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Extrinsic allergic alveolitis
Extrinsic
Allergic
Robert G. Fraser, M.D., F.R.C.P.(C),
E
XTRINSIC allergic alveolitis (synonyms: alveolar hypersensitivity, respiratory membrane hypersensitivity, interstitial granulomatous pneumonitis, extrinsic allergic pneumonia) is a term introduced by Pepys to denote a group of diseases characterized by a response of the lungs to specific antigens contained in a wide variety of organic dusts of such fine particle size that they can penetrate into the most distal lung parenchyma. 18,46,47,50
The list of diseases and the antigens associated with them has increased steadily since “farmer’s lung” was first clearly described in 19248 and now contains a multitude of conditions ranging from this condition, probably the most common and most widely recognized, through bird-fancier’s lung to such unlikely conditions as pituitary-snuff disease and hen-litter hypersensitivity. Regardless of the name of the disease and the specific exposure involved, there exists a striking similarity in the clinical, pathologic, and roentgenologic features of all of these diseases, although it must be emphasized that the immunopathology and the exact criteria required to make the diagnosis are by no means clearly defined. However, the following list includes those criteria that, if fulfilled in toto, would justify confident inclusion in the group of extrinsic allergic alveolitis; whether or not any specific organic dust deserves to be so categorized will depend largely on the number of criteria fulfilled. 1) Exposure to an organic dust of small enough particle size to penetrate into the most distal lung parenchyma. 2) Episodes of dyspnea, usually unassociated with a wheeze, accompanied by a dry cough and sometimes fever and malaise, developing a few hours after exposure to the relevant antigen. Robert G. Fraser, M.D., F.R.C.P.0 Professor of Diagnostic Radiology, McGill University, Montreal, Quebec, Canada. J.A.P. Par& M.D.: Associate Professor of Medicine, McGill University, Montreal, Quebec, Canada. Reprint requests should be addressed to Dr. Robert G. Fraser, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A IAI. 0 I975 by Grune & Stratton, Inc. Seminarsin
Roentgenology,
Vol.
X, No. 1 (January),
1975
Alveolitis and J.A.P. Park, M.D.
3) Auscultatory evidence of bilateral crepitation heard best over the lung bases. 4) Roentgenographic manifestations consisting of a diffuse micronodular pattern, commonly associated in the acute stage with an air space component. A “honeycomb” pattern is the end result of repeated or long-term exposure. 5) Pulmonary function tests revealing a reduction in vital capacity, carbon-monoxide diffusing capacity (transfer factor), po, and static compliance. There is little or no evidence of airway obstruction. 6) A “late” reaction to intracutaneous injection of the appropriate antigen. 7) The presence in the serum of precipitins against the suspected antigen. 8) The development, some hours after provocation with the specific antigen, of pyrexia, dyspnea, and cough, with or without impairment of pulmonary function and the appearance of abnormalities on the chest roentgenogram. 9) Histopathologic features in the lung parenchyma that, while not diagnostic, are sufficiently characteristic to be compatible with the diagnosis. 10) Resolution of the episodic systemic and respiratory symptoms after cessation of exposure to the antigen with, in time, disappearance of precipitins from the serum.65 11) Development of irreversible interstitial pulmonary fibrosis after repeated or continuous exposure to the antigen. This is manifested by a persistence of dyspnea on exertion, abnormal pulmonary function test values, and roentgenographic changes.‘r~*’ In view of these similarities, the descriptions to follow will apply to all diseases within the broad category of extrinsic allergic alveolitis. It will suffice to describe the individual diseases only insofar as they deviate from the usual pattern. EPIDEMIOLOGY
The great majority of instances of allergic alveolitis reported to date has occurred as a result of occupational or environmental exposure. Table 1 lists the definite, probable, and improbable causes 31
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Table
Definite causes Farmer’s lung Mushroom-worker’s
1. Causes of Extrinsic Source
Disease
Moldy lung
of
Allergic
Antigen
hay
Bagassosis Alveolitis from contaminated forced-air apparatus Bird-fancier’s lung Maltworker’s lung Maple bark disease Wood-pulp worker’s Sequoiosis
Moldy barley, malt Contaminated maple Moldy pulp Moldy sawdust
bark
M. faeni M. vulgaris M. faeni M. vulgaris M. vulgaris Thermophilic
actinomycetes
Serum proteins and droppings Aspargillus clavatus Cryptostroma corticala Altarnaria Graphium Aureobasidium pullulans Pituitary hormone Sitophilus granarius Penicillium frequentens Penicillium casei Fish meal Coffee bean dust
Pituitary snuff-taker’s lung Grain-weevil hypersensitivity Suberosis Cheesewasher’s lung Fishmeal-worker’s lung Coffee-worker’s lung Probable causes Poultry-keeper’s lung
Pituitary snuff Contaminated wheat Moldy cork dust Moldy cheese Animal food factory Coffee bean
Smallpox-handler’s lung Lycoperdonosis Detergent-worker’s lung Starch spray lung disease Improbable causes Thatched roof lung disease Fibrosis in blackfat-tobacco smokers Vineyard-sprayer’s lung Furrier’s lung
Patients with smallpox Lycoperdon species “Enzyme” detergents Starch spray
Serum proteins and droppings Variola virus Lycoperdon spores Bacillus subtilis Soil repellant
Thatched roofs Blackfat-tobacco
Roofing material Blackfat-tobacco
“Bordeaux mixture” Fox and astrakhan fur
Copper sulphate Fur dust
Poultry
of the disease, together with the source of the particles and the specific antigens, where known. The responsible antigens vary widely, not only in the group as a whole but in individual diseases. Lacey and Lacey4’ estimated that a farmer working in an atmosphere of moldy hay would inhale so many particles that 750,000 per minute would be deposited on air space walls where they might activate immunologic reactions. Similar figures have been given for moldy bagasse.60The small size of the antigenic particles is extremely important. Hargreave3’ stated that the allergenic particles are all smaller than 6~, permitting penetration to the peripheral respiratory tissue. Although the great majority of cases of allergic alveolitis are occupational in nature, exciting causes have also been found within the home, originating for example within a heating system,22
PARE
Alveolitis
Antigen
Mushroom postspawning compost Bagasse Contaminated humidifier or air conditioner Budgerigar, pigeon, parakeet
disease
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solution
a humidifier,76 an air conditioner,3 and spray starch.” These incidents emphasize the importance of meticulous history-taking in attempting to uncover environmental atmospheric exposure coincident with the development of acute respiratory symptoms. CLINICAL
MANIFESTATIONS
As more and more cases of extrinsic allergic alveolitis are reported, it is becoming clear that the diagnosis must be based primarily on clinical findings. Many reports serve to emphasize the importance of placing reliance on the clinical rather than the roentgenologic manifestations of these diseases: A normal chest roentgenogram does not exclude the diagnosis and is not at all unusual in the presence of a classical clinical picture.11,16,28 In all these diseases, the clinical picture varies
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ALVEOLITIS
widely according to the degree of antigenic exposure. The classical acute onset occurs in perhaps no more than a third of the patients’s and is characterized by the development, within 4-8 hr after exposure, of dyspnea, cough, malaise, chills, fever, and sometimes hemoptysis.2’48 Individuals who develop this acute type of onset have usually been exposed intermittently to high concentrations of antigen, as typically occurs in pigeon breeders.” The more common form of onset is insidious, with gradual progression of dyspnea and cough and with such systemic symptoms as fever, chills, malaise, aches and pains, and weight 10ss.‘~,~ This type of onset tends to occur in patients exposed more or less continuously to small amounts of antigenic dust, such as from a budgerigar or parrot in the house. 74 Farmer’s lung frequently presents in this insidious manner. In a small percentage of patients, usually those with a history of allergy, the clinical presentation may suggest “asthmatic bronchitis.” The asthmatic episode occurs within a few minutes of exposure and may be repeated as a late response some 4-6 hr after the initial episode of bronchospasm.48>67 The subsequent course of events depends on whether exposure to the antigenic material continues. Repeated exposure usually is associated with exacerbations of the acute episode; eventually, the patient may become a respiratory cripple due to pulmonary fibrosis. In those instances where there is doubt as to the etiology, supporting evidence may be obtained by challenging the patient with an aerosol of the antigen under suspicion, or by documenting a remission coincident with removal of the patient from the environment. However, should a patient with a highly suggestive environmental history manifest a diffuse micronodular pattern roentgenographically or impaired values on pulmonary function testing, the diagnosis can be reasonably assumed without the additional support of a positive antigenic challenge. Pulmonary function tests are extremely useful not only in the assessmentof the effects of antigen in its natural environment but also when the antigen is administered by aerosol as a challenge. In general, there is a slight-to-moderate reduction in FEV, , proportional to a decrease in vital capacity. Decreased values for static lung compliance, diffusing capacity (transfer factor) and po, are all considered indications of disease involving the lung
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parenchyma. There is little doubt that increased “stiffness” of the lungs, as reflected in a decrease in compliance, is compatible with abnormality of the alveolar wall; however, the abrupt decrease in diffusing capacity and po, characteristic of the “acute” naturally occurring or provocative allergic response is much more suggestive of ventilation/ perfusion inequality. More sophisticated measurements of bronchiolar function will almost certainly implicate diffuse bronchiolar obstruction as the responsible morphologic abnormality for these changes in function; in fact, there is a growing abundance of pathologic evidence to support this contention (see below). Removal of patients from their hazardous environment frequently results in restoration of pulmonary function to normal, but in some cases function may continue to be impaired even after the chest roentgenogram has returned to normal.7s This has been shown to be the case in mushroom worker’s disease and is in keeping with a more prolonged clinical illness.” IMMUNOLOGIC
MANIFESTATIONS
