Diagnostic Significance of Increased Bronchoalveolar Lavage Fluid Eosinophils1 , 2
JAMES N. ALLEN,3 W. BRUCE DAVIS, and ERIC R. PACHT
Introduction
Bronchoalveolar lavage (HAL) is frequently used as a diagnostic and staging procedure in a variety of pulmonary diseases (1-5). Normal HAL fluid contains less than 1070 eosinophils (2), but increased eosinophils have been observed in interstitial lung diseases (6-11),chronic eosinophilic pneumonia (12-16),drug-induced lung disease (17),asthma (18- 20), acute eosinophilic pneumonia (21- 23), Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome (AIDS) (24-26), and filarial infection (27). Although the incidence of HAL eosinophilia has been reported in several specific diseases (6, 7, 12, 24), littie is known about its incidence or diagnostic significance across a broad spectrum of pulmonary diseases commonly encountered in a general hospital patient population. To determine the common causes and differential diagnosis of BAL eosinophilia, we retrospectively reviewed the HAL cellular differentials on 1,075 consecutive patients over a 33-month period. Forty-eight of these patients had HAL differentials showing 5070 or more eosinophils. The clinical characteristics, chest radiographs, pulmonary function tests, and laboratory findings of these patients are reviewed. Methods
Patient Selection One thousand seventy-fivepatients were evaluated by fiberoptic bronchoscopy with bronchoalveolar lavage for diagnostic purposes by the Pulmonary Division at Ohio State University Hospital from January 1987 through September 1989. Sixteenpatients wereexcluded because of insufficient clinical information, leaving 1,059 patients available for the study. None of these 16patients had increased numbers of BAL eosinophils. The pulmonary attending physicians' diagnoses at the time of bronchoscopy are listed in table 1. Information was obtained retrospectively from the bronchoscopy log, hospital and clinic charts, and microbiology division records. Patients 642
SUMMARY We determined the Incidence of Increased bronchoalveolar IlVIge (BAL) fluid eosinophil percentages In 1,059consecutive patients undergoing bronchoscopy with BAL over a 33-month period. Forty-eight (48) patients were found to have 5% or more BAL eoslnophlls. The most common causes for Increased BAL eoslnophlls ware Interstitial lung diseases (40% of patients), acquired Immunodeficiency syndrome (AIDS)-assoclated pneumonia (17%of petlents), Idlopethlc eosinophilic pneumonia (15% of patients), and drug-Induced lung disease (12% of patients). Together, these four diagnoses accounted for 84% of all patients. In contrast, eoslnophlls ware uncommon In the BAL of patients with the adUlt respiratory distress syndrome, lung cancer, communlty-acqulred pneumonia, or Immunocompromlslng diseases other than AIDS. The finding of Increased BAL eoslnophlls WlS most helpful In patients presenting with unexplained pulmonary Infiltrates. In these patients, this finding WlS often an Importsnt clue to the final diagnosis. We conclude that although the findIng of an Increased percentage of BAL eoslnophllsls uncommon, when present It Is relatively specific for a limited number of diseases. AM REV RESPIR DIS 1990; 142:842-647
were included in the study if 5010 or more eosinophils were present on the BAL cellular differential.
Patient Diagnoses For the purpose of this study, idiopathic pulmonary fibrosis was diagnosed if patients had pulmonary function tests demonstrating restrictive physiology, diffuse idiopathic interstitial infIltrates on chest radiographs, a compatible clinical history, and lung biopsy demonstrating fibrosis and/or BAL demonstrating an inflammatory alveolitis. All patients with sarcoidosis had lung biopsies revealingnoncaseating granulomas in the absence of infection. Systemic lupus erythematosus-associated interstitial lung disease was diagnosed in patients with a previous diagnosis of systemic lupus erythematosus who developed interstitial infiltrates accompanied by pulmonary function abnormalities in the absence of infection. A diagnosis of AIDS was made if a patient tested positively for the HIV antigen by the western blot analysis and developed an opportunistic infection. P. carinii pneumonia and cryptococcal pneumonia werediagnosed on the basis of BAL examination. The diagnosis of Staphylococcus aureus pneumonia in a patient with AIDS was based on clinical and radiographic findings plus positive blood and sputum cultures. The diagnostic criteria for the patients with acute eosinophilic pneumonia have been previously described (21). Chronic eosinophilic pneumonia was diagnosed if a patient had chronic dyspnea, idiopathic interstitial in-
filtrates on chest radiographs, restrictive physiology, pulmonary eosinophilia, and prompt resolution of clinical and radiographic abnormalities after the administration of corticosteroids. Drug-induced lung disease was diagnosed if pulmonary disease developed as a complication of a drug overdose or if it developed shortly after the initiation of a medication and resolved once the offending medication was removed. In these patients, there was no other identifiable cause of the patient's lung disease. The diagnosis of Hodgkin's disease was based on histologic findings. Asthma was considered to be present if patients had recurrent reversible bronchospasm in the absence of a history of cigarette smoking. Chronic bronchitis was diagnosed if a patient had a history of cigarette smoking and recurrent bouts of cough with sputum production. The diagnosis of Toxocara infection was based on serologic fmdings in association with an appropri(Receivedin originalform December 18,1989and in revised form March 29, 1990) 1 From the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, The Ohio State University Hospitals, Columbus, Ohio. 2 Correspondence and requests for reprints should be addressed to James N. Allen, M.D., N-325 Means Hall, 1654 Upham Drive, Columbus, OH 43210. J Parker B. Francis Fellow in Pulmonary Research.
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TABLE 1
value. A reduced diffusing capacity was defined as being less than 80070 of the predicted value after correction for the total lung capacity and hemoglobin concentration.
DIAGNOSIS PRIOR TO BRONCHOSCOPY IN 1,059 PATIENTS
Prebronchoscopy Diagnosis
Number of Patients (%)'
AIDS-associated pneumonia Immunocompromised with infiltrates Interstitial lung disease Bone marrow transplant with infiltrates Normal hosts with unexplained infiltrates Suspected cancer Pneumonia Normal volunteer Adult Respiratory Distress Syndrome Cough Suspected bronchiolitis obliterans Suspected tuberculosis Unexplained hemoptysis Asthma Unexplained hypoxemia Total
239 199 183 75 71 69 65 46 29 22 20 19 17 3 2
Patients with Increased BAL Eosinophils (%)t
(22.6) (18.8) (17.3) (7.1) (6.7) (6.5) (6.1) (4.3) (2.7) (2.1) (1.9) (1.8) (1.6) (0.3) (0.2)
1,059 (100)
Statistical Analysis All results are expressed as mean ± standard error of the mean.
