Hypersensitivity pneumonias

Hypersensitivity

Pneumonias

Paul J. Friedman

HEN A PATIENT presents acutely with “pneumonia, ” it is important to ask the clinician if the inflammatory process could be caused by allergy or hypersensitivity. Several clues should be sought, some radiologic, most clinical. A history of respiratory allergy should alert you to the possibility of a flareup of a chronic disease, especially if there have been previous similar episodes. A history of taking a new drug is a tipoff, particularly if it is a common offender, such as furadantin, penicillin, sulfa derivatives, or gold. Exposure to organic dust or fungal spores is an important lead, especially if a heavy dose was inhaled 4 to 6 hours before symptoms started. A concurrent skin reaction, varying from an erythematous rash to exfoliative dermatitis, is a valuable clue to allergy. Finally, the presence of eosinophilia-from 6% to as high as 50%-is a strong indication that a hypersensitivity reaction is taking place.” Let us deal with drug reactions first. Note that I am considering true allergic reactions, with the drug molecule probably acting as a hapten, not with drug toxicity, which is dependent mainly on dose (such as with bleomycin). The typical clinical picture includes fever and shortness of breath or cough, hardly distinguishable from pulmonary infection. Eosinophilia is common. The radiograph depicts either signs of interstitial edema (septal lines and fuzzy vessels), hazy patches of alveolar filling, or dense irregular infiltrates, especially in the lung periphery (Fig. 1). A small pleural effusion is frequent. Nodular or mass lesions may occur with granulomatous vasculitis, most commonly associated with sulfa drugs. Asthmatic symptoms occur with several drugs (notably aspirin), and a lupus-like syndrome results from many different agents (25 on one recent list). Some drug reactions are insidious, but these are not the subject of this discussion. Many develop hours to days after starting a drug, and clear on its withdrawal; relief of symptoms is usually accelerated by administration of corticosteroids.73’0.14 The pathologic effects of these drug reactions may include edema, proteinaceous exudate and

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Seminars in Roentgenology,

Vol. XV, No. 1 (January),

1980

replacement of alveolar lining cells secondary to alveolar damage, interstitial pneumonia, eosinophilic pneumonia, or pulmonary vasculitis. Transfusion reactions, also the result of antigenantibody combination, nowadays more commonly related to leukocyte than to red cell incompatibility, typically result in pulmonary edema, interstitial or diffusely patchy, with radiologic findings similar to those discussed above.” Other pulmonary infiltrates accompanied by eosinophilia vary in the acuteness of their presentation. Eosinophilic pneumonia, the most common of the syndromes in this category, usually presents as a progressive chronic disease. Cases with acute or recurrent onset simulate acute pneumonia clinically, but often provide good radiologic and laboratory clues to their correct nature. The histology of eosinophilic pneumonia consists primarily of an interstitial reaction of lymphocytes and mononuclear cells enriched by numerous eosinophils in the alveolar spaces. To this may be added vasculitis, with small vessel damage and leakage of fluid and cells into the alveoli, and bronchiolitis, with partial or complete occlusion of airways, sometimes extending sufficiently far proximally as to cause subsegmental atelectasis. If you think about the resultant radiographic changes, you can see that a large variety may result. The minimal radiographic finding with an eosinophilic lung reaction is a nonspecific accentuation of normal markings, particularly peripheral small vessels, recalling the possibility of an acute drug allergy. Characteristic findings of eosinophilic pneumonia include hazy alveolar filling, most typical in the periphery of the lung, extending to the pleural surface, bands of atelectasis, and a tendency to change before treatment Paul J. Friedman, M.D.: Professor of Radiology, University of California Medical Center, Department of Radiology, San Diego, Ca. Reprint requests should be addressed to Paul J. Friedman, M.D.. University of California Medical Center, University Hospital, Department of Radiology, 225 Dickinson Street, San Diego, CA 92103. 0 1980 by Grune & Stratton, Inc. 0037-I 98X/80/1501M009$02.00/0

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Probably pulmonary reaction to gold Fig. 1. therapy. This 6%year-old woman had chronic rheumatoid arthritis with progressive shortness of breath and nonproductive cough. (Al Extensive upper lobe in6ltration and volume loss. with stringy infiltrates in the lower lobes. A chest film was normal two weeks before. History of a recant series of gold injections. followed by a generalized dasquamativa rash that resolved with one paranterel dose of steroids: subsequent onset of respiratory symptoms. IB) Almost complete clearing of radiographic findings, after 6 days of daily steroid administration, with marked resolution of symptoms.

