RW’ERSENSITMTY

PNEUMONITIS

ABSTRACT.Hypersensitivity pneumonitis or extrinsic allergic alveolitis is an immunologically mediated lung disease caused by repeated inhalations of organic antigens. The basic histologic lesion consists of a diffuse mononuclear cell infiltration of alveolar wall, alveoli, terminal bronchioles, and neighboring interstitium. The inflammation is often followed by granulomas, which then may progress to fibrosis. Although there is no single radiologic, physiologic, or immunologic test specific for hypersensitivity pneumonitis, the diagnosis can often be suspected on the basis of a compatible temporal relationship of pulmonary symptoms to the history of environmental or occupational exposure. Once the diagnosis is suspected, the presence of serum precipitating antibodies (IgG), suppressor cytotoxic lymphocytosis in bronchoalveolar lavage fluid, and granulomatous alveolitis in lung biopsy specimens are extremely helpful in confirming the diagnosis. In patients where the diagnosis is confirmed, avoidance of the causative antigen is the best therapy, although corticosteroids are used to suppress inflammation. Once the fibrosis is set in, the patient may gradually slide into respiratory failure, car pubnonale, and death.

IN BRIEF Hypersensitivity pneumonitis or extrinsic allergic alveolitis, a diffuse inflammatory disease of the pulmonary interstitium and the peripheral airways, is caused by repeated inhalation of organic dusts consisting of protein particles of animal and plant origin. Although the incidence of hypersensitivity pneumonitis in the general population is not known, in some farming communities, the prevalence of farmer’s lung, the most common type of extrinsic allergic alveolitis

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ranges from 1% to 8%. On the other hand, the pigeon breeder’s disease occurs in 6% to 15% of those who raise pigeons. A host of organic antigens can cause hypersensitivity pneumonitis, but of the many people exposed to common antigens, only a few develop the disease. Why the inhalation of antigen does not always lead to the same type of immune response in all similarly exposed individuals remains a mystery. Although the immune response is governed by the nature, amount, and duration of the antigen exposure, as well as the immune status and genetic background of the individual, it is also clear that type III immunocomplex reaction and regulatory T-lymphocytes modulate granuloma formation. In patients with hypersensitivity pneumonitis, the bronchoalveolar lavage shows suppressor/cytotoxic T-lymphocytes. The activation of alveolar macrophage appears to play a central role in the production of granulomatous alveolitis. Histopathology of the disease in the early stages shows infiltration of the alveolar walls by polymorphs, lymphocytes, plasma cells, and macrophages. In subacute stages granulomas appear that are usually small, poorly formed, and loosely arranged. The granulomas are more prominent in the center of acini and in the walls of respiratory bronchioles. In advanced or chronic stages the granulomatous alveolitis is replaced by interstitial fibrosis and honeycombing. Although three clinically distinct presentations of hypersensitivityacute, subacute, and chronic-are described, in practice only acute and chronic syndromes are discernible. Symptoms of acute hypersensitivity pneumonitis include cough, fever, tightness of the chest, and malaise. These symptoms appear 4 to 8 hours after the most recent exposure to the offending antigen. This symptom complex may be mistaken for an episode of viral or mycoplasma pneumonia. In the chronic stage, the patient complains of only progressive dyspnea with or without cough. Ultimately, chronic irreversible pulmonary fibrosis may lead to polycythemia and car pulmonale. Chest x-ray films in the acute disease usually show diffuse, soft, finely nodular infiltration. Hilar adenopathy is absent. In the chronic form, linear-reticular shadows, honeycombing, and progressive fibrosis (particularly of the upper lobes) may occur. Skin tests are of limited help in the diagnosis, but precipitating UgG) antibodies are present in as many as 90% of the patients. Bronchoalveolar lavage fluid in acute disease consists of mainly suppresssor/cytotoxic T-lymphocytes. Immunoglobulin G and immunoglobulin M are also increased. Although a lung biopsy specimen may strongly suggest the diagnosis of granulomatous alveolitis, tissue diagnosis is not always mandatory. Furthermore, in some cases, it is difficult to differentiate between sarcoidosis and hypersensitivity pneumonitis. Perhaps the best way of establishing the diagnosis of hypersensitivity pneumonitis is to reproduce a clinical symptom416

DM,

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complex by subjecting the patient to inhalation challenge with the offending agent. However, the use of an inhalation challenge is controversial and could be dangerous. The most important step in the diagnosis is the recognition of environmental or occupational e)cl,osure. The best treatment for hypersensitivity is avoidance of antigenic exposure. This is often difficult for the patient because of attachment to hobbies, economic hardships associated with giving up the job, and affection for pets. In severe cases, corticosteroids for 2 to 4 weeks produce a rapid resolution of clinical, functional, and chest radiographic abnormality. In chronic forms of the disease, corticosteroids may delay the onset of further damage.

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Om Prakash Sharma, M.D., was born in India, graduated from Victoria College, and attended G.R. Medical Collegeboth in his native land. He then attended the London School of Tropical Medicine and Hygiene. He served internships in medicine in India, Scotland, and England, and a residency at Albert Einstein Medical College in the Bronx, where he also served a fellowship in cardiopulmonary medicine. Dr. Sharma is currently Professor of Medicine at the University of Southern California School of Medicine. He is the author of four books and more than ZOO articles and short papers on sarcoidosis, hypersensitivity pneumonitis, and other pulmonary disorders. 418

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HYPERSENSITMTY

PNEUMONITIS

HISTORY In 1700, De Morbis Art$cium appeared in Modena, Italy. This treatise, by Bernardino Ramazzini da Carpi, was reprinted in Padua in 1713. In the chapter related to the Diseases of Sifters, Measurers, and Handlers of Grain, the author described the occurrence of dry cough, cachexia, and asthma, in grain handlers1 The clinical syndrome, however, remained forgotten for more than 200 years, until 1932, when Campbell gave us the classic picture of farmer’s lung disease by describing a peculiar pneumonia-like illness that occurred in Westmoreland, England.’ In 1936, Fawcitt discussed seven new cases of farmer’s lung and called the disease a mycosis.3 In the same decade Towey et al. described another type of hypersensitivity pneumonitis, maple-bark lung? In 1946, Tome11 coined the term “Thresher’s Lung” for a pneumonia-like illness that occurred in individuals exposed to moldy grain during the threshing process5 Jack Pepys of London was the first to provide a serologic link between moldy hay and the farmer’s lung disease. Pepys et al. also demonstrated that the chief culprit in moldy hay was a thermophilic actinomycete, Thermopolyspora polyspora, which caused the illness.6 During the last three decades, many different forms of hypersensi tivity pneumonitides have been described. Bagassosis was described by Jamison et al.,’ mushroom worker’s lung by Bringhurst et al.,’ parakeet breeder by Pearsall et al.,’ and goose and duck feather hypersensitivity by Pleassner.” Modern studies have clarified the nature, course, and prognosis of the illness, the literature is now replete with reviews and articles elucidating the clinical, radiologic, immunologic, physiologic, and biochemical aspects of hypersensitivity pneumonitis.‘l-l6 DEFINITION Hypersensitivity pneumonitis is an immunologically mediated lung disease caused by repeated inhalations of an organic antigen. In Europe and the United Kingdom the disease is also known as exDM,Jdy1991

419

trinsic allergic alveolitis. The basic histologic lesion consists of a diffuse mononuclear cell infiltration of the pulmonary interstitium, alveoli, and terminal bronchioles. The inflammation is often followed by granulomas, which then may progress to fibrosis. Unlike sarcoidosis and other granulomalous disease, hypersensitivity pneumonitis remains a lung disease and is not associated with any extrathoracic manifestations. Since there is no single radiologic, physiologic, or immunologic test specific for hypersensitivity pneumonitis, the diagnosis is often based (and almost always suspected) on the basis of a compatible temporal relationship of the symptoms to the history of environmental or occupational exposure. Once the diagnosis is suspected, an assessment of the activity and severity of the disease is made by appropriate use of immunologic tests, bronchoalveolar lavage, gallium-67 lung scan, and procedures used to obtain a lung biopsy specimen. An inhalation challenge using the offending antigen under strict medical supervision may be the only way of establishing the diagnosis in difficult situations.

RISK FACTORS Although many people are exposed to common organic antigens, only a few develop the syndrome of hypersensitivity pneumonitis. It appears that the response of an individual to the antigenic challenge may depend on a few or all of the following factors.

IMMUNOLOGIC

RlZACTIVITY

OF THE

HOST

About 10% of the population has high atopic status, and is prone to develop IS/pe I or IgE-dependent reaginic responses early in life; whereas individuals with low atopic reactivity may develop Type I responses in later years. About 5OW of nonatopic individuals, if heavily exposed to suitable antigen, may demonstrate Arthus reaction or Type III response.17 However, it appears that only 5% to 15% of persons regularly exposed to organic agents ever succumb to hypersensitivity pneumonitis.‘” Clearly, there are many as yet undefined factors that modify the susceptibility to hypersensitivity pneumonitis.

HLA ASSOCIATIONS

Earlier evidence indicated that genetic and immunologic responsiveness as determined by HLA typing might play a role in the devel420

DA4, July1991

opment of hypersensitivity pneumonitis, particularly in patients with pigeon breeder’s and farmer’s lung diseases.1s-23 Others have not been able to demonstrate consistently such a relationship, and it appears for now that hypersensitivity pneumonitis is not related to HLA haplotype.24-26

ROLE

OF PI ERYTHROCI’TE

ANTIGEN

Radermecker et al. reported the occurrence of antibodies to the Pl (P blood groups) erythrocyte antigen in a large number of pigeon breeders with P.2 blood group antigens.27 Effer and co-workers also found a greater incidence of Pl antibodies in P2 pigeon breeders as compared with the general P2 population.” The hypothesis that Plpositive pigeon breeders are less responsive to pigeon antigens and to the development of the disease did not get much s~pport.~~ Koskimies and colleagues studied Gm allotypes of the patients with farmer’s lung B-lymphocytes; 70% of the patients reacted with sera from multiparous women, whereas only 25% to 40% of the controls reacted similarly. T-lymphocytes showed no such reaction. The significance of these B-cell reactions in reference to Gm allotypes is not kI10Wll.30 Moore et al., however, in a study using allotype markers, did not find any association between serum allotypes (Gm and Am) and development of pigeon breeder’s disease.31

SMOKING

Most patients with hypersensitivity pneumonitis are nonsmokers. In a study of 442 dairy farmers, Homma et al. discovered that the prevalence rates of antibodies to M. faeni and T. vulgar-is were higher in nonsmokers.22 The reasons for this phenomenon, which also occurs in sarcoidosis, is unknown. Since smoking increases the number of alveolar macrophages, it is conceivable that activated macrophages enhance the ability of the lung to clear antigens and thus decrease the inflammatory response to certain types of inhalants. In addition, activated macrophages may exert an immunosuppressive reaction.

NATURE

OF THE ANTIGENZC

MATERIAL

Hypersensitivity pneumonitis results from inhalation of organic particles, particularly of animal and vegetable origin, that are usually disseminated as aerosolized dust. Occasionally, reactive inorganic compounds may also induce hypersensitivity pneumonitis.

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SIZE

OF THE ANTIGENIC

PARTICLES

Dust particles of 1 to 5 pm may be inhaled into the alveoli during a brief exposure, and set up an inflammation reaction. The larger particles, however, are trapped in bronchioles where they produce bronchospasm and bronchiolitis.

