Chronic eosinophilic pneumonia followed by polyarteritis nodosa complicating the course of bronchial asthma Report of a case Frederick Philadelphia,
C. Cogen, M.D., Robert L. Mayock,
M.D., and Burton
Zweiman,
M.D.
Pa.
The syndrome of pulmonary infiltrates with eosinophilia (PIE) occurs rarely in the asthmatic patient. An unusual case is presented in which progressive bronchoconstriction and exaggerated blood eosinophilia preceded the recognition of two seemingly unrelated diseases, each of which can independently result in hypereosinophilia and the PIE syndrome. In the male patient studied, the jrst illness, biopsy-proved chronic eosinophilic pneumonia, was responsive to corticosteroid therapy. Four uneventful years later, polyarteritis nodosa with eventual pulmonary involvement developed. A careful search for specific underlying pulmonary and systemic diseuse is in order when hypereosinophilia occurs in the clinically unstable asthmatic patient
The clinical syndrome of pulmonary infiltrates with a prominent blood eosinophilia (PIE) may infrequently be superimposed upon a pre-existing asthmatic condition resulting in increased bronchospasm, pulmonary function deterioration, and hypereosinophilia.’ Diagnostic considerations in such circumstances include unusual disorders of presumed varied pathogenesis such as: (1) bronchopulmonary aspergillosis, (2) chronic eosionophilic pneumonia, (3) parasitic infestation, (4) drug or toxin exposure, or (5) one of the several presentations of systemic vasculitis.’ We have followed the clinical course of a patient with long-standing asthma who sequentially manifested discreet episodes of chronic eosinophilic pneumonia and then polyarteritis nodosa. These two occurrences were separated by a 4-yr period of relatively stable health. This association has not been previously reported. The description of this clinical -__ From the Sections of Allergy and Clinical Immunology and Pulmo-
nary Diseases,Departmentof Medicine, Hospital of the University of Pennsylvania. Supported in part by National Institutes of Health Grant No. 1 T32 AI 07031-01. Received for publication June 10, 1977. Accepted for publication Sept. 15, 1977. Reprint requests to: Dr. Frederick C. Cogen, Allergy and Clinical Immunology Section, 512 Johnson Pavilion, 36th and Hamilton Walk, Philadelphia, Pa. 19174.
picture and discussion of the possible interrelationships involved comprise the basis of this report. CASEREPORT A 47-yr-old male carpenter had a long-standing history of seasonal allergic rhinitis and extrinsic asthma beginning at age 13. At approximately age 20, the asthma became perennial with both extrinsic and intrinsic components; however, the bronchospasm was mild and well controlled with various bronchodilators. The patient was admitted for the first time to the Hospital of the University of Pennsylvania in 1972 with a 7-wk history of fevers, a progressive cough, wheezing, and dyspnea. There was no history to suggest recent drug reaction, parasitic infection, or relevant occupational exposures. Diffuse wheezing and rales were detected on physical examinations. Blood leukocyte levels ranges from 10,000 to 14,000 with an eosinophilia of from 17% to 22%. A chest roentgenogram showed new infiltrates in both the right upper and lower lobes with a predominantly peripheral distribution in the right upper lobe infiltrate (Fig. 1). Pulmonary function studies revealed an obstructive and restrictive pattern. Arterial blood gas analyses showed a PO, of 58, Pco2 of 43, and a pH of 7.47. Sputum cultures were negative for acid-fast bacilli, fungi, and bacterial pathogens and contained multiple eosinophils without fungal elements. Pathologic sections from open lung biopsy were consistent with a diagnosis of chronic eosinophilic pneumonia without evidence of vasculitis (Fig. 2). Prednisone, 60 mg daily, was added to the bronchodilator regimen. Within 3 days, there was impressive Vol. 60, No. 6, pp. 377-382
378
Cogen, Mayock,
and Zweiman
FIG. 1. Chest film. Chronic eosinophilic pneumonia; right upper and right lower infiltrates with peripheral distribution of right upper lobe infiltrate.
