Idiopathic Acute Eosinophilic Pneumonia A Study of 22 Patients Francois Philit, Benedicte Etienne-Mastroıanni, Antoine Parrot, Claude Guerin, Dominique Robert, ¸ ´ ´ ¨ ´ Jean-Francois Cordier, and the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” ¸ Pulmonaires (GERM“O”P) ´ ´ ˆ ˆ Service d’Assistance Respiratoire et Reanimation Medicale, Hopital de la Croix Rousse; Service de Pneumologie, Hopital Louis Pradel, ˆ Lyon; and Service de Pneumologie, Hopital Tenon, Paris, France Idiopathic acute eosinophilic pneumonia (IAEP) is characterized by METHODS acute febrile respiratory failure associated with diffuse radiographic infiltrates and pulmonary eosinophilia. We conducted a multicenter Recruitment of Cases retrospective study to characterize this rare clinical entity further This study was undertaken by the Groupe d’Etudes et de Recherche sur and to improve its diagnostic criteria. A total of 13 male and 9 les Maladies “Orphelines” Pulmonaires (GERM“O”P), a collaboration female patients (mean age: 29 15.8 years) presented with severe among French pulmonary physicians that was founded in 1993 and hypoxemia (PaO2/fraction of inspired oxygen ratio 156 74.1) dedicated to the study of rare (so-called orphan) pulmonary diseases. requiring mechanical ventilation in 14 cases. Bronchoalveolar la- By January 2001, more than 1,300 cases of orphan pulmonary diseases vage was performed on all patients and showed 54.4 19.2% had been reported to the GERMOP registry. eosinophils on differential cell count, but no open-lung biopsies In June 1999, we sent a letter to 5,300 physician specialists in inten- were done. No clinical differences were found between patients sive care and/or respiratory medicine in France, Belgium, and Switzer- seen at less than 7 days (n 15) or at 7 to 31 days (n 7) from land asking them to report to the registry the cases of IAEP they had the onset of IAEP. A total of 12 patients met the clinical criteria of previously observed. acute lung injury, and eight of these patients met the criteria for Selection of Cases acute respiratory distress syndrome. All patients recovered, either spontaneously (6) or on corticosteroid treatment (16). No relapses In November 1999, a detailed questionnaire was sent to each physician occurred. We conclude that: (1 ) diagnostic criteria of IAEP are com- who had reported cases of IAEP to the registry. We asked the physicians patible with a duration of symptoms for up to 1 month, but the to consult their medical records and report the following data: past medical history; recent occupational, environmental, and medical his- response to corticosteroid treatment is not diagnostic because of tory; smoking history; medications; clinical and biologic data; imaging, possible spontaneous recovery; (2 ) IAEP should be considered as especially computed tomography scans, pulmonary function tests, bron- differential diagnosis of acute lung injury or acute respiratory dis- choalveolar lavage (BAL) data, medical treatment, use of mechanical tress syndrome; (3 ) bronchoalveolar lavage eosinophilia obviates ventilation, and outcome. the need for lung biopsy in IAEP. The following criteria were required for inclusion in the study: (1 ) acute onset of febrile respiratory manifestations ( 1 month duration Keywords: pulmonary eosinophilia; bronchoalveolar lavage; respiratory before consultation); (2 ) bilateral diffuse inﬁltrates on chest radiogra- distress syndrome, adult phy; (3 ) hypoxemia, with PaO2 on room air less than 60 mm Hg, and/ or PaO2/fraction of inspired oxygen (FIO2) less than or equal to 300, and/ Idiopathic acute eosinophilic pneumonia (IAEP) is charac- or oxygen saturation on room air less than 90%; (4 ) lung eosinophilia, terized by acute febrile respiratory failure, diffuse bilateral with greater than 25% eosinophils on BAL differential cell count, or lung inﬁltrates on chest X-rays, and pulmonary eosinophilia eosinophilic pneumonia at lung biopsy; and (5 ) absence of exposure (1–3). Because blood eosinophilia is usually not prominent to drugs known to cause pulmonary eosinophilia, of evidence of infec- at presentation, IAEP may be mistaken for acute lung injury tion, or of other known causes of eosinophilic lung disease. (ALI), including its most severe form—acute respiratory dis- We received 34 completed questionnaires for analysis, but 12 cases tress syndrome (ARDS) (4, 5). IAEP is a rare disorder, and were excluded for various reasons. In seven cases the onset of clinical symptoms occurred more than 30 days before consultation. In three less than 100 cases have been reported to date, with the largest cases, IAEP