INTENSITY

OF EXPOSURE

A farmer working with a moderate exposure of moldy hay may inhale as many as 750,000 spores per minute. About half of all nonatopic individuals, if subjected to heavy exposure, may develop Arthus or Type III reaction. Hypersensitivity to avian antigens, depending on the exposure, causes two distinct syndromes: (1) an acute response occurring 2 to 6 hours after exposure characterized by dyspnea, malaise, fever, and chills; and (2) chmnic syndrome characterized by progressive dyspnea occurring over a period of weeks to months. Thus intermittent heavy exposure produces acute hypersensitivity pneumonitis, whereas mild and persistent challenge favors chronic and insidious disease.“‘, 33,34, 35

HISTOPATHOLOGY

Although extrapulmonary granuloma formation may occur rarely in hypersensitivity pneumonitis, the lungs are the organs predominantly affected by the disease.3”-3” The morphologic features of the pulmonary involvement include alveolitis, luminal and mural granulomata, intraalveolar buds, bronchiolitis, and interstitial fibrosis. Vasculitis is rare.

ACUTE

STAGE

In early stages the alveolar walls become infiltrated by polymorphs, lymphocytes, plasma cells, and macrophages (Fig 1, A). Eosinophils are infrequent.40-4” The alveolar spaces contain an amorphous pmteinaceous exudate mixed with inflammatory cells. Many alveoli may show edema and hemorrhage. Although the alveolar capillaries may contain fibrin platelet thrombi, Reyes et al. have found no evidence of vasculitis in a series of 60 consecutive biopsies from patients with farmer’s lung disease.46

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D.M July 1991

FIG 1. Hrstological features of hypersensitivity pneumonitis. A, The earliest change consists of edema and moderate interstitral lymphocytic rnfrltration. Occasional, foamy macrophages may be seen (HE x60). B, A focal granulomatous lesion resembling a sarcord granuloma and interstitial infiltration involving alveolar walls and first and second respiratory bronchioles. (HE x 100). C, Clefted granulomas, not characteristic of hypersensitivity pneumonitrs, may be seen, particularly in pigeon breeder’s lung disease. (HE x 125). D, Granuloma with extensive edema, alveolitis, and parenchymal disruption in hypersensitivity pneumonitis (HEX), E, A typical noncaseating granuloma of sarcoidosis should be distinguished from hypersensitivity pneumonitis on the basis of clinical, biochemical, radiographic, and immunological features (HEX).

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SUBACUTE STAGE In the subacute

stage the following

are the main features.

Granuloma Formation.-Although noncaseating in appearance, the granulomas of hypersensitivity pneumonitis differ in many ways from those caused by sarcoidosis (Table 1). In hypersensitivity pneumonitis granulomas are small, poorly formed, and loosely arranged and have a high concentration of lymphocytes. Scattered throughout the parenchyma, the granulomas are more frequently found in the center of acini and in walls of respiratory bronchioles (Fig 1, B). Rarely, a small necrotic area may be present in the center of a granuloma; the caseation is absent. These changes may appear within 3 weeks of an antigenic insult and may resolve within a year.44 Zntraalveolar B&%-About two thirds of the patients show intraalveolar protuberances composed of fibroblasts, myofibroblasts, and macrophages. BronchioZitis.-The focal granulomatous inflammation may tend into the terminal and respiratory bronchioles. The walls of airways are damaged by mucosal ulceration, and the lumen may blocked by granulomatous tissue (Fig 1, C). Lung function studies such patients reveal airway obstruction.4i-4Y

exthe be in

Zntraalveolar Macrophages.Macrophages with pale foamy cytoplasm are commonly found in the alveolar lumen in acute as well as subacute stages. Foreign Body Particles.-More than half of the cases reported by Emanuel et al. showed birefringent polarizing particles in the cytoplasm of foreign body giant cells4’ Interstitial Znjiftration.-The degree of interstitial infiltration varies with the intensity of the disease. In early stages the cellular picture mostly consists of lymphocytes, plasma cells, and histiocytes. The histiocytic infiltration is frequently observed in patients with pigeon breeder’s lung. TABLE Histologic

1. Features

of Sarcoidosis

and

Hypersensitivity

Pneumonitis

Features

Sarcoidosis

Hypersensitivitv

Alveolitis Granulomas:

Minimal Peripheral Absent Absent Present

Extensive Centrilobular Present Present in 50% Present

Location Foreign bodies Bronchiolitis obliterans Fibrosis [chronic) 424

Pneumonitis

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CHRONIC STAGE In chronic stages the granulomatous alveolitis is replaced by interstitial fibrosis and honeycombing (Fig 1, D). At this stage it is difficult to distinguish hypersensitivity pneumonitis from chronic interstitial fibrosis arising from other causes, although the lungs show more severe involvement of the upper lobes in hypersensitivity pneumonitis. Destruction of the normal lung architecture results in extensive honeycombing. Many patients at this stage develop car pulmonale. Diferentiaf Diagnosis.-Although granulomatous alveolitis is the characteristic feature of hypersensitivity pneumonitis, it is by no means specific; other conditions such as sarcoidosis; mycobacterial, fungal, and protozoal infections; and vasculitides have to be differentiated (Table 2). It is imperative that the biopsy material should be subjected to special stains for acid-fast bacilli and fungi, examined by polarizing light, and submitted for electron microscopic examination whenever possible. In certain cases minerologic examination may be mecessq (Fig 1, El. Electron-microscopic Features.Electron microscopy confirms and enhances the light microscopic features of predominantly lymphocytic alveolitis, noncaseating granulomata, and intraalveolar buds. The latter develop from organized fibrinous and proteinaceous exudates oozing from alveolar capillaries into alveolar cavities. Sometimes, one may find atypical lymphocytes called the “hand mirror” cells. These cells have also been observed in acute lymphoblastic leukemia and lymphomas. Some of the features of hypersensitivity pneumonitis alveolitis, with or without fibrosis, are distinct from the alveolitis due to other causes.50-52 IMMUNOPATHOGENESIS A host of organic antigens cause hypersensitivity pneumonitis. The similarity of pulmonary lesions and clinical features suggests that the pathogenesis of the illness evolves around many known, and some unknown, immune and non-immune pathways. The immune mechanisms involve both immune complex or Type III and cellular hypersensitivity or Type IV reactions; whereas non-immune factors include genetic predisposition and alternate complement (C3) activationF3 IMMUNE

COMPLEX (TYPE III)

In 1962, Pepys et al. observed that precipitating antibodies against moldy hay antigen were present in 87% of patients with farmer’s 1ung.54 Rankin et al. found that the antibodies disappear from serum DA4,Jdy1991

425

TB = tuberculosis;

EXA = extrinsic

Present Present Present Rare Minimal Rare Rare

Granuloma Caseation Necrosis Inclusion bodies Alveolitis Vasculitis Bmnchiolitis

of Common

TB

Features

2.

Features

Histologic

TABLE

allergic

70%

Granulomas

alveolitis.

Present Absent Absent Present Present Present Rare

Sarcoidosis

Pulmonary

Present Rare Rare Ram Prominent Absent Present Common

EAA Present Absent Present RaIX Absent Absent Absent

Fungi Present Present Present Rare Absent Absent Absent

Leprosy Present Absent May be present Rare Absent Absent Absent

Brucellosis

Rare Absent Common Absent Present Present Absent

Wegener’s Granuloma

Disease Present Rare Rare Present 80% Pmminent Rare Rare

Chronic Beryllium

are also present in a small number in 1 to 5 years.55 The precipitins of asymptomatic farmers exposed to moldy hay. Thus both falsepositive and false-negative precipitin tests are common.56 In a study of 471 farmers, 4% had farmer’s lung disease. Of those individuals with a typical history of farmer’s lung, only 14% had antibodies to T. faeni.57Smyth et al. studied English farmers in Devon; 15% of those with farmer’s lung disease had no serum precipitins5’ Although the presence of precipitins antibodies is not an absolute criterion for diagnosing the disease, in the past this observation had led many clinicians to believe that hypersensitivity pneumonitis was primarily an immune complex disease. Immunofluorescent studies have not yielded data to support this contention. Wenzel et al. found antigen and the third component of complement ((23) but failed to demonstrate significant amounts of immunoglobulins in lung biopsy specimens from patients with farmer’s lung disease.59 These findings are not typical of an Arthus Type III reaction where immune complexes clearly involve capillary walls. On the other hand, Ghose and coworkers were able to detect antigen, immunoglobulin fragments, and C3 in lung biopsy specimens from pigeon breeder’s lung disease patients. Immunofluorescent studies of lung biopsy specimens from pigeon breeder’s lung disease patients did not show any antigen, immunoglobulin, complement, or vasculitis.41 Furthermore, the serum complement levels in acute hypersensitivity pneumonitis remain normal.6o Do these negative studies rule out the possibility that immune complex disease is involved in the pathogenesis of hypersensitivity pneumonitis? Perhaps not. Animal studies of Cochrane and Koffler indicate that antigen, immunoglobulins, and complement can be detected only in early stages before extensive phagocytosis ensues.” Brentjens et al., and Spector and Heesom argue that granulomatous inflammation, a characteristic feature of the disease, can be caused only by immune complexes in the equivalence zone.62 Recently, Pesci et al. have shown that both Clq and C3 are present in bronchoalveolar lavage fluid of the patients with hypersensitivity pneumonitis. These findings and the presence of immunocomplexes in BAL indicate that in the pathogenesis of early phase of hypersensitivity pneumonitis, immune complexes play a role .63 Nevertheless, the presence of typical noncaseating ‘sarcoidlike’ granulomas in hypersensitivity pneumonitis argues strongly for the role of delayed hypersensitivity mechanisms.64 LMXAYELl

HYPERSENSITlVlTY

WYPE

IV)

Earlier studies have shown that patients with farmer’s lung and pigeon breeder’s diseases have circulating sensitized lymphocytes that, when exposed to the offending antigen, undergo blast-transformation and produce migration inhibition factor (MIF) .65--(i8Although DM,

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in vitro tests for delayed-type hypersensitivity (Type IV) discriminate between patients with hypersensitivity pneumonitis and those with asymptomatic individuals, a small number of asymptomatic persons have sensitized lymphocytes capable of producing migration inhibition factor on exposure to antigen. Thus it appears that delayed hypersensitivity mechanisms are activated in hypersensitivity pneumonitis long before the appearance of clinical disease. The process most likely starts as a local pulmonary response to an inhaled antigen. Lymphocytes recovered from the lower respiratory tract by bronchoalveolar lavage are activated T-lymphocytes.“‘, 7o Schuyler et al. have shown that lymphocytes in bronchoalveolar lavage from patients with bird fancier’s lung are sensitized to pigeon serum but the peripheral blood lymphocytes are not.” If bronchoalveolar lavage is performed early, about 24 hours after antigen challenge, the lavage fluid shows heavy accumulation of neutrophils, which is followed by a rapid increase of T-lymphocytes7” Unlike sarcoidosis, however, the percentage of T-lymphocytes is very high, often 60% to 70%, and the number of suppressomzytotoxic cells is usually well above 40% of the total lymphocyte population.“‘, 74 This increase in number and percentage of suppressor/cytotoxic cells is present in asymptomatic individuals exposed to antigen as well as in the patients with symptoms.75P77 The presence of activated lymphocytes in BAL merely reflects the local inflammatory response since the alveolitis is not related to activity, functional alteration, or progression of the disease.7x It is conceivable that chemotactic factors released from activated lymphocytes attract monocytes, which lead to granuloma formation-the exact mechanisms that lead to granuloma formation and fibrosis remain unclear.7g Keller et al. have stressed that abnormalities in T-cells are important in the initiation and development of hypersensitivity pneumonitis.80

ALTERNATE

COMPLEMENT

(C3) PATHWAY

ACTIKATION

Early neutrophilic alveolitis in the disease appears to be due to activation of the alternative pathway of complement.81 The presence of complement in macrophages and in alveolar walls with antigen and antibody may be due to alternate pathway activation of C3. Edwards and associates produced histologic lesions resembling those of farmer’s lung in rats and rabbits by intrathecal instillation of mouldy hay dust. Because M. faeni activated the alternate complement pathway when added in vitro to human serum, they concluded that an ability to activate the complement combined with the particulate nature of the antigen produced the lung lesions.82 428