In individuals exposed to various organic dust antigens, the development of symptoms and signs 4-6 hr following exposure suggests not only a causal relationship but an immunologic mechanism.42*49 This delayed onset of clinical manifestations is characteristic of so-called “immunecomplex” disease, classified by Coombs and Cell as an Arthus type III immunologic reaction.12 In this type of reaction, antigen is believed to combine with precipitating IgG or IgM antibodies, forming aggregates that fix complement. The resulting complexes are chemotactic for polymorphonuclear leukocytes that ingest them and then undergo disruption, liberating lysosome enzymes that cause tissue damage. Precipitins Patients with hypersensitivity alveolitis often show a high titer of specific IgG precipitating antibodies. Characteristically, these titers fall with clinical improvement, after removal from the exciting cause. Arthus skin reactivity has been passively transferred to laboratory animals with serum from affected patients. 6o Immunofluorescent studies have shown high concentrations of antigen in the walls of bronchioles, along with immunoglobulins IgC, IgA, and IgM and with C3 comple-
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merit.” Similarly, deposits of IgG and complement along alveolar capillaries have been demonstrated in patients with coffee worker’s lung. 72 Precipitating antibodies specific for organic dust antigens have long been considered the hallmark of extrinsic allergic alveolitis.42Y43However, although the demonstration of precipitins provides important circumstantial evidence implicating a specific organic dust as a cause of alveolitis, some patients show no evidence of precipitins by commonly accepted methods.11Y28In contrast, precipitins can sometimes be demonstrated in asymptomatic individuals who have been exposed to an organic antigen commonly accepted as a cause of hypersensitivity alveolitis. Many instances of this clinicalimmunologic dissociation have been reported. In a survey of 200 pigeon breeders, none of whom had clinical evidence of disease, Fink and associates found precipitating antibodies in 40%; the only correlation seemed to be with duration and degree of exposure to birds.23 In another study FLH (Farmer’s Lung Hay) antigens reacted with the serum of 18% of farmers who had been exposed to moldy hay but who had no history suggestive of the disease.M,48 Many other examples of this phenomenon are recorded.1”32Y59V61-63 Considerable variation exists in the incidence of positive precipitins to FLH antigen or Micropolyspora fueni in patients with clinically diagnosed farmer’s lung. 28Y44Y48 This discrepancy appears to result, at least in part, from the acuteness or chronicity of the illness. In a study of 45 patients with farmer’s lung, all 11 patients with acute disease showed positive reactions compared with only 18 (53%) of 34 patients with chronic disease.Similar results were noted by others.52 In summary, it may be concluded that the demonstration of precipitins indicates that a patient has been exposed to the specific antigen. The greater the exposure, the greater the likelihood of showing precipitating antibodies. Precipitins may be present in healthy asymptomatic subjects but are not found in unexposed persons3’
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positive with other allergens, notably with material obtained from birds. Intracutaneous tests are of use in identifying late or “dual” reactions.* Hargreave and Pepys found that late reactions correlated well with the presence of extrinsic allergic alveolitis and precipitating antibodies.32 In patients with bird fancier’s lung, positive late reactions were observed in 84%, but only in patients who had clinical evidence of disease. Allergen Inhalation Tests
Skin Tests
Allergen inhalation tests (challenge test) with extracts of appropriate antigens may be performed without risk.32 They are particularly useful when the diagnosis is in doubt or when the clinical situation suggests involvement by an organic antigen not previously described. Reactions to inhalation tests may be immediate, late, or dual. Immediate reactions are classically seen in atopic individuals exposed to specific antigens to which they have become previously sensitized.32 Asthmatic patients characteristically produce bronchospasm but no fever or leukocytosis. Lute reactions usually appear within 4-6 hr after the challenge and usually clear within 24-48 hr. They may be associated with evidence of bronchospasm, but more frequently they reveal a restrictive rather than an obstructive pattern on pulmonary function testing. The systemic response to an inhalation challenge is identical to that seen with the naturally occurring disease and includes fever, chills, malaise, and anorexia; leukocytosis is a common feature. Dual reaction refers to a combined immediate and late response. They occur less frequently in extrinsic allergic alveolitis than late reactions alone. Patients with positive dual or late reactions almost invariably have serum precipitins to the antigen employed in the inhalation test.3’ Positive late reactions in which both respiratory and systemic symptoms are manifested have been described following inhalation of a variety of antigens, including those associated with farmer’s 1ung,4378bagassosis,34malt-worker’s lung,” birdfancier’s 1ung,33*53 mushroom-worker’s lung,36 fish-meal worker’s lung,’ and wood-pulp worker’s
Skin tests with FLH antigen or M. faeni are of no diagnostic value, since they cause positive reactions in both exposed and unexposed individuals, presumably because of their action as nonspecific irritants. Prick and intracutaneous tests may be
*A “dual” reaction consists of an immediate wheal and flare followed 3-4 hr later by the development of erythema and swelling at the site of puncture. This skin reaction usually resolves in 2448 hr.
EXTRINSIC
ALLERGIC
ALVEOLITIS
disease.64 A positive response to challenge with specific antigens correlates closely with the results of skin testing and provides further evidence for a hypersensitivity state in this group of diseases.32 Although the use of animal models for the investigation of the immune pathogenesis of allergic alveolitis is of comparatively recent origin, the information obtained to date supports many of the views expressed above.19~24~37~3s~s4~55~65 PATHOLOGIC
CHARACTERISTICS
The histologic features of the many different varieties of extrinsic allergic alveolitis are strikingly similar and, with few exceptions, do not permit differentiation of one from another. The exceptions lie in maple bark disease, in which the fungus may be identified, and in bagassosis, in which vegetable fibers may be seen.29 As might be anticipated, the pathologic characteristics depend partly on the intensity of exposure to the allergen and partly on the stage of the disease at which the biopsy is taken.70 Three stages may be recognized, the acute, subacute, and chronic. The Acute Stage The earliest lesions that have been described were in a 17-yr-old boy who died lo-12 days after the onset of clinical disability following exposure to a large concentration of moldy hay.’ The lesions were centrilobular in position, involving respiratory bronchioles and adjacent vessels and alveoli. The bronchioles in the center of the lesion showed an obstructive bronchiolitis, often with destruction of their walls. There were also histologic features typical of the Arthus reaction-acute vasculitis of the aveolar capillaries, fibrin thrombi, and an infiltration of neutrophiIs, eosinophils, and mononuclear cells. It is worth noting that this patient represents a most unusual example of acute farmer’s lung. Although precipitins to moldy hay and to M. faeni were found in his serum, his clinical course was unique in that death occurring during the acute phase of extrinsic allergic alveolitis is rare indeed. There is little doubt that bronchiolitis is a common feature of this disease, ranging in incidence In some cases, the from 25% 100%.20~56~64~65~77 bronchiolar lesions have been described as obstructive and organizing, presenting the appearance of bronchiolitis obliterans.
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In an immunofluorescent study of lung tissue from four patients with farmer’s lung, Wenzel and colleagues 77 found high concentrations of antibody to M. faeni in the walls of bronchioles in the lungs of two of the patients who were acutely ill but not in the two with more chronic disease. Immunoglobulins IgG, IgA, and IgM were found in plasma cells and lymphocytes scattered throughout the diseased lungs. Neither necrotizing vascular lesions nor polymorphonuclear leukocytes were observed in numbers usually seen in Arthus reactions, leading these investigators to suggest that extrinsic allergic alveolitis may not be a pure type III immune reaction but may also contain elements of a type II cytoxic reaction. In fact, they suggested that the histologic picture might also indicate a type IV “delayed hypersensitivity” reaction. The Subacute Stage Biopsies examined at a slightly later stage (l-2 mo after the onset of the acute stage) reveal noncaseating “histiocytic” granulomas, closely resembling those seen in sarcoidosis.1s>29The granulomas are present in the peribronchiolar tissues and cause localized thickening of alveolar walls (Fig. 1). There may be a striking interstitial pneumonitis of mononuclear cells. There is generally no evidence of fibrosis in the interstitial tissues, although reticulin may be increased. Giant cells of both Ianghans25 and foreign body types*’ are often seen, the latter frequently containing birefringent material. During this stage, intra-alveolar exudation may be present. According to Hargreave and his co-workers,29 some of the giant cells contain lanceolate spaces, a finding that is not a feature of any other form of alveolitis. Obstructive bronchiolitis is a common feature, ranging in incidence from 25% to 100% of cases.2o’65 Although sarcoid-like granulomas have been shown to arise as the result of the formation of antigen-antibody complexes,30*45366they are more commonly associated with type IV allergy. The Chronic Stage Over the course of the next several months, the lesions become nonspecific as the granulomas disappear and fibrosis supervenes.20~27~29341 ,‘* Interstitial pneumonitis and doubly refractile material persist. The degree of ensuing fibrosis is variable; the upper zones are affected most.64 Fibrosis may
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Fig. 1. Photomicrographs of left lung biopsy from the patient whose roentgenograms are illustrated in Fig. 2. (A) Noncaseating granulomatous lesion that is both interstitial and intra-alveolar. The granulomas consist largely of epitheloid cells with occasional multinucleated giant cells. Under higher magnification (61, there is much extraneous doubly-refractile material, some of which appears to lie within the granulomas in the form of long crystals. The interstitial granulomas abut on vessels and bronchioles. The intra-alveolar granulomas form distinct nodular masses and probably represent the acinar lesions seen in Fig. 26. The general appearance is consistent with farmer’s lung. (From Fraser RG, Pare JAP;*6 reproduced with permission of W.B. Saunders Co.)
be localized and peribronchial, forming focal masses with adjacent irregular emphysema, or it may be more diffuse, producing microcysts resembling those of fibrosing alveolitis. The endresult is a variable mixture of scarring, pneumonitis, honeycombing, and emphysema.