8 (17)
2 (4) 19 (40) 1 (2) 13 (27)
o
Results
1 (2)
The 1,059patients who underwent bronchoalveolar lavage represented a wide spectrum of pulmonary disease (table 1). Forty-eight (4.5%) of these patients had 5070 or more eosinophils on BAL. There were 20 female and 28 male patients who ranged from 11 to 80 yr of age. Thirty patients underwent BAL as inpatients and 18 as outpatients. Table 2 lists the final diagnoses of the 48 patients with increased BAL eosinophils. The most common cause of BAL eosinophilia was idiopathic pulmonary fibrosis (14 patients), followed by AIDS-associated P. carinii pneumonia (6 patients), druginduced lung disease (6 patients), acute eosinophilic pneumonia (5 patients), and sarcoidosis (3 patients). Systemic lupus erythematosus, AIDS-associated pneumonia other than P. carinii pneumonia, chronic eosinophilic pneumonia, Hodgkin's disease, and asthma each accounted for 2 patients. Chronic bronchitis, helminth infection, bone marrow transplant-associated cryptococcalpneumonia, and bacterial pneumonia each accounted for 1 patient. The prebronchoscopy diagnosis of unexplained infiltrates (table 1) deserves special mention because 11 of our 48 patients with BAL eosino-
o 1 (2) 2 (4)
o o o 1 (2)
o 48 (100)
• Percentage of the 1,059 patients undergoing bronchoalveolar lavage. Percentage of the 48 patients having increased BAL eosinophils.
t
ate clinical history. Disseminated cryptococcal infection was diagnosed in a bone marrow transplant recipient from whom Cryptococcusneoformans was cultured from the blood, bone marrow, spinal fluid, and BAL fluid. Bacterial pneumonia was diagnosed in an otherwise healthy patient who had positive sputum cultures in conjunction with compatible clinical and radiographic findings.
Bronchoalveolar Lavage Fiberoptic bronchoscopy and bronchoalveolar lavage was performed as previously described (2, 28). After administering local anesthesia of the nose and pharynx with 4% lidocaine, the bronchoscope was inserted into the nose of nonintubated patients or through the endotracheal tube of patients receiving mechanical ventilation. The tip of the bronchoscope was wedged in a distal portion of a bronchus, usually in the right middle lobe or lingula, and bronchoalveolar lavage was performed by instilling five 20-ml aliquots of sterile saline through the bronchoscope. All samples were cytocentrifuged and the pellets were examined for cellular differentials with the use ofthe Diff-Quik'"stain (AHS Del Caribe, Aguada, PR). In each sample, 300 cells were counted by a laboratory technician experienced in BAL cellular analysis or by an attending pathologist. In patients with suspected opportunistic pneumonia, samples werealso examined with a battery of tests consisting of Gram's, acid-fast, and toluidine blue stains by the microbiology division. Bacterial, fungal, mycobacterial, viral, and Legionella cultures were obtained as clinically indicated. Additionally, when malignancy was suspected, a Papanicolaou stain was examined by a cytologist. A review of 46 normal volunteers undergoing BAL for research purposes in our laboratories during the study period revealed
the following normal values for BAL cellular differentials: 89.3 ± 1.2% alveolar macrophages, 8.9 ± 1.1%lymphocytes, 1.3 ± 0.3% neutrophils, and 0.5 ± 0.1% eosinophils.
Lung Physiology Pulmonary function tests were performed with the use of a Collins DS system (Warren E. Collins, Braintree, MA), according to the standards of the American Thoracic Society (29, 30). Lung volumes were determined by the helium dilution technique, and diffusing capacities were determined by the singlebreath technique. Obstructive lung disease was defined as a forced expiratory volume in 1 s to forced vital capacity ratio of lessthan 75%. Restrictive lung disease was defined as a total lung capacity of lessthan 80% of the predicted
TABLE 2 FINAL DIAGNOSIS IN PATIENTS WITH GREATER THAN 5% BAL EOSINOPHILS Diagnosis
Number of Patients (%)'
Interstitial lung disease Idiopathic pulmonary fibrosis Sarcoidosis Systemic lupus erythematosus AIDS-associated pneumonia Pneumocystis carinii Other Idiopathic eosinophilic lung diseases Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Drug-induced lung disease Hodgkin's disease Asthma Chronic bronchitis Helminthic infection Bone marrow transplant Bacterial pneumonia
19 14 3 2
(40) (29) (6) (4) 8 (17) 6 (13)
Total
48 (100)
2 (4)
7 (15) 5 (10) 2 (4) 6 (12) 2 (4) 2 (4) 1 (2)
1 (2) 1 (2) 1 (2)
• Percentage of 48 patients with increased BAL eosinophils.
Mean BAL Eosinophil % (range)
13 (5-51) 6 (5-8) 5 (5-5) 20 (7-43) 7 (5-10) 42 35 16 5 8 28 17
9 6
(28-57) (21-50) (5-32) (5-6) (6-11)
644
philia were in this category at the time patients except one who had sarcoidosis. of bronchoscopy, including 5 of the 6 pa- There was no clear relationship between tients with the final diagnosis of drug- the degree of hypoxemia and the percentinduced lung disease, all 5 patients with age of BAL eosinophils. acute eosinophilic pneumonia, and the Discussion patient with helminth infection. In these patients, the finding of BAL eosinophils Increased BAL eosinophil percentages was instrumental in determining the fi- have been reported in several pulmonary nal diagnosis. diseases (6, 7, 12,24). Wehave found that The most common symptom of pa- the incidence of BAL eosinophilia is reltients with increased BAL eosinophil per- atively low, occurring in only 4.5% of all centages was dyspnea, which was noted BALs performed at our hospital over a by 81OJo of patients; cough was noted by 21-month period. Furthermore, BAL eo67% and chest pain by 31OJo of patients. sinophilia was relatively specific for a Crackles were noted on physical exami- small number of diseases in our patient nation in 71% of patients, whereas fever population, with four syndromes (interand audible wheezing was less frequent stitial lung disease, AIDS-associated (40% and 12%, respectively). pneumonia, idiopathic eosinophilicpneuEighteen patients with increased BAL monia, and drug-induced lung disease) eosinophils werecigarette smokers. There accounting for 84% of patients. It apwas no relationship between BAL eosin- pears from our patients, as well as a reophil numbers and smoking history. viewof the literature, that increased BAL Interestingly, all 5 patients with acute eosinophils can have different prognoseosinophilic pneumonia were cigarette tic and therapeutic implications dependsmokers. ing on the patients' primary illness. Total peripheral blood eosinophil Interstitial Lung Disease counts were available in 40 of the 48 patients. The mean eosinophil count was Interstitial lung disease was the most 575 ± 179/mm3 (normal 50 to 350/ common cause of increased BAL eomm'), The highest mean peripheraleosino- sinophils; 5% or more BAL eosinophils phil counts were seen in chronic eosin- werefound in 10% (19/183) of all patients ophilic pneumonia (2,624 ± 2,624/mm 3 ) , with interstitial lung disease who underhelminth infection (2,072/mm3 ) , drug- went BAL. Of the patients with interstiinduced