improvement in both pulmonary symptomatology and the chest roentgenogmm appearance. He was eventually discharged and was given xanthine bronchodilators and tapering doses of steroids. Follow-up chest roentgenogram 4 wk later was completely normal (Fig. 3). Allergy evaluation in September, 1973, showed multiple positive skin tests and hyposensitization with clinically relevant pollens, mold, and dust was started. He remained improved on little or no steroid treatment from this time with differential leukocyte counts showing no eosinophilia. In January, 1976, the asthma inexplicably worsened. Small doses of prednisone, and later nebulized beclomethasome therapy, were added; however, he continued to experience progressive cough, wheezing, and dyspnea over a 4-mo period. Chest films continued to show no parencymal abnormalities, with an unchanging picture since discharge from his previous hospitalization. When the asthmatic symptoms did not improve after prednisone was increased to 60 mg/day for 1 wk, he was admitted for the second time to the Hospital of the University of Pennsylvania. Additional past medical history included a prior urticarial reaction to penicillin. His family history was negative for atopy. He denied cigarettes, alcohol, illicit drug abuse, or exposure to toxins. No history of liver disease or blood transfusion was elicited. A diagnosis of chronic undifferentiated schizophrenia had been made in 1972, but the patient remained functional in both work and social relationships. On physical examination, he was anxious and in moderate respiratory distress. Blood pressure was 120/85
J. ALLERGY
CLIN. IMMUNOL. DECEMBER 1977
without paradox, temperature was 98”, pulse was 90, respiration was 24. Examination of the eyes, ears, nose and throat and funduscopic examination were unremarkable. The lungs showed diffuse wheezes and rhonchi. Cardiac, abdominal and neurologic examinations were normal. Laboratory studies included a hemoglobin of 17.2, white blood cell count of 13,300 with 8% eosinophils, and total eosinophil count of 2,963. Urinalysis on several occasions showed no abnormalities. Blood urea nitrogen, glucose, calcium phosphate, uric acid, bilirubin, amylase, creatine phosphokinase, serologic test for syphilis, and electrocardiogram were all normal. Chest roentgenogram on admission was normal. A skin test with 5 U of purified protein derivative and sputum cultures for acid-fast bacilli and fungi were negative. Mild elevations in serum lactic dehydroginase and serum glutamic oxaloactate transaminase were noted, but hepatitis-associated antigen was absent and bilirubin and alkaline phosphatase were normal. Antinuclear antibodies and cryoglobulins were not detected. Serum levels of total hemolytic complement activity, C3 and Cq, were all mildly elevated. The patient was treated for refractory asthma with intravenous aminophylline and 30 mg of daily prednisone. Despite this dose of steroid, he continued to wheeze significantly. By the ninth hospital day, nocturnal fever occurred; a sedimentation rate of 54 and an eosinophil count of 25% of 15,600 total white blood cell count were noted. He complained of sudden unilateral amblyopia, but an opthalmologist found no objective sign of disease. On the eleventh day, the asthma was improved but he complained of numbness in one hand. A consulting neurologist could find no evidence of central or peripheral nervous system disease. The patient then complained of migratory dysesthesia, motor weakness, and vague abdominal pains. On the eighteenth day, electromyographic and nerve conduction velocity (NCV) studies revealed a mild axonal polyneuropathy; and a repeat opthalmologic examination now detected two infarcts in the right retina. A progressive mononeuritis multiplex developed with bilateral foot drop and severe dysfunction of the left median nerve. Marked elevation of the sedimentation rate and total eosinophil count persisted despite 40 mg prednisone daily. Blood pressure and renal studies remained normal. Quadriceps muscle and sural nerve biopsies confirmed the clinical impression of systemic vasculitis (Fig. 4). Because of evidence of progressive disease by the thirty-seventh hospital day, steroid dosage was increased to 100 mg of methyl prednisolone given intravenously daily. The neurologic symptoms subsequently stabilized and wheezing ceased. The chest film remained normal and the sedimentation rate and eosinophil count returned toward normal. However, on the fifty-fifth hospital day, a new fluffy irregular infiltrate was noted in the left upper lobe; this infiltrate gradually disappeared over several days. Because of progression of the neuropathy by the sixtyfifth day, cyclophosphamide was added and prednisone was reduced to 80 mg daily. One week later, the development of pneumocystis carinii pneumonia, proved by bronchial brushings, prompted the discontinuation of cyclophos-
VOLUME NUMBER
60 6
Eosinophilic
FIG. 2. Lung biopsy, 1972. Alveoli are filled with an exudate rophages, and eosinophils. Extensive infiltration of eosinophils eosinophilic pneumonia complicating asthma. (x320.)
further reduction of steroid dosage, and the addition of trimethoprlm-sulfamethoxazole. The pneumo-
phamide,
cystis pneumonia nerve conduction
responded. By the eightieth day repeat studies indicated some healing of the
neuropathy and the patient slowly began to regain function in various extremities. Steroid treatment was gradually transferred to an alternate-day dose program with subsequent slou reduction
of dosage.
Motor and sensory function slowly improved, with the patient gradually increasing activity to the point at which he currently returned
walks up to 5 miles a day. Asthmatic symptoms when the prednisone dose was reduced below a
level of 15 mg every other day. However, there has beenno recurrence of pulmonary infiltrates, eosinophilia, or new neurologic signs. Asthmatic symptomshave beenrelatively well csontrolledby increasing the aminophylline dosage. DISCUSSION Mild peripheral eosinophilia is a hallmark of bronchial asthma, occurring in both the extrinsic and the intrinsic forms. Total eosinophil counts ranged from 300 to 1,2OO/cu mm in a recent study of a series of intrinsic asthmatic patients.” The terms pulmonary eosinophilia, eosinophilic infiltration of the lung, or PIE may all conveniently be used to refer to bronchopulmonary changes resulting in transient and variable radiographic shadows accompanied by blood eosinophilia. The lung changes and the blood eosinophilia are thought to be related.4* I3 In the case reported here, episodic deterioration in pulmonary status with increasing cough, wheezing, and dyspnea
pneumonia
followed
by polyarteritis
nodosa
379
of desquamative alveolar lining cells, macpopulating interstitial areas, consistent with
was accompanied by pronounced hypereosinophilia on two separate occasions separated by four relatively uneventful years. The first admission was prompted by increased bronchoconstriction accompanied by pulmonary and constitutional symptoms and x-ray evidence of consolidation. Clinical and radiographic improvement followed corticosteroid therapy. For the next 4 yr the patient remained relatively well. A progressive worsening of asthmatic symptoms preceded the second admission. It is conceivable that this increasing asthma over a 5-mo period was the first manifestation of a systemic vasculitis; unfortunately, no histologic study of the lung tissue was carried out at this time. During the subsequent hospitalization the appearance of striking blood eosinophilia despite treatment with large parenteral doses of various corticosteroids alerted his physicians to the possibility of serious underlying disease complicating the asthma. The severe bronchospasm, fever, constitutional symptoms, abdominal pain, retinal infarction, and progressing mononeuritis multiplex with confirmatory biopsy evidence of vasculitis pointed to the diagnosis of polyarteritis nodosa. The pulmonary infiltrates appeared rather suddenly several weeks after the patient developed overt neuropathy, and just as mysteriously disappeared several days later without change in clinical status or therapy. At present, there is little clinical evidence of active vasculitis although asthma is still present. In 1952, Croften and associates5 classified pulmo-
380
Cogen, Mayock,
FIG. 3. Chest film chronic eosinophilic
J. ALLERGY
and Zweiman
4 wk after initiation pneumonia.