ROENTGENOLOGIC
MANIFESTATIONS
As with the pathologic manifestations, the roentgenographic changes vary with the stage of the disease. Early in the course of the acute stage of the disease, the chest roentgenogram may show no discernible abnormality. In one case,‘* the chest
EXTRINSIC
ALLERGIC
ALVEOLITIS
roentgenogram was perfectly normal when lung biopsy showed diffuse interstitial granulomatous inflammation. Once roentgen changes are visible, however, they usually parallel the severity of the clinical symptoms.25 They consist of granular or nodular mottling scattered diffusely throughout both lungs, without zonal predominance although commonly less evident in the apices and bases (Fig. 2A). The individual nodules range from 1 mm or less up to several millimeters in diameter. They may be quite discrete, although usually ill-defined. The pattern has been likened to snowflakes25 or to a sand storm.2 Although this fine nodular pattern is characteristic of the acute and subacute stages of the disease, we have seen cases of farmer’s, mushroomworker’s, and bird-fancier’s lung in which acinar shadows have been visualized, particularly in the lower lung zones (Fig. 2B). Unger and colleagues also described acinar shadows in the acute stage of bird-fancier’s lung.71 In our experience, hilar lymph node enlargement is variable. Frank25 found no evidence of hilar or mediastinal lymph node enlargement in 27 patients with farmer’s lung, and suggested that this should permit ready differentiation from sarcoidosis. That this is not invariably true is evidenced by one patient we have seen in whom the diagnosis of farmer’s lung was proved by biopsy and by the presence of precipitating antibodies in the serum, who showed clear-cut roentgenographic evidence of hilar lymph node enlargement. Hilar node enlargement is said to be a common finding in mushroom-worker’s lung.58 Furthermore, in sarcoidosis diffuse pulmonary involvement is frequently present without lymph node enlargement, so that the size of hilar nodes can hardly be expected to discriminate between sarcoidosis and extrinsic alveolar pneumonitis. In addition to the roentgen changes already described, Hargreave et al. described “patchy clouding” in 11 of 41 patients with bird-fancier’s lung.29 It is possible that this represents patchy air-space consolidation, although it was not specifically identified as such. They observed septal lines in the costophrenic recesses in nine of the 41 patients, presumably resulting from lymphatic overload. The subsequent course of the roentgenographic change depends on whether exposure is continued. If the patient is removed from the environment, the chest roentgenogram may return to normal, in from 10 days to several weeks.65 Should exposure
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be continued or repeated, the diffuse nodular pattern characteristic of the acute and subacute stages is replaced by changes characteristic of diffuse interstitial fibrosis (Fig. 3)-a medium-to-coarse reticular pattern, loss of lung volume, a “honeycomb” pattern, and sometimes compensatory overinflation of the lung zones that are least affected. The loss of lung volume (cicatrization atelectasis) tends to show a striking upper zone predominance. Of the 4 1 patients with bird-fancier’s lung studied by Hargreave and his associates, 20 showed lobar shrinkage, and in 17 of these the upper lobes were predominantly affected; in half of these the atelectasis was restricted to the upper zones. Ring shadows measuring 5-8 mm in diameter categorize the late stages of interstitial fibrosis, creating a honeycomb pattern indistinguishable from the late stages of fibrosing alveolitis (or perhaps more typically of histiocytosis-X in view of its upper zone anatomic bias). This pattern was observed in 19 of the 41 cases of Hargreave and colleagues.29 Overinflation, particularly of lower lung zones in compensation for upper zone fibrosis, is not infrequent. In any study of a disease in which the basic criteria for diagnosis are clinical, it is not unusual for a number of patients to show no chest roentgenographic abnormalities. For example, in their survey of the farming population of three districts in Scotland, Grant et al. 28 found roentgen abnormalities in only a minority of cases of presumed disease. Similar reports have appeared of malt workers” and bird breeders16 with a classical clinical presentation of allergic alveolitis and precipitating antibodies in the serum but whose chest roentgenograms have been normal. In contrast, among 200 pigeon breeders without clinical evidence of disease, an abnormal roentgenographic pattern was found in 10 (S%).23 Although, as the authors suggest, this incidence may have been due to roentgenologic overreading, it is also quite possible that, in a minority of people, exposure to antigens may lead to roentgenographically apparent pulmonary hypersensitivity reactions without production of symptoms. NOTES
ON SPECIFIC
DISEASES
Farmer’s Lung Farmer’s lung is the earliest described and most thoroughly understood of the conditions causing extrinsic allergic alveolitis. Although it has been
Fig. 2. This 25-yr-old woman, the wife of a farmer. was admitted with a 2-wk history of moderate dyspnea, mildly productive cough, and daily temperature rise to 103°C. She was slightly cyanotic. (A) Magnified view of the lower half of the right lung reveals a medium reticulonodular pattern possessing a predominantly nodular component. The full film showed the disease to be widespread with relative sparing of the apices and costophrenic sulci. After a course of antibiotic therapy, during which her clinical status improved somewhat, she was discharged without a diagnosis. Several months later, during which she had continued to live on the farm, she was readmitted following the acute onset of dyspnea, cough, and high fever. The chest roentgenogram at this time (B) revealed definite evidence of extension of the disease. An acinar pattern had been superimposed on the reticulonodular pattern seen earlier. This was regarded as evidence of involvement of the air spaces of the lung and was felt to represent en acute exacerbation reexposure. The histologic sections illustrated in Fig. 1 are from a biopsy taken at this time. (From Fraser RG, Pare JAP;*e reproduced in modified form with permission of W.B. Saunders Co.)
EXTRINSIC
ALLERGIC
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Fig. 3. For a number of years, this 60-yr-old man maintained a loft of racer pigeons. During the past year, he had noted gradually increasing dyspnea on exertion, although at no time had he experienced episodes of acute respiratory illness. A PA roentgenogram (A) reveals a widespread coarse reticulonodular pattern without anatomic predilection. Precipitins to pigeon feathers were demonstrated in his serum and a confident diagnosis of pigeonfancier’s lung was made. Despite warnings, the patient refused to remove himself from the noxious environment and during the following months, his dyspnea increased in severity and became associated with a dry, hacking cough. Eighteen months after his original investigation, a PA roentgenogram (6) revealed remarkable deterioration. The pattern had become very coarsely reticular and, in some areas, almost cyst-like or “honeycomb” in nature. Marked elevation of the diaphragm indicated a striking loss of lung volume, due to fibrosis and cicatrization. The upper lobe predominance often seen in the late stages of the disease was not observed in this patient.As anticipated, pulmonary function studies now revealed a severe restrictive pattern.
recognized for centuries, the earliest clear descriptions in English appeared in 1924 and 1932.8,68 Many of the earlier reports originated in Great Britain-and Scandinavia, labeling the disease with such names as thresher’s lung, harvester’s lung, bronchomycosis feniseciorum (mycosis of haymakers or harvesters), and Norwegian hemp disease. Farmer’s lung is the prototype of extrinsic allergic alveolitis, and the bulk of the material in this article originates from studies of farmers exposed to thermophilic actinomycetes. Traditional descriptions probably reflect the type of patient who is likely to be seen in a large medical
center,49’52 whereas more recent studies** indicate that many farmers have the clinical syndrome without showing all the immunologic and roentgenologic manifestations commonly described in the disease. The clinical picture varies according to the degree of exposure to antigens in moldy hay and to the degree of sensitivity of the subject. The classical acute onset occurs in perhaps no more than a third of cases,44the more common form being insidious and characterized by gradual progression of dyspnea, cough, and weight loss, and by fever, chills, malaise, and aches and pains.18*44 Pepys and Jenkins44’48 found that approximately 90% of
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patients with farmer’s lung have precipitating antibodies to thermophilic actinomycetes, 87% being to M. faeni and 3% to other actinomycete antigens. Mushroom- Worker S Lung Since the first description of mushroom-worker’s lung in 1959: three further reports on this form of hypersensitivity pneumonitis have appeared.“, ‘3136 The specific antigens, M. faeni and Micromonospora vulgaris are the same as in farmer’s lung. The culture of mushrooms requires a process of steam pasteurization to destroy microorganisms; temperatures during this process rise to 60°C at 100% humidity, which encourages the rapid growth of thermophilic actinomycetes. Subsequently, the compost is spread on trays and mixed with mushroom mycelia grown on manure and grain. This process, which is called “spawning,” gives rise to clouds of dust. Although the clinical and immunologic features are very similar to those of farmer’s lung, the incidence of visible hilar lymph node enlargement is said to be higher.” Bagassosis This disease occurs from inhalation of bagasse fibers contaminated with the specific antigen M. vulgaris. 31,61-63 Bagasse is a fibrous material that remains after the sugar-containing juice has been extracted from sugar cane and is composed almost entirely of cellulose and other complex plant carbohydrates. Bagassosisis more likely to occur as a result of exposure to freshly produced bagasseor bagassefibers stored indoors than to moldy bagasse stored outside.62 A curious development noted by some patients with bagassosis is an aversion to smoking cigarettes.” Bird-Fancier’s Lung Although this hypersensitivity disease (synonyms: pigeon breeder’s lung, bird-breeder’s lung) is commonly associated with budgerigars and pigeons, it was originally described in a breeder of parakeets43 and has recently been noted in two other parakeet fanciers.” The antigen consists of protein contained. in bird serum, droppings, or feathers. Riley and associatess6 encountered two cases in wives of pigeon breeders, one of whom was exposed only to her husband’s coveralls. Exposure to chickens can produce the disease;‘13’ however, a thorough survey of poultry workers did not uncover a single symptomatic individual.lg
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Hypersensitivity Pneumonitis Due to Forced-Air Equipment There have been three recent well-documented reports of extrinsic allergic alveolitis resulting from humidifiers and air conditioners contaminated by a thermophilic actinomycete resembling Culture of this organism from the M. faeni. 3~22Y76 equipment, the provocation of typical attacks on inhalation of the offending antigen, and the remissions induced by removing the patients from the environment clearly established a cause-andeffect relationship, and once again underlines the importance of careful history-taking in any patient presenting with diffuse interstitial lung disease. The other types of extrinsic allergic alveolitis possess no particular characteristics to distinguish them from those described above except for the nature of occupational exposure and the specific allergen (Table 1). As might be anticipated, other diseases of a similar or identical nature crop up from time to time, for example, “cheesewashers’ “coffee-worker’s disease,“14 “furrier’s lung,“‘l lung,)‘72 “paprika-splitter’s lung,“3s “lycoperdonosis,“6g and “hen litter hypersensitivity.“3g There is little doubt that the future will bring other diseases of an identical nature related to unusual occupational exposure.