lung disease (690 ± 242/mm3 ) , tiallung disease, idiopathic pulmonary and idiopathic pulmonary fibrosis (650 fibrosis was the most common cause of ± 425/mm3) . Normal peripheral blood BAL eosinophilia, accounting for 14paeosinophil counts were seen in the HIV- tients. Other investigators have found associated pneumonias,sarcoidosis, Hodg- that BAL eosinophilia occurs frequentkin's disease, systemic lupus erythem- ly in idiopathic pulmonary fibrosis and atosus-associated lung disease, acute eo- may be present in as many as 45% of pasinophilic pneumonia, and the patient tients (6, 7, 12). Additionally, increased with bone marrow transplant-associated BAL eosinophil percentages have been demonstrated to portend a poor prognocryptococcal pneumonia. Chest radiographs were available for sis in idiopathic pulmonary fibrosis (6, all patients with increased BAL eosino- 9, 11) and have been shown to correlate phil percentages. The radiographic find- with more severe clinical impairment at ings werediverseand weregenerally those the time of initial diagnosis (10). of the patient's underlying disease. There Three patients with sarcoidosis were was no common radiographic abnormal- found to have BAL eosinophilia. The ality specific to the patients with increased veolitis of sarcoidosis is typically comBAL eosinophils. 1\vo patients had nor- posed of lymphocytes, especiallyT helper mal chest radiographs at the time of their lymphocytes (31). However, eosinophils bronchoscopy; one had chronic eosino- accounting for more than 5% of BAL philic pneumonia and the other had drug- effector cells have been noted to occur induced lung disease. in up to 7% of patients with sarcoidosis Pulmonary function tests were abnor- (12). All three of our patients had relamal in all 28 patients in whom they were tively modest percentages of eosinophils obtained. Restrictivelung physiology was (5,6, and 8%) but had high percentages seen in 21 patients, obstructive physiolo- of lymphocytes (31,21,and 29%, respecgy was seen in 15patients, and a reduced tively) on BAL. diffusing capacity was seen in 14patients. 1\vo patients with increased BAL eoArterial blood gases were measured in 37 sinophils had interstitial lung disease aspatients. The Pol was diminished in all sociated with systemiclupus erythemato-
ALLEN, DAVIS, AND PACHT
sus. BAL eosinophilia has been previously reported to be common in patients with this entity, which occurred in up to 26% of patients (12).
Acquired Immunodeficiency Syndrome (AIDS) Increased eosinophils werefound in 3.3% (8/239) of patients with AIDS undergoing BAL. Sixof these patients werefound to have P. carinii pneumonia, one had cryptococcal pneumonia, and one had S. aureus pneumonia. Other investigators have found that BAL eosinophils > 5% may be found in as many as 15070 of patients with AIDS-associated P. carinii pneumonia (24). All but one of our patients improved with antimicrobial therapy directed toward the specific pathogen identified, and none received corticosteroids. The single patient who died received initial treatment for P. carinii and responded with complete clearance of both the Pneumocystis organisms and the eosinophils in a second BAL done 2 wk later. However, he ultimately died from progressive respiratory failure. Idiopathic Eosinophilic Pneumonia There are at least four idiopathic pulmonary eosinophilic syndromes, including Churg-Strauss syndrome (allergicgranulomatosis) (32), simple pulmonary eosinophilia (Leffler's syndrome) (33), chronic eosinophilic pneumonia (34, 35), and acute eosinophilic pneumonia (21, 22). Because the cause of all ofthese syndromes is unknown, it is possible that they represent a varied host response to a common group of as-yet-to-be identified etiologic agents. Acute eosinophilic pneumonia accounted for 10% (5/48) of the patients with 5070 or more BAL eosinophils. Four of these patients have been previously reported (21). The fifth patient was a man, 65 yr of age, who had new diffuse pulmonary infiltrates and was unable to be weaned from the mechanical ventilator after an uncomplicated abdominal aneurysm repair. All the patients with acute eosinophilic pneumonia had very high percentages of BAL eosinophils (mean = 40% eosinophils), and in no patient was the correct diagnosis suspected prior to BAL. Corticosteroids were curative in all patients. The distinction of acute eosinophilic pneumonia from other causes of respiratory failure is critical because of the prompt and dramatic response to corticosteroids by patients with this syndrome. 1\vo patients had chronic eosinophilic
645
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pneumonia. Both had relativelyhigh percentages of BAL eosinophils (500/0 and 21%) and both had dramatic clinical improvement following corticosteroid therapy. Chronic eosinophilic pneumonia is known to be commonly associated with BAL eosinophilia (12-16, 36, 37) and, in fact, in the appropriate clinical setting, BAL eosinophilia alone without a lung biopsy may be adequate for diagnosis (16).
Drug-induced Lung Disease In six patients, BAL eosinophilia was attributed to drug-induced lung disease. The implicated drugs included methotrexate, tamoxifen, nitrofurantoin, aspirin, naproxen, and antiarrhythmic agents. Pulmonary disease complicates methotrexate therapy in 5 to 8% of patients receiving the drug either as an antineoplastic agent (38) or as a treatment for rheumatoid arthritis (39) and accounted for one of our patients. However, despite the frequency with which peripheral blood eosinophilia accompanies methotrexate-induced lung disease (38), previous reports utilizing BAL have described a lymphocytic alveolitis (40, 41); to our knowledge, this is the first report of BAL eosinophilia in conjunction with methotrexate-induced lung disease. The patient involved had been receivingmethotrexate for 2 yr for refractory rheumatoid arthritis when he developed an 8-day history of dyspnea, which rapidly progressed to respiratory failure. His BAL demonstrated 20% eosinophils and 12% lymphocytes, and he had complete resolution of all clinical, laboratory, and radiographic abnormalities after the drug was discontinued and a brief course of corticosteroids was administered. The patient with tamoxifen-induced lung disease had been receiving that medication as adjunctive therapy for breast cancer for 4 months when she developed subacute onset of cough and a left lower lobe infiltrate. There was mild peripheral blood eosinophilia (50/0) and her BAL demonstrated a mixed alveolitis composed of eosinophils (14%) and lymphocytes (19%). Her symptoms, radiographic abnormalities, and peripheral blood eosinophilia resolvedafter tamoxifen was discontinued; peripheral blood eosinophilia alone without symptoms or pulmonary infiltrates recurred when the medication was later resumed. To the best of our knowledge, tamoxifen has not been previously reported to cause lung disease. Nitrofurantoin is well known to cause interstitial lung disease (17)and has been reported to cause blood eosinophilia (42).