DA4, July1991

MECHANISM

OF ALVEOLITIS

AND GRANULOMA

FORMATION

The process of alveolitis, granuloma formation and fibrosis in hypersensitivity pneumonitis is triggered by an inhaled antigen. Early in the disease, immune complexes containing immunoglobulins or immunoglobulins with the antigen may appear. The cellular picture is characterized by the accumulation of inflammatory cells, mostly T-lymphocytes and macrophages. A number of other cells including neutrophils, eosinophils, B-lymphocytes, basophils, and mast cells may also be present. This initial cellular response is known as alveolitis. The inhaled antigen that initiates the immune response is taken up first by a macrophage or monocyte, which may destroy or modify the antigen and may present it to specific T-lymphocytes.83-85 The macrophages that so function are activated as demonstrated by their capacity to release interleukin-1 and display antigens on the cell surface. Once the antigen has been presented to specific T-lymphocytes, the latter respond by releasing other lymphokines including IL-2. Since both IL-l and IL-2 are chemoattractants for peripheral blood lymphocytes, additional lymphocytes are recruited to the site of action. In animal models of hypersensitivity pneumonitis, increased number of T-cells accumulate at the site of granuloma formation.86 The lung T-lymphocytes release other lymphokines, including macrophage migration inhibitory factor (MIF) and other macrophage activating factors that attract and interact with monocytes/macrophages, which are building blocks of granuloma formations7’ ” The process may remain active until either the antigen is removed or the antigen load is markedly reduced. Why the inhalation of antigen does not always lead to the same type of immune response in all similarly exposed individuals is not clearly understood. Although the immune response is governed by the nature, amount, and duration of antigen exposure, as well as the immune status and genetic background of the individual, it is also clear that regulatory T-lymphocytes modulate granuloma formation.89 In animal models, helper T-lymphocytes appear early in the disease but, later, suppressor T-cells predominate coinciding with diminishing granulomatous reaction. Perhaps, the suppressor T-cells slow down the disease process.” In patients with hypersensitivity pneumonitis, the bronchoalveolar lavage shows suppressor Tlymphocytosis.‘* In these patients granulomas are neither prominent, nor well formed, nor extensive. Keller et al. have demonstrated that asymptomatic nonhuman primate models have increased suppressor cell activity that is absent in symptomatic animals.s2 Furthermore, Bicherson et al. have shown that the disease process in animals resolves despite continued exposure to antigen.s3 It is possible that proliferation of suppressor T-cells provides protection against the granulomatous process. DA4, July

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429

CLINICAL

FEATURES

Fuller described three clinically distinct presentations sensitivity pneumonitis: acute, subacute, and chronic.g4 only acute and chronic syndromes are discernible.g5-s8

of hyperIn practice

ACUTE STAGE Classical symptoms of acute hypersensitivity pneumonitis include cough, fever, tightness of the chest, malaise, and body aches. These symptoms appear 4 to 8 hours after the most recent exposure to the offending antigen. As a rule most patients are quite oblivious to the relationship between their work and their clinical symptoms, but a good occupational history punctuated by a few leading questions is all that is needed to link the two together. Occasionally, the symptom complex is mistakenly treated as an episode of flu or a walking pneumonia. If not recognized and properly managed, the cough becomes persistent and “hacking.” Expectoration, if present, is scanty; hemoptysis is rare. Examination of the lungs reveals fine crepitant rales. Duration of the attack usually lasts from 12 to 48 hours or more, but symptoms recur after the next inhalational exposure to the causative antigen. SUBACUTE STAGE Not infrequently, the acute stage may become severe. Cough becomes more troublesome and dyspnea persistent. In some cases anorexia, malaise, and weight loss may dominate the picture. At this stage, both the doctor and the patient start entertaining thoughts of other diagnostic possibilities, including tuberculosis, carcinoma, and connective tissue disorders. Occasionally, the patient improves after being admitted to a hospital because he or she is unwittingly removed from the environment and the antigen exposure. CHRONIC STAGE Acute and subacute manifestations may progress to the stage of chronic alveolitis and fibrosis. The clinical episodes are now less dramatic, and the patient complains only of progressive dyspnea with or without cough. This presentation is common in patients with bird fancier’s lung and budgerigar lung. Cyanosis may occur. Finger clubbing has been reported. Ultimately, chronic irreversible pulmonary fibrosis may lead to polycythemia and car pulmonale. Less frequently, car pulmonale is the initial complaint, which brings the patient-particularly from a farming community-to medical attention. 430

DM, July1991

RADIOLOGIC

FINDINGS

IN HYPERSENSITIVITY

PNEUMONITIS

The radiologic changes in hypersensitivity pneumonitis reflect interstitial lung tissue involvement. Abnormalities vary from an apparently normal chest roentgenogram to widespread honeycombing and fibrosis. The extent of radiologic features correlates poorly with the severity of the symptoms. One can roughly classify the roentgenographic abnormalities into acute and chronic.

ACUTE HYPERSENSZTZVZTY PNE UMONZTZS A chest roentgenogram during the acute episode of hypersensitivity may be normal. In a study of 26 patients with mushroom worker’s lung only eight (30% 1 showed roentgenographic abnormalities.ss The roentgenographic features when present include bilateral ground-glass haziness with loss of definition of the pulmonary vessels, fine nodular shadows varying from 1 mm or less to 3 to 4 mm in diameter, and linear striated shadows. Although abnormalities are diffuse, occasionally the apices and bases may be spared. Between acute attacks the chest roentgenogram may revert to normal. Monkare et al. reported chest roentgenographic abnormalities in 34 (36%) of 93 patients with hypersensitivity pneumonitis.“’ Patchy pneumonitis occurred in 11 (27%) of 41 patients with bird fancier’s lung described by Hargreave and colleagues?o1 Occasionally, dense consolidation may occur particularly in the lower lung fields. Although the acute radiologic changes do not correlate with pulmonary function tests, it has been reported by Hapke that extensive roentgenographic goes hand in hand with the impaired lung diffusing capacity” (Fig 2). Subacute.-In the subacute stage, fine linear shadows and small nodules produce a reticulonodular appearance. The differential diagnosis is wide (Table 3). Hilar adenopathy is not a feature of hypersensitivity pneumonitis. Pleural effusion, pneumothorax, and empyema do not occur. Chronic.-If the patient is not removed from the offending environment, the acute and subacute changes give way to chronic diffuse interstitial fibrosis characterized by coarse reticulonodular infiltrates, particularly in the upper and mid lung zones. As the disease progresses, the upper lobes shrink and develop ring shadows and bronchiectatic areas. The loss of volume in the upper zones is followed by compensatory overinflation of the lower lung fields. This selective upper lobe involvement occurred in 19 (46%) of 41 cases in one series.” The differential diagnosis at this stage includes tuberculosis, fungal infections, and sarcoidosis. This appearance is in DM

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FIG 2. Radiographic features of hypersensitivity pneumonitls. A, A postero-anterior chest roentgenogram showing bilateral lower lung field haziness In a middle-age woman with progressive dyspnea. She and her husband possessed pigeons. Her lung biopsy showed the picture consistent with hypersensitivity pneumonitis (pigeon breeder’s disease). B, Patchy, peripheral densities In the right lung field and vague hazy infiltrate in a woman who had two canaries (budgerigars) at home. Her respiratory symptoms of cough and dyspnea were found to be due to Budgerigar lung disease. C, This postero-anterior chest roentgenogram shows hyperexpanded lungs with increased bronchial markings and ground glass haziness. The patient demonstrated features of reversible airway obstruction and was treated for asthma with the diagnosis of pigeon breeder’s lung disease established. About 10% of the patients with hypersensitivity lung disease may present with airway obstructlon.

marked contradistinction to idiopathic pulmonary fibrosis (Table 41 (Fig 3). High resolution computed tomography (HRCT) appears to be of value in diagnosing and evaluating different types of interstitial lung diseases. However, its role in the assessment of hypersensitivity pneumonitis remains uncertain.lo2

TABLE

3.

Differential Diagnosis of Hypersensitivity Pneumonitis 1 Tuberculosis 2 Sarcoidosis 3 4 5 6

Pneumoconiosis Sclerodwma Rheumatoid lung Lupus e1ythema10sus

7 Eosinophilic granuloma X Lymphangitic carcinomatosis 9 Fungal inkctions 10 11 1Z 1:s

432

Pneumocystis carinii Drug reactions Hemosidwosis Idiopathic pulmonayv

pneumonia

fibrosis

DA4 July

1991

FIG 3. Roentgenographic diagnosis of sarcoidosts. A, Brlateral hilar adenopathy is the hallmark of sarcoidosis. It is absent in hypersensitivity pneumonitis. Bilateral hilar adenopathy rn sarcoidosis is usually self-limiting. B, A postero-anterior view of the chest, showing bilateral lung disease involving the upper half of both lung fields. The patient was thought to have hypersensitivity pneumonitis, but an open lung specimen showed histiocytosis-x (eosrnophilic granuloma). C, Bilateral upper lung interstitial disease with honeycombrng may occur in hypersensitivity pneumonitis.

PULMONARY

FUNCTION

TESTS

The lung function changes in hypersensitivity pneumonitis are neither specific nor diagnostic because similar abnormalities are found in other diseases, including sarcoidosis, fibrosing alveolitis, collagen vascular diseases, drug-induced lung disease, and other interstitial lung diseases. In acute and subacute hypersensitivity pneumonitis, lung volumes are reduced and gas transfer is impaired. FEVl/FVC ratio usually remains normal, but maximum mid-flow rates and FEF 25-75 may be decreased. These abnormalities in flow rates are most likely due to bronchiolitis, which occurs in hypersensitivity pneumonitis. The pressure volume curve is usually shifted down and to the right, resulting from the patchy pneumonitis.lo4 Arterial blood gas abnormalities include hypoxemia, hypocapnia, and respiratory alkalosis.lo5 In chronic hypersensitivity pneumonitis, the pattern of lung funcDhf,

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1991

433

TABLE 4. Differential Diagnosis of Pulmonary Diseases That May Involve Selectively the Upper Lung Fields 1 2 3 4 5 6 7 8

Tuberculosis (typical and atypical) Histoplasmosis Coccidioidomycosis Allergic bmnchopulmonary aspergillosis Sarcoidosis Pmgressive massive fibrosis Ankylosing spondylitis Radiation pneumonitis

tion impairment differs from that described in the acute stage. These changes reflect the extensive bronchiolitis and fibrosis found in the chronic stage of the disease.@ The gas exchange impairment is predominant in only a small number of the patients. Airway obstruction, however, is a dominant feature. The flow rates are universally reduced, with an additional element of increased lung compliance (reduced recoil). The latter observation is consistent with the pathologic changes of emphysema described in these patients.“’ In the chronic stage of the disease, the correlation of clinical, roentgenographic, and pulmonary function abnormalities is rather poor. Chest roentgenograms may be normal or near normal, whereas abnormalities in lung function are marked. Pulmonary function tests may be normal after the resolution of acute disease, but in chronically ill patients impaired lung functions are expected to remain. Many patients have increased bronchial reactivity.lo7 The lung function measurements in patients with hypersensitivity pneumonitis may not be of much help in establishing the specific cause of the disease, but they are important in monitoring the course of illness and assessing the disability. ROLE OF SKIN TESTS The skin tests are not helpful in hypersensitivity pneumonitis. In 1965, Pepys and Jenkins observed that moldy hay antigen did not incite any reaction in their nonatopic individuals.“’ Freedman et al. obtained similar results and concluded that skin testing with moldy hay antigen was not helpful in differentiating the farmer’s lung patients from asymptomatic contacts.‘0g Williams reported nonspecific cutaneous response in some farmer’s lung patients.ll’ Morel1 et al., however, obtained different results: They applied Micropolyspora ,faeni antigen to 26 patients with farmer’s lung and 25 asymptomatic farmers. Of these, 15 (83.3%) of 18 patients with farmer’s lung had an 434