REFERENCES 1. Avila R: Extrinsic allergic alveolitis in workers exposed to fish meal or poultry. Clin Allergy 1:343-346, 197 1 2. Baldus WP, Peter JB: Farmer’s lung. A report of two cases. N Engl J Med 262:700-705, 1960 3. Banaszak EF, Thiede WH, Fink JH: Hypersensitivity pneumonitis due to contamination of an air conditioner. N Engl J Med 283:271-276,197O 4. Barbee RA, Dickie HA, Rankin J: Pathogenicity of specific glycopeptide antigen in farmer’s lung. Proc Sot Biol Med 118:546-550, 1965 5. Barrowcliffe DF, Arblaster PG: Farmer’s lung: A study of an early acute fatal case. Thorax 23:490-500, 1968 6. Bringhurst LS, Byrne RN, Gershon-Cohen J: Respiratory disease of mushroom workers. Farmer’s lung. JAMA 171:15-18,1959 7. Biitikofer E, deWeck AL: Poultry keeper’s lung. Ger Med Mon 15:245-253, 1970 8. Cadhan FT: Asthma due to grain rusts. JAMA 83:27, 1924 9. Caldwell JR, Pearce DE, Spencer C, et al: Immunologic mechanisms in hypersensitivity pneumonitis. J Allergy Clin Immunol 52:225-230, 1973
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ALLERGIC
ALVEOLITIS
10. Chan-Yeung M, Grzybowsli S, Schonell ME: Mushroom workers’ lung. Am Rev Resp Dis 105:819-822, 1972 11. Channel1 S, Blythe W, Lloyd M, et al: Allergic alveolitis in maltworkers: A clinical, mycological and immunological study. Quart J Med 38:351-376,196Y 12. Coombs RRA, Gel1 PGH: Classifications of allergic reactions responsible for clinical hypersensitivity and disease, in Cell and Coombs (eds): Clinical aspects of immunology (ed 2). Philadelphia, Davis, 1968, p 575 13. Craig DB, Donevan RE: Mushroom-worker’s lung. Can Med Assoc J 102:1289-1293,197O 14. de Week AL, Gutersohn J, Biitikofer E: La maladie des laveurs de fromage (“Kasewascherkrankheit”): une forme particuliere du syndrome du poumon du fermier. Schweiz Med Wochenschr 99:872-876, 1969 15. Dickie HA, Rankin J: Farmer’s lung. An acute granulomatous interstitial pneumonitis, occurring in agricultural workers. JAMA 167:1069-1076, 1958 16. Dinda P, Chatterjee SS, Riding WD: Pulmonary function studies in bird breeder’s lung. Thorax 24:374378,1969 17. do Pica GA, Layton CR Jr, Clayton JW, et al: Acute pulmonary reaction to spray starch with soil repellant. Am Rev Resp Dis 108:1212-1215,1973 18. Editorial. Allergic alveolitis. Br Med J 3:691-692, 1967 19. Elman AJ, Tebo T, Fink JN, et al: Reactions of poultry farmers against chicken antigens. Arch Environ Health 17:98-100, 1968 20. Emanuel DA, Wenzel Fl, Bowerman Cl, et aI: Farmer’s lung. Clinical, pathologic and immunologic study of twenty-four patients. Am J Med 37:392401, 1964 21. Fink JN: Environment and pulmonary hypersensitivity. Ann Intern Med 74:293-294,197l 22. Fink JN, Banaszak EF, Thiede WH, et al: Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann Intern Med 74: 80-83, 197 1 23. Fink JN, Schlueter DP, Sosman AJ, et al: Clinical survey of pigeon breeders. Chest 621277-281, 1972 24. Fink JN, Hensley GT, Barboriak JJ: Chemical nature of agents and airway responses. Report of Workshop III. Abstract presented by Chase MW and Rankin J. Ann NY Acad Sci 221:205-208, 1974 25. Frank RC: Farmer’s lung-a form of pneumoconiosis due to organic dusts. Am J Roentgen01 79:189215, 1958 26. Fraser RG, Par6 JAP: Diagnosis of Diseases of the Chest. Philadelphia, Saunders, 1970 27. Fuller C: Farmer’s lung. Dis Chest 42:176-180, 1962 28. Grant IWB, Blyth W, Wardrop VE, et al: Prevalence of farmer’s lung in Scotland. A pilot survey. Br Med J 1:530-534,1972 29. Hargreave F, Hinson KF, Reid L, et al: The radiological appearances of allergic alveolitis due to bird sensitivity (bird fancier’s lung). Clin Radio1 23: l-10, 1972 30. Hargreave FE: Review article: Extrinsic allergic alveolitis. Can Med Assoc J 108:1150-1154,1973
41
31. Hargreave FE, Pepys J, Holford-Strevens V: Bagassosis. Lancet 1:619-620, 1968 32. Hargreave FE, Pepys J: Allergic respiratory reactions in bird fanciers provoked by allergen inhalation provocation test. J AlIergy Clin Immunol50:157-173, 1972 33. Hargreave FE, Pepys J, Longbottom JL, et al: Bird breeder’s (fancier’s) lung. Lancet 1:445-449, 1966 34. Hearn CE, Holford-Strevens V: Immunological aspects of bagassosis. Br J lnd Med 25:283-292,1968 35. Hunter D: The diseases of occupation (ed 4). Boston, Little, Brown, 1969 36. Jackson E, Welch KMA: Mushroom worker’s lung. Thorax 25:25-30,197O 37. Joubert JR, Hogg JC, Moroz LA: Allergic alveolitis -Immune pathogenesis in an animal model. Abstract presented at the XII International Congress of Diseases of the Chest, July 7-12, 1974, London 38. Kawai T, Salvaggio J, Lake W, et al: Experimental production of hypersensitivity pneumonitis with bagasse and thermophilic actinomycete antigen. J Allergy Clin Immunol50:276-288, 1972 39. Korn DS, Florman AL, Bribetz I: Recurrent pneumonitis with hypersensitivity to hen litter. JAMA 205: 4445,1968 40. Lacey J, Lacey ME: Spore concentrations in the air of farm buildings. Trans Br Mycology Sot 47:547, 1964 41. Page M, van Zandt HC: Farmer’s lung. Report of a case with lung biopsy. Am Rev Resp Dis 87:576-581, 1963 42. Parish WE: Farmer’s lung. I. An immunological study of some antigenic components of moldy foodstuffs. Thorax 18:83-89,1963 43. Pearsall HR, Morgan EH, Tesluk H, et al: Parakeet dander pneumonitis. Acute psittacokeratopneumoconiosis. Report of a case. Bull Mason Clinic 14:127-137, 1960 44. Pepys J: Pulmonary hypersensitivity disease due to inhaled organic antigens (editorial). Ann Intern Med 64: 943-947,1966 45. Pepys J: Immunologic approaches in pulmonary disease caused by inhaled materials. Ann NY Acad Sci 221:27-35,1974 46. Pepys J: Hypersensitivity to inhaled organic antigens. J R Co11 Physicians Lond 2:42, 1967 47. Pepys J: Hypersensitivity diseases of the lungs due to fungi and organic dusts. Monograph in Allergy (ed 4). Basel, Karger, 1969 48. Pepys J, Jenkins PA: Precipitin (F.L.H.) test in farmer’s lung. Thorax 20:21-35,1965 49. Pepys J, Jenkins PA, Festenstein GN, et al: Farmer’s lung. Thermophilic actinomycetes as a source of “farmer’s lung hay” antigen. Lancet 2:607-611, 1963 50. Pepys J, Turner-Warwick M, Dawson PL, et al: Arthus (Type III) skin test reactions in man: Clinical and immunopathological features, in Rose et aI (eds): Allergology. Excerpta Med Int Congress Series 162:22I, 1968 51. Pimental JC: Furrier’s lung. Thorax 25:387-398, 1970 52. Rankin J, Kobayashi M, Barbee RA, et al: Pulmonary granulomatoses due to inhaled organic antigens. Med Clin N Am 51:459-482,1967
42 53. Reed CE, Sosman A, Barbee RA: Pigeon-breeder’s lung. A newly observed interstitial pulmonary disease. JAMA 193:261-265,1965 54. Richerson HB, Cheng FH, Bauserman SC: Acute experimental hypersensitivity pneumonitis in rabbits. Am Rev Resp Dis 104:568-575, 1971 55. Richerson HB: Acute experimental hypersensitivity pneumonitis in the guinea pig. J Lab Clin Med 79:745757,1972 56. Riley DJ, Saldana M: Pigeon breeder’s lung: subacute course and the importance of indirect exposure. Am Rev Resp Dis 107:456460,1973 57. Sahn SA, Richerson HB: Extremes of clinical presentation in parakeet-fancier’s lung. Arch Intern Med 130:913-917,1972 58. Sakula A: Mushroom-worker’s lung. Br Med J 3:708-710,1967 59. Salvaggio JE: Diagnostic significance of serum precipitins in hypersensitivity pneumonitis. Chest 62:242, 1972 60. Salvaggio JE: Hypersensitivity pneumonitis: Pandora’s box. N Engl J Med 283:314-315, 1970 61. Salvaggio J, Arquembourg P, Seabury J, et al: Bagassosis.IV. Precipitins against extracts of thermophilic actinomycetes in patients with bagassosis.Am J Med 46: 538-544,1969 62. Salvaggio JE, Buechner HA, Seabury J, et al: Bagassosis: I. Precipitins against extracts of crude bagassein the serum of patients. Ann Intern Med 64:748-758, 1966 63. Salvaggio JE, Seabury JH, Buechner HA, et al: Bagassosis: demonstration of precipitins against extracts of thermophilic actinomycetes in the sera of affected individuals. J Allergy 39:106, 1967 64. Schlueter DP, Fink JN, Hensley GT: Wood-pulp workers’ disease: A hypersensitivity pneumonitis caused by Alternaria. Ann Intern Med 77:907-914, I972 65. Seal RM, Hapke EJ, Thomas GO, et al: The pathology of the acute and chronic stagesof farmer’slung. Thorax 23:469489,1968
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66. Spector WC, Heeson N: The production of granulomata by antigen-antibody complexes. J Path01 Bacterial 98:31-39, 1969 67. Staines FH, Forman JA: A survey of “farmer’s lung.” J Co11Gen Practit 4:351-382, 1961 68. Stott H: Pulmonary disease amongst sisal workers. Br J Ind Med 15:23-37, 1958 69. Strand RD, Neuhauser EB, Sornberger CF: Lycoperdonosis. N Engl J Med 277:89-91, 1967 70. Totten RS, Reid DH, Davis HD, et al: Farmer’s lung. Report of two casesin which lung biopsies were performed. Am J Med 25:803-809,1958 71. Unger JD, Fink JN, Unger GF: Pigeon breeder’s disease. A review of the roentgenographic pulmonary findings. Radiology 90:683-687, 1968 72. Van Toorn DW: Coffee worker’s lung: A new example of extrinsic allergic alveolitis. Thorax 25:399-405, 1970 73. Velican C, Latis G, Popa M, et al: Investigations concerning the pre-radiological stage of silicosis. Br J Ind Med 16:4042,1959 74. Warren WP: Hypersensitivity pneumonitis due to exposure to budgerigars. Chest 62:170-174, 1972 75. Weill H, Buechner HA, Gonzales E, et al: Bagassosis: A study of pulmonary function in 20 cases. Ann Intern Med 64:737-747,1966 76. Weiss WI, TourvilIe DR, Livingstone NJ, et al: Hypersensitivity pneumonitis due to contamination of a home humidifier. J Allergy 47:113-114, 1971 77. Wenzel FJ, Emanuel DA, Gray RL: Immunofluorescent studies in patients with farmer’s lung. J Allergy 48:224-229,197l 78. Williams JV: Inhalation and skin tests with extracts of hay and fungi in patients with farmer’s lung. Thorax 18:182-196, 1963 79. Williams JV: Pulmonary function studies in patients with farmer’s lung. Thorax 18:255-263, 1963