Our patient had taken nitrofurantoin chronically for recurrent urinary tract infections and had a 2-month history of cough, dyspnea, and pleuritic chest pain associated with diffuse interstitial pulmonary infiltrates. His BAL demonstrated 15% eosinophils and 31% lymphocytes; however, his peripheral blood count and differential were normal. After a brief course of corticosteroids and discontinuation of nitrofurantoin, all symptoms ceased. One patient developed fatal adult respiratory distress syndrome (ARDS) after a salicylate overdose. A BAL performed prior to the patient's death revealed the presence of 5% eosinophils and 40% neutrophils. Salicylates are known to cause ARDS (43); however,the usual BAL finding in typical ARDS is an increased percentage of neutrophils without eosinophils (44). Another nonsteroidal, anti-inflammatory drug (naproxen) has been reported to cause pulmonary eosinophilia (45) and was responsible for BAL eosinophilia accompanied by peripheral blood eosinophilia in one of our patients. This patient developed dyspnea and hypoxemia associated with a normal chest radiograph and 32% BAL eosinophils shortly after beginning a course of naproxen for degenerativearthritis. Symptoms and peripheral blood eosinophilia resolved after discontinuing naproxen and after a brief course of corticosteroids. Antiarrhythmic agents were implicated as the cause of BAL eosinophilia in one patient who had recently undergone mitral valvereplacement followinga myocardial infarction and who received a brief course of quinidine followedby procainamide. A BAL was performed because of the presence of new pulmonary infiltrates and hypoxemia, and demonstrated 12% eosinophils and 64% neutrophils. Although the infiltrates and hypoxemia improved after quinidine was discontinued, and after the administration of a short course of corticosteroids, the patient died of complications of his underlying heart disease. Procainamide and quinidine have both been noted to cause drug-induced systemic lupus erythematosus with associated interstitial lung disease (46-48). Because both of these drugs were administered in close temporal proximity to the development of the patient's pulmonary disease,it was not possible to determine which of the two medications was responsible.
Hodgkin's Disease Increased BAL eosinophils were found in two patients with Hodgkin's disease.
Both patients developeda several-dayhistory of cough and new bilateral pulmonary infiltrates. In neither case was an infectious agent identified, and both patients improved spontaneously. Although lung eosinophils may accompany the malignant inftltratesin pulmonary Hodgkin's disease (49), pulmonary eosinophilia can also occur secondary to cytotoxic agents used in the treatment of this malignancy (50). Both of these patients had recently receivedcombination chemotherapy, and it is unclear if the BAL eosinophilia was secondary to drug effect or pulmonary Hodgkin's disease.
Asthma The eosinophil plays a key role in the pathogenesis of asthma, and, in fact, asthma has been referred to as "chronic eosinophilic bronchitis" (51). Both BAL and blood eosinophilia are common (18-20). Two of our patients with increased BAL eosinophilia had asthma. An additional patient with presumed chronic bronchitis from cigarette smoking was found to have a very high BAL eosinophil percentage (28%). It is possible that this patient may have had a component of asthma.
Helminth Infection Pulmonary eosinophilia is known to be caused by a number of helminths including Ascarislumbricoides, Ankylostomum
braziliense, Trichuris trichiura, Taenia saginata, Distomum hepaticum, Strongyloides intesiinalis, Toxacara canis, and the filariae (Wuchereria bancrofti and Brugia malayiy (27,33,52). One of our patients with an elevated BAL eosinophil percentage had Toxacara canis (viscerallarva migrans)associatedwith cough, dyspnea, chest pain, peripheral blood eosinophilia, and diffuse alveolar inftltrates on chest X-ray. He improved completely with only supportive care.
Bacterial Pneumonia Only one of 65 immunocompetent patients who underwent bronchoscopy in order to identify the cause of pneumonia was found to have BAL eosinophilia. This patient was diagnosed with Branhame//a catarrhalis pneumonia on the basis of sputum culture, clinical findings, and radiographic findings.
Bone Marrow Transplant Despite the fact that BAL was performed in a large number of bone marrow transplant patients in our study (75), only one patient was found to have> 5% BAL eosinophils. That patient was an ll-yr-old
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girl with acute myelogenous leukemia who had received bone marrow transplantation 4 months previously. She was admitted with graft-versus-host disease complicated by disseminated cryptococcal infection that ultimately caused her death. A BAL done 2 wk after admission revealed the presence of 9010 eosinophils and 80% neutrophils. Although pulmonary eosinophilia has been noted with fungal infections (52, 53), it is equally possible that the BAL eosinophilia noted in this case was caused by either drug effect or graft-versus-host disease. Summary In conclusion, BAL eosinophil percentages of 5% or more was a relatively uncommon occurrence, being present in only 4.5% of all BAL performed at our hospital during a 33-month period. The most frequent causes of an increased BAL eosinophil percentage in our patient population were the interstitial lung diseases, AIDS-associated pneumonias, the idiopathic eosinophilic pneumonias, and drug-induced lung diseases. These four syndromes accounted for 84% of all patients with 5% or more BAL eosinophils. In contrast, BAL eosinophilia is rare in immunocompromised patients without AIDS, patients with ARDS, patients with lung cancer,and patients with communityacquired pneumonia. BAL has achieved success in diagnosing a variety of pulmonary infections. Since BAL eosinophilia is most frequently seen in a limited number of syndromes, this finding extends the importance of BAL as a diagnostic tool in patients presenting with unexplained pulmonary infiltrates. In all patients with BAL eosinophilia, it is important to establish the etiology ofthe finding because it can have different therapeutic implications depending on the underlying disease. These findings help place perspective on pulmonary eosinophilia for both clinicians formulating differential diagnoses and pulmonary researchers investigatingfacets of pulmonary cell biology. References 1. Reynolds HY. Bronchoalveolar lavage. Am Rev Respir Dis 1987; 135:250--63. 2. Hunninghake GW, Gadek JE, Kawanami 0, Ferrans VJ, Crystal RG. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol 1979; 97:149-206. 3. Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolar lavage: role in the pathogenesis, diagnosis, and management of interstitial lung disease. Ann Int Med 1985; 102:93-108.
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lar lavage in the evaluation of methotrexate lung disease. Thorax 1987; 42:652-5. 42. Holmberg L, Boman G. Pulmonary reactions to nitrofurantoin; 447 cases reported to the Swedish Adverse Drug Reaction Committee 1966-1976. Eur J Respir Dis 1981; 62:180-9. 43. Heffner JE, Sahn SA. Salicylate-induced pulmonary edema: clinical features and prognosis. Ann Int Med 1981; 95:405-9. 44. Weiland JE, Davis Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome: clinical and pathophysiologic significance. Am Rev Respir Dis 1986; 133:218-25.
w.B,
45. Nader DA, Schillaci RF. Pulmonary infiltrates with eosinophilia due to naproxen. Chest 1983; 83:280-2. 46. Weinstein A. Drug-induced systemic lupus erythematosus. Prog Clin Immunol 1980; 4:1-21. 47. Blomgren SE, Condemi JJ, Vaughan JH. Procainamide-induced lupus erythematosus: clinical and laboratory observations. Am J Med 1972; 52:338-48. 48. Dubois EL. Procainamide induction of a systemic lupus erythematosus-like syndrome: presentation of six cases, review of the literature, and analysis and follow-up of reported cases. Medicine 1969; 48:217-28.