DM,

July

1991

immediate Type I reaction; 18 (100%) had a positive late reaction, and 8 (44%) showed a delayed response. Of the 25 asymptomatic farmers, 28% responded with a Type I reaction, 68% showed a late response, and the delayed reaction occurred in only 4% of individuals. The authors concluded that the intradermal injection with moldy hay was an effective way of diagnosing farmer’s lung.*” In bird breeder’s disease, the skin test has been shown to be helpful.“” Unfortunately, many asymptomatic pigeon breeders also have a positive skin test reactivity. Thus skin tests appear to be of limited diagnostic value in hypersensitivity pneumonitis.“‘, “I I” BRONCHOALVEOLAR

LAVAGE

Bronchoalveolar lavage has been widely used to study the pathogenesis of interstitial lung disease. In hypersensitivity pneumonitislike sarcoidosis, lymphocytes are the most commonly increased cells in bronchoalveolar lavage fluid, but the lymphocyte count usually is very high (often greater than 60% 1. It is worth keeping in mind that lymphocyte counts alone are insufficient to differentiate between sarcoidosis and hypersensitivity pneumonitis. In acute hypersensitivity pneumonitis (i.e., within 24 hours of antigen exposure) an increase in the number of neutrophils occurs that is followed by the lymphocyte outpouring.72, 77 Most of the lymphocytes are T-cell, which-when challenged with an appropriate antigenrelease lymphokines. This increase in T-lymphocytes comprises predominantly CDS+ cells, hence the CD4KD8 ratio is very low (0.5 vs 1.8 controls).sOS” In sarcoidosis there is a preponderance of CD4 cells.73’ 74 The increase in BAL lymphocytes in hypersensitivity pneumonitis is associated with increases in mast cells.lf4 Costabel et al. reported the occurrence of plasma cells in BAL in 12 of 20 patients with hypersensitivity pneumonitis.l15 Whether this new finding proves to be of diagnostic value remains to be established (Fig 4). After the acute stage, the number of lymphocytes increases and the neutrophil count goes down. In general, patients with a few neutrophils and large numbers of T-lymphocytes in BAL have mild or easily reversible disease. The lung disease tends to be persistent and poorly responsive to therapy if lymphocyte and neutrophil counts remain high.“” The chronic phase of the disease is characterized by granuloma formation of infiltration of T-lymphocytes and macrophages. Mornex et al. in a recent study reported the presence of Tlymphocytes bearing class II histocompatibility antigens (HLA-DR) and activated T-cell markers (MLRl-31 in the BAL effluent’l’ There seems to be no relationship between the intensity of the lymphocytic alveolitis and functional abnormalities.“8 BAL fluid in hypersensitivity pneumonitis patients also conDM,

July

1991

435

FIG 4. Bronchoalveolar Most

of these

lavage lymphocytes

IS predominantly are

suppressorkytotoxic

lymphocytic

in

hypersensitivity

pneumonltts.

in nature.

tains higher levels of immunoglobulins compared with normal conall three immunoglobulins-IIgG, IGM, and trols .iZ,1’9 Although &A-are increased in symptomatic individuals, IgG and IgA levels are about four times higher than those found in asymptomatic subjects.l’” Some of the immunoglobulin is the antibody directed against the offending antigen. IgG antibody is most likely derived from serum and IgA from the lung. When BAL is subjected to gel chromatography and analyzed for IgG, with a hemagglutinating method, considerably higher titers of IgG, are found.i21 It is surmised that in certain hypersensitivity pneumonitis, particularly in pigeon breeder’s disease, this selective increase in IgG, may be associated with homoc-ytotropic and reaginic funclion.

DIAGNOSIS

OF RYPERSENSITMTY

PNEUMONITIS

1. Think of hypersensitivity pneumonitis. The most important step in the diagnosis of hypersensitivity pneumonitis is to include it in the differential diagnosis of diffuse interstitial pulmonary infiltration with or without fibrosis. The condition may be indistinguishable from sarcoidosis and idiopathic pulmonary fibrosis, particularly in its chronic stage. 2. Recognize the temporal relationship between the appearance of symptoms and occupational or environmental e)cposure. In the acute form of disease the symptoms of fever, tightness of the chest, cough, and dyspnea usually occur 4 to 8 hours after the antigenic challenge. This represents an early stage that only rarely 436

DA4, July

1991

becomes chronic if the episodes are prevented. It is of paramount importance to recognize the entity at this stage because the pathologic changes are reversible.

3. Chest roentgenograms

are not spec$c.

The radiographic features of the disease range from an apparently normal chest x-ray film to an extensive fibronodular and reticular inliltration. The differential diagnosis of the radiographic abnormality is wide.

4. Lung -function monitis.

tests are not diagnostic

of hypersensitivity

pneu-

In the early stage, lung function tests are either normal or reveal a mild degree of “restrictive” abnormality characterized by decrease in vital capacity and total lung capacity and a reduction in the difising capacity. In the chronic stage, these defects became more pronounced and are irreversible. Airway obstruction is present in about 10% to 20% of the patients.

5. Routine

laboratory

tests are unhelpful.

Eosinophilia is rare in hivpersensitivity tion rate may be moderately elevated.

pneumonitis.

Sedimenta-

6. Serum precipitins. Specific serum precipitating antibodies UgO are found in almost all patients with hypersensitivity pneumonitis; however, as many as 40% of asymptomatic individuals exposed to the same antigens also have precipitins in their serum. Thus the test is sensitive but it lacks specificity.

7. Skin tests. Reliable standardized

antigens

are not available

for skin testing.

8. Lung biopsy. Although a lung biopsy specimen may strongly suggest the diagnosis of hypersensitivity, tissue diagnosis is not always required particularly in patients with a typical clinical history and a consistent occupational exposure. Furthermore, at times it is difficult to distinguish hypersensitivity pneumonitis from other granulomatous diseases, especially sarcoidosis.

9. Bronchoalveolar

lavage.

Suppressor T-cell lymphocytes in bronchoalveolar lavage fluid may be of value in separating hypersensitivity pneumonitis from Salkcoidosis. 10. Inhalational challenge. Perhaps the best way of establishing the diagnosis of h.ypersensitivity pneumonitis is to reproduce the clinical syndrome by subjecing the patient to an inhalation challenge with the offending antigen. It should be remembered, however, that the use of challenge test is dangerous and controversial. Recause of the concern about the protocol and safety of the test, it should be performed under strict medical supeivision. DA4, July

1991

437

11. The most important step in the diagnosis is the recognition occupational and environmental e)cposure (Table 5).

of

TREATMENT In most of the cases of hypersensitivity pneumonitis, adequate treatment has been avoidance of the antigen along with minor symptomatic therapy with antiinflammatory drugs and, if needed, bronchodilators. In severe cases, administration of corticosteroids for 2 to 4 weeks produces a resolution of clinical, functional, and radiologic findings. In chronic forms of the disease, corticosteroids may delay the onset of further respiratory damage. A few cases disTABLE Causes

Fungal

Chemical

Bacterial

Uncertain

438

5. of Hvoersensitivitv

causes

causes

causes

causes

Pneumonitis Condition

Antigen

Farmer’s lung Air conditioner lung Bagassosis Mushroom worker’s lung Maltworker’s lung Cheese washer’s lung Maple bark stripper’s disease Sequoiosis Woodworker’s disease Suberosis Paprika splitter’s lung Dry rot lung “Dog house disease” Lycoperdonosis Sp2itlese lung Bird breeder’s lung Rat handler’s lung Wheat weevil disease Furrier’s lung Pituitary snuff taker’s lung Isocyanate lung Pauli’s reagent lung Vineyard sprayer’s lung Hard metal disease Cmmolyn sodium lung Washing powder lung Bacillus subtilis alveolitis Bacillus sereus alveolitis Sauna lung New Guinea lung Ramin lung Insecticide lung

Thermophilic actinomycetes Thermophilic actinomycetes Thermophilic actinomycetes Thermophilic actinomycetes Aspergillus clavatus Penicillium casei Cryptostmma corticale Aureobasidium pullulans Cryptostmma corticale Penicillium frequentans Mucor Merulius lacrymans Aspergillus versicolol Lycoperdon Rotyris cinerea Avian protein, blood Rat protein Wheat weevil Animal fur Ox and pork protein TDI, MD1 Pauli’s reagent Bordeaux mixture Cobalt Cromolyn sodium B. subtilis enzymes 8. subtilis B. sereus

Lake water I?) Hut thatch (?I Ramin wood I?1 Pyrethrum (?J DM, July

1991

play a continuing fibrosis: of these, a small number will develop car pulmonale. A partial prevention may be accomplished by wearing a face mask during exposure in only rare situations.

FARMER'S

LUNG

Farmer’s lung, the best known and most extensively studied of all forms of hypersensitivity pneumonitis, is caused by exposure to moldy dusts generated by the threshing of wet hay and the handling of straw and other decomposing vegetable material.15’ X6)y4,122S lz3 Hay, when stored in bins on a farm, is often damp. The humidity and heat are conducive to the growth of microorganisms. The dust, with a vast number of protein particles, enters the respiratory tract and initiates alveolar inflammation. The organisms that instigate the reaction are the thermophilic actinomycetes: M. polyspora, M. faeni, T. candidus, T. vulgar-is, and others. Any farmer working with the hay or other moldy material is a potential victim. The majority of patients are men between the ages of 17 and 70 corresponding to the population of farmers, but women, children, and other residents of farming communities have reportedly developed the illness-particularly in those parts of the world where barns containing moldy hay are directly connected to the living quarters, thus exposing the family members and friends to antigenic contact. Usually, farmer’s lung disease occurs frequently in poor farming communities where workers must directly thresh and handle hay, thus exposing themselves to “thresh clouds” containing the antigen. In more technologically advanced farming, where workers handle the threshing of hay via machines, the incidence of the disease is low. Geographic and seasonal factors also determine the distribution of the disease. Common in agricultural areas of the world, the disease is most prominent in cold and humid regions. Because of damp weather, ideal to the growth of thermophilic actinomycetes, autumn and winter are the seasons with the highest incidence of the disease. In Britain, certain areas have an incidence of 10 per 100,000 population, whereas in other damp and less wealthy areas, the rate may be as high as 10 per 1,000.124 In Devon, the disease is a prominent cause of disability in farmers. In wet areas of Scotland, the incidence of 8% has been estimated by Grant et al., whereas, for the entire United Kingdom, the prevalence rate is 2%.lz5 The variability, in part, may also be due to diagnostic differences.‘““S lz7 In the classic farmer’s lung disease, any combination of cough, fever, dyspnea, anorexia, chest pain, headache, chills, and malaise may occur~34'128. 129 In acute cases, symptoms appear 4 to 8 hours after exposure to the antigen and subside within 1 day. Subacute cases may hold symptoms for longer. The chronic form displays LhwJuly1991