of steroids
for
nary eosinophilic syndromes. They commented on a peculiar group of patients, most of them asthmatic, who presented with signs of general toxicity, wheezing, and blood eosinophilia. Interesting infiltrates noted on chest roentgenograms were described as “clouds of smoke rising after an explosion in the region of the hilum and drifting up against the chest wall peripherally. ” In 1969, Carrington and colleagues6 identified a distinctive syndrome which they called chronic eosinophilic pneumonia. Nine young and middle-aged women presented with dyspnea, high fever, night sweats, and weight loss and were frequently initially diagnosed as having pulmonary tuberculosis. Chest roentgenograms revealed pneumonic infiltrates in a peculiar peripheral pattern simulating a “photographic negative of the acute pulmonary edema pattern.” Lung biopsies showed leukocytic-predominantly eosinophilic-exudation into alveolar and interstitial spaces. Multinucleated histiocytic giant cells, some of which contained Charot-Leyden crystals, were also present in the affected alveoli. Frank vasculitis was not found. A recent retrospective review by Gaensler and Canington indicates a high correlation of characteristic radiographic features with biopsy-proved cases of chronic eosinophilic pneumonia. Yet, lung biopsy was necessary to confirm the diagnosis in approximately one quarter of cases.
CLIN. IMMUNOL. DECEMBER 1977
Rapid and dramatic improvement in clinical status, associated clearing in chest roentgenograms, and improvement in pulmonary function abnormalities occurs routinely after initiation of corticosteroid therapy in chronic eosinophilic pneumonia.6, 8 These observations have prompted the suggestion that a therapeutic trial of steroids may serve as an additional aid. Our patient’s rapid clinical improvement during the first admission is quite consistent with past experiences in chronic eosinophilic pneumonia. A background of atopy is common in these patients. Six of the 9 patients in the original series by Canington and associate@ were atopic. Five of them had allergic rhinitis and 6 developed asthma either prior to or coincident with the onset of eosinophilic pneumonia. Peripheral eosinophilia was not found in each of the 9 patients. Two of the 3 nonasthmatics patients failed to develop blood eosinophilia. Of the 6 asthmatic patients, however, 5 developed significant hypereosinophilia. It would seem, then, that the combination of the asthmatic state and the development of chronic eosinophilic pneumonia can result in exaggerated blood eosinophilia which may not be seen if either condition occurs alone. The course of treated chronic eosinophilic pneumonia is felt to be benign.4* 6-8 Three of 9 patients studied by Carrington and co-workers6 relapsed with similar manifestations while off steroids. Of interest is the observation that the infiltrates, when they recurred, were nearly identical in extent, shape, and location to those noted in the original episode. Relapse occurred as early as 1 and as late as 46 mo, and 1 patient relapsed twice. Several reports have suggested, as a possible etiology, a hypersensitivity phenomenon with predilection for specific areas of the lung; however, the etiology of chronic eosinophilic pneumonia remains unknown. Polyarteritis nodosa is a virulent multisystem disease classically involving medium-sized or small vessels in a segmental manner. Vascular lesions are characterized by a leukocytoclastic vasculitis in the media and adventitia frequently evolving to fibrinoid necrosis. Polyarteritis may be the first human collagen-vascular disease in man caused by a host response to a virus; recent evidence has suggested that the pathogenesis in many of the patients suffering from polyarteritis involves the deposition of circulating immune complexes containing hepatitis surface antigen in vessel walls with the subsequent activation of the complement system.g Pulmonary involvement in polyarteritis nodosa is not uncommon. Kussmaul and Maier’s’O original description of the disease made no mention of lung involvement. However, Wilson and Alexander” found
VOLUME NUMBER
60 6
Eosinophilic
pneumonia
followed
by polyarteritis
FIG. 4. Sural nerve biopsy, 1976. Leukocytoclastic vasculitis. Inflammatory cells are present extensive fibrinoid necrosis involving the media of the arterial vessel. (x 180.)
