Wilson C.B., Dixon F.J.: Anti-glomerular basement membrane antibody induced glomerulonephritis. Kidney Int. 3:74, 1973. 7. Dixon F.J.: The role of antigen-antibody complexes in disease. Harvey Lect. 58:21, 1963. 8. Cochrane C.G., Janoff A.: The Arthus reaction: A model of neutrophil and complement mediated injury, in Zweifach B.W., Grant L., McCluskey R.T. (eds.): The Inflammatory Process, ed. 2. New York, Academic Press, 1974, Vol. 3, p. 85. 9. Rocklin R.E., Bendtzen K., Greineder D.: Mediators of immunity: Lymphokines and monokines. Adv. Immunol. 29:55, 1980. 10. Becker E.L., Austen K.F.: Anaphylactic reactions, in Miescher, P.A., M~iller-Eberhard H.J. (eds.): Textbook of Immunology. New York, Grune & Stratton, 1968, Vol. 1. 11. Pepys J.: Immunologic approaches in pulmonary disease caused by inhaled materials. Ann. N.Y. Acad. Sci. 221:27, 1974. 12. Cochrane C.G., Dixon F.J.: Immune complex injury, in Samter M. (ed.): Immunological Diseases, ed. 3. Boston, Little, Brown & Co., 1978, p. 210. 13. Dixon F.J., Feldman J.D., Vasquez J.J.: Experimental glomerulonephritis: The pathogenesis of a laboratory model resembling a spectrum of human glomerulonephritis. J. Exp. Med. 113:899, 1961. 14. Benacerraff B., Green I.: Cellular hypersensitivity. Annu. Rev. Med. 20:141, 1969. 15. Mekbel S., Von Lichtenberg F.: Granuloma formation in the laboratory mouse. II. Reaction to Ascaris suis eggs in the pre-sensitized host. J. Infect. Dis. 110:253, 1962. 61

16. Ramazzini B.: De Morbis Artificum Diatriba, 1713. Chicago, University of Chicago Press, 1940. 17. Campbell J.M.: Acute symptoms following work with hay. Br. Med. J. 2:1143, 1932. 18. Burke G.W., Carrington C.B., Strauss R., et al.: Allergic alveolitis caused by home humidifiers. Unusual clinical features and electron microscopic findings. JA.M.A. 238:2705, 1977. 19. Pepys J.: Hypersensitivity Diseases of the Lungs Due to Fungi and Organic Dusts. Basel, S. Karger, 1969. 20. Reed C.E.: Allergic mechanisms in extrinsic allergic alveolitis, in Brent L., Holborow J. (eds.): Progress in Immunology H. Amsterdam, North-Holland Publishing Co., 1974, Vol. 4, p. 277. 21. Bernardo J., Hunninghake G.W., Gadek J.E., et al.: Acute hypersensitivity pneumonitis: Serial changes in lung lymphocyte subpopulations after exposure to antigen. Am. Rev. Respir. Dis. 120:985, 1979. 22. Edwards J.H., Wagner J.C., Seal R.M.E.: Pulmonary responses to particulate materials capable of activating the alternative pathway of complement. Clin. Allergy 6:155, 1976. 23. Bice D.E., Salvaggio J., Hoffman E., et al.: Adjuvant properties of Micropolyspora faenii. J. Allergy Clin. Immunol. 57:207, 1976. 24. Fink J.N., Salvaggio J. (eds.): NIAID workshop on antigens in hypersensitivity pneumonitis. J. Allergy Clin. Immunol. 61:199, 1978. 25. Lacey J., Lacey M.E.: Spore concentrations in the air of farm buildings. Tr. Br. Mycol. Soc. 47:547, 1964. 26. Grant I.W.B., Blyth W., Wordrop V.E.: Prevalence of farmer's lung in Scotland: A pilot survey. Br. Med. J. 1:530, 1972. 27. Chmelik F., do Pico G., Reed C.E., et al.: Farmer's lung. J. Allergy Clin. Immunol. 54:180, 1974. 28. Emanuel D.A., Wenzel F.J., Lawton B.R.: Pulmonary mycotoxicosis. Chest 67:293, 1975. 29. Reed C.E., Sosman A., Barbee R.A.: Pigeon breeder's lung. A newly observed interstitial pulmonary disease. J.A.M.A. 193:261, 1965. 30. Allen D.H., Basten A., Woolcock A.J., et al.: HLA and bird breeder's hypersensitivity pneumonitis. Monogr. Allergy 11:7, 1977. 31. Sennekamp J., Rittner C., Vogel F., et al.: Distribution of the HL-A antigens in patients with pigeon breeder's lung. Schweiz. Med. Wochenschr. 108:315, 1978. 32. Rodey G.E., Fink J.N., Koethe S., et al.: A study of HLA-A, B, C, and DR specificities in pigeon breeder's disease. Am. Rev. Respir. Dis. 119:755, 1979. 33. Jamison S.C., Hopkins J.: Bagassosis. A fungus disease of the lung. New Orleans Med. Surg. J. 93:580, 1941. 34. Banaszak E.F., Thiede W.H., Fink J.N.: Hypersensitivity pneumonitis due to contamination of an air conditioner. N. Engl. J. Med. 283:271, 1970. 35. Grant I.W.B., Blackadder E.S., Greenberg M., et al.: Extrinsic allergic alveolitis in Scottish maltworkers. Br. Med. J. 1:490, 1976. 36. Tower J.W., Sweaney H.C., Huron W.H.: Severe bronchial asthma ap62