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Fig. 2. Eosinophilic pneumonia. A U-yearold woman with anorexia and productive cough. The film shows bilateral alveolar infiltration, changed in distribution from admission 3 weeks earlier. There was a history of chronic sinusitis but no known allergies. The WBC was 14,600, with 41% eosinophils. Eosinophilic pneumonia was shown on lung biopsy. The hazy peripheral left basal infiltrate is characteristic of eosinophilic pneumonia. The right upper lobe changes are less specific but also common in this syndrome. Lung biopsy showed airspace filling and interstitial thickening with abundant clusters of eosinophils.

is given (Figs. 2 and 3). The term Loefler pneumonia may be given properly to such cases when the symptoms are mild, the infiltrates of recent onset and shifting, and the eosinophilia easy to document. One of the radiographic manifestations that should lead directly to a suspicion of eosinophilic pneumonia is the so-called reverse butterfly configuration: a typically symmetric peripheral alveolar process of the upper lobes (Fig. 4). Hilar lymph node enlargement is usually absent or minimal, but striking exceptions have been seen. A small pleural effusion may be present.4 It is not unusual for these pneumonias to begin to regress as soon as a patient is hospitalized, before treatment is instituted; this is presumably due to isolation of the patient from the offending extrinsic antigen. In other cases, there is no improvement until steroid treatment is begun, and then the response is dramatic. Diagnosis is difficult in a significant proportion of patients with these pathologic and radiologic findings who fail to show peripheral eosinophilia.

When there is a considerable component of either vasculitis or bronchiolitis, the hazy peripheral infiltrates of uncomplicated eosinophilic pneumonia appear as multifocal dense shadows that may be irregular in outline (Fig. 5). Consolidation may progress to the lobar level, giving a radiographic appearance indistinguishable from that of pulmonary infection, reminiscent of the acute pneumonia with autoimmune vasculitis that occurs in systemic lupus erythematosus. Vasculitis complicating asthma may be due to the Churg-Strauss syndrome (allergic granulomatosis and angiitis)’ or less often to periarteritis nodosa. In either case, the systemic vasculitis and eosinophilia may occasionally be accompanied by pulmonary infiltrates (Fig. 6). Another important clinicopathologic category must be mentioned. This is the so-called microgranulomatous reaction. In the context of allergic lung disease, small collections of mononuclear cells, lymphocytes, plasma cells, and often giant cells are found in nodules that are smaller and less well formed than those of sarcoidosis or

PAUL J. FRIEDMAN

Fig. 3. Eosinophilic pneumonia in a 69-yearold woman with fever and cough for two weeks and rheumatoid arthritis for many years. The WBC was 16.669 with 6% eosinophils. Sputum cultures were negative. (A) Note the upper lobe confluent infiltrates, probable small left pleural effusion, and questionable hilar adenopathy. This radiographic pattern is not diagnostic, but hypersensitivity should be considered with upper lobe infiltration of this type when tuberculosis is excluded. Note also Fig. 1. The patient was treated with antibiotics without improvement. (B) Lung biopsy showed eosinophilic pneumonia. with some chronic elements. The most striking findings are septal thickening and fibrosis. Interstitial and airspace involvement are seen. Eosinophils are common but not abundant. Granulomatous nodularity is not present. Elastic tissue stain. Original magnification 39x. Bronchiolitis obliterans was noted on other sections.

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Fig. 4. (A) A M-year-old woman with the characteristic appearance of eosinophilic pneumonia in the left upper lobe, and mottled infiltration on the right. (6) This closeup shows the “reversed pulmonary edema” configuration, similar to that shown in the left lower lobe in Fig. 2. Small bilateral pleural effusions and minimal hilar lymph node enlargement are also shown.

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Fig. 5. Shaggy. somewhat nodular infiltrates in a 55-year-old woman with fever. shortness of breath, and slight wheezing, but no cough. She had a history of mild chronic asthma; the acute symptoms were related to exposure to blooming filbert trees. Biopsy showed probable nongranulomatous hypersensitivity pneumonia with mononuclear cells, plasma cells, eosinophils. bronchiolitis obliterans, and focal necrotizing angiitis.