49. Linder J, Rennard S. Bronchoalveolar lavage. Chicago: American Society of Clinical Pathologists, 1988; 174-6. 50. Cooper JA, White DA, Matthay RA. Druginduced pulmonary disease, part 1: cytotoxic drugs. Am Rev Respir Dis 1986; 133:321-40. 51. Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989; 321:1517-27. 52. Liebow AA, Carrington CB. The eosinophilic pneumonias. Medicine 1969; 48:251-85. 53. Lombard CM, Thzelaar MD, Krasne DL. Pulmonary eosinophilia in coccidioidal infections. Chest 1987; 91:734-6.
JAMES N. ALLEN,3 W. BRUCE DAVIS, and ERIC R. PACHT
Introduction
Bronchoalveolar lavage (HAL) is frequently used as a diagnostic and staging procedure in a variety of pulmonary diseases (1-5). Normal HAL fluid contains less than 1070 eosinophils (2), but increased eosinophils have been observed in interstitial lung diseases (6-11),chronic eosinophilic pneumonia (12-16),drug-induced lung disease (17),asthma (18- 20), acute eosinophilic pneumonia (21- 23), Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome (AIDS) (24-26), and filarial infection (27). Although the incidence of HAL eosinophilia has been reported in several specific diseases (6, 7, 12, 24), littie is known about its incidence or diagnostic significance across a broad spectrum of pulmonary diseases commonly encountered in a general hospital patient population. To determine the common causes and differential diagnosis of BAL eosinophilia, we retrospectively reviewed the HAL cellular differentials on 1,075 consecutive patients over a 33-month period. Forty-eight of these patients had HAL differentials showing 5070 or more eosinophils. The clinical characteristics, chest radiographs, pulmonary function tests, and laboratory findings of these patients are reviewed. Methods
Patient Selection One thousand seventy-fivepatients were evaluated by fiberoptic bronchoscopy with bronchoalveolar lavage for diagnostic purposes by the Pulmonary Division at Ohio State University Hospital from January 1987 through September 1989. Sixteenpatients wereexcluded because of insufficient clinical information, leaving 1,059 patients available for the study. None of these 16patients had increased numbers of BAL eosinophils. The pulmonary attending physicians' diagnoses at the time of bronchoscopy are listed in table 1. Information was obtained retrospectively from the bronchoscopy log, hospital and clinic charts, and microbiology division records. Patients 642
SUMMARY We determined the Incidence of Increased bronchoalveolar IlVIge (BAL) fluid eosinophil percentages In 1,059consecutive patients undergoing bronchoscopy with BAL over a 33-month period. Forty-eight (48) patients were found to have 5% or more BAL eoslnophlls. The most common causes for Increased BAL eoslnophlls ware Interstitial lung diseases (40% of patients), acquired Immunodeficiency syndrome (AIDS)-assoclated pneumonia (17%of petlents), Idlopethlc eosinophilic pneumonia (15% of patients), and drug-Induced lung disease (12% of patients). Together, these four diagnoses accounted for 84% of all patients. In contrast, eoslnophlls ware uncommon In the BAL of patients with the adUlt respiratory distress syndrome, lung cancer, communlty-acqulred pneumonia, or Immunocompromlslng diseases other than AIDS. The finding of Increased BAL eoslnophlls WlS most helpful In patients presenting with unexplained pulmonary Infiltrates. In these patients, this finding WlS often an Importsnt clue to the final diagnosis. We conclude that although the findIng of an Increased percentage of BAL eoslnophllsls uncommon, when present It Is relatively specific for a limited number of diseases. AM REV RESPIR DIS 1990; 142:842-647
were included in the study if 5010 or more eosinophils were present on the BAL cellular differential.
Patient Diagnoses For the purpose of this study, idiopathic pulmonary fibrosis was diagnosed if patients had pulmonary function tests demonstrating restrictive physiology, diffuse idiopathic interstitial infIltrates on chest radiographs, a compatible clinical history, and lung biopsy demonstrating fibrosis and/or BAL demonstrating an inflammatory alveolitis. All patients with sarcoidosis had lung biopsies revealingnoncaseating granulomas in the absence of infection. Systemic lupus erythematosus-associated interstitial lung disease was diagnosed in patients with a previous diagnosis of systemic lupus erythematosus who developed interstitial infiltrates accompanied by pulmonary function abnormalities in the absence of infection. A diagnosis of AIDS was made if a patient tested positively for the HIV antigen by the western blot analysis and developed an opportunistic infection. P. carinii pneumonia and cryptococcal pneumonia werediagnosed on the basis of BAL examination. The diagnosis of Staphylococcus aureus pneumonia in a patient with AIDS was based on clinical and radiographic findings plus positive blood and sputum cultures. The diagnostic criteria for the patients with acute eosinophilic pneumonia have been previously described (21). Chronic eosinophilic pneumonia was diagnosed if a patient had chronic dyspnea, idiopathic interstitial in-
filtrates on chest radiographs, restrictive physiology, pulmonary eosinophilia, and prompt resolution of clinical and radiographic abnormalities after the administration of corticosteroids. Drug-induced lung disease was diagnosed if pulmonary disease developed as a complication of a drug overdose or if it developed shortly after the initiation of a medication and resolved once the offending medication was removed. In these patients, there was no other identifiable cause of the patient's lung disease. The diagnosis of Hodgkin's disease was based on histologic findings. Asthma was considered to be present if patients had recurrent reversible bronchospasm in the absence of a history of cigarette smoking. Chronic bronchitis was diagnosed if a patient had a history of cigarette smoking and recurrent bouts of cough with sputum production. The diagnosis of Toxocara infection was based on serologic fmdings in association with an appropri(Receivedin originalform December 18,1989and in revised form March 29, 1990) 1 From the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, The Ohio State University Hospitals, Columbus, Ohio. 2 Correspondence and requests for reprints should be addressed to James N. Allen, M.D., N-325 Means Hall, 1654 Upham Drive, Columbus, OH 43210. J Parker B. Francis Fellow in Pulmonary Research.
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TABLE 1
value. A reduced diffusing capacity was defined as being less than 80070 of the predicted value after correction for the total lung capacity and hemoglobin concentration.