Allergic
Robert G. Fraser, M.D., F.R.C.P.(C),
E
XTRINSIC allergic alveolitis (synonyms: alveolar hypersensitivity, respiratory membrane hypersensitivity, interstitial granulomatous pneumonitis, extrinsic allergic pneumonia) is a term introduced by Pepys to denote a group of diseases characterized by a response of the lungs to specific antigens contained in a wide variety of organic dusts of such fine particle size that they can penetrate into the most distal lung parenchyma. 18,46,47,50
The list of diseases and the antigens associated with them has increased steadily since “farmer’s lung” was first clearly described in 19248 and now contains a multitude of conditions ranging from this condition, probably the most common and most widely recognized, through bird-fancier’s lung to such unlikely conditions as pituitary-snuff disease and hen-litter hypersensitivity. Regardless of the name of the disease and the specific exposure involved, there exists a striking similarity in the clinical, pathologic, and roentgenologic features of all of these diseases, although it must be emphasized that the immunopathology and the exact criteria required to make the diagnosis are by no means clearly defined. However, the following list includes those criteria that, if fulfilled in toto, would justify confident inclusion in the group of extrinsic allergic alveolitis; whether or not any specific organic dust deserves to be so categorized will depend largely on the number of criteria fulfilled. 1) Exposure to an organic dust of small enough particle size to penetrate into the most distal lung parenchyma. 2) Episodes of dyspnea, usually unassociated with a wheeze, accompanied by a dry cough and sometimes fever and malaise, developing a few hours after exposure to the relevant antigen. Robert G. Fraser, M.D., F.R.C.P.0 Professor of Diagnostic Radiology, McGill University, Montreal, Quebec, Canada. J.A.P. Par& M.D.: Associate Professor of Medicine, McGill University, Montreal, Quebec, Canada. Reprint requests should be addressed to Dr. Robert G. Fraser, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A IAI. 0 I975 by Grune & Stratton, Inc. Seminarsin
Roentgenology,
Vol.
X, No. 1 (January),
1975
Alveolitis and J.A.P. Park, M.D.
3) Auscultatory evidence of bilateral crepitation heard best over the lung bases. 4) Roentgenographic manifestations consisting of a diffuse micronodular pattern, commonly associated in the acute stage with an air space component. A “honeycomb” pattern is the end result of repeated or long-term exposure. 5) Pulmonary function tests revealing a reduction in vital capacity, carbon-monoxide diffusing capacity (transfer factor), po, and static compliance. There is little or no evidence of airway obstruction. 6) A “late” reaction to intracutaneous injection of the appropriate antigen. 7) The presence in the serum of precipitins against the suspected antigen. 8) The development, some hours after provocation with the specific antigen, of pyrexia, dyspnea, and cough, with or without impairment of pulmonary function and the appearance of abnormalities on the chest roentgenogram. 9) Histopathologic features in the lung parenchyma that, while not diagnostic, are sufficiently characteristic to be compatible with the diagnosis. 10) Resolution of the episodic systemic and respiratory symptoms after cessation of exposure to the antigen with, in time, disappearance of precipitins from the serum.65 11) Development of irreversible interstitial pulmonary fibrosis after repeated or continuous exposure to the antigen. This is manifested by a persistence of dyspnea on exertion, abnormal pulmonary function test values, and roentgenographic changes.‘r~*’ In view of these similarities, the descriptions to follow will apply to all diseases within the broad category of extrinsic allergic alveolitis. It will suffice to describe the individual diseases only insofar as they deviate from the usual pattern. EPIDEMIOLOGY
The great majority of instances of allergic alveolitis reported to date has occurred as a result of occupational or environmental exposure. Table 1 lists the definite, probable, and improbable causes 31
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Table
Definite causes Farmer’s lung Mushroom-worker’s
1. Causes of Extrinsic Source
Disease
Moldy lung
of
Allergic
Antigen
hay
Bagassosis Alveolitis from contaminated forced-air apparatus Bird-fancier’s lung Maltworker’s lung Maple bark disease Wood-pulp worker’s Sequoiosis
Moldy barley, malt Contaminated maple Moldy pulp Moldy sawdust
bark
M. faeni M. vulgaris M. faeni M. vulgaris M. vulgaris Thermophilic
actinomycetes
Serum proteins and droppings Aspargillus clavatus Cryptostroma corticala Altarnaria Graphium Aureobasidium pullulans Pituitary hormone Sitophilus granarius Penicillium frequentens Penicillium casei Fish meal Coffee bean dust
Pituitary snuff-taker’s lung Grain-weevil hypersensitivity Suberosis Cheesewasher’s lung Fishmeal-worker’s lung Coffee-worker’s lung Probable causes Poultry-keeper’s lung
Pituitary snuff Contaminated wheat Moldy cork dust Moldy cheese Animal food factory Coffee bean
Smallpox-handler’s lung Lycoperdonosis Detergent-worker’s lung Starch spray lung disease Improbable causes Thatched roof lung disease Fibrosis in blackfat-tobacco smokers Vineyard-sprayer’s lung Furrier’s lung
Patients with smallpox Lycoperdon species “Enzyme” detergents Starch spray
Serum proteins and droppings Variola virus Lycoperdon spores Bacillus subtilis Soil repellant
Thatched roofs Blackfat-tobacco
Roofing material Blackfat-tobacco
“Bordeaux mixture” Fox and astrakhan fur
Copper sulphate Fur dust
Poultry
of the disease, together with the source of the particles and the specific antigens, where known. The responsible antigens vary widely, not only in the group as a whole but in individual diseases. Lacey and Lacey4’ estimated that a farmer working in an atmosphere of moldy hay would inhale so many particles that 750,000 per minute would be deposited on air space walls where they might activate immunologic reactions. Similar figures have been given for moldy bagasse.60The small size of the antigenic particles is extremely important. Hargreave3’ stated that the allergenic particles are all smaller than 6~, permitting penetration to the peripheral respiratory tissue. Although the great majority of cases of allergic alveolitis are occupational in nature, exciting causes have also been found within the home, originating for example within a heating system,22
PARE
Alveolitis
Antigen
Mushroom postspawning compost Bagasse Contaminated humidifier or air conditioner Budgerigar, pigeon, parakeet
disease
AND
(?I
solution
a humidifier,76 an air conditioner,3 and spray starch.” These incidents emphasize the importance of meticulous history-taking in attempting to uncover environmental atmospheric exposure coincident with the development of acute respiratory symptoms. CLINICAL
MANIFESTATIONS
As more and more cases of extrinsic allergic alveolitis are reported, it is becoming clear that the diagnosis must be based primarily on clinical findings. Many reports serve to emphasize the importance of placing reliance on the clinical rather than the roentgenologic manifestations of these diseases: A normal chest roentgenogram does not exclude the diagnosis and is not at all unusual in the presence of a classical clinical picture.11,16,28 In all these diseases, the clinical picture varies
EXTRINSIC
ALLERGIC
ALVEOLITIS
widely according to the degree of antigenic exposure. The classical acute onset occurs in perhaps no more than a third of the patients’s and is characterized by the development, within 4-8 hr after exposure, of dyspnea, cough, malaise, chills, fever, and sometimes hemoptysis.2’48 Individuals who develop this acute type of onset have usually been exposed intermittently to high concentrations of antigen, as typically occurs in pigeon breeders.” The more common form of onset is insidious, with gradual progression of dyspnea and cough and with such systemic symptoms as fever, chills, malaise, aches and pains, and weight 10ss.‘~,~ This type of onset tends to occur in patients exposed more or less continuously to small amounts of antigenic dust, such as from a budgerigar or parrot in the house. 74 Farmer’s lung frequently presents in this insidious manner. In a small percentage of patients, usually those with a history of allergy, the clinical presentation may suggest “asthmatic bronchitis.” The asthmatic episode occurs within a few minutes of exposure and may be repeated as a late response some 4-6 hr after the initial episode of bronchospasm.48>67 The subsequent course of events depends on whether exposure to the antigenic material continues. Repeated exposure usually is associated with exacerbations of the acute episode; eventually, the patient may become a respiratory cripple due to pulmonary fibrosis. In those instances where there is doubt as to the etiology, supporting evidence may be obtained by challenging the patient with an aerosol of the antigen under suspicion, or by documenting a remission coincident with removal of the patient from the environment. However, should a patient with a highly suggestive environmental history manifest a diffuse micronodular pattern roentgenographically or impaired values on pulmonary function testing, the diagnosis can be reasonably assumed without the additional support of a positive antigenic challenge. Pulmonary function tests are extremely useful not only in the assessmentof the effects of antigen in its natural environment but also when the antigen is administered by aerosol as a challenge. In general, there is a slight-to-moderate reduction in FEV, , proportional to a decrease in vital capacity. Decreased values for static lung compliance, diffusing capacity (transfer factor) and po, are all considered indications of disease involving the lung