a significant incidence (18%) of bronchial asthma in a consecutive analysis of 300 cases of polyarteritis nodosa. In almost every case, the asthma, which was of the intrinsic type, preceded the onset of multisystern disease, often by many years. Asthma during the acute flare of vasculitis was severe and was associated with hypereosinophilia in 94% of patients. In contrast, eosinophil counts were normal in nearly all nonasthmatic patients with polyarteritis. Rose and Spencer’* found 32 cases of polyarteritis nodosa with lung involvement in a British series of 111 patients. Those patients with lung involvement commonly presented ,with wheezing and eosinophilia. In addition, hemoptysis, pleuritic pain, and soft irregular infiltrates often located in upper lobes were seen. The mortality rate of untreated patients with pulmonary lesions was greater than in the untreated group with no pulmonary involvement. Divertie and Olseni observed blood eosinophilia in 30% of 125 patients with polyarteritis. Thirteen of the 125 had a PIE picture which occurred as part of the systemic disease. Allergic granulomatous angiitis is a variant of polyarteritis nodosa occurring in the atopic patient. The majority of patients have involvement of peripheral and central nervous systems in addition to widespread organ involvement. In contrast to polyarteritis, however, the lung is involved in nearly all cases.14, Is Asthma with hypereosinophilia was present in all of the original 13 cases of Churg and Strauss? 11 of the 13 also developed pulmonary
nodosa
381
in the intima and
Skin lesions mimicking rheumatoid infiltrates. nodules are common in allergic angiitis. The pathologic picture seen in this disorder is one of a granulomatous vasculitis. The case reported here is unusual in several respects. Chronic eosinophilic pneumonia is rare in men. All 9 patients in the original series by Carrington and co-workers and 24 of 29 reported more recently were women. 6, 7 We are not aware of this rare condition evolving into a picture of either a systemic or pulmonary vasculitis . Eosinophilic pneumonia, when it reoccurs, should occur as another case of eosinophilic pneumonia. Kinsella and Simpson16 reported a case of so-called “Loeffler’s pneumonia” terminating in polyarteritis nodosa. The patient was a 57-yr-old woman presenting initially with a cough, rales, and a small upper lobe infiltrated. Moderate blood eosinophilia was present. The patient recovered without specific therapy but began to suffer from recurrent episodes of asthma. Five years later she presented with a progressive systemic vasculitis and exaggerated eosinophilia. No mention is made of pulmonary signs or symptoms or of an abnormality on chest roentgenogram. Unfortunately, the original admission for the PIE syndrome is not well defined. Based on the clinical material and x-rays presented, however, the diagnosis of chronic eosinophilic pneumonia was unlikely. Looking at the clinical picture from the other direction, chronic eosinophilic pneumonia has not previ-
332 Cogen. Mayock, and
J. ALLERGY
Zweiman
ously been described to our knowledge as either a forerunner of, or a complication of, a systemic vasculitis. It is interesting to speculatethat our patient’s eosinophilic pneumonia was the first manifestation of a systemicvasculitis. This is highly unlikely considering the absenceof vasculitis on lung biopsy, the absenceof multisystem disease,and, more importantly, the 4-yr period of clinical stability betweenepisodes. Although the clinical findings in our patient’s second admission suggesta diagnosis of allergic granulomatous angiitis, the absence of skin lesions and of a granulomatousreaction in the biopsy material makes the diagnosis of polyarteritis with pulmonary involvement more likely. We therefore must conclude, for the present at least, that our asthmatic patient developed two rare clinical presentations of possible immune etiology, each of which were associatedwith blood eosinophilia and pulmonary infiltration and each of which seemingly occurred independently of one another or, perhaps,as part of a yet unrecognized single clinical syndrome. REFERENCES 1. Ford, R.: Transient pulmonary eosinophilia and asthma, Am. Rev. Resp. Dis. 93~191, 1965. 2. Patterson, R., Irons, J., Kelly, J., Mattson, J., and Oh, S.: Pulmonary infiltrates with eosinophilia, J. ALLERGYCLIN. IMMUNOL. 53~245, 1974. 3. Horn, B., Robin, E., Theodore, J., and Van Kessel, A.: Total eosinophil counts in the managementof bronchial asthma, N. Engl. J. Med. 292~1152,1975.
CLIN. IMMUNOL. DECEMBER 1977
4. Scadding, J. G.: Eosinophilic infiltration of the lungs in asthmatics, Proc. R. Sot. Med. 64r381, 1971. 5. Croften, .I. W., Livingston, J. L., Oswald, N. C., and Roberts, A.: Pulmonary eosinophilia, Thorax 7: 1, 1952. 6. Carrington, C., Addington, W., Goff, A., Madoff, I., Marts, A., Schwaber, J., and Gaensler, E.: Chronic eosinophilic pneumonia, N. Engl. J. Med. 280:787, 1969. 7. Gaensler, E., and Carrington, C.: Peripheral opacities in chronic eosinophilic pneumonia. 1. The photographicnegative of pulmonary edema, Am. J. Roentgenol. 128:1, 1977. 8. Rodgers, R., Christiansen,J., Coalson, I., and Patterson,C.: Eosinophilic pneumonia, Chest 68:665, 1975. 9. Sergent,J., Lockshin, M., Christian, C., and Gocke, D.: Vasculitis with hepatitis B antigenemia, Medicine 55: 1, 1976. 10. Kussmaul, A., and Maier, R.: Uber eine bisher nicht beschriebene eigenthumlicheArterienerkrankung, die mit Morbis Brightii und rapid Fortschreten def allgemeiner Muskellahmung einherght, Dtsch. Arch. Klin. Med. 1:484, 1866. 11. Wilson, K., and Alexander, H.: The relationship of periarteritis nodosato bronchial asthmaand other forms of hypersensitivities, J. Lab. Clin. Med. 3Ot195, 1945. 12. Rose, G., and Spencer, H.: Polyarteritis nodosa, Q. J. Med. 26:1, 1957. 13. Divertie, M., and Olsen, A.: Pulmonary infiltration associated with blood eosinophilia (PIE): A clinical study of Loeffler’s syndrome and of periarteritis nodosa with PIE syndrome, Proc. Mayo Clin. 37:340, 1960. 14. Rosenberg, T., Medsger, T., DeCicco, F., and Fireman, P.: Allergic granulomatousangiitis, J. ALLERGYCLIN. IMMUNOL. 55~56, 1975. 15. Churg, J., and Strauss, L.: Allergic granulomatosis, allergic angiitis, and periartentis nodosa, Am. J. Pathol. 27~277, 1951. 16. Kinsella, D., and Simpson, H.: Loeffler’s pneumonia terminating in fatal periarteritis nodosa, J. A. M. A. 202~867, 1967.