was related to other diseases (legionnaires’ disease, Churg- series including only 15 patients (1, 6). Some of the proposed Strauss syndrome, and idiopathic chronic eosinophilic pneumonia diagnostic criteria for IAEP are debatable: the delay between [ICEP], respectively). One case had no evidence of lung eosinophilia, ﬁrst symptoms and diagnosis, the necessity for surgical lung and in one case there was a high probability of cocaine inhalation in biopsy to conﬁrm the diagnosis, and the need for steroid ther- a heroin-addicted patient. apy for recovery. We conducted a retrospective study of 22 cases of IAEP to improve our characterization of this clinical Data Analysis entity and, especially, to reﬁne the relevant diagnostic criteria. The remaining 22 cases had all been seen between 1991 and 1999, except for 1 case seen in 1981. For analysis, they were divided into two groups on the basis of the duration of respiratory symptoms before the onset of IAEP: less than 7 days and 7 to 30 days. The 7-day threshold was chosen because it corresponded to one of the criteria proposed for (Received in original form December 18, 2001; accepted in final form July 15, 2002) the diagnosis of IAEP (1). But patients with duration of symptoms Supported by grant HCL-PHRC 93-97.005 from the Ministere de l’Emploi et de ` between 7 and 30 days may also be considered as possible cases of la Solidarite, Paris, France. ´ IAEP, as suggested by Tazelaar and coworkers (6). ALI was deﬁned Correspondence and requests for reprints should be addressed to Prof. Jean- as a pulmonary disorder characterized by an acute onset, bilateral Francois Cordier, GERM“O”P, Hopital Louis Pradel, BP Lyon-Montchat 69394, ¸ ˆ inﬁltrates on frontal chest radiography, pulmonary artery wedge pres- Lyon cedex 03, France. E-mail: firstname.lastname@example.org sure less than or equal to 18 mm Hg when measured or no evidence This article has an online data supplement, which is accessible from this issue’s of left atrial hypertension, and a PaO2/FIO2 less than or equal to 300 mm table of contents online at www.atsjournals.org Hg (4). Patients with ALI and a PaO2/FIO2 less than or equal to 200 mm Am J Respir Crit Care Med Vol 166. pp 1235–1239, 2002 Hg were deﬁned as having ARDS (4). Numerical data are expressed as DOI: 10.1164/rccm.2112056 mean SD and compared using the unpaired t test. The number of Internet address: www.atsjournals.org patients in the different groups was evaluated using the chi-square test. 1236 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 166 2002 TABLE 1. CHARACTERISTICS AND CLINICAL MANIFESTATIONS AT PRESENTATION IN 22 PATIENTS WITH IDIOPATHIC ACUTE EOSINOPHILIC PNEUMONIA Number of Patients and/or Mean Values Percentage of Patients Sex, male/female 13/9 Age, yr 29 15.8 Current smokers 8 36 Recent smokers, 3 mo 6 27 Duration of symptoms, d 8.3 8.5 Temperature, C 22 (38.8 0.7) 100 Dyspnea 22 100 Cough 18 81 Chest pain 11 50 Myalgia 7 31 Abdominal pain 6 27 Crackles on chest auscultation 15 68 RESULTS Imaging Patient Characteristics At initial presentation, chest radiographs showed bilateral pul- monary inﬁltrates in all patients. Diffuse bilateral airspace opaci- A total of 13 of our 22 patients were male, and the mean age ties (50%), mixed airspace and interstitial opacities (22%), and at diagnosis was 29 15 years (range, 15–86 years). Eight pa- interstitial opacities (18%) were the three most frequent radio- tients were current smokers, and six of them had started smoking graphic patterns. Only two patients had localized bilateral air- less than 3 months (but more than 1 week) before the onset of IAEP. Two patients had pre-existing atopy, but no previous space opacities. Pleural effusion was evident in two patients, but history of asthma was recorded. Fourteen patients developed no migratory opacities were found. The inﬁltrates disappeared IAEP during summer or fall. Four patients had been involved after an average of 27 24 days after hospitalization in 21 in unusual occupational activities in the days immediately before patients for whom repeated chest X-rays were available. The the onset of IAEP: indoor renovation work (n 2), gasoline questionnaire that was sent to physicians who reported cases of tank cleaning (n 1), and explosion of a tear gas bomb (n IAEP did not enquire about the presence of Kerley B lines 1). One patient had been taking acetylsalicylic acid because of on the initial chest radiographs, so their incidence cannot be coronary heart disease for years before the onset of IAEP. His evaluated. treatment was transiently interrupted and then resumed after Fourteen patients underwent chest computed tomography, recovery from IAEP, which did not relapse. 