439

gradually developing symptoms with permanent dyspnea and progressive impairment of lung functions. Physical examination may reveal fever, tachycardia, and tachypnea. Auscultation of the lungs may show inspiratory crackles over the lower parts. Rhonchi may be present in 10% to 20% of the patients. Some patients may be asymptomatic but still have alveolitis. In the acute stage the chest film shows a bilateral alveolar infiltrate, similar to pulmonary edema but without cardiac enlargement. Indeed, patients may be misdiagnosed and treated for heart failure. Only when they fail to respond are they referred to a specialist for further evaluation. In chronic stages reticulonodular linear shadows appear, which finally give way to fibrosis and honeycombing. Peripheral leukocytosis is common in acute stages. Eosinophilia is rare. Standard precipitin tests are usually positive for one or more of the thermophilic actinomycetes found in samples of suspected farm matefid.130’ 132,57 Cutaneous tests are not very helpful.lll, 133 The lung function changes consist of reduced vital capacity, residual volume, and total lung capacity. The diffusing capacity is impaired.lo3 Alveolar-arterial oxygen difference is wide, and it further increases on exercise testing, The lung compliance is reduced. In acute disease most of these abnormalities improve with or without treatment within 3 to 4 weeks. Bronchial hyperactivity to methacholine and histamine occurs in many patients; significant airway obstruction, when present, portends poor prognosis.107’ 134 Respiratory acidosis and hypercapnia occur very late in the disease. Pepys and Jenkins obtained positive reactions in the immunoelectrophoretic test to “farmer’s lung hay” antigens in 182 (89%) of 205 subjects with farmer’s lung disease and in 28 08%) of 122 farmers, who had been exposed to moldy hay but had no evidence of farmer’s lung disease.13’ The role of these antibodies in the pathogenesis of hypersensitivity pneumonitis and its evaluation remains cloudy. These antibodies usually are of IgG and IgM class.‘35 Serum IgA elevations may occur, but the total IgE levels remain normal. Serum complement fixation test is helpful in monitoring the course of the disease because complement levels reflect clinical activity of the immunocomplex reaction.81’ 136

BRONCHOALVEOLAR

LAVAGE

The presence of T-suppressor lymphocytosis in the bronchoalveolar lavage is useful in those ambiguous situations where sarcoidosis and diffuse interstitial fibrosis cannot be separated on the clinical, radiologic, and histologic grounds.74, ‘17, 137 Pulmonary mycotoxicosis, an unusual and rather difficult diagnosis, can often be separated from farmer’s lung disease on the basis of cellular morphology of 440

OA4, July1991

bronchoalveolar lavage fluid.13’ The inhalational challenge in appropriate cases creates a typical clinical picture. A rise in temperature and pulse rate are associated with a fall in vital capacity. The patient usually has cough and tightness of the chest, and a few inspiratory tales may appear in the lung fields.13’ A lung biopsy specimen is rarely needed for the diagnosis of farmer’s lung disease, if an adequate history of exposure is available and the clinical, radiologic, and serologic studies are consistent with the diagnosis. However, the lung biopsy is mandatory if another disease is suspected. Many authorities prefer an open lung biopsy through a limited thoracotomy. However, we have been able to obtain sufficient tissue in order to establish the diagnosis via a transbronchial approach. The differential diagnosis of acute farmer’s lung disease includes viral and mycoplasmal illnesses: bacterial and fungal illnesses such as miliary tuberculosis, acute histoplasmosis, coccidioidomycosis; occupational disorders (e.g., silo-filler’s disease and acute silicosis); and immune-mediated drug reactions. The diagnosis of chronic farmer’s lung disease encompasses all the conditions that result in diffuse pulmonary fibrosis (Tables 6 and 7). Regardless of the presentation, the diagnosis of farmer’s lung will not be missed if a careful history of occupational exposure is secured. In more than two thirds of cases, adequate treatment includes TABLE

6.

Chest Roentgenographic Granulomatous Diseases

Features

of Frequently

Encountered

Pulmonary

Features

TB

Sarcoidosis

EAA

CBD

WG

Hodgkin’s Disease

H&W adenopathy Parenchymal infiltrate

Unilateral

Bilateral

Absent

Rare

Absent

Unilateral

May be miliary

Diffuse

Diffuse

Rare

Uncommon

Cavity information Mediastinal adenopathy Pleural effusion Large nodules

Common

More in lower and mid fields Rare

Rare

Rare

Common

Rare

May occur Common

Uncommon

Absent

Absent

Absent

Common

Rare

Absent

Absent

Rare

Absent

May occur

Absent

Absent

Common

May occur Common

EAA = extrinsic

allergic

TB = tuberculosis; er’s granulomatosis.

DM,July

1991

alveolitis;

CBD = chronic

beryllium

disease; WG = Wegen-

441

TABLE

7.

Differences

Between

Sarcoidosis

and

Extrinsic

Allergic

Alveolitis

Features

Sarcoidosis

Extrinsic

Age b-1

20-50

Symptoms

Asymptomatic, dyspnea, fever, weight loss Common: eyes, skin, liver, spleen Bilateral hilar adenopathy with or without pulmonary infiltration Depressed Absent T-lymphocyte (helper) predominance

Any Any

Multisystem Chest

involvement

roentgenogram

Delayed hypersensitivity Precipitin antibodies Brunchoalveolar lavage

Inhalational Treatment

challenge

Not applicable Corticostemids

Fmm

OF? Disease-a-Month

1990; 9:576. Used

Sharma

by

Allergic

Alveolitis

None No adenopathy, widespread

basal or infiltration

Normal Present T-lymphocyte (suppressor) predominance Positive Prevention, corticostemids

permission

avoidance of the antigen, use of antiinflammatory drugs, and, if needed, bronchodilators. In acute cases, administration of corticosteroids for 2 to 4 weeks produces a resolution of clinical, functional, and chest x-ray findings. In chronic forms of farmer’s lung, corticosteroids may delay the onset of further respiratory damage. In a small number of cases continuing fibrosis and car pulmonale develop. Prevention is accomplished by wearing a face mask during exposure and by thoroughly drying hay before storage.140S 143 PIGEON

BREEDER’S

LUNG: BIRD

FANCIER’S

LUNG

Bird fancier’s lung is second only to farmer’s lung as the most well-known and most extensively studied disease.lU Here, the interstitial alveolitis is acquired by the inhalation of protein material derived from the excreta and feathers of certain birds. The exact chemical composition of the antigen is uncertain, although recent research has isolated a component of pigeon droppings that reacts specifically with the sera of individuals suffering from pigeon fancier’s 1ung.14’ Still, it is believed that there may be several antigenic sources, each contributing to the onset of disease. This theory draws some support from the fact that excreta, feathers, and even avian sera can generate a hypersensitivity response in patients under laboratory testing. Many birds can induce the disease. Pigeons, ducks, canaries, pheasants, and geese can all instigate bird fancier’s lung. Parakeets give rise to a particularly severe form of the disease with progressive 442

DM,

July

1991

dyspnea. Unlike farmer’s lung, there seem to be no geographical factors influencing the prevalence of bird fancier’s lung, and because domestic pets such as canaries, pigeons, and parakeets are kept within the home, seasonal factors become less significant. Cases are reported from Belgium, England, France, the United States, and Mexico, as well as other countries with smaller numbers of bird fanciers and breeders. The disease can be caused by exposure to just one bird.146 Many reports have described individuals with hypersensitivity pneumonitis who have owned only one or two pet birds. Pigeons and other birds excrete nitrogenous wastes in the form of uric acid. Because very little water is needed in the release of excreta, the droppings dry quickly and form “miniature dust storms” when cages are cleaned, shaken, or disturbed in any manner. Bird fancier’s lung predominantly affects women, ages 20 to 65. This is because on most bird breeding farms and even in domestic situations women are more often responsible for the care of the birds. In my practice, 80% of the patients with bird fancier’s lung are women. Nevertheless, adult males and children still comprise a significant number of cases. The common symptoms of bird fancier’s lung are exertional dyspnea, cough, and loss of weight. Galy and Dorsit reported a loss of weight of 25 kg in a period of 6 months for an individual who raised doves .147 Mild fever, chills, headache, and general malaise also occur. Of interest is the generally long period of contact with the antigenie source before symptoms develop. Individuals can be exposed for 2 months to 30 years before showing any symptoms. Physical examination may be normal or may reveal crepitant rales. Leukocytosis is common with a moderate eosinophilia, which rarely exceeds 10% .14' Chest roentgenograms may be normal, but this should not be considered evidence enough to disregard the diagnosis of bird fancier’s lung. Perhaps the most important lead in the detection of this disease is detailed history, since many patients do not even dream of considering their birds’ causing disease. An interesting example is the case of bird fancier’s lung in a woman whose part-time occupation was tying fish bait. In the process, she would put the apparatus in between her teeth and twist on an additional element of the bait. Unfortunately, the bait included a single canary feather. Thus each successive time she held the bait in her mouth, she exposed herself to canary feathers, which ultimately caused the disease. Such correlations are essential in order to effectively diagnose hypersensitivity pneumonitis. Clubbing of the fingers is common in pigeon breeder’s disease, and it provides help in predicting clinical prognosis.14’ The lesions resemble those observed in other types of hypersensitivity pneumonitides. Alveolar and interstitial infiltrate consists of lymphocytes, plasma cells, and histiocytes. The presence of foamy DA4, July

1991

443

histiocytes in the acute forms and clefted granulomas in the latter stages have been emphasized by many authorsX5’ (Fig 4). Miliary or micronodular shadows occur characteristically at the bases and lower fields.15’* 15’ Occasionally, patchy pneumonic infiltrates may be present. Hilar adenopathy, pleural effusion, pneumothorax, and cavitation are not seen. In the chronic form, diffuse interstitial shadowing may produce a honeycomb appearance. The degree of radiologic abnormalities correlates poorly with severity of the symptoms.153 Precipitating antibodies to pigeon antigens are present in very high titers. The antibodies are primarily of IgG class, but IgM and IgA antibodies are also present. The total serum IgE levels are not high in pigeon breeder’s disease.l’l, 154,155 Precipitin antibodies are also found in asymptomatic pigeon breeders. Elgefors et al. have shown that as many as 60% of the clinically well bird breeders may show the presence of precipitins,156 which clearly indicates that factors other than the presence of complement-fixing antibodies are involved in the pathogenesis of the disease. Intracutaneous tests using pigeon serum antigen or extracts of pigeon droppings produce a dual reaction, the immediate and the delayed occurring at 4 to 8 hours.157 In a typical acute patient with acute pigeon breeder’s lung, the lung function tests demonstrate restrictive ventilatory impairment .158,159 The best treatment for bird fancier’s lung is avoidance of antigenic exposure. This is often difficult for the patient because of the attachment to the birds. If the disease is at an early mild stage, the wearing of masks during exposure could be adequate. For more serious cases, however, removal from exposure is a must. Corticosteroid treatment is effective for clearing symptoms and stopping further respiratory deficiency. In cases with extensive fibrosis, cardiac insufficiency occurs with right side heart failure.105,106 Allen et al. studied nine patients at intervals from 8 to 30 months. Four (44%) patients recovered completely; whereas the others developed progressive lung damage. They concluded that the older the patient and the longer the time of exposure to antigen after symptoms had appeared, the worse the prognosis.1”o2 16’ SUMMER-TYPE

RYPERSENSITMTY

PNEUMONITIS

Summer-type hypersensitivity pneumonitis (STHP) is a disease seemingly unique to Japan.163 Characteristically, the symptoms occur in the summer months of June to October and then resolve, only to reoccur in the next and following summers. In 1978, Miyagawa and co-workers observed that serum samples from all their patients with STHP contained antibodies against Cryptococcus neoformans. However, they failed to isolate the organism from the patients’ close 444