tuberculosis, and usually not accompanied by tissue eosinophils. These microgranulomas are seen in extrinsic allergic alveolitis, the typical lung reaction to sensitizing organic dusts or fungal spores. The most common entity in this group is “farmer’s lung,” a reaction to fungal spores from moldy hay. Clinically important antigens are also found in bird feathers or droppings, coffee beans, and fungi from cork dust, sawdust or wood pulp, barley or malt, and air conditioner or humidifier condensate. Blood eosinophilia is not a feature of extrinsic allergic alveolitis. The condition appears to result from a combination of Type III and Type IV hypersensitivity reactions. Though most casesare clearly related to chronic exposure and sensitization, some patients have acute symptoms, particularly after a heavy inhalation exposure.2*329* Radiologically, the acute form of these hypersensitivity pneumonias is varied. In some patients, the pattern is that of a mild nonspecific interstitial edema. A more specific pattern is a hazy or slightly granular clouding of the lower lung fields (Fig. 7). Curiously enough, the progressive changes in farmer’s lung typically involve the upper lung zones,just as in sarcoido-

sis, which they resemble. With acute exacerbation of a chronic exposure, alveolar filling is superimposed on scarring or atelectasis. Since bronchiectasis may result from chronic exposure, particularly in occupational cases, the combined changes may be confusing indeed.‘,” I haven’t said much about aspergillus yet, saving this ubiquitous antigen for last. Best known is the syndrome of allergic bronchopulmonary aspergillosis (ABPA), in which an asthmatic patient harbors this fungus in the bronchial tree, reacting intermittently with a flareup of eosinophilic pneumonia. We are not concerned here with the technicality of whether the diagnosis requires a positive skin test as well as the demonstration of precipitins, but rather with radiologic clues to the diagnosis. The acute episodesmay cause the symptoms of acute pneumonia, or may be evident only on the radiograph. The pneumonia is not typically peripheral, as with other eosinophilic pneumonias, but often shows multiple, patchy, dense alveolar shadows (Fig. 8). This may be superimposedon a nonspecific background of fine scarring, residual from previous episodes. A much more helpful pattern is that of mucoid

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Allergic granulomatosis and angiitis Fig. 6. (Churg-Strauss syndrome). A 26-year-old woman with fever, cough, and rash. The WBC was 14,900 with 27% eosinophils: proteinuria 3+. (A) Note the patchy bilateral infiltrates and hilar adenopathy. The findings had progressed for 5 days on antibiotic treatment. (B) After 6 days of corticosteroid therapy, considerable clearing of all findings has occurred. Biopsy of the skin showed vasculitis; transbronchial biopsy showed eosinophilic peribronchial infiltration.

PAUL J. FRIEDMAN

Fig. 7. This is the most characteristic radiographic appearance of extrinsic allergic alveolitis, with either acute or insidious onset, as in bird fancier’s or air conditioner lung. Chronic or recurrent exposure leads to fibrosis, which is not evident here. This 46year-old man had slowly progressive shortness of breath for 4 years: p0, at rest was 48. and pulmonary function tests showed restriction. A lung biopsy revealed the findings of microgranulomatous hypersensitivity, with considerable bronchiolitis and peripheral obstructive pneumonia.

impaction. Though many patients with this syndrome do not have radiologically manifest mucoid impaction, it is well worth looking for this in any acute pneumonia, especially in a known asthmatic. Cylindrical shadows, ranging from the size of normal bronchi to about 2 cm in diameter, produced by mucus in dilated bronchi, may be seen. As is well known, a smooth oval outline or a branched configuration is characteristic. Equally important signs are the thickened walls of bronchi that have been the site of previous impactions; these may appear as central bronchiectasis or as cystic structures without obvious bronchial connection. These may contain air-fluid levels during flareups.8S’2 Bronchocentric granulomatosis is a related syndrome in which necrotizing bronchitis occurs. This condition seems to complicate fungal hypersensitivity in asthmatics, but its cause is obscure in nonasthmatics. Radiographic findings include those of ABPA, as well as mass-like shadows,suggestiveof a vasculitis, as in Wegener’s granulomatosis.6 Aspergillus may also cause eosinophilic pneu-

monia of the usual type; it may also be responsible for microgranulomatous extrinsic allergic pneumonitis (Fig. 9). The variability of clinical manifestations caused by a single microbial agent is not unique to aspergillus. It is well documented that a single antigen, such as an occupationally inhaled organic dust, may cause manifestations ranging from asthma to bronchiolitis to chronic bronchiectasis. Reviewing these manifestations of allergy, there are several radiographic patterns that recur, regardless of etiology. One is peripheral hazy alveolar filling. Another is coarse atelectasis, often transitory. Multiple patchy densities, either hazy or dense and irregular, are usually allergic in nature, since both airway and vascular lesions produce such patterns. Mucoid impaction and bronchiectasis are often associated with allergic reactions. Recurrent infiltrates, either in the same or a different location, strongly suggest hypersensitivity. Noncardiogenie pulmonary edema may also have an allergic basis.