33
parenchyma. There is little doubt that increased “stiffness” of the lungs, as reflected in a decrease in compliance, is compatible with abnormality of the alveolar wall; however, the abrupt decrease in diffusing capacity and po, characteristic of the “acute” naturally occurring or provocative allergic response is much more suggestive of ventilation/ perfusion inequality. More sophisticated measurements of bronchiolar function will almost certainly implicate diffuse bronchiolar obstruction as the responsible morphologic abnormality for these changes in function; in fact, there is a growing abundance of pathologic evidence to support this contention (see below). Removal of patients from their hazardous environment frequently results in restoration of pulmonary function to normal, but in some cases function may continue to be impaired even after the chest roentgenogram has returned to normal.7s This has been shown to be the case in mushroom worker’s disease and is in keeping with a more prolonged clinical illness.” IMMUNOLOGIC
MANIFESTATIONS
In individuals exposed to various organic dust antigens, the development of symptoms and signs 4-6 hr following exposure suggests not only a causal relationship but an immunologic mechanism.42*49 This delayed onset of clinical manifestations is characteristic of so-called “immunecomplex” disease, classified by Coombs and Cell as an Arthus type III immunologic reaction.12 In this type of reaction, antigen is believed to combine with precipitating IgG or IgM antibodies, forming aggregates that fix complement. The resulting complexes are chemotactic for polymorphonuclear leukocytes that ingest them and then undergo disruption, liberating lysosome enzymes that cause tissue damage. Precipitins Patients with hypersensitivity alveolitis often show a high titer of specific IgG precipitating antibodies. Characteristically, these titers fall with clinical improvement, after removal from the exciting cause. Arthus skin reactivity has been passively transferred to laboratory animals with serum from affected patients. 6o Immunofluorescent studies have shown high concentrations of antigen in the walls of bronchioles, along with immunoglobulins IgC, IgA, and IgM and with C3 comple-
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merit.” Similarly, deposits of IgG and complement along alveolar capillaries have been demonstrated in patients with coffee worker’s lung. 72 Precipitating antibodies specific for organic dust antigens have long been considered the hallmark of extrinsic allergic alveolitis.42Y43However, although the demonstration of precipitins provides important circumstantial evidence implicating a specific organic dust as a cause of alveolitis, some patients show no evidence of precipitins by commonly accepted methods.11Y28In contrast, precipitins can sometimes be demonstrated in asymptomatic individuals who have been exposed to an organic antigen commonly accepted as a cause of hypersensitivity alveolitis. Many instances of this clinicalimmunologic dissociation have been reported. In a survey of 200 pigeon breeders, none of whom had clinical evidence of disease, Fink and associates found precipitating antibodies in 40%; the only correlation seemed to be with duration and degree of exposure to birds.23 In another study FLH (Farmer’s Lung Hay) antigens reacted with the serum of 18% of farmers who had been exposed to moldy hay but who had no history suggestive of the disease.M,48 Many other examples of this phenomenon are recorded.1”32Y59V61-63 Considerable variation exists in the incidence of positive precipitins to FLH antigen or Micropolyspora fueni in patients with clinically diagnosed farmer’s lung. 28Y44Y48 This discrepancy appears to result, at least in part, from the acuteness or chronicity of the illness. In a study of 45 patients with farmer’s lung, all 11 patients with acute disease showed positive reactions compared with only 18 (53%) of 34 patients with chronic disease.Similar results were noted by others.52 In summary, it may be concluded that the demonstration of precipitins indicates that a patient has been exposed to the specific antigen. The greater the exposure, the greater the likelihood of showing precipitating antibodies. Precipitins may be present in healthy asymptomatic subjects but are not found in unexposed persons3’
AND
PARE
positive with other allergens, notably with material obtained from birds. Intracutaneous tests are of use in identifying late or “dual” reactions.* Hargreave and Pepys found that late reactions correlated well with the presence of extrinsic allergic alveolitis and precipitating antibodies.32 In patients with bird fancier’s lung, positive late reactions were observed in 84%, but only in patients who had clinical evidence of disease. Allergen Inhalation Tests
Skin Tests
Allergen inhalation tests (challenge test) with extracts of appropriate antigens may be performed without risk.32 They are particularly useful when the diagnosis is in doubt or when the clinical situation suggests involvement by an organic antigen not previously described. Reactions to inhalation tests may be immediate, late, or dual. Immediate reactions are classically seen in atopic individuals exposed to specific antigens to which they have become previously sensitized.32 Asthmatic patients characteristically produce bronchospasm but no fever or leukocytosis. Lute reactions usually appear within 4-6 hr after the challenge and usually clear within 24-48 hr. They may be associated with evidence of bronchospasm, but more frequently they reveal a restrictive rather than an obstructive pattern on pulmonary function testing. The systemic response to an inhalation challenge is identical to that seen with the naturally occurring disease and includes fever, chills, malaise, and anorexia; leukocytosis is a common feature. Dual reaction refers to a combined immediate and late response. They occur less frequently in extrinsic allergic alveolitis than late reactions alone. Patients with positive dual or late reactions almost invariably have serum precipitins to the antigen employed in the inhalation test.3’ Positive late reactions in which both respiratory and systemic symptoms are manifested have been described following inhalation of a variety of antigens, including those associated with farmer’s 1ung,4378bagassosis,34malt-worker’s lung,” birdfancier’s 1ung,33*53 mushroom-worker’s lung,36 fish-meal worker’s lung,’ and wood-pulp worker’s
Skin tests with FLH antigen or M. faeni are of no diagnostic value, since they cause positive reactions in both exposed and unexposed individuals, presumably because of their action as nonspecific irritants. Prick and intracutaneous tests may be
*A “dual” reaction consists of an immediate wheal and flare followed 3-4 hr later by the development of erythema and swelling at the site of puncture. This skin reaction usually resolves in 2448 hr.
EXTRINSIC
ALLERGIC
ALVEOLITIS
disease.64 A positive response to challenge with specific antigens correlates closely with the results of skin testing and provides further evidence for a hypersensitivity state in this group of diseases.32 Although the use of animal models for the investigation of the immune pathogenesis of allergic alveolitis is of comparatively recent origin, the information obtained to date supports many of the views expressed above.19~24~37~3s~s4~55~65 PATHOLOGIC
CHARACTERISTICS
The histologic features of the many different varieties of extrinsic allergic alveolitis are strikingly similar and, with few exceptions, do not permit differentiation of one from another. The exceptions lie in maple bark disease, in which the fungus may be identified, and in bagassosis, in which vegetable fibers may be seen.29 As might be anticipated, the pathologic characteristics depend partly on the intensity of exposure to the allergen and partly on the stage of the disease at which the biopsy is taken.70 Three stages may be recognized, the acute, subacute, and chronic. The Acute Stage The earliest lesions that have been described were in a 17-yr-old boy who died lo-12 days after the onset of clinical disability following exposure to a large concentration of moldy hay.’ The lesions were centrilobular in position, involving respiratory bronchioles and adjacent vessels and alveoli. The bronchioles in the center of the lesion showed an obstructive bronchiolitis, often with destruction of their walls. There were also histologic features typical of the Arthus reaction-acute vasculitis of the aveolar capillaries, fibrin thrombi, and an infiltration of neutrophiIs, eosinophils, and mononuclear cells. It is worth noting that this patient represents a most unusual example of acute farmer’s lung. Although precipitins to moldy hay and to M. faeni were found in his serum, his clinical course was unique in that death occurring during the acute phase of extrinsic allergic alveolitis is rare indeed. There is little doubt that bronchiolitis is a common feature of this disease, ranging in incidence In some cases, the from 25% 100%.20~56~64~65~77 bronchiolar lesions have been described as obstructive and organizing, presenting the appearance of bronchiolitis obliterans.