3.2 3 days after their initial chest radiograph on an average. Steroid treatment had not been initiated for 10 of these patients, Clinical Presentation and 4 others had been on corticosteroids for 1 to 4 days before The characteristics and clinical manifestations at presentation their computed tomography. The most common computed to- are listed in Table 1. The delay between the onset of symptoms mography ﬁnding was bilateral airspace opacities (93%), associ- and the diagnosis of IAEP ranged from 1 to 30 days and exceeded ated with bilateral pleural effusion in 71% of cases (Figure 1). 7 days in seven patients. No signiﬁcant difference was observed in the characteristics and clinical manifestations at presentation Laboratory Findings between patients seen at less than 7 days or at 7 to 30 days after Laboratory ﬁndings at the time of hospitalization are presented the onset of IAEP (Table 2). in Table 3. Eight patients had peripheral blood eosinophilia TABLE 2. CLINICAL CHARACTERISTICS AT THE TIME OF HOSPITALIZATION AND OUTCOME OF PATIENTS IN THE 7 DAYS ONSET AND 7 TO 30 DAYS ONSET GROUPS* Onset 7 d (n 15) 7–30 d Onset (n 7) Duration of symptoms, d 3.6 1.8 18.2 8.7 Age, yr 25 10 35 23 Current smokers 6/15 2/7 Temperature, C 38.9 0.7 38.7 0.6 PaO2/FIO2 145 76 184 76 Need of MV 10/15 4/7 WBC, 109/L 22 12 18 5 Neutrophils, 109/L 19 12 14 2 Eosinophils, 109/L 0.55 0.53 1.7 2.5 BAL macrophages, % 20 13 16 13 BAL neutrophils, % 14 14 8 11 BAL lymphocytes, % 13 12 11 13 BAL eosinophils, % 51 18 64 15 Normalization of chest radiograph (time since hospitalization, d) 29 26 27 24 Definition of abbreviations: BAL bronchoalveolar lavage; IAEP idiopathic acute eosinophilic pneumonia; WBC white blood cells. * No significant difference was observed in the clinical characteristics between patients seen at 7 days or at 7 to 30 days after the onset of IAEP. Philit, Etienne-Mastroıanni, Parrot, et al.: Acute Eosinophilic Pneumonia ¨ 1237 TABLE 3. BLOOD AND LUNG LABORATORY FINDINGS AT THE TIME OF HOSPITALIZATION Parameter Mean SD 9 WBC, 10 /L 20.7 10.9 Neutrophils, 109/L 17.6 10.4 Eosinophils, 109/L 0.98 1.5 C reactive protein, mg/L 121.1 93.7 PaO2 on room air, mm Hg (n 12) 46 8 PaO2/FIO2 (n 9) 118 49 SpO2 on room air, % (n 1) 86 Total BAL cell count, cells/ L 765.6 527.7 BAL eosinophils, % 54.4 19.2 BAL macrophages, % 19.4 13.5 Figure 2. Peripheral blood eosinophil counts on hospitalization and 6 BAL neutrophils, % 13.0 14.0 4 days later. BAL lymphocytes, % 12.5 12.7 Definition of abbreviations: BAL bronchoalveolar lavage; WBC white blood cells. of eosinophils in the pleural ﬂuid was 38 14 (range, 22–51), and one patient had pleural ﬂuid lymphocytosis (61%) without eosinophilia. No patient underwent transbronchial or open-lung greater than 0. 5 109/L. A second peripheral white blood cell biopsy. count, done 6 4 days (range, 1–15) after hospitalization in 21 patients, showed eosinophilia greater than 0. 5 109/L in an Management of Respiratory Failure additional seven cases (Figure 2). Overall, eosinophilia greater A total of 16 patients were admitted to the intensive care unit than 0. 5 109/L was present in 15 of 22 patients (68%) at some and 6 other patients to a respiratory ward. At the time of hospital- time during the course of IAEP. ization, all patients presented with severe hypoxemia: mean PaO2/ All patients underwent BAL on hospitalization, and the mean FIO2 was 156 74 (range, 60–238) in 21 patients, and transcutane- percentage of eosinophils in BAL was 54 19% (range, 27–81). ous oxygen saturation was 86% in 1 patient breathing room Six patients underwent a second BAL, 2 to 44 days later, and air. Among 16 patients admitted to the intensive care unit, 14 ﬁve of them had persistent BAL eosinophilia (23 13%; range, required mechanical ventilation. Eight of them were intubated 4–37%). Two patients underwent a third BAL at 2 and 4 months, on hospitalization to the intensive care unit and underwent me- respectively, after the ﬁrst procedure, and both of them then chanical ventilation for 9.1 4.8 days. Six other patients received had a normal differential cell count. In one patient, the BAL noninvasive mechanical ventilation with either continuous posi- eosinophilia had resolved at 6 days after the ﬁrst BAL. The tive airway pressure (n 5) for a mean duration of 4.2 2.9 BAL ﬂuid from 20 patients was sterile, as determined by routine days or pressure support ventilation (n 1) for 8 days. No failure culture, but the BAL ﬂuid from two patients was contaminated of noninvasive mechanical ventilation