C. Cogen, M.D., Robert L. Mayock,
M.D., and Burton
Zweiman,
M.D.
Pa.
The syndrome of pulmonary infiltrates with eosinophilia (PIE) occurs rarely in the asthmatic patient. An unusual case is presented in which progressive bronchoconstriction and exaggerated blood eosinophilia preceded the recognition of two seemingly unrelated diseases, each of which can independently result in hypereosinophilia and the PIE syndrome. In the male patient studied, the jrst illness, biopsy-proved chronic eosinophilic pneumonia, was responsive to corticosteroid therapy. Four uneventful years later, polyarteritis nodosa with eventual pulmonary involvement developed. A careful search for specific underlying pulmonary and systemic diseuse is in order when hypereosinophilia occurs in the clinically unstable asthmatic patient
The clinical syndrome of pulmonary infiltrates with a prominent blood eosinophilia (PIE) may infrequently be superimposed upon a pre-existing asthmatic condition resulting in increased bronchospasm, pulmonary function deterioration, and hypereosinophilia.’ Diagnostic considerations in such circumstances include unusual disorders of presumed varied pathogenesis such as: (1) bronchopulmonary aspergillosis, (2) chronic eosionophilic pneumonia, (3) parasitic infestation, (4) drug or toxin exposure, or (5) one of the several presentations of systemic vasculitis.’ We have followed the clinical course of a patient with long-standing asthma who sequentially manifested discreet episodes of chronic eosinophilic pneumonia and then polyarteritis nodosa. These two occurrences were separated by a 4-yr period of relatively stable health. This association has not been previously reported. The description of this clinical -__ From the Sections of Allergy and Clinical Immunology and Pulmo-
nary Diseases,Departmentof Medicine, Hospital of the University of Pennsylvania. Supported in part by National Institutes of Health Grant No. 1 T32 AI 07031-01. Received for publication June 10, 1977. Accepted for publication Sept. 15, 1977. Reprint requests to: Dr. Frederick C. Cogen, Allergy and Clinical Immunology Section, 512 Johnson Pavilion, 36th and Hamilton Walk, Philadelphia, Pa. 19174.
picture and discussion of the possible interrelationships involved comprise the basis of this report. CASEREPORT A 47-yr-old male carpenter had a long-standing history of seasonal allergic rhinitis and extrinsic asthma beginning at age 13. At approximately age 20, the asthma became perennial with both extrinsic and intrinsic components; however, the bronchospasm was mild and well controlled with various bronchodilators. The patient was admitted for the first time to the Hospital of the University of Pennsylvania in 1972 with a 7-wk history of fevers, a progressive cough, wheezing, and dyspnea. There was no history to suggest recent drug reaction, parasitic infection, or relevant occupational exposures. Diffuse wheezing and rales were detected on physical examinations. Blood leukocyte levels ranges from 10,000 to 14,000 with an eosinophilia of from 17% to 22%. A chest roentgenogram showed new infiltrates in both the right upper and lower lobes with a predominantly peripheral distribution in the right upper lobe infiltrate (Fig. 1). Pulmonary function studies revealed an obstructive and restrictive pattern. Arterial blood gas analyses showed a PO, of 58, Pco2 of 43, and a pH of 7.47. Sputum cultures were negative for acid-fast bacilli, fungi, and bacterial pathogens and contained multiple eosinophils without fungal elements. Pathologic sections from open lung biopsy were consistent with a diagnosis of chronic eosinophilic pneumonia without evidence of vasculitis (Fig. 2). Prednisone, 60 mg daily, was added to the bronchodilator regimen. Within 3 days, there was impressive Vol. 60, No. 6, pp. 377-382
378
Cogen, Mayock,
and Zweiman
FIG. 1. Chest film. Chronic eosinophilic pneumonia; right upper and right lower infiltrates with peripheral distribution of right upper lobe infiltrate.