35
In an immunofluorescent study of lung tissue from four patients with farmer’s lung, Wenzel and colleagues 77 found high concentrations of antibody to M. faeni in the walls of bronchioles in the lungs of two of the patients who were acutely ill but not in the two with more chronic disease. Immunoglobulins IgG, IgA, and IgM were found in plasma cells and lymphocytes scattered throughout the diseased lungs. Neither necrotizing vascular lesions nor polymorphonuclear leukocytes were observed in numbers usually seen in Arthus reactions, leading these investigators to suggest that extrinsic allergic alveolitis may not be a pure type III immune reaction but may also contain elements of a type II cytoxic reaction. In fact, they suggested that the histologic picture might also indicate a type IV “delayed hypersensitivity” reaction. The Subacute Stage Biopsies examined at a slightly later stage (l-2 mo after the onset of the acute stage) reveal noncaseating “histiocytic” granulomas, closely resembling those seen in sarcoidosis.1s>29The granulomas are present in the peribronchiolar tissues and cause localized thickening of alveolar walls (Fig. 1). There may be a striking interstitial pneumonitis of mononuclear cells. There is generally no evidence of fibrosis in the interstitial tissues, although reticulin may be increased. Giant cells of both Ianghans25 and foreign body types*’ are often seen, the latter frequently containing birefringent material. During this stage, intra-alveolar exudation may be present. According to Hargreave and his co-workers,29 some of the giant cells contain lanceolate spaces, a finding that is not a feature of any other form of alveolitis. Obstructive bronchiolitis is a common feature, ranging in incidence from 25% to 100% of cases.2o’65 Although sarcoid-like granulomas have been shown to arise as the result of the formation of antigen-antibody complexes,30*45366they are more commonly associated with type IV allergy. The Chronic Stage Over the course of the next several months, the lesions become nonspecific as the granulomas disappear and fibrosis supervenes.20~27~29341 ,‘* Interstitial pneumonitis and doubly refractile material persist. The degree of ensuing fibrosis is variable; the upper zones are affected most.64 Fibrosis may
FRASER
36
AND
PARi
Fig. 1. Photomicrographs of left lung biopsy from the patient whose roentgenograms are illustrated in Fig. 2. (A) Noncaseating granulomatous lesion that is both interstitial and intra-alveolar. The granulomas consist largely of epitheloid cells with occasional multinucleated giant cells. Under higher magnification (61, there is much extraneous doubly-refractile material, some of which appears to lie within the granulomas in the form of long crystals. The interstitial granulomas abut on vessels and bronchioles. The intra-alveolar granulomas form distinct nodular masses and probably represent the acinar lesions seen in Fig. 26. The general appearance is consistent with farmer’s lung. (From Fraser RG, Pare JAP;*6 reproduced with permission of W.B. Saunders Co.)
be localized and peribronchial, forming focal masses with adjacent irregular emphysema, or it may be more diffuse, producing microcysts resembling those of fibrosing alveolitis. The endresult is a variable mixture of scarring, pneumonitis, honeycombing, and emphysema.
ROENTGENOLOGIC
MANIFESTATIONS
As with the pathologic manifestations, the roentgenographic changes vary with the stage of the disease. Early in the course of the acute stage of the disease, the chest roentgenogram may show no discernible abnormality. In one case,‘* the chest
EXTRINSIC
ALLERGIC
ALVEOLITIS
roentgenogram was perfectly normal when lung biopsy showed diffuse interstitial granulomatous inflammation. Once roentgen changes are visible, however, they usually parallel the severity of the clinical symptoms.25 They consist of granular or nodular mottling scattered diffusely throughout both lungs, without zonal predominance although commonly less evident in the apices and bases (Fig. 2A). The individual nodules range from 1 mm or less up to several millimeters in diameter. They may be quite discrete, although usually ill-defined. The pattern has been likened to snowflakes25 or to a sand storm.2 Although this fine nodular pattern is characteristic of the acute and subacute stages of the disease, we have seen cases of farmer’s, mushroomworker’s, and bird-fancier’s lung in which acinar shadows have been visualized, particularly in the lower lung zones (Fig. 2B). Unger and colleagues also described acinar shadows in the acute stage of bird-fancier’s lung.71 In our experience, hilar lymph node enlargement is variable. Frank25 found no evidence of hilar or mediastinal lymph node enlargement in 27 patients with farmer’s lung, and suggested that this should permit ready differentiation from sarcoidosis. That this is not invariably true is evidenced by one patient we have seen in whom the diagnosis of farmer’s lung was proved by biopsy and by the presence of precipitating antibodies in the serum, who showed clear-cut roentgenographic evidence of hilar lymph node enlargement. Hilar node enlargement is said to be a common finding in mushroom-worker’s lung.58 Furthermore, in sarcoidosis diffuse pulmonary involvement is frequently present without lymph node enlargement, so that the size of hilar nodes can hardly be expected to discriminate between sarcoidosis and extrinsic alveolar pneumonitis. In addition to the roentgen changes already described, Hargreave et al. described “patchy clouding” in 11 of 41 patients with bird-fancier’s lung.29 It is possible that this represents patchy air-space consolidation, although it was not specifically identified as such. They observed septal lines in the costophrenic recesses in nine of the 41 patients, presumably resulting from lymphatic overload. The subsequent course of the roentgenographic change depends on whether exposure is continued. If the patient is removed from the environment, the chest roentgenogram may return to normal, in from 10 days to several weeks.65 Should exposure
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be continued or repeated, the diffuse nodular pattern characteristic of the acute and subacute stages is replaced by changes characteristic of diffuse interstitial fibrosis (Fig. 3)-a medium-to-coarse reticular pattern, loss of lung volume, a “honeycomb” pattern, and sometimes compensatory overinflation of the lung zones that are least affected. The loss of lung volume (cicatrization atelectasis) tends to show a striking upper zone predominance. Of the 4 1 patients with bird-fancier’s lung studied by Hargreave and his associates, 20 showed lobar shrinkage, and in 17 of these the upper lobes were predominantly affected; in half of these the atelectasis was restricted to the upper zones. Ring shadows measuring 5-8 mm in diameter categorize the late stages of interstitial fibrosis, creating a honeycomb pattern indistinguishable from the late stages of fibrosing alveolitis (or perhaps more typically of histiocytosis-X in view of its upper zone anatomic bias). This pattern was observed in 19 of the 41 cases of Hargreave and colleagues.29 Overinflation, particularly of lower lung zones in compensation for upper zone fibrosis, is not infrequent. In any study of a disease in which the basic criteria for diagnosis are clinical, it is not unusual for a number of patients to show no chest roentgenographic abnormalities. For example, in their survey of the farming population of three districts in Scotland, Grant et al. 28 found roentgen abnormalities in only a minority of cases of presumed disease. Similar reports have appeared of malt workers” and bird breeders16 with a classical clinical presentation of allergic alveolitis and precipitating antibodies in the serum but whose chest roentgenograms have been normal. In contrast, among 200 pigeon breeders without clinical evidence of disease, an abnormal roentgenographic pattern was found in 10 (S%).23 Although, as the authors suggest, this incidence may have been due to roentgenologic overreading, it is also quite possible that, in a minority of people, exposure to antigens may lead to roentgenographically apparent pulmonary hypersensitivity reactions without production of symptoms. NOTES
ON SPECIFIC
DISEASES
Farmer’s Lung Farmer’s lung is the earliest described and most thoroughly understood of the conditions causing extrinsic allergic alveolitis. Although it has been
Fig. 2. This 25-yr-old woman, the wife of a farmer. was admitted with a 2-wk history of moderate dyspnea, mildly productive cough, and daily temperature rise to 103°C. She was slightly cyanotic. (A) Magnified view of the lower half of the right lung reveals a medium reticulonodular pattern possessing a predominantly nodular component. The full film showed the disease to be widespread with relative sparing of the apices and costophrenic sulci. After a course of antibiotic therapy, during which her clinical status improved somewhat, she was discharged without a diagnosis. Several months later, during which she had continued to live on the farm, she was readmitted following the acute onset of dyspnea, cough, and high fever. The chest roentgenogram at this time (B) revealed definite evidence of extension of the disease. An acinar pattern had been superimposed on the reticulonodular pattern seen earlier. This was regarded as evidence of involvement of the air spaces of the lung and was felt to represent en acute exacerbation reexposure. The histologic sections illustrated in Fig. 1 are from a biopsy taken at this time. (From Fraser RG, Pare JAP;*e reproduced in modified form with permission of W.B. Saunders Co.)
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Fig. 3. For a number of years, this 60-yr-old man maintained a loft of racer pigeons. During the past year, he had noted gradually increasing dyspnea on exertion, although at no time had he experienced episodes of acute respiratory illness. A PA roentgenogram (A) reveals a widespread coarse reticulonodular pattern without anatomic predilection. Precipitins to pigeon feathers were demonstrated in his serum and a confident diagnosis of pigeonfancier’s lung was made. Despite warnings, the patient refused to remove himself from the noxious environment and during the following months, his dyspnea increased in severity and became associated with a dry, hacking cough. Eighteen months after his original investigation, a PA roentgenogram (6) revealed remarkable deterioration. The pattern had become very coarsely reticular and, in some areas, almost cyst-like or “honeycomb” in nature. Marked elevation of the diaphragm indicated a striking loss of lung volume, due to fibrosis and cicatrization. The upper lobe predominance often seen in the late stages of the disease was not observed in this patient.As anticipated, pulmonary function studies now revealed a severe restrictive pattern.