DIAGNOSIS PRIOR TO BRONCHOSCOPY IN 1,059 PATIENTS
Prebronchoscopy Diagnosis
Number of Patients (%)'
AIDS-associated pneumonia Immunocompromised with infiltrates Interstitial lung disease Bone marrow transplant with infiltrates Normal hosts with unexplained infiltrates Suspected cancer Pneumonia Normal volunteer Adult Respiratory Distress Syndrome Cough Suspected bronchiolitis obliterans Suspected tuberculosis Unexplained hemoptysis Asthma Unexplained hypoxemia Total
239 199 183 75 71 69 65 46 29 22 20 19 17 3 2
Patients with Increased BAL Eosinophils (%)t
(22.6) (18.8) (17.3) (7.1) (6.7) (6.5) (6.1) (4.3) (2.7) (2.1) (1.9) (1.8) (1.6) (0.3) (0.2)
1,059 (100)
Statistical Analysis All results are expressed as mean ± standard error of the mean.
8 (17)
2 (4) 19 (40) 1 (2) 13 (27)
o
Results
1 (2)
The 1,059patients who underwent bronchoalveolar lavage represented a wide spectrum of pulmonary disease (table 1). Forty-eight (4.5%) of these patients had 5070 or more eosinophils on BAL. There were 20 female and 28 male patients who ranged from 11 to 80 yr of age. Thirty patients underwent BAL as inpatients and 18 as outpatients. Table 2 lists the final diagnoses of the 48 patients with increased BAL eosinophils. The most common cause of BAL eosinophilia was idiopathic pulmonary fibrosis (14 patients), followed by AIDS-associated P. carinii pneumonia (6 patients), druginduced lung disease (6 patients), acute eosinophilic pneumonia (5 patients), and sarcoidosis (3 patients). Systemic lupus erythematosus, AIDS-associated pneumonia other than P. carinii pneumonia, chronic eosinophilic pneumonia, Hodgkin's disease, and asthma each accounted for 2 patients. Chronic bronchitis, helminth infection, bone marrow transplant-associated cryptococcalpneumonia, and bacterial pneumonia each accounted for 1 patient. The prebronchoscopy diagnosis of unexplained infiltrates (table 1) deserves special mention because 11 of our 48 patients with BAL eosino-
o 1 (2) 2 (4)
o o o 1 (2)
o 48 (100)
• Percentage of the 1,059 patients undergoing bronchoalveolar lavage. Percentage of the 48 patients having increased BAL eosinophils.
t
ate clinical history. Disseminated cryptococcal infection was diagnosed in a bone marrow transplant recipient from whom Cryptococcusneoformans was cultured from the blood, bone marrow, spinal fluid, and BAL fluid. Bacterial pneumonia was diagnosed in an otherwise healthy patient who had positive sputum cultures in conjunction with compatible clinical and radiographic findings.
Bronchoalveolar Lavage Fiberoptic bronchoscopy and bronchoalveolar lavage was performed as previously described (2, 28). After administering local anesthesia of the nose and pharynx with 4% lidocaine, the bronchoscope was inserted into the nose of nonintubated patients or through the endotracheal tube of patients receiving mechanical ventilation. The tip of the bronchoscope was wedged in a distal portion of a bronchus, usually in the right middle lobe or lingula, and bronchoalveolar lavage was performed by instilling five 20-ml aliquots of sterile saline through the bronchoscope. All samples were cytocentrifuged and the pellets were examined for cellular differentials with the use ofthe Diff-Quik'"stain (AHS Del Caribe, Aguada, PR). In each sample, 300 cells were counted by a laboratory technician experienced in BAL cellular analysis or by an attending pathologist. In patients with suspected opportunistic pneumonia, samples werealso examined with a battery of tests consisting of Gram's, acid-fast, and toluidine blue stains by the microbiology division. Bacterial, fungal, mycobacterial, viral, and Legionella cultures were obtained as clinically indicated. Additionally, when malignancy was suspected, a Papanicolaou stain was examined by a cytologist. A review of 46 normal volunteers undergoing BAL for research purposes in our laboratories during the study period revealed
the following normal values for BAL cellular differentials: 89.3 ± 1.2% alveolar macrophages, 8.9 ± 1.1%lymphocytes, 1.3 ± 0.3% neutrophils, and 0.5 ± 0.1% eosinophils.
Lung Physiology Pulmonary function tests were performed with the use of a Collins DS system (Warren E. Collins, Braintree, MA), according to the standards of the American Thoracic Society (29, 30). Lung volumes were determined by the helium dilution technique, and diffusing capacities were determined by the singlebreath technique. Obstructive lung disease was defined as a forced expiratory volume in 1 s to forced vital capacity ratio of lessthan 75%. Restrictive lung disease was defined as a total lung capacity of lessthan 80% of the predicted
TABLE 2 FINAL DIAGNOSIS IN PATIENTS WITH GREATER THAN 5% BAL EOSINOPHILS Diagnosis
Number of Patients (%)'
Interstitial lung disease Idiopathic pulmonary fibrosis Sarcoidosis Systemic lupus erythematosus AIDS-associated pneumonia Pneumocystis carinii Other Idiopathic eosinophilic lung diseases Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Drug-induced lung disease Hodgkin's disease Asthma Chronic bronchitis Helminthic infection Bone marrow transplant Bacterial pneumonia
19 14 3 2
(40) (29) (6) (4) 8 (17) 6 (13)
Total
48 (100)
2 (4)
7 (15) 5 (10) 2 (4) 6 (12) 2 (4) 2 (4) 1 (2)
1 (2) 1 (2) 1 (2)
• Percentage of 48 patients with increased BAL eosinophils.