improvement in both pulmonary symptomatology and the chest roentgenogmm appearance. He was eventually discharged and was given xanthine bronchodilators and tapering doses of steroids. Follow-up chest roentgenogram 4 wk later was completely normal (Fig. 3). Allergy evaluation in September, 1973, showed multiple positive skin tests and hyposensitization with clinically relevant pollens, mold, and dust was started. He remained improved on little or no steroid treatment from this time with differential leukocyte counts showing no eosinophilia. In January, 1976, the asthma inexplicably worsened. Small doses of prednisone, and later nebulized beclomethasome therapy, were added; however, he continued to experience progressive cough, wheezing, and dyspnea over a 4-mo period. Chest films continued to show no parencymal abnormalities, with an unchanging picture since discharge from his previous hospitalization. When the asthmatic symptoms did not improve after prednisone was increased to 60 mg/day for 1 wk, he was admitted for the second time to the Hospital of the University of Pennsylvania. Additional past medical history included a prior urticarial reaction to penicillin. His family history was negative for atopy. He denied cigarettes, alcohol, illicit drug abuse, or exposure to toxins. No history of liver disease or blood transfusion was elicited. A diagnosis of chronic undifferentiated schizophrenia had been made in 1972, but the patient remained functional in both work and social relationships. On physical examination, he was anxious and in moderate respiratory distress. Blood pressure was 120/85
J. ALLERGY
CLIN. IMMUNOL. DECEMBER 1977
without paradox, temperature was 98”, pulse was 90, respiration was 24. Examination of the eyes, ears, nose and throat and funduscopic examination were unremarkable. The lungs showed diffuse wheezes and rhonchi. Cardiac, abdominal and neurologic examinations were normal. Laboratory studies included a hemoglobin of 17.2, white blood cell count of 13,300 with 8% eosinophils, and total eosinophil count of 2,963. Urinalysis on several occasions showed no abnormalities. Blood urea nitrogen, glucose, calcium phosphate, uric acid, bilirubin, amylase, creatine phosphokinase, serologic test for syphilis, and electrocardiogram were all normal. Chest roentgenogram on admission was normal. A skin test with 5 U of purified protein derivative and sputum cultures for acid-fast bacilli and fungi were negative. Mild elevations in serum lactic dehydroginase and serum glutamic oxaloactate transaminase were noted, but hepatitis-associated antigen was absent and bilirubin and alkaline phosphatase were normal. Antinuclear antibodies and cryoglobulins were not detected. Serum levels of total hemolytic complement activity, C3 and Cq, were all mildly elevated. The patient was treated for refractory asthma with intravenous aminophylline and 30 mg of daily prednisone. Despite this dose of steroid, he continued to wheeze significantly. By the ninth hospital day, nocturnal fever occurred; a sedimentation rate of 54 and an eosinophil count of 25% of 15,600 total white blood cell count were noted. He complained of sudden unilateral amblyopia, but an opthalmologist found no objective sign of disease. On the eleventh day, the asthma was improved but he complained of numbness in one hand. A consulting neurologist could find no evidence of central or peripheral nervous system disease. The patient then complained of migratory dysesthesia, motor weakness, and vague abdominal pains. On the eighteenth day, electromyographic and nerve conduction velocity (NCV) studies revealed a mild axonal polyneuropathy; and a repeat opthalmologic examination now detected two infarcts in the right retina. A progressive mononeuritis multiplex developed with bilateral foot drop and severe dysfunction of the left median nerve. Marked elevation of the sedimentation rate and total eosinophil count persisted despite 40 mg prednisone daily. Blood pressure and renal studies remained normal. Quadriceps muscle and sural nerve biopsies confirmed the clinical impression of systemic vasculitis (Fig. 4). Because of evidence of progressive disease by the thirty-seventh hospital day, steroid dosage was increased to 100 mg of methyl prednisolone given intravenously daily. The neurologic symptoms subsequently stabilized and wheezing ceased. The chest film remained normal and the sedimentation rate and eosinophil count returned toward normal. However, on the fifty-fifth hospital day, a new fluffy irregular infiltrate was noted in the left upper lobe; this infiltrate gradually disappeared over several days. Because of progression of the neuropathy by the sixtyfifth day, cyclophosphamide was added and prednisone was reduced to 80 mg daily. One week later, the development of pneumocystis carinii pneumonia, proved by bronchial brushings, prompted the discontinuation of cyclophos-
VOLUME NUMBER
60 6
Eosinophilic
FIG. 2. Lung biopsy, 1972. Alveoli are filled with an exudate rophages, and eosinophils. Extensive infiltration of eosinophils eosinophilic pneumonia complicating asthma. (x320.)
further reduction of steroid dosage, and the addition of trimethoprlm-sulfamethoxazole. The pneumo-
phamide,
cystis pneumonia nerve conduction
responded. By the eightieth day repeat studies indicated some healing of the
neuropathy and the patient slowly began to regain function in various extremities. Steroid treatment was gradually transferred to an alternate-day dose program with subsequent slou reduction
of dosage.
Motor and sensory function slowly improved, with the patient gradually increasing activity to the point at which he currently returned
walks up to 5 miles a day. Asthmatic symptoms when the prednisone dose was reduced below a
level of 15 mg every other day. However, there has beenno recurrence of pulmonary infiltrates, eosinophilia, or new neurologic signs. Asthmatic symptomshave beenrelatively well csontrolledby increasing the aminophylline dosage. DISCUSSION Mild peripheral eosinophilia is a hallmark of bronchial asthma, occurring in both the extrinsic and the intrinsic forms. Total eosinophil counts ranged from 300 to 1,2OO/cu mm in a recent study of a series of intrinsic asthmatic patients.” The terms pulmonary eosinophilia, eosinophilic infiltration of the lung, or PIE may all conveniently be used to refer to bronchopulmonary changes resulting in transient and variable radiographic shadows accompanied by blood eosinophilia. The lung changes and the blood eosinophilia are thought to be related.4* I3 In the case reported here, episodic deterioration in pulmonary status with increasing cough, wheezing, and dyspnea
pneumonia
followed
by polyarteritis
nodosa
379
of desquamative alveolar lining cells, macpopulating interstitial areas, consistent with
was accompanied by pronounced hypereosinophilia on two separate occasions separated by four relatively uneventful years. The first admission was prompted by increased bronchoconstriction accompanied by pulmonary and constitutional symptoms and x-ray evidence of consolidation. Clinical and radiographic improvement followed corticosteroid therapy. For the next 4 yr the patient remained relatively well. A progressive worsening of asthmatic symptoms preceded the second admission. It is conceivable that this increasing asthma over a 5-mo period was the first manifestation of a systemic vasculitis; unfortunately, no histologic study of the lung tissue was carried out at this time. During the subsequent hospitalization the appearance of striking blood eosinophilia despite treatment with large parenteral doses of various corticosteroids alerted his physicians to the possibility of serious underlying disease complicating the asthma. The severe bronchospasm, fever, constitutional symptoms, abdominal pain, retinal infarction, and progressing mononeuritis multiplex with confirmatory biopsy evidence of vasculitis pointed to the diagnosis of polyarteritis nodosa. The pulmonary infiltrates appeared rather suddenly several weeks after the patient developed overt neuropathy, and just as mysteriously disappeared several days later without change in clinical status or therapy. At present, there is little clinical evidence of active vasculitis although asthma is still present. In 1952, Croften and associates5 classified pulmo-
380
Cogen, Mayock,
FIG. 3. Chest film chronic eosinophilic
J. ALLERGY
and Zweiman
4 wk after initiation pneumonia.