parently due to fungus spores found in maple bark. J.A.M.A. 99:453, 1932. 37. Strand R.D., Neuhauser E.B.D., Sornberger C.F.: Lycoperdonosis. N. Engl. J. Med. 277:89, 1967. 38. Avila R., Villar T.G.: Suberosis. Respiratory disease of cork workers. Lancet 1:620, 1968. 39. Fraser R.G., Pare J.A.P.: Extrinsic allergic alveolitis. Semin. Roentgenol. 10:1, 1975. 40. Unger G.F., Scanlon G.T., Fink J.N., et al.: A radiologic approach to hypersensitivity pneumonitis. Radiol. Clin. North Am. 11:339, 1973. 41. Unger J.D., Fink J.N., Unger G.F.: Pigeon breeder's disease. A review of the roentgenographic pulmonary findings. Radiology 90:683, 1968. 42. Stolz J.L., Arger P.H., Benson J.M.: Mushroom worker's lung. Radiology 119:61, 1976. 43. Hapke E.J., Seal R.M.E., Thomas G.O.: Farmer's lung. Thorax 23:451, 1968. 44. Allen D.H., Williams G.V., Woolcock A.J.: Bird breeder's hypersensitivity pneumonitis: Progress studies of lung function after cessation of exposure to the provoking antigen. Am. Rev. Respir. Dis. 114:555, 1976. 45. Braun S.R., do Pico G.A., Tsiatis A., et al.: Farmer's lung disease: Long term clinical and physiologic outcome. Am. Rev. Respir. Dis. 119:185, 1979. 46. Pepys J., Jenkins P.A.: Precipitin (FLH) test in farmer's lung. Thorax 20:21, 1965. 47. Fink J.N., Sosman A.J., Barboriak J.J., et al.: Pigeon breeder's disease: A clinical study of a hypersensitivity pneumonitis. Ann. Intern. Med. 68:1205, 1968. 48. Barboriak J.J., Fink J.N., Sosman A.J., et al.: Precipitating antibody against pigeon antigens in sera of asymptomatic pigeon breeders. J. Lab. Clin. Med. 83:372, 1973. 49. Moore V.L., Fink J.N., Barboriak J.J.: Immunologic events in pigeon breeder's disease. J. Allergy Clin. Immunol. 53:319, 1974. 50. Roberts R.C., Zais D.P., Emanuel D.A.: The frequency of precipitins to trichloroacetic acid-extractable antigens from thermophilic Actinomycetes in farmer's lung patients and asymptomatic farmers. Am. Rev. Respir. Dis. 114:23, 1976. 51. do Pico G.A., Reddan W.G., Chmelik F., et al.: The value of precipitating antibodies in screening for hypersensitivity pneumonitis. Am. Rev. Respir. Dis. 113:451, 1976. 52. Fink J.N., Moore V.L., Barboriak J.J.: Cell-mediated hypersensitivity in pigeon breeders. Int. Arch. Allergy Appl. Immunol. 49:831, 1975. 53. Allen D.H., Basten A., Williams G.V., et al.: Familial hypersensitivity pneumonitis. Am. J. Med. 59:505, 1975. 54. Salvaggio J., Arquembourg P., Seabury J., et al.: Bagassosis. IV. Precipitating antibodies against extracts of thermophilic Actinomycetes in patients with bagassosis. Am. J. Med. 46:538, 1969. 55. Kawai T., Salvaggio J., Arquembourg P., et al.: Precipitating antibod63