DM,

July1991

surroundings.164 Furthermore, bronchial challenge tests using C. neoformans failed to reproduce typical symptoms and signs of the disease. In 1984, Shimazu et al. isolated Trichosporon cutaneum from the houses of patients with summer-type alveolitis. Twenty (95.2%) of the 21 patients with the disease showed high titers of anti-T. cutaneum antibody in serum; whereas, only 9% of the controls showed any antibodies in their serum.‘“” One of the patients also responded to bronchial challenge with T. cutaneum. Thus, fol the time being, it appears that T. cutaneum is the causative agent of summer-type hypersensitivity pneum0nitis.l”” Corticosteroids are effective in suppressing acute symptoms and in improving lung functions. Isolation of the patients from their homes and changing the environment usually ameliorate symptoms. BAGASSOSIS Bagassosis is acquired by inhaling bagasse, the residual product of the extraction of sugar juice from sugar cane.lG7 Bagasse is used in the manufacture of insulation panels, paper, and some explosives. Almost always, the bagasse is allowed to sit in the hot and humid climates of the sugar processing plants for many months before industrial use. During this time, the once fibrous bagasse pulp becomes powdery and moldy. The analysis of moldy bagasse may reveal over 240 million fungal spores per gram and numerous other organisms of a bacterial nature. The workers who handle this bagasse dust often suffer from this type of hypersensitivity pneumonitis. Through immunologic studies, the actual etiologic agents responsible for bagassosis have been determined. Thermophilic actinomycetes such as A4. faeni, M. vulgar-is, and T. vzdgaris give positive precipitin tests in a majority of reported cases.16s’ 16’ Most significant, however, is the isolation of T. sacchari from bagasse, which generates positive precipitin and inhalation response in the patients with bagassosis. These microorganisms, found so abundantly in bagasse dust, initiate alveolar and interstitial inflammation in a way similar to that which causes farmer’s lung. Bagassosis commonly affects men between the ages of 18 and 50 years. This correlates well to the population of bagasse handlers in the sugar industry. The disease has been reported with a moderate hequency in all of Europe, Cuba, India, Puerto Rico, South America, Madagascar, Hawaii, and sugar processing areas of the mainland United States. Once the illness is suspected, skin tests with any of the mentioned thermophilic actinomycetes are of diagnostic help. Chest roentgenogram shows bilateral shadowing more dense in the hilar regions. Inhalation challenge to T. sacchari establishes the diagnosis. The bronO&f, July

1991

445

choalveolar lavage fluid shows polymorphonuclear leukocytes and lymphocytes. The lymphocytes are generally more prominent. Bagassosis can be prevented by employing the following procedures: (1) open bagasse sacks under water; (2) thoroughly dry the product before handling; and (3) wear masks during handling the bagasse. Anything that inhibits fungal growth and reduces the amount of dust in the atmosphere is of help. It is also advisable to handle the bagasse mechanically. Except in severe cases, corticosteroid treatment is unnecessary. Usually, avoidance of the antigenic exposure is all that is necessary to prevent alveolitis. Early detection, of course, is necessary to prevent fibrosis and severe respiratory impairment. Most cases of bagassosis, if discovered early, revert to normal after the exposure to bagasse is terminated.

DETERGENT Detergent

WORKER’S

LUNG

worker’s

lung develops from exposure to protolytic ena common ingredient of detergents. Any worker handling such substances is at risk of developing the disease. The disease, however, has occurred in consumers of the final detergent product in domestic use and in individuals with indirect exposure to the enzymes. Breathlessness is the main symptom. It can be so severe that the patient may be unable to walk or even talk.l” Cough, weakness, chest pain, mild fever, and small production of sputum are common. A few cases show immediate response (Type I), but the delayed, Type III response where symptoms occur about 8 hours after exposure to antigen is common. In severe disease the duration of the sickness can be as long as 6 weeks and the patient is bedridden for about 2 weeks. This is long compared with other forms of hypersensitivity pneumonitis. Sometimes asymptomatic individuals can be stricken with insidious dyspnea due to gradually developing pulmonary fibrosis. Thus it is important to detect the disease as early as possible. The chest roentgenogram may show increased reticulation and nodular shadows. Obstructive lung function is confirmed by reduced FEVI and FEV/FVC ratio. A few patients may have eosinophilia. Perhaps the most useful test in a clinical evaluation of the disease is the cutaneous prick test with diluted antigen. Nearly all cases of detergent worker’s lung have yielded immediate positive responses. The general outcome of the disease is variable. Some patients, after their discontinued exposure to the antigen, return to normal, whereas others continue with alveolitis and acute pulmonary fibrosis.

zymes of the Bacillus subtilis,

446

i3~ July 1991

Since the development of the cotton gin at the onset of the industrial revolution, byssinosis, a pulmonary disease commonly mistaken for chronic bronchitis and hypersensitivity pneumonitis, has been found in workers involved in the manufacture of cotton products. The illness occurs specifically in workers handling cotton, flax, or hemp. The inhalation of dusts formed from processing these materials gives rise to byssinosis. The incidence of the disease is roughly proportional to the concentration of dust in the environment. The antigen most likely is the bract of the cotton flower. The presence of histamine liberators in the dust is suspected to contribute to symptoms. Another theory suggests that a nonspecific irritant action of the bract plays an important role in generating an immune response. HUMIDIFIER

LUNG

Humidifier lung results from the inhalation of thermophilic actinomycetes that grow in contaminated humidifier vents, air conditioners, heating systems, and saunas. M. faeni and T. candidus are the commonly isolated organisms. It has also been suggested that protozoa and other microorganisms may cause humidifier lung. Gainer et al. described an epidemic of humidifier lung in 26 of 50 employees of a large factory with 3,000 employees. Individuals suffering from hypersensitivity pneumonitis worked in four separate rooms ventilated by a single heating-cooling unit. The illness consisted of a “flu-like” syndrome with fever, chills, headache, cough, and dyspnea. Most of the subjects affected demonstrated precipitating antibodies to a large number of molds and fungi known to cause hypersensitivity pneumonitis. Removal of the humidification unit resulted in “cure” of the symptoms.*74 Unlike many forms of hypersensitivity pneumonitis, humidifier lung is not restricted to a specific occupation. Indeed, it occurs in all aspects of rural and urban life An office worker, a sauna bather, and even a driver of a car with a contaminated air conditioner can be at risk for developing the disease. 175-17s Patients suffering from humidifier lung experience the acute form of HP, characterized by cough, dyspnea, fever, chills, and malaise.17g’ Iso Attacks occur usually 6 to 8 hours after exposure to antigen and are associated with leukocytosis and diffuse pulmonary infi1trates.l” The chronic form is difficult to recognize because of the insidious onset of dyspnea. A chest roentgenogram may show interstitial fibrosis. Treatment is adequate if exposure is discontinued. A thorough cleaning of the humidifier or the air conditioner and subsequent periodic cleaning to prevent regrowth of the organisms can eradicate the DA4, July1991

447

disease. This is also the best means of prevention. The chronic illness presents a problem because alveolitis can continue, resulting in pulmonary fibrosis. This should be treated with corticosteroids.182,183

SILICONE

INDUCED

GRANULOMATOUS

PNEUMONITIS

For more than three decades silicone (polydimethylsiloxane) has been used to obliterate wrinkles, smoothen out facial imperfections, and augment body contours. In the beginning, the substance was thought to be biologically inert, but recent reports indicate that silicone can induce local and systemic hypersensitivity granulomatous reactions in laboratory animals and in humans.ls8 In 1964, Miyoshi and his colleagues described two patients who, after augmentation mammoplasty using silicone derivatives, developed a connective tissue-like syndrome.18s Since then, many more case reports describing the occurrence of clinical syndromes resembling scleroderma, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue, and primary biliary cirrhosis have apThe clinical spectrum of silicone induced pulmonary Pe=dTs0-1g3 diseases includes asymptomatic alveolitis, acute pneumonitis, and of hypersensitivity fatal pulmonary edema.‘s4-1s6 The occurrence pneumonitis resulting from illicit subcutaneous injections of silicone has been demonstrated by Chastre et al. in their elegant study of 13 transsexual men.ls7 Their findings include the following: (1) Silicone fluid can induce acute pneumonitis, which can be followed in some patients by acute respiratory failure; (2) acute silicone pneumonitis may occur after many years of local trauma to tissues containing silicone; (3) latent silicone pneumonitis may occur if the patient develops the inflammation of the past injection site; (4) silicone alveolitis is characterized by increased macrophages, neutrophils, and eosinophils; and (5) the recovery of silicone from bronchoalveolar lavage cells and fluid is useful in establishing the diagnosis. Why do some patients develop autoimmune syndromes after polydimethylsiloxane fluid exposure, while others develop acute systemic syndromes and still others develop a syndrome of hypersensitivity pneumonitis?1s8-*ss Perhaps the dose of the polydimethylsiloxane exposure determines the systemic manifestation. Most of the variable autoimmune syndromes followed mammary prosthesis augmentation with polydimethylsiloxane fluid, whereas the acute systemic syndromes followed massive (in most cases illicit) injections of silicone directly into tissue. Thus it is conceivable that critical dose might separate the acute immune response from the chronic reaction. The particularly chronic response might probably be a function of the genetic susceptibility of the individual.“““J ‘01 448

DA4 July

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FUEL-CHIP

INDUCED

HYPERSENSITIVITY

PNEUMONITIS

Fuel-chip disease is acquired by intermittent exposure to fuel chips made of wood and peat. An alternative to electrical heating, fuel chips are used significantly in only a few countries. Finland, in particular, is of some concern. Alexander et al. report that industries, hospitals, and communities with up to 7,000 inhabitants are heated with fuel chips.ls4 The material, which can be over 40% damp, is at a constant temperature of over 65” C. These conditions are conducive to the growth of molds. Indeed over 3 million colonies of three types of mold were found in one sample of the dust formed from a fuel chip. The microorganism most likely to cause the disease is Penicillium species the most abundant of the molds that grow in fuel chips. Of the cases reported, all complained of cough, dyspnea, fever, and headache. Unlike farmer’s lung disease, symptoms in fuelchip induced hypersensitivity pneumonitis appeared 1 to 3 hours after contact with the dust and lasted only 4 to 6 hours. Clinical examination shows many crepitant rales in both lungs during inspiration. 185,186 In all cases, removal from exposure to the antigenic source was sufficient for the disease to subside. However, some patients could still use the fuel chips form of heating only after they thoroughly washed the storeroom where chips were heated. Also, the patients should be advised to wear masks before handling or moving fuel chips. In the future, attention should be paid to the dry storage and careful handling of wood and peat fuel chips to prevent attacks of fuel chip pneumonitisXs7 MUSHROOM

WORKER’S

LUNG

Although very little is known about mushroom worker’s lung, we do know that it is an interstitial alveolitis caused by the thermophilic actinomycete found in mushroom compost and ActinobiJida dichotomica, a microorganism present in mushrooms themselves.202-204 Jackson and Welch found that the serum of their patients gave a positive precipitin test for dilute extract of mushroom but a negative result for Thermopolyspora and Micropolyspora vulgaris, two hilic actinomycetes involved in mushroom culture procedure.205 Lacey isolated ActinobiJida dichotomica from mushroom extract, supporting the theory that the microorganism might be the cause.‘06 Sakula uncovered precipitin antibodies against M. faeni and T. vulgaris in his patientsFo7 The case reports show that individuals handling mushrooms in commercial processing plants can develop disease from inhalation of dust containing the microorganism. That this inhalation must be the cause of a hypersensitivity response is shown DM.