recognized for centuries, the earliest clear descriptions in English appeared in 1924 and 1932.8,68 Many of the earlier reports originated in Great Britain-and Scandinavia, labeling the disease with such names as thresher’s lung, harvester’s lung, bronchomycosis feniseciorum (mycosis of haymakers or harvesters), and Norwegian hemp disease. Farmer’s lung is the prototype of extrinsic allergic alveolitis, and the bulk of the material in this article originates from studies of farmers exposed to thermophilic actinomycetes. Traditional descriptions probably reflect the type of patient who is likely to be seen in a large medical
center,49’52 whereas more recent studies** indicate that many farmers have the clinical syndrome without showing all the immunologic and roentgenologic manifestations commonly described in the disease. The clinical picture varies according to the degree of exposure to antigens in moldy hay and to the degree of sensitivity of the subject. The classical acute onset occurs in perhaps no more than a third of cases,44the more common form being insidious and characterized by gradual progression of dyspnea, cough, and weight loss, and by fever, chills, malaise, and aches and pains.18*44 Pepys and Jenkins44’48 found that approximately 90% of
40
patients with farmer’s lung have precipitating antibodies to thermophilic actinomycetes, 87% being to M. faeni and 3% to other actinomycete antigens. Mushroom- Worker S Lung Since the first description of mushroom-worker’s lung in 1959: three further reports on this form of hypersensitivity pneumonitis have appeared.“, ‘3136 The specific antigens, M. faeni and Micromonospora vulgaris are the same as in farmer’s lung. The culture of mushrooms requires a process of steam pasteurization to destroy microorganisms; temperatures during this process rise to 60°C at 100% humidity, which encourages the rapid growth of thermophilic actinomycetes. Subsequently, the compost is spread on trays and mixed with mushroom mycelia grown on manure and grain. This process, which is called “spawning,” gives rise to clouds of dust. Although the clinical and immunologic features are very similar to those of farmer’s lung, the incidence of visible hilar lymph node enlargement is said to be higher.” Bagassosis This disease occurs from inhalation of bagasse fibers contaminated with the specific antigen M. vulgaris. 31,61-63 Bagasse is a fibrous material that remains after the sugar-containing juice has been extracted from sugar cane and is composed almost entirely of cellulose and other complex plant carbohydrates. Bagassosisis more likely to occur as a result of exposure to freshly produced bagasseor bagassefibers stored indoors than to moldy bagasse stored outside.62 A curious development noted by some patients with bagassosis is an aversion to smoking cigarettes.” Bird-Fancier’s Lung Although this hypersensitivity disease (synonyms: pigeon breeder’s lung, bird-breeder’s lung) is commonly associated with budgerigars and pigeons, it was originally described in a breeder of parakeets43 and has recently been noted in two other parakeet fanciers.” The antigen consists of protein contained. in bird serum, droppings, or feathers. Riley and associatess6 encountered two cases in wives of pigeon breeders, one of whom was exposed only to her husband’s coveralls. Exposure to chickens can produce the disease;‘13’ however, a thorough survey of poultry workers did not uncover a single symptomatic individual.lg
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Hypersensitivity Pneumonitis Due to Forced-Air Equipment There have been three recent well-documented reports of extrinsic allergic alveolitis resulting from humidifiers and air conditioners contaminated by a thermophilic actinomycete resembling Culture of this organism from the M. faeni. 3~22Y76 equipment, the provocation of typical attacks on inhalation of the offending antigen, and the remissions induced by removing the patients from the environment clearly established a cause-andeffect relationship, and once again underlines the importance of careful history-taking in any patient presenting with diffuse interstitial lung disease. The other types of extrinsic allergic alveolitis possess no particular characteristics to distinguish them from those described above except for the nature of occupational exposure and the specific allergen (Table 1). As might be anticipated, other diseases of a similar or identical nature crop up from time to time, for example, “cheesewashers’ “coffee-worker’s disease,“14 “furrier’s lung,“‘l lung,)‘72 “paprika-splitter’s lung,“3s “lycoperdonosis,“6g and “hen litter hypersensitivity.“3g There is little doubt that the future will bring other diseases of an identical nature related to unusual occupational exposure.
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10. Chan-Yeung M, Grzybowsli S, Schonell ME: Mushroom workers’ lung. Am Rev Resp Dis 105:819-822, 1972 11. Channel1 S, Blythe W, Lloyd M, et al: Allergic alveolitis in maltworkers: A clinical, mycological and immunological study. Quart J Med 38:351-376,196Y 12. Coombs RRA, Gel1 PGH: Classifications of allergic reactions responsible for clinical hypersensitivity and disease, in Cell and Coombs (eds): Clinical aspects of immunology (ed 2). Philadelphia, Davis, 1968, p 575 13. Craig DB, Donevan RE: Mushroom-worker’s lung. Can Med Assoc J 102:1289-1293,197O 14. de Week AL, Gutersohn J, Biitikofer E: La maladie des laveurs de fromage (“Kasewascherkrankheit”): une forme particuliere du syndrome du poumon du fermier. Schweiz Med Wochenschr 99:872-876, 1969 15. Dickie HA, Rankin J: Farmer’s lung. An acute granulomatous interstitial pneumonitis, occurring in agricultural workers. JAMA 167:1069-1076, 1958 16. Dinda P, Chatterjee SS, Riding WD: Pulmonary function studies in bird breeder’s lung. Thorax 24:374378,1969 17. do Pica GA, Layton CR Jr, Clayton JW, et al: Acute pulmonary reaction to spray starch with soil repellant. Am Rev Resp Dis 108:1212-1215,1973 18. Editorial. Allergic alveolitis. Br Med J 3:691-692, 1967 19. Elman AJ, Tebo T, Fink JN, et al: Reactions of poultry farmers against chicken antigens. Arch Environ Health 17:98-100, 1968 20. Emanuel DA, Wenzel Fl, Bowerman Cl, et aI: Farmer’s lung. Clinical, pathologic and immunologic study of twenty-four patients. Am J Med 37:392401, 1964 21. Fink JN: Environment and pulmonary hypersensitivity. Ann Intern Med 74:293-294,197l 22. Fink JN, Banaszak EF, Thiede WH, et al: Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann Intern Med 74: 80-83, 197 1 23. Fink JN, Schlueter DP, Sosman AJ, et al: Clinical survey of pigeon breeders. Chest 621277-281, 1972 24. Fink JN, Hensley GT, Barboriak JJ: Chemical nature of agents and airway responses. Report of Workshop III. Abstract presented by Chase MW and Rankin J. Ann NY Acad Sci 221:205-208, 1974 25. Frank RC: Farmer’s lung-a form of pneumoconiosis due to organic dusts. Am J Roentgen01 79:189215, 1958 26. Fraser RG, Par6 JAP: Diagnosis of Diseases of the Chest. Philadelphia, Saunders, 1970 27. Fuller C: Farmer’s lung. Dis Chest 42:176-180, 1962 28. Grant IWB, Blyth W, Wardrop VE, et al: Prevalence of farmer’s lung in Scotland. A pilot survey. Br Med J 1:530-534,1972 29. Hargreave F, Hinson KF, Reid L, et al: The radiological appearances of allergic alveolitis due to bird sensitivity (bird fancier’s lung). Clin Radio1 23: l-10, 1972 30. Hargreave FE: Review article: Extrinsic allergic alveolitis. Can Med Assoc J 108:1150-1154,1973
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42 53. Reed CE, Sosman A, Barbee RA: Pigeon-breeder’s lung. A newly observed interstitial pulmonary disease. JAMA 193:261-265,1965 54. Richerson HB, Cheng FH, Bauserman SC: Acute experimental hypersensitivity pneumonitis in rabbits. Am Rev Resp Dis 104:568-575, 1971 55. Richerson HB: Acute experimental hypersensitivity pneumonitis in the guinea pig. J Lab Clin Med 79:745757,1972 56. Riley DJ, Saldana M: Pigeon breeder’s lung: subacute course and the importance of indirect exposure. Am Rev Resp Dis 107:456460,1973 57. Sahn SA, Richerson HB: Extremes of clinical presentation in parakeet-fancier’s lung. Arch Intern Med 130:913-917,1972 58. Sakula A: Mushroom-worker’s lung. Br Med J 3:708-710,1967 59. Salvaggio JE: Diagnostic significance of serum precipitins in hypersensitivity pneumonitis. Chest 62:242, 1972 60. Salvaggio JE: Hypersensitivity pneumonitis: Pandora’s box. N Engl J Med 283:314-315, 1970 61. Salvaggio J, Arquembourg P, Seabury J, et al: Bagassosis.IV. Precipitins against extracts of thermophilic actinomycetes in patients with bagassosis.Am J Med 46: 538-544,1969 62. Salvaggio JE, Buechner HA, Seabury J, et al: Bagassosis: I. Precipitins against extracts of crude bagassein the serum of patients. Ann Intern Med 64:748-758, 1966 63. Salvaggio JE, Seabury JH, Buechner HA, et al: Bagassosis: demonstration of precipitins against extracts of thermophilic actinomycetes in the sera of affected individuals. J Allergy 39:106, 1967 64. Schlueter DP, Fink JN, Hensley GT: Wood-pulp workers’ disease: A hypersensitivity pneumonitis caused by Alternaria. Ann Intern Med 77:907-914, I972 65. Seal RM, Hapke EJ, Thomas GO, et al: The pathology of the acute and chronic stagesof farmer’slung. Thorax 23:469489,1968
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66. Spector WC, Heeson N: The production of granulomata by antigen-antibody complexes. J Path01 Bacterial 98:31-39, 1969 67. Staines FH, Forman JA: A survey of “farmer’s lung.” J Co11Gen Practit 4:351-382, 1961 68. Stott H: Pulmonary disease amongst sisal workers. Br J Ind Med 15:23-37, 1958 69. Strand RD, Neuhauser EB, Sornberger CF: Lycoperdonosis. N Engl J Med 277:89-91, 1967 70. Totten RS, Reid DH, Davis HD, et al: Farmer’s lung. Report of two casesin which lung biopsies were performed. Am J Med 25:803-809,1958 71. Unger JD, Fink JN, Unger GF: Pigeon breeder’s disease. A review of the roentgenographic pulmonary findings. Radiology 90:683-687, 1968 72. Van Toorn DW: Coffee worker’s lung: A new example of extrinsic allergic alveolitis. Thorax 25:399-405, 1970 73. Velican C, Latis G, Popa M, et al: Investigations concerning the pre-radiological stage of silicosis. Br J Ind Med 16:4042,1959 74. Warren WP: Hypersensitivity pneumonitis due to exposure to budgerigars. Chest 62:170-174, 1972 75. Weill H, Buechner HA, Gonzales E, et al: Bagassosis: A study of pulmonary function in 20 cases. Ann Intern Med 64:737-747,1966 76. Weiss WI, TourvilIe DR, Livingstone NJ, et al: Hypersensitivity pneumonitis due to contamination of a home humidifier. J Allergy 47:113-114, 1971 77. Wenzel FJ, Emanuel DA, Gray RL: Immunofluorescent studies in patients with farmer’s lung. J Allergy 48:224-229,197l 78. Williams JV: Inhalation and skin tests with extracts of hay and fungi in patients with farmer’s lung. Thorax 18:182-196, 1963 79. Williams JV: Pulmonary function studies in patients with farmer’s lung. Thorax 18:255-263, 1963