56. 57. 58. 59.

60.

61. 62. 63. 64. 65. 66. 67. 68. 69.

ies against organic dust antigens in humaw sera by counterimmunoelectrophoresis. Chest 64:420, 1973. Scribner G.H., Barboriak J.J., Fink J.N.: Prevalence of precipitins in groups at risk of developing hypersensitivity pneumonitis. Clin. Allergy 10:91, 1980. Williams J.V.: Inhalation and skin tests with extracts of hay and fungi in patients with farmer's lung. Thorax 18:182, 1963. Hunninghake G.W., Gadek J.E., Kawanami O., et al.: Inflammatory and immune processes in the human lung in health and disease: Evaluation by bronchoalveolar lavage. Am. J. Pathol. 97:149, 1979. Reynolds H.Y., Fulmer J.D., Kazmierowski J.A., et al.: Analysis of cellular and protein content of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J. Clin. Invest. 59:165, 1977. Moore V.L., Pedersen G.M., Hansen W.C., et al.: A study of lung lavage materials in patients with hypersensitivity pneumonitis: In vitro response to mitogen and antigen in pigeon breeder's disease. J. Allergy Clin. Immunol. 65:365, 1980. Seal R.M.E., Hapke E.J., Thomas G.O., et al.: The pathology of the acute and chronic stages of farmer's lung. Thorax 23:469, 1968. Barrowcliff D.F., Arblaster P.G.: Farmer's lung: A study of an early acute fatal case. Thorax 23:490, 1968. Roberts R.C., Moore V.L.: Immunopathogenesis of hypersensitivity pneumonitis. Am. Rev. Respir. Dis. 116:1075, 1977. Schatz M., Patterson R., Fink J.: Immunopathogenesis of hypersensitivity pneumonitis. J. Allergy Clin. Immunol. 60:27, 1977. Hensley G.T., Garancis J.C., Cherayil G.D., et al.: Lung biopsies of pigeon breeder's disease. Arch. Pathol. 87:572, 1969. Seal R.M.E., Thomas G.O., Griffiths J.J.: Farmer's lung. Proc. R. Soc. Med. 56:271, 1963. Salvaggio J.E.: Diagnosis and management of hypersensitivity pneumonitis. Hosp. Pract. 93:93, 1980. Keller R.H., Fink J.N., Lyman S., et al.: Altered immunoregulation in hypersensitivity pneumonitis. Clin. Res. 28:505A, 1980. Bernardo J., Gadek J., Hunninghake G., et al.: Acute hypersensitivity pneumonitis (HP): Mechanism of parenchymal neutrophil accumulation. Am. Rev. Respir. Dis. 119:59A, 1979.

SELF-ASSESSMENT ANSWERS 1. 2. 3. 4. 5. 6. 7~

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8. 9. 10. 11. 12. 13. 14.

c e a a, c e b d

15. 16. 17. 18. 19. 20. 21.

a, c a b c c d d, e

22. 23. 24. 25. 26. 27. 28.

c, d a, c True False False False False

29. 30. 31. 32. 33.

True False True True True