of steroids
for
nary eosinophilic syndromes. They commented on a peculiar group of patients, most of them asthmatic, who presented with signs of general toxicity, wheezing, and blood eosinophilia. Interesting infiltrates noted on chest roentgenograms were described as “clouds of smoke rising after an explosion in the region of the hilum and drifting up against the chest wall peripherally. ” In 1969, Carrington and colleagues6 identified a distinctive syndrome which they called chronic eosinophilic pneumonia. Nine young and middle-aged women presented with dyspnea, high fever, night sweats, and weight loss and were frequently initially diagnosed as having pulmonary tuberculosis. Chest roentgenograms revealed pneumonic infiltrates in a peculiar peripheral pattern simulating a “photographic negative of the acute pulmonary edema pattern.” Lung biopsies showed leukocytic-predominantly eosinophilic-exudation into alveolar and interstitial spaces. Multinucleated histiocytic giant cells, some of which contained Charot-Leyden crystals, were also present in the affected alveoli. Frank vasculitis was not found. A recent retrospective review by Gaensler and Canington indicates a high correlation of characteristic radiographic features with biopsy-proved cases of chronic eosinophilic pneumonia. Yet, lung biopsy was necessary to confirm the diagnosis in approximately one quarter of cases.
CLIN. IMMUNOL. DECEMBER 1977
Rapid and dramatic improvement in clinical status, associated clearing in chest roentgenograms, and improvement in pulmonary function abnormalities occurs routinely after initiation of corticosteroid therapy in chronic eosinophilic pneumonia.6, 8 These observations have prompted the suggestion that a therapeutic trial of steroids may serve as an additional aid. Our patient’s rapid clinical improvement during the first admission is quite consistent with past experiences in chronic eosinophilic pneumonia. A background of atopy is common in these patients. Six of the 9 patients in the original series by Canington and associate@ were atopic. Five of them had allergic rhinitis and 6 developed asthma either prior to or coincident with the onset of eosinophilic pneumonia. Peripheral eosinophilia was not found in each of the 9 patients. Two of the 3 nonasthmatics patients failed to develop blood eosinophilia. Of the 6 asthmatic patients, however, 5 developed significant hypereosinophilia. It would seem, then, that the combination of the asthmatic state and the development of chronic eosinophilic pneumonia can result in exaggerated blood eosinophilia which may not be seen if either condition occurs alone. The course of treated chronic eosinophilic pneumonia is felt to be benign.4* 6-8 Three of 9 patients studied by Carrington and co-workers6 relapsed with similar manifestations while off steroids. Of interest is the observation that the infiltrates, when they recurred, were nearly identical in extent, shape, and location to those noted in the original episode. Relapse occurred as early as 1 and as late as 46 mo, and 1 patient relapsed twice. Several reports have suggested, as a possible etiology, a hypersensitivity phenomenon with predilection for specific areas of the lung; however, the etiology of chronic eosinophilic pneumonia remains unknown. Polyarteritis nodosa is a virulent multisystem disease classically involving medium-sized or small vessels in a segmental manner. Vascular lesions are characterized by a leukocytoclastic vasculitis in the media and adventitia frequently evolving to fibrinoid necrosis. Polyarteritis may be the first human collagen-vascular disease in man caused by a host response to a virus; recent evidence has suggested that the pathogenesis in many of the patients suffering from polyarteritis involves the deposition of circulating immune complexes containing hepatitis surface antigen in vessel walls with the subsequent activation of the complement system.g Pulmonary involvement in polyarteritis nodosa is not uncommon. Kussmaul and Maier’s’O original description of the disease made no mention of lung involvement. However, Wilson and Alexander” found
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Eosinophilic
pneumonia
followed
by polyarteritis
FIG. 4. Sural nerve biopsy, 1976. Leukocytoclastic vasculitis. Inflammatory cells are present extensive fibrinoid necrosis involving the media of the arterial vessel. (x 180.)