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Fig. 8. Allergic bronchopulmonary aspergillosis. This 48-year-woman had shortness of breath, fever and productive cough. She had had asthmatic symptoms for only about 2 months. Workup for tuberculosis was negative. This was one of many hospitalizations for recurrent symptoms that always improved after a few days, without specific treatment. (A) Note the band of infiltrate and atelectasis in the left upper lobe, the left apical density, and the ill-defined shaggy hilar structures. (6) Four years later, another of a long series of films with varying abnormalities. This film shows shaggy shadows centrally and peripherally. The left apical density has cleared to reveal bronchiectasis. Representative laboratory studies revealed a WBC of 17,SCMJ with 4% eosinophils. Two years later, hypersensitivity to aspergillus was sought and found.

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Fig. 9. Recurrent granulomatous allergic pneumonia probably caused by documented hypersensitivity to aspergilIus. (A) Soft patchy infiltrates in en acutely ill 64-year-old man with chills, fever, malaise, and myalgia. He had attacks like this since age 16. the last 4 years ago. In the pest, antibiotic treatment brought about slow resolution each time. On the present admission he had daily fever to as high as 105”. though his WBC was 9366. He gradually improved without specific therapy. fB) Photomicrograph from lung biopsy. Note the patchy distribution of pulmonary infiltrate, without edema or interstitial pneumonia. High power view showed microgranulomatous infiltration. Giemsa stain. Original magnification 63x. (Cl Detail of the inflammatory infiltration centered on a small airway. Grenulomatous infiltrate and organizing exudate. Hematoxylin and eosin stein. Original magnification 167 X.

It is clear, therefore, that the radiologist’s role is to raise the suspicion of an allergic background for an acute pneumonia; in a few instances it may even be possible to suggest a specific cause.

ACKNOWLEDGEMENT The Averill A. Liebow Pulmonary Pathology Collection is supported in part by the Division of Lung Diseases, NHLBI, National Institutes of Health.

REFERENCES 1. Chumbley LE, Harrison EG Jr, DeRemee RA: Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc 52:477484,197l 2. Fink JN, Banaszak EF, Baroriak JJ, et al: Interstitial

lung disease due to contamination of forced air systems. Ann Intern Med 84:406-413, 1976 3. Fraser RC, Pari JAP: Extrinsic allergic alveolitis. Semin Roentgen01 10:31-42, 1975 4. Gaensler EA, Carrington CB: Peripheral opacities in

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chronic eosinophilic pneumonia. The photographic negative of pulmonary edema. Am J Roentgen01 128: l-l 3, 1977 5. Hargreave F, Hinson KF, Reid L, et al: The radiological appearance of allergic alveoiitis due to bird sensitivity (bird fancier’s lung). Clin Radio1 23:1-10, 1972 6. Katzenstein A-L, Liebow AA, Friedman PJ: Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 111:497-537, 1975 7. Larsson S, Cronberg S, Denneberg T, et al: Pulmonary reaction to nitrofurantoin. Stand J Respir Dis 54:103-l 10, 1973 8. McCarthy DS, Simon G, Hargreave FE: The radiological appearances in allergic broncho-pulmonary aspergillosis. Clin Radio1 21:366-375, 1970 9. Pepys J, Simon G: Asthma, pulmonary eosinophilia, and allergic alveolitis. Med Clin North Am 57:573-591, 1973

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10. Rosenow EC III: The spectrum of drug-induced pulmonary disease. Ann Intern Med 77:977-991, 1972 1 I. Schleuter DP: Response of the lung to inhaled antigens. Am J Med 57: 4766492, 1974 12. Simon G: Type I immunologic reactions in the lung. Semin Roentgen01 10:2 l-29, 1975 13. Unger GF, Scanlon GT, Fink JN, et al: A radiologic approach to hypersensitivity pneumonias. Radio1 Clin North Am 11:339-356,1973 14. Winterbauer RH, Wilske KR, Wheelis RF: Diffuse pulmonary injury associated with gold treatment. N Engl J Med 294:919-921, 1976 15. Wolf CFW, Canale VC: Fatal pulmonary hypersensitivity reaction to HL-A incompatible blood transfusion: report of a case and review of the literature. Transfusion 16:135-140, 1976