leading to endotracheal by Nocardia otitidis, and Enterococcus fecalis and Candida albi- intubation occurred. Two patients admitted to the intensive care cans, respectively; both patients recovered without speciﬁc anti- unit for respiratory failure also had transient hemodynamic insta- biotic treatment. Five patients with pleural effusion underwent bility at the beginning of mechanical ventilation and needed diagnostic thoracocentesis; in four patients the mean percentage vasopressors. Pulmonary artery catheterization performed in these two patients showed normal cardiac output and systemic vascular resistances. No renal or hepatic failure was observed in any of our 22 patients. In the group of 15 patients with onset of IAEP at less than 7 days, 10 developed respiratory failure requiring mechanical ventilation. Eight patients were intubated, and two received noninvasive mechanical ventilation. A total of 12 of these 15 patients conformed to the deﬁnition of ALI, and 8 of these ﬁtted the criteria for ARDS, respectively. Four of the seven patients with a 7- to 30-day onset of IAEP required mechanical ventila- tion: noninvasive mechanical ventilation was given in three cases, and endotracheal mechanical ventilation was required by one patient. Treatment and Follow-up Most of the patients (19 of 22) received empirical antibiotic treatment for possible severe community-acquired pneumonia, with -lactams associated with macrolides or ﬂuoroquinolone. A total of 16 patients were treated with systemic corticosteroids, within 2 days of the diagnosis of IAEP for 12 patients and within 3 to 5 days for the remaining 4. In all cases, initial treatment consisted of intravenous methylprednisolone, followed by oral prednisone. The mean duration of corticosteroid treatment was 89 56 days. The 6 patients who did not receive steroids had Figure 1. Computed tomography of the chest in a patient with IAEP, the same PaO2/FIO2 (156 69) at the time hospitalization as did showing bilateral alveolar opacities and pleural effusion. the 16 steroid-treated patients (156 78) (p 0.99). 1238 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 166 2002 All 22 patients were discharged alive from both the intensive It may be argued that allowing a duration of symptoms for longer care unit and then from the hospital. Four patients were lost to than 7 days in the diagnosis of IAEP could lead to confusion follow-up after hospital discharge. The remaining 18 patients between IAEP and ICEP. However, the mean time between were followed for an average of 12.7 15.8 months after diagno- onset of symptoms and diagnosis of ICEP is distinctly longer, sis (range: 6 days to 30 months). A normal chest radiograph was with a mean of 19.7 weeks (14). IAEP also differs from ICEP eventually observed in 21 patients, with a mean delay of 27 by the absence of asthma, which is present in about half of the 24 days after diagnosis. Patients not treated with steroids tended patients with ICEP, a higher proportion of smokers (only 6.5% to normalize their chest radiograph earlier than treated patients in ICEP), a moderate male predominance contrasting with a did, at 19 20 versus 33 26 days, respectively (p 0.26). No striking female predominance in ICEP (sex ratio: 2.1), and espe- relapse occurred among the 18 patients with available follow-up. cially respiratory failure (3, 14). In the GERMOP series of 62 Fourteen patients had pulmonary function tests after recovery, cases of ICEP, no patient required mechanical ventilation (14), showing a mean FEV1 of 91 9% and a mean FVC of 91 whereas, in the present study, 14 of 22 patients with IAEP needed 14% of the predicted value. No death was recorded. endotracheal or noninvasive mechanical ventilation. Imaging features are also different, with diffuse, rather than uniquely DISCUSSION peripheral, airspace opacities in IAEP (15, 16). Pleural effusion is a further distinctive radiologic feature of IAEP (15, 16), seen This study reports a series of 22 patients with IAEP characterized in at least 50% of our patients, in contrast to only 6.5% of by hypoxemic respiratory failure developing within 1 month after patients with ICEP (14). Finally, patients with IAEP do not the onset of symptoms, diffuse bilateral inﬁltrates at imaging, generally relapse, unlike about half of the patients with ICEP. pulmonary eosinophilia at BAL, rapid recovery either spontane- The presentation of IAEP closely resembles that of ALI or ously or with steroid therapy, and no relapse. Because of the ARDS (4) or of acute interstitial pneumonia (17) (see Table E1 retrospective nature of this study on a very