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by the presence of antibodies to the organisms in patient sera and the radiologic findings of alveolitis with acute pulmonary fibrosis. Symptoms are those of classic hypersensitivity pneumonitis, though a bit more severe. Removal from exposure to antigen is the only form of treatment. The symptoms and alveolitis usually regress, and corticosteroid treatment is unnecessary. SPiiTLESE

LUNG

Spatlese lung is caused by the inhalation of gray thrush, a moldy substance that covers the surface of grapes used to make wine.zo8 The thrush reacts with the skin of the grape to destroy acidic substances and thus give the grape a more intense sweetness. Chemical analysis has shown this thrush to consist largely of Borrytis cinera. Also, small amounts of Alternaria tenues and Arthrobotrys superba are found. Workers having to harvest and prepare the grapes for fermentation are exposed to dust formed by the thrush and are thus the major at-risk group. Patients suffer from attacks of cough, dyspnea, and fever. Usually, the attacks occur only during late fall, corresponding to the collection and handling of grapes. However, in one case exertional dyspnea was present year around with the patient showing obstructive-type lung function defect, and the chest x-ray revealing interstitial pulmonary fibrosis. Standard precipitin tests are usually negative. Treatment at this stage is generally a total removal from antigenic exposure. Corticostemids are generally indicated in acute stages. CHEESE WORKER’S

DISEASE

Cheese worker’s disease is a form of hypersensitivity pneumonitis caused by the organism Penicillium roqueforti, a distinctive ingredient of blue cheese.“’ Workers who must handle the process blue cheese are constantly exposed to the antigen on the job and thus constitute the major at-risk population. Patients with cheese worker’s disease complain of cough, exertional dyspnea, headache, and general malaise. Physical examination of the chest can reveal bibasilar crackles. Symptoms usually occur 4 to 6 hours after exposure to the cheese and continue for 1 to 3 days. The most useful element in the diagnosis is a careful patient history. If exposure to P. roquefirti is discovered, diagnosis can be aided by standard precipitin tests, bmnchoalveolar lavage (BALI and chest mentgenogram studies. The BAL fluid should show T-lymphocyte predominance and subnormal amounts of alveolar macrophages. In addition, chest mentgenogram may reveal bilateral interstitial infiltration. Once the disease is detected, the most effective treatment is 4.50

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reduced or discontinued exposure to the antigen. Because the disease has been studied only recently, the prevalence in at-risk populations is uncertain. Unlike cheese washer’s disease, where control of antigenic exposure is achieved by the use of plastic wrappings, cheese worker’s disease presents a potential commercial problem to producers of blue cheese, since l? roqueforti is an essential ingredient.

CHEESE WASHER’S

DISEASE

Cheese washer’s disease is a chronic form of hypersensitivity pneumonitis caused by the inhalation of Penicillium casei, the mold that develops on the surface of cheese aged in damp cellars.z10-212 As part of the process of production, cheese workers are required to wash off the mold at intervals, thus exposing themselves to clouds of dust containing P. casei. Those who develop a hypersensitive response to this mold suffer from cough, dyspnea, mild fever, and malaise. Because of the chronic nature of the disease, symptoms are gradually manifested through continual periodic exposure to the antigen. Respiratory function measurements are usually normal or indicate a slight restrictive defect. A problem arising in diagnosis is the possibility of extrinsic asthma in the cheese washer. Sometimes both the asthma and pneumonitis can exist together. A possible differentiation between the two is found in examination of the serum, in which specific precipitating antibodies to the fungus are found in hypersensitivity pneumonitis patients, but no such antibodies are present in asthmatics. Also, the asthma patient should display wheezing suggestive of bronchial obstruction, whereas sufferers of cheese worker’s disease usually show no obstruction in the airways. In general, the illness is mild and reversible. Removal from exposure to the cheese dust will surely relieve symptoms. The chance of continuing alveolitis and pulmonary fibrosing is less than that from the chronic form of farmer’s lung. However, this is somewhat of a speculation, since no information on the general course of the disease long after removal from antigen is to be found. In the United States, over 900 million pounds of cheese are manufactured yearly. Still, there have been no documented cases of cheese worker’s disease. This is because American cheese is aged with plastic wrappings to reduce the onset of surface mold and factors such as humidity and temperature are precisely controlled.Z13 In Europe, however, the traditional process of aging cheese is still practiced in damp cellars with exposed surface of cheese allowing P. casei to form. Consequently, most cases of cheese washer’s hypersensitivity pneumonitis are reported in Europe. DMJuly1391

451

WOOD

DUST

DISEASES

Many types of hypersensitivity pneumonitis have been reported to be caused by wood dusts. Cedar, mahogany, iroko, sequoia, maple, doussie, and redwood have all been associated with intrinsic allergic alveolitis.214-217 The antigen is the mold that develops on the wood either after it has been cut and stored or during the timber processing of the living tree. In wood handling envirionments, the disease is quite frequent, especially in hot, humid areas that are conducive to the growth of molds. Some molds that may cause allergic alveolitis are listed as follows: (1) Alternaria in handlers of wood p~lp,~*~ (2) Coniosporium corticale and Cryptostroma corticale in workers who strip bark from the maple tree (coniosporosis),“,21Y-221 (3) Thuya plicata in handlers of moldy red cedar,‘““’ 223 and (4) Penicillium species in handlers of fuel chips. Of the other wood sources, no specific antigen has been isolated, yet molds or possibly microparticles of wood itself may be the etiologic source.224 Patients can be exposed to the wood in any number of ways. Occupational exposure in the paper industry, dust exposure from lumberjack work, even exposure to wood in those who work with wood as a hobby can induce the lung disease. Clinical features include cough, dyspnea, tightness of the chest, and mild sputum production. Also common are fever, chills, loss of weight, weakness, and general malaise. SyVmptoms occur in two phases with either an immediate reaction to the exposure or a delayed reaction 3 to 6 hours after exposure and last up to 1 day. Lung function abnormality includes both restrictive and obstructive impairments. Chest roentgenogram studies are generally normal; occasionally, nodular shadowing may occur. Skin tests are unhelpful. The inhalation challenge when appropriate is the best way to establish the diagnosis. Of primary importance in diagnosis is a careful history that will indicate exposure to the wood dust. Effective treatment for patients found to have wood dust disease is the removal from the environment where exposure occurs. This will usually alleviate all symptoms. It is important to emphasize the total avoidance of the antigen exposure, since even a passing exposure can induce an immediate type of reaction. For symptomatic patients, administration of prednisolone is effective. Prevention of disease can be achieved by using dryer storage bins for timber, by wearing masks during wood-related work, and by using filters in milling processes. MAPLE

BARK

STRIPPER’S

LUNG

Maple trees are used for the construction of railway sleepers and manufacturing paper. Cryptostroma corticale, a mold, germinates 452

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1991

between the wood and the bark. Inhalation of the spores of C. cortitale results in a clinical syndrome of hypersensitivity pneumonitis popularly known as maple bark strippers lung.“* “’ Emanuel et al. demonstrated granulomatous alveolitis and interstitial pneumonitis on these patients. Tewksbury et al. have produced pulmonary granulomatosis in the guinea pig by the injection or inhalation of Cryptostroma corticale spores.221

SUBEROSIS The inhalation of dust formed in the production of bottle corks, discs, and insulation sheets causes the form of hypersensitivity pneumonitis called suberosis.2253 226 The particles of cork seem small enough to enter the bronchial tract and continue to the interstitial spaces of the alveo-capillary junction. Molina reports two types of reaction: (1) a predominantly bronchial affliction with cough, anorexia, mild fever, and thoracic discomfort, and (21 an attack with symptoms of classical HP.‘14 Either stage if untreated may progress to severe respiratory insufficiency. Skin test, inhalation challenge, and precipitin tests are useful in establishing the diagnosis.

SISAL WORKER’S

LUNG

Sisal fibres, used in manufacturing threads, bags, and welcome mats, are derived from the leaves of agave from Mexico. Serum precipitins against sisal antigen are present and may be helpful in establishing the diagnosis in an individual with a positive occupational history?27

VINEYARD

SPRAYER’S LUNG

Here the pneumonitis is caused not by the inhalation of organic particles, but by inorganic copper sulphate. The copper sulphate is sprayed on grapevines by vineyard workers in order to eliminate the growth of mildew. The specific solution, known as the Bordeaux Mixture, is utilized predominantly in Italy and France. When workers spray the vines, they are exposed to vast quantities of the aerosolized Bordeaux Mixture. It is believed that molecules of copper sulphate or even quantities of copper itself enter the alveolar interstices and generate a hypersensitivity response. No actual evidence for this etiology is present. In the reported cases, pulmonary biopsy specimens have demonstrated high amounts of copper. Dyspnea is the most common symptom. The prevention of this disease requires the wearing of masks during spraying procedures.228 DM, July1991

453

NEW GUINEA

LUNG

New Guinea lung was first reported in 1966 by Blackburn and Green.zzs The population of the territory of Papua in New Guinea provides the only sufferers of the disease. It is caused by the inhalation of fungal and vegetable dusts generated from the thatched huts in which the people live. The thatches are made of grasses and dried roots. During the rainy season the thatches become damp and moldy. The patients have precipitin antibodies against fungal and vegetable matter from the huts. COFFEE WORKER’S

LUNG

In 1970, Van Toorn reported the case of a 46-year-old man who had developed dyspnea, fatigue, and listlessness for 3 months.230 A chest roentgenogram showed bilateral nodular infiltrate. Skin tests to various antigens including tuberculin and fungi and allergy panel were negative. Lung biopsy specimens showed extensive alveolitis, consisting of lymphocytes, large mononuclear cells, eosinophils, and plasma cells. Poorly formed granulomas were present, but no true noncaseating granulomata were observed. Immunofluorescent studies revealed deposition of IgG and complement along the alveolar capillaries and the alveolar basement membrane. Because the patient had worked in a coffee roasting factory for more than 20 years, serum precipitin antibodies against coffee bean dust were measured. A precipitation reaction on agar gel occurred between the serum of the patient and 1: 1 diluted extract of the coffee bean dust. Van Toorn, quite justifiably, christened the entity as “coffee workers 1ung.1231 PITUITARY

SNUFF TAKER’S

LUNG

Pituitary snuff is a finely ground mixture of the dried posterior lobes of porcine and bovine pituitary glands with an inert soluble powder, often lactose. The snuff is commonly used in the long-term management of diabetes insipidus. The prolonged intranasal insufflation of the powder may not only induce Type I or asthmatic response but also produce precipitating antibodies in the serum. Mahon et al. described three patients with diabetes insipidus, who, while being treated with posterior pituitary snuff, developed dyspnea, cough, and wheezing. The chest roentgenograms showed diffuse fine miliary infiltrates. Lung biopsy specimens revealed the striking interstitial infiltrate of lymphocytes, plasma cells, and eosinophils. Skin prick and intracutaneous tests using porcine and bovine pituitary snuff extracts produced Type I (immediate, IgE454

DM,

July

1991

dependent) and Type III (arthus-type) reactions. Serum precipitins against porcine and bovine antigens were present. The lung disease in the three patients described was due to the hypersensitivity pneumonitis caused by the pituitary snuff. In one part, the symptoms subsided when the snuff was discontinued, emphasizing the preventive aspect of the illness.232 SPOROBOLOMYCES RYPERSENSITMTY

INDUCED PNEUMONITIS

Sporobohmyces is a common yeast-like fungus found in graingrowing areas of the world. The fungal spores are less than 5 pm in size and thus small enough to cause hypersensitivity pneumonitis. Cockcroft et al. described a B-year-old horseback rider with clinical, radiographic, and physiologic abnormalities suggestive of hypersensitivity pneumonitis. Exposure to the barn had produced the clinical syndrome. Serum precipitin antibodies against Sporoboiomyces were present; however, precipitins against other fungi and horses were absent. Lymphocyte stimulation to Sporobdomyces in vitro was positive. Straw from the barn showed Sporobolomyces in culture. Cessation of exposure to the barn resulted in clinical improvement .233 Thus the diagnosis of extrinsic allergic alveolitis in this patient was amply supported by immunologic means. Since the fungus is frequently found in the cereal grain-growing communities, it may be prudent to remember it as a cause, albeit infrequent, of unexplained hypersensitivity pneumonitis. FURRIER’S