Mean BAL Eosinophil % (range)
13 (5-51) 6 (5-8) 5 (5-5) 20 (7-43) 7 (5-10) 42 35 16 5 8 28 17
9 6
(28-57) (21-50) (5-32) (5-6) (6-11)
644
philia were in this category at the time patients except one who had sarcoidosis. of bronchoscopy, including 5 of the 6 pa- There was no clear relationship between tients with the final diagnosis of drug- the degree of hypoxemia and the percentinduced lung disease, all 5 patients with age of BAL eosinophils. acute eosinophilic pneumonia, and the Discussion patient with helminth infection. In these patients, the finding of BAL eosinophils Increased BAL eosinophil percentages was instrumental in determining the fi- have been reported in several pulmonary nal diagnosis. diseases (6, 7, 12,24). Wehave found that The most common symptom of pa- the incidence of BAL eosinophilia is reltients with increased BAL eosinophil per- atively low, occurring in only 4.5% of all centages was dyspnea, which was noted BALs performed at our hospital over a by 81OJo of patients; cough was noted by 21-month period. Furthermore, BAL eo67% and chest pain by 31OJo of patients. sinophilia was relatively specific for a Crackles were noted on physical exami- small number of diseases in our patient nation in 71% of patients, whereas fever population, with four syndromes (interand audible wheezing was less frequent stitial lung disease, AIDS-associated (40% and 12%, respectively). pneumonia, idiopathic eosinophilicpneuEighteen patients with increased BAL monia, and drug-induced lung disease) eosinophils werecigarette smokers. There accounting for 84% of patients. It apwas no relationship between BAL eosin- pears from our patients, as well as a reophil numbers and smoking history. viewof the literature, that increased BAL Interestingly, all 5 patients with acute eosinophils can have different prognoseosinophilic pneumonia were cigarette tic and therapeutic implications dependsmokers. ing on the patients' primary illness. Total peripheral blood eosinophil Interstitial Lung Disease counts were available in 40 of the 48 patients. The mean eosinophil count was Interstitial lung disease was the most 575 ± 179/mm3 (normal 50 to 350/ common cause of increased BAL eomm'), The highest mean peripheraleosino- sinophils; 5% or more BAL eosinophils phil counts were seen in chronic eosin- werefound in 10% (19/183) of all patients ophilic pneumonia (2,624 ± 2,624/mm 3 ) , with interstitial lung disease who underhelminth infection (2,072/mm3 ) , drug- went BAL. Of the patients with interstiinduced lung disease (690 ± 242/mm3 ) , tiallung disease, idiopathic pulmonary and idiopathic pulmonary fibrosis (650 fibrosis was the most common cause of ± 425/mm3) . Normal peripheral blood BAL eosinophilia, accounting for 14paeosinophil counts were seen in the HIV- tients. Other investigators have found associated pneumonias,sarcoidosis, Hodg- that BAL eosinophilia occurs frequentkin's disease, systemic lupus erythem- ly in idiopathic pulmonary fibrosis and atosus-associated lung disease, acute eo- may be present in as many as 45% of pasinophilic pneumonia, and the patient tients (6, 7, 12). Additionally, increased with bone marrow transplant-associated BAL eosinophil percentages have been demonstrated to portend a poor prognocryptococcal pneumonia. Chest radiographs were available for sis in idiopathic pulmonary fibrosis (6, all patients with increased BAL eosino- 9, 11) and have been shown to correlate phil percentages. The radiographic find- with more severe clinical impairment at ings werediverseand weregenerally those the time of initial diagnosis (10). of the patient's underlying disease. There Three patients with sarcoidosis were was no common radiographic abnormal- found to have BAL eosinophilia. The ality specific to the patients with increased veolitis of sarcoidosis is typically comBAL eosinophils. 1\vo patients had nor- posed of lymphocytes, especiallyT helper mal chest radiographs at the time of their lymphocytes (31). However, eosinophils bronchoscopy; one had chronic eosino- accounting for more than 5% of BAL philic pneumonia and the other had drug- effector cells have been noted to occur induced lung disease. in up to 7% of patients with sarcoidosis Pulmonary function tests were abnor- (12). All three of our patients had relamal in all 28 patients in whom they were tively modest percentages of eosinophils obtained. Restrictivelung physiology was (5,6, and 8%) but had high percentages seen in 21 patients, obstructive physiolo- of lymphocytes (31,21,and 29%, respecgy was seen in 15patients, and a reduced tively) on BAL. diffusing capacity was seen in 14patients. 1\vo patients with increased BAL eoArterial blood gases were measured in 37 sinophils had interstitial lung disease aspatients. The Pol was diminished in all sociated with systemiclupus erythemato-
ALLEN, DAVIS, AND PACHT
sus. BAL eosinophilia has been previously reported to be common in patients with this entity, which occurred in up to 26% of patients (12).
Acquired Immunodeficiency Syndrome (AIDS) Increased eosinophils werefound in 3.3% (8/239) of patients with AIDS undergoing BAL. Sixof these patients werefound to have P. carinii pneumonia, one had cryptococcal pneumonia, and one had S. aureus pneumonia. Other investigators have found that BAL eosinophils > 5% may be found in as many as 15070 of patients with AIDS-associated P. carinii pneumonia (24). All but one of our patients improved with antimicrobial therapy directed toward the specific pathogen identified, and none received corticosteroids. The single patient who died received initial treatment for P. carinii and responded with complete clearance of both the Pneumocystis organisms and the eosinophils in a second BAL done 2 wk later. However, he ultimately died from progressive respiratory failure. Idiopathic Eosinophilic Pneumonia There are at least four idiopathic pulmonary eosinophilic syndromes, including Churg-Strauss syndrome (allergicgranulomatosis) (32), simple pulmonary eosinophilia (Leffler's syndrome) (33), chronic eosinophilic pneumonia (34, 35), and acute eosinophilic pneumonia (21, 22). Because the cause of all ofthese syndromes is unknown, it is possible that they represent a varied host response to a common group of as-yet-to-be identified etiologic agents. Acute eosinophilic pneumonia accounted for 10% (5/48) of the patients with 5070 or more BAL eosinophils. Four of these patients have been previously reported (21). The fifth patient was a man, 65 yr of age, who had new diffuse pulmonary infiltrates and was unable to be weaned from the mechanical ventilator after an uncomplicated abdominal aneurysm repair. All the patients with acute eosinophilic pneumonia had very high percentages of BAL eosinophils (mean = 40% eosinophils), and in no patient was the correct diagnosis suspected prior to BAL. Corticosteroids were curative in all patients. The distinction of acute eosinophilic pneumonia from other causes of respiratory failure is critical because of the prompt and dramatic response to corticosteroids by patients with this syndrome. 1\vo patients had chronic eosinophilic
645
SAL EOSINOPHILS
pneumonia. Both had relativelyhigh percentages of BAL eosinophils (500/0 and 21%) and both had dramatic clinical improvement following corticosteroid therapy. Chronic eosinophilic pneumonia is known to be commonly associated with BAL eosinophilia (12-16, 36, 37) and, in fact, in the appropriate clinical setting, BAL eosinophilia alone without a lung biopsy may be adequate for diagnosis (16).
Drug-induced Lung Disease In six patients, BAL eosinophilia was attributed to drug-induced lung disease. The implicated drugs included methotrexate, tamoxifen, nitrofurantoin, aspirin, naproxen, and antiarrhythmic agents. Pulmonary disease complicates methotrexate therapy in 5 to 8% of patients receiving the drug either as an antineoplastic agent (38) or as a treatment for rheumatoid arthritis (39) and accounted for one of our patients. However, despite the frequency with which peripheral blood eosinophilia accompanies methotrexate-induced lung disease (38), previous reports utilizing BAL have described a lymphocytic alveolitis (40, 41); to our knowledge, this is the first report of BAL eosinophilia in conjunction with methotrexate-induced lung disease. The patient involved had been receivingmethotrexate for 2 yr for refractory rheumatoid arthritis when he developed an 8-day history of dyspnea, which rapidly progressed to respiratory failure. His BAL demonstrated 20% eosinophils and 12% lymphocytes, and he had complete resolution of all clinical, laboratory, and radiographic abnormalities after the drug was discontinued and a brief course of corticosteroids was administered. The patient with tamoxifen-induced lung disease had been receiving that medication as adjunctive therapy for breast cancer for 4 months when she developed subacute onset of cough and a left lower lobe infiltrate. There was mild peripheral blood eosinophilia (50/0) and her BAL demonstrated a mixed alveolitis composed of eosinophils (14%) and lymphocytes (19%). Her symptoms, radiographic abnormalities, and peripheral blood eosinophilia resolvedafter tamoxifen was discontinued; peripheral blood eosinophilia alone without symptoms or pulmonary infiltrates recurred when the medication was later resumed. To the best of our knowledge, tamoxifen has not been previously reported to cause lung disease. Nitrofurantoin is well known to cause interstitial lung disease (17)and has been reported to cause blood eosinophilia (42).