a significant incidence (18%) of bronchial asthma in a consecutive analysis of 300 cases of polyarteritis nodosa. In almost every case, the asthma, which was of the intrinsic type, preceded the onset of multisystern disease, often by many years. Asthma during the acute flare of vasculitis was severe and was associated with hypereosinophilia in 94% of patients. In contrast, eosinophil counts were normal in nearly all nonasthmatic patients with polyarteritis. Rose and Spencer’* found 32 cases of polyarteritis nodosa with lung involvement in a British series of 111 patients. Those patients with lung involvement commonly presented ,with wheezing and eosinophilia. In addition, hemoptysis, pleuritic pain, and soft irregular infiltrates often located in upper lobes were seen. The mortality rate of untreated patients with pulmonary lesions was greater than in the untreated group with no pulmonary involvement. Divertie and Olseni observed blood eosinophilia in 30% of 125 patients with polyarteritis. Thirteen of the 125 had a PIE picture which occurred as part of the systemic disease. Allergic granulomatous angiitis is a variant of polyarteritis nodosa occurring in the atopic patient. The majority of patients have involvement of peripheral and central nervous systems in addition to widespread organ involvement. In contrast to polyarteritis, however, the lung is involved in nearly all cases.14, Is Asthma with hypereosinophilia was present in all of the original 13 cases of Churg and Strauss? 11 of the 13 also developed pulmonary
nodosa
381
in the intima and
Skin lesions mimicking rheumatoid infiltrates. nodules are common in allergic angiitis. The pathologic picture seen in this disorder is one of a granulomatous vasculitis. The case reported here is unusual in several respects. Chronic eosinophilic pneumonia is rare in men. All 9 patients in the original series by Carrington and co-workers and 24 of 29 reported more recently were women. 6, 7 We are not aware of this rare condition evolving into a picture of either a systemic or pulmonary vasculitis . Eosinophilic pneumonia, when it reoccurs, should occur as another case of eosinophilic pneumonia. Kinsella and Simpson16 reported a case of so-called “Loeffler’s pneumonia” terminating in polyarteritis nodosa. The patient was a 57-yr-old woman presenting initially with a cough, rales, and a small upper lobe infiltrated. Moderate blood eosinophilia was present. The patient recovered without specific therapy but began to suffer from recurrent episodes of asthma. Five years later she presented with a progressive systemic vasculitis and exaggerated eosinophilia. No mention is made of pulmonary signs or symptoms or of an abnormality on chest roentgenogram. Unfortunately, the original admission for the PIE syndrome is not well defined. Based on the clinical material and x-rays presented, however, the diagnosis of chronic eosinophilic pneumonia was unlikely. Looking at the clinical picture from the other direction, chronic eosinophilic pneumonia has not previ-
332 Cogen. Mayock, and
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ously been described to our knowledge as either a forerunner of, or a complication of, a systemic vasculitis. It is interesting to speculatethat our patient’s eosinophilic pneumonia was the first manifestation of a systemicvasculitis. This is highly unlikely considering the absenceof vasculitis on lung biopsy, the absenceof multisystem disease,and, more importantly, the 4-yr period of clinical stability betweenepisodes. Although the clinical findings in our patient’s second admission suggesta diagnosis of allergic granulomatous angiitis, the absence of skin lesions and of a granulomatousreaction in the biopsy material makes the diagnosis of polyarteritis with pulmonary involvement more likely. We therefore must conclude, for the present at least, that our asthmatic patient developed two rare clinical presentations of possible immune etiology, each of which were associatedwith blood eosinophilia and pulmonary infiltration and each of which seemingly occurred independently of one another or, perhaps,as part of a yet unrecognized single clinical syndrome. REFERENCES 1. Ford, R.: Transient pulmonary eosinophilia and asthma, Am. Rev. Resp. Dis. 93~191, 1965. 2. Patterson, R., Irons, J., Kelly, J., Mattson, J., and Oh, S.: Pulmonary infiltrates with eosinophilia, J. ALLERGYCLIN. IMMUNOL. 53~245, 1974. 3. Horn, B., Robin, E., Theodore, J., and Van Kessel, A.: Total eosinophil counts in the managementof bronchial asthma, N. Engl. J. Med. 292~1152,1975.
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4. Scadding, J. G.: Eosinophilic infiltration of the lungs in asthmatics, Proc. R. Sot. Med. 64r381, 1971. 5. Croften, .I. W., Livingston, J. L., Oswald, N. C., and Roberts, A.: Pulmonary eosinophilia, Thorax 7: 1, 1952. 6. Carrington, C., Addington, W., Goff, A., Madoff, I., Marts, A., Schwaber, J., and Gaensler, E.: Chronic eosinophilic pneumonia, N. Engl. J. Med. 280:787, 1969. 7. Gaensler, E., and Carrington, C.: Peripheral opacities in chronic eosinophilic pneumonia. 1. The photographicnegative of pulmonary edema, Am. J. Roentgenol. 128:1, 1977. 8. Rodgers, R., Christiansen,J., Coalson, I., and Patterson,C.: Eosinophilic pneumonia, Chest 68:665, 1975. 9. Sergent,J., Lockshin, M., Christian, C., and Gocke, D.: Vasculitis with hepatitis B antigenemia, Medicine 55: 1, 1976. 10. Kussmaul, A., and Maier, R.: Uber eine bisher nicht beschriebene eigenthumlicheArterienerkrankung, die mit Morbis Brightii und rapid Fortschreten def allgemeiner Muskellahmung einherght, Dtsch. Arch. Klin. Med. 1:484, 1866. 11. Wilson, K., and Alexander, H.: The relationship of periarteritis nodosato bronchial asthmaand other forms of hypersensitivities, J. Lab. Clin. Med. 3Ot195, 1945. 12. Rose, G., and Spencer, H.: Polyarteritis nodosa, Q. J. Med. 26:1, 1957. 13. Divertie, M., and Olsen, A.: Pulmonary infiltration associated with blood eosinophilia (PIE): A clinical study of Loeffler’s syndrome and of periarteritis nodosa with PIE syndrome, Proc. Mayo Clin. 37:340, 1960. 14. Rosenberg, T., Medsger, T., DeCicco, F., and Fireman, P.: Allergic granulomatousangiitis, J. ALLERGYCLIN. IMMUNOL. 55~56, 1975. 15. Churg, J., and Strauss, L.: Allergic granulomatosis, allergic angiitis, and periartentis nodosa, Am. J. Pathol. 27~277, 1951. 16. Kinsella, D., and Simpson, H.: Loeffler’s pneumonia terminating in fatal periarteritis nodosa, J. A. M. A. 202~867, 1967.