LUNG

Cortez Pimental demonstrated that prolonged inhalation of dusts containing animal hairs can produce pulmonary alveolitis and fibrosis.234 The patient described had worked as a furrier for 13 years making stoles and coats from fox and astrakhan fur. The patient complained of malaise, weakness, and weight loss. Initially, he was diagnosed to have tuberculosis, but when the antituberculosis chemotherapy produced no improvement the patient was subjected to a right lower lobe resection. The lung biopsy specimens showed noncaseating granulomata surrounded by lymphocytic infiltration. Many hair shafts were seen within the granuloma. The author was able to produce similar granulomatous reaction in the guinea pigs subjected to the inhalation of fur dusts. Thus an accurate occupational history coupled with the demonstration of a granulomatous response led to the introduction of the new term “furrier’s lung.” DM, July

1991

465

A peculiar form of hypersensitivity pneumonitis caused by Aspergillus clavatus occurs among maltworkers.235’ 236J237 Most of the cases of maltworker’s lung have been reported from Scotland.2383 23g Grant et al. reported an incidence of 5.2% in Scottish maltworkers. Moist germinating barley on the brewery floor becomes contaminated with the fungus. More modern methods of germination, however, have reduced the incidence of this type of hypersensitivity pneumonitis. PAPRIKA

SPLITTER’S

LUNG

The Turkish invaders introduced paprika to Eastern Europe in the sixteenth century. The plant became popular because of its medicinal value, and the red pepper industry became an important source of revenue. Paprika splitters, mainly women, would cut open the fruit and strip out a series of thin pale ribs, which were discarded because of their high content of capaiscin. The women inhaled spores of the mold, Mucor stolonifkr, during the splitting process and developed cough, expectoration, dyspnea, loss of weight, and sometimes hemoptysis. The lungs at autopsy showed extensive fibrosis and bronchiectasis. When the danger was recognized and attributed to paprika, the chief botanist of the Paprika Research Institute in Szeged, Hungary, cultivated a variety of plant in which the fruit had ribs containing much less of capaiscin. This obviated the need of a paprika splitter because the red pepper can be obtained by grinding the fruit whole and caused the disappearance of paprika splitter’s lung disease.240 GRAIN WEEVIL

DISEASE

Lunn and Hughes, in 1967, reported that grain handlers may develop a hypersensitivity pneumonitis if the grain is contaminated with the common weevil, Sitophilus granarius.241 Serum precipitins against the weevil are found in affected patients. If the patient is not removed from the contaminated granary, flour mill, or similar occupational exposure, the lungs become progressively fibrotic. The proper use of mask and extractor fan go a long way in preventing the disease.242 FEATHER-PICKER’S

DISEASE

Poultry workers who clean, sort, and process duck and goose feathers may develop fatigue, general malaise, nausea, headache, 456

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1991

paroxysms of cough, and dyspnea. Occasionally, fever as high as 103.0’ F may occur. The symptoms usually subside after 3 to 4 days because a certain tolerance develops. The type, extent, and histology of pulmonary lesions are not completely understood. The disease was first reported in France.243 SMALLPOX

HANDLER’S

LUNG

Smallpox handler’s lung is now only of historical interest because the pox is no longer the scourge of the human race. In days long past, however, the doctors, nurses, paramedical staff, and respiratory therapists who looked after the patients suffering from smallpox were in danger of developing a clinical syndrome characterized by fever, cough, headaches, and tightness of the chest. Physical examination revealed only scattered inspiratory rales. Fine, diffuse nodular infiltration was present on chest roentgenograms. This hypersensitivity pneumonitis was most likely due to inhalation of clouds of smallpox scabs produced during bed making, combing, or drying the patient and other such seemingly benign chores.243J 244,245 POTATO

RIDDLER’S

LUNG

Potatoes, after harvesting, are stored in pits covered with straw and hay. Before marketing, the potatoes are removed and riddled (sieved). During the process the riddler is exposed to a cloud of dust containing thermophilic actinomycetes. Greene and Bannan reported the occurrence of two cases of hypersensitvity pneumonitis following exposure to potato riddling?46 Both patients attributed their symptoms to working with potatoes. The caveat here is that an unwitting exposure to stored and decayed vegetable material may cause repeated attacks of farmer’s lung-type alveolitis and progressive lung damage. Furthermore, farmers in the potato farming areas should be made aware of the dangers of stored, moldy potatoes. ALGINATE

PULMONARY

HYPERSENSITIVITY

A&mates, derived from dry seaweed, are complex polymerized polysaccharides. These salts of alginic acid are widely used in food, textile, and pharmaceutical industries as stabilizing, thickening, and fixing agents. The process of extraction of alginate starts with milling of the dry seaweed. Chemical extraction is then carried out in a liquid phase, until the salts are dried, milled, and collected. Thus the workers are exposed first to dust clouds during the unloading, milling, and collection of the purified alginate salts. Henderson and colleagues found evidence of pulmonary hypersensitivity to seaweed m4,

July

1991

457

dust in 7% of the total workforce, and evidence of precipitating antibody to sodium alginate and seaweed extracts in the serum of 4.5% of the employees. Inhalation challenge in symptomatic individuals showed a dual response with immediate airways obstruction, and a delayed loss of lung volume and diffusing capacity. However, none of the affected workers showed radiographic evidence of allergic alveolitis-indicating, perhaps, the existence of mild disease. BERYLLIOSIS Beryllium-because of its two extremely useful properties, lightness, and tensile strength-is extensively used in alloys, certain plastics, ceramics, rocket fuels, and as a “window” in x-ray tubes. It is, however, highly toxic. Inhalation of beryllium produces two types of lung disease. Acute berylliosis and chronic granulomatous pneumonitis. It is the latter that resembles hypersensitivity pneumonitis. Symptoms are slow to manifest and include dyspnea on exertion, cough, weight loss, fatigue, anorexia, and weakness. Clubbing of the fingers may be present. Chest roentgenograms show diffuse fine miliary or granular infiltrate. Hilar adenopathy alone is uncommon. The lung function tests show a restrictive type of impairment. In severe cases, pulmonary hypertension may appear late in the course of the disease .248 Recent studies indicate that cell-mediated immune mechanisms are involved in the pathogenesis of chronic berylliosis. Many of the immunologic changes are similar to those observed in hypersensitivity pneumonitis .24g,250 Beryllium, the specific class II restricted antigen, stimulates local proliferation and accumulation of berylliumspecific CD4 helper-inducer T-cells in the lung. These CD4+ T-cells are primed to recognize beryllium specifically and to proliferate through interleukind pathway onward to granuloma formation and fibrosis.251 Recently introduced laser microprobe mass spectrophotometry NAMMS) detects even low concentrations of beryllium and has been proved invaluable in identifying the element in granulomas. In an extensive study, beryllium was detected in the granulomas of patients with chronic beryllium disease (CBD) but not in those with sarcoidosis and other granulomatous disorders.252 HARD METAL

PNEUMOCONIOSIS

Hard metal disease was first reported by Jobs and Balhausen in 1940.253 However, Demedts et al. confirmed that cobalt was the cause of the distinctive pneumoconiosis observed in diamond polishers.Z54 There are three types of lung involvement that result from 468

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inhalation of “hard metal” dust: hard metal asthma, hypersensitivity pneumonitis, and chronic interstitial fibrosis. Reversible interstitial pneumonitis similar to hypersensitivity pneumonitis has been attributed to cobalt inhalation. The diagnosis is established by a positive occupational history of exposure, and bronchoalveolar lavage or lung biopsy that reveals characteristic multinucleated giant cells. There are significant changes by specific inhalation provocation tests to cobalt or by lung function measurements at the place of work.255’ 256 RADIATION

PNEUMONITIS

Radiation pneumonitis occurs within 3 months after thoracic irradiation, and it is generally regarded to be direct radiation-inhaled lung injury. Investigators in Sydney, however, surmise that the cause of lung damage is more likely to be an immunologically-mediated hypersensitivity pneumonitis. Four patients who developed pneumonitis after unilateral thoracic irradiation for carcinoma of breast were studied with bronchoalveolar lavage, gallium scan of the lung, and respiratory function tests. On the irradiation side of the chest, all four patients showed an increase in total cells recovered and marked lymphocytosis in both relative and absolute terms. However, surprisingly, a similar prominent lymphocytosis was noted in the lavage fluid obtained from the non-irradiated lung. Likewise, gallium scan showed increased uptake in both irradiated and nonirradiated lungs, providing further evidence that the changes extended well outside the irradiated area.257 PULMONARY DRUG-INDUCED GRANULOMATOUS PNEUMONITIS Aspiration of mineral oil can induce granulomatous pulmonary reaction, which may be similar to that of hypersensitivity pneumonitis. Diagnosis depends on lung biopsy, which shows fat-laden alveolar macrophages. History of chronic use of nasal drops containing paraffin or other types of oily aerosolized material is essential. Corticosteroids are the drug of choice.258, 25sSX’ “Talc granulomatosis” or intravenous talcosis is a granulomatous lung disease caused by injection of drugs that are intended for oral use. The particulate fillers in such drugs may lead to either a granulomatous interstitial reaction or granulomatous vasculitis.261-263 Methotrexate, phenylbutazone, potassium iodide and carbamazepine can produce diffuse parenchymd changes similar to hypersensitivity pneumonitis.264-26” At present, the number of drugs that cause granulomatous inflammation of the lungs is small. In the future, many more pharmaceutical m4,

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agents and chemicals will be added to this list. It is important that these drug-induced granulomatous syndromes not be confused with hypersensitivity pneumonitis and other granulomatous disorders.““’ REFERENCES

1. Ramazzini B: De Morbis Art$cium Diatriba, 1913. Chicago, University of Chicago Press, 1940. 2. Campbell JA: Acute symptoms following work with hay. Br Med J 1932; 2:1143- 1144. 3. Fawcitt R: Fungoid conditions of lungs. Br J Radial 1936; 9:172-195. 4. Towey JW, Sweaney HC, Huron WH: Severe bronchial asthma apparently due to fungus spores found in maple bark. JAM4 1932; 99:453-459. 5. Tornell E: Thresher’s lung: fungoid disease resembling tuberculosis OI Morbus Schaumann. Acta Med Stand 1946; 125:191- 219. 6. Pepys J, Riddell RW, Citron KM et al: Precipitins against extracts of hay and moulds in the serum of patients with farmer’s lung, aspergillosis, asthma, and sarcoidosis. Th0ra.x 1962; 17:366-374. 7. Jamison SG, Hopkins J: Bagassosis: a fungus disease of the lung. N Ore Med Surg J 1941; 93:580-582. 8. Bringhurst LS, Byrne PN, Gershon-Cohen J: Respiratory disease of mushroom workers. JAMA 1959; 171:X-18. 9. Pearsall HR, Morgan EH, Teslu H et al: Parakeet dander pneumonitis: acute psittaco-kerato-pneumonconiosis. Bull Mason Clin 1960; 14:127- 137. 10. Plessner MM: Une maladie des trieur de plumes: la fierre de canard. Arch Ma1 Praf

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11. Hapke EJ, Seal RME, Thomas GO: Farmer’s lung. Thor= 12. Peppy J: Hypersensitivity disease of the lungs due to dusts. Monogr Allergy 4, Karger, Basel, 1969. 13. Sharma OP: Hypersensitivity lung disease: a clinical Basel, 1990. 14. Richerson HB: Hypersensitivity pneumonitis: pathology Clin

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18. Christensen LT, Schmidt CD, Robbins L: Pigeon breeder’s disease-a prevalence study and review. Clin Allergy 1975; 5:417-422. 19. Allen D, Barten A, Williams G, et al: Familial hypersensitivity pneumonitis. Am

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21. Rittner C, Sennekamp J, Vogel F: HLA B-8 in pigeon fancier’s lung. Lancet 1975; 2:1303- 1306. 22. Moore VL, Hensley GT, Fink JN: An animal model of hypersensitivity pneumonitis in the rabbit. J Clin lnvest 1975; 56:937-944. 23. Allen DH, Barten A, Williams GV, et al: Familial hypersensitivity pneumonitis. Am J Med 1975; 59505. 460

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