Our patient had taken nitrofurantoin chronically for recurrent urinary tract infections and had a 2-month history of cough, dyspnea, and pleuritic chest pain associated with diffuse interstitial pulmonary infiltrates. His BAL demonstrated 15% eosinophils and 31% lymphocytes; however, his peripheral blood count and differential were normal. After a brief course of corticosteroids and discontinuation of nitrofurantoin, all symptoms ceased. One patient developed fatal adult respiratory distress syndrome (ARDS) after a salicylate overdose. A BAL performed prior to the patient's death revealed the presence of 5% eosinophils and 40% neutrophils. Salicylates are known to cause ARDS (43); however,the usual BAL finding in typical ARDS is an increased percentage of neutrophils without eosinophils (44). Another nonsteroidal, anti-inflammatory drug (naproxen) has been reported to cause pulmonary eosinophilia (45) and was responsible for BAL eosinophilia accompanied by peripheral blood eosinophilia in one of our patients. This patient developed dyspnea and hypoxemia associated with a normal chest radiograph and 32% BAL eosinophils shortly after beginning a course of naproxen for degenerativearthritis. Symptoms and peripheral blood eosinophilia resolved after discontinuing naproxen and after a brief course of corticosteroids. Antiarrhythmic agents were implicated as the cause of BAL eosinophilia in one patient who had recently undergone mitral valvereplacement followinga myocardial infarction and who received a brief course of quinidine followedby procainamide. A BAL was performed because of the presence of new pulmonary infiltrates and hypoxemia, and demonstrated 12% eosinophils and 64% neutrophils. Although the infiltrates and hypoxemia improved after quinidine was discontinued, and after the administration of a short course of corticosteroids, the patient died of complications of his underlying heart disease. Procainamide and quinidine have both been noted to cause drug-induced systemic lupus erythematosus with associated interstitial lung disease (46-48). Because both of these drugs were administered in close temporal proximity to the development of the patient's pulmonary disease,it was not possible to determine which of the two medications was responsible.
Hodgkin's Disease Increased BAL eosinophils were found in two patients with Hodgkin's disease.
Both patients developeda several-dayhistory of cough and new bilateral pulmonary infiltrates. In neither case was an infectious agent identified, and both patients improved spontaneously. Although lung eosinophils may accompany the malignant inftltratesin pulmonary Hodgkin's disease (49), pulmonary eosinophilia can also occur secondary to cytotoxic agents used in the treatment of this malignancy (50). Both of these patients had recently receivedcombination chemotherapy, and it is unclear if the BAL eosinophilia was secondary to drug effect or pulmonary Hodgkin's disease.
Asthma The eosinophil plays a key role in the pathogenesis of asthma, and, in fact, asthma has been referred to as "chronic eosinophilic bronchitis" (51). Both BAL and blood eosinophilia are common (18-20). Two of our patients with increased BAL eosinophilia had asthma. An additional patient with presumed chronic bronchitis from cigarette smoking was found to have a very high BAL eosinophil percentage (28%). It is possible that this patient may have had a component of asthma.
Helminth Infection Pulmonary eosinophilia is known to be caused by a number of helminths including Ascarislumbricoides, Ankylostomum
braziliense, Trichuris trichiura, Taenia saginata, Distomum hepaticum, Strongyloides intesiinalis, Toxacara canis, and the filariae (Wuchereria bancrofti and Brugia malayiy (27,33,52). One of our patients with an elevated BAL eosinophil percentage had Toxacara canis (viscerallarva migrans)associatedwith cough, dyspnea, chest pain, peripheral blood eosinophilia, and diffuse alveolar inftltrates on chest X-ray. He improved completely with only supportive care.
Bacterial Pneumonia Only one of 65 immunocompetent patients who underwent bronchoscopy in order to identify the cause of pneumonia was found to have BAL eosinophilia. This patient was diagnosed with Branhame//a catarrhalis pneumonia on the basis of sputum culture, clinical findings, and radiographic findings.
Bone Marrow Transplant Despite the fact that BAL was performed in a large number of bone marrow transplant patients in our study (75), only one patient was found to have> 5% BAL eosinophils. That patient was an ll-yr-old
ALLEN, DAVIS, AND PACHT
646
girl with acute myelogenous leukemia who had received bone marrow transplantation 4 months previously. She was admitted with graft-versus-host disease complicated by disseminated cryptococcal infection that ultimately caused her death. A BAL done 2 wk after admission revealed the presence of 9010 eosinophils and 80% neutrophils. Although pulmonary eosinophilia has been noted with fungal infections (52, 53), it is equally possible that the BAL eosinophilia noted in this case was caused by either drug effect or graft-versus-host disease. Summary In conclusion, BAL eosinophil percentages of 5% or more was a relatively uncommon occurrence, being present in only 4.5% of all BAL performed at our hospital during a 33-month period. The most frequent causes of an increased BAL eosinophil percentage in our patient population were the interstitial lung diseases, AIDS-associated pneumonias, the idiopathic eosinophilic pneumonias, and drug-induced lung diseases. These four syndromes accounted for 84% of all patients with 5% or more BAL eosinophils. In contrast, BAL eosinophilia is rare in immunocompromised patients without AIDS, patients with ARDS, patients with lung cancer,and patients with communityacquired pneumonia. BAL has achieved success in diagnosing a variety of pulmonary infections. Since BAL eosinophilia is most frequently seen in a limited number of syndromes, this finding extends the importance of BAL as a diagnostic tool in patients presenting with unexplained pulmonary infiltrates. In all patients with BAL eosinophilia, it is important to establish the etiology ofthe finding because it can have different therapeutic implications depending on the underlying disease. These findings help place perspective on pulmonary eosinophilia for both clinicians formulating differential diagnoses and pulmonary researchers investigatingfacets of pulmonary cell biology. References 1. Reynolds HY. Bronchoalveolar lavage. Am Rev Respir Dis 1987; 135:250--63. 2. Hunninghake GW, Gadek JE, Kawanami 0, Ferrans VJ, Crystal RG. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol 1979; 97:149-206. 3. Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolar lavage: role in the pathogenesis, diagnosis, and management of interstitial lung disease. Ann Int Med 1985; 102:93-108.
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