rare disorder, exhaus- in the online data supplement). Tazelaar and coworkers (6) tive data could not be obtained for every patient (particularly reported the pathologic features of acute and organizing diffuse with respect to an exhaustive search for a precise cause of IAEP, alveolar damage, together with interstitial and alveolar eosino- the detailed pattern and distribution of abnormalities at chest philia in their patients with acute eosinophilic pneumonia. An- imaging, and follow-up after discharge). The beneﬁt of steroid other case of IAEP, with ARDS and diffuse alveolar damage on treatment could not be evaluated precisely because the modal- lung biopsy has been reported in a previously healthy adolescent ities of corticosteroid treatment were not established prospec- (18). A total of 12 of our patients with a diagnosis of IAEP less tively. than 7 days after onset of symptoms met the clinical criteria of The causes of eosinophilic pneumonia are many (see Table E1 ALI, and 8 of them met those of ARDS, as deﬁned by the North in the online data supplement), including infections (especially American–European Consensus Committee (4). However, clini- parasitic), hypersensitivity to drugs or inhaled agents, and sys- cal features that distinguish IAEP from ARDS in our patients temic idiopathic eosinophilic disorders, all of which may have should be emphasized: (1 ) no organ dysfunction other than respi- an acute presentation (1, 3, 7). No such causes were present ratory failure occurred. Thus, we did not observe multiple organ in our patients; thus, IAEP was considered to be idiopathic. failure during the course of IAEP. Two patients had hemody- However, as reported previously (8–11), 6 of the 8 smokers in namic instability at the beginning of mechanical ventilation, but this series had started smoking less than 3 months previously. they did not develop shock. Only one case of IAEP associated Challenge with smoking has been reported to be positive in with distributive shock has been reported in the literature (19). some patients with IAEP (8–11), but tolerance may develop in (2 ) The prognosis of IAEP is excellent because all our patients some patients who resume smoking (9–11). IAEP has also been had a favorable outcome, contrasting with the mortality of pa- reported after exposure to smoke from ﬁreworks (12). In some tients with ARDS that remains between 30 and 40% (20, 21). patients, IAEP has been reported to develop after exposure to The absence of multiple organ failure in patients with IAEP is dust (7, 13). Four patients in our series had engaged in potentially one possible explanation for this favorable outcome. (3 ) Patients causative occupational activities in the days preceding the onset with IAEP have BAL eosinophilia, whereas patients with ARDS of IAEP, namely indoor renovation work, gasoline tank cleaning, have a high percentage of neutrophils on BAL (22). (4 ) We and the explosion of a tear gas bomb. Whether inhalation of found no clinical disorder associated with IAEP that could have cigarette smoke or exposure to other environmental agents is led to direct or indirect lung injury, such causes are usually the speciﬁc cause of IAEP is not known. Given the high incidence observed in ALI or ARDS (20). of smoking and the rarity of IAEP, it is unlikely that smoking Some authors consider that surgical lung biopsy is a necessary is the simple cause of IAEP. However, exposure to smoke or diagnostic tool for IAEP, particularly for ruling out a diagnosis other environmental agents may facilitate or contribute to the of infection (18, 19). IAEP was recognized by BAL in all our development of IAEP from another unknown cause or it may patients, and no surgical lung biopsy was performed. In this induce an eosinophilic reaction in individuals with an unex- series, BAL ﬂuid culture and staining for fungi and other infec- plained predisposition. Smoking was more frequent among pa- tious agents were systematically performed and were considered tients in this and in other series of IAEP than in our series of negative in most cases. All patients recovered, and none of them ICEP, where it was distinctly rare (6.5%) (14). had a clinical course evocative of infectious, especially fungal, In seven of our patients, symptoms had been present for more pneumonia. Pope-Harman and coworkers (1) suggested that than 1 week at the time of diagnosis of IAEP. Apart from this lung biopsy may be considered in immunocompromised patients duration of symptoms, they fulﬁlled the other criteria of IAEP developing IAEP and especially in patients with potential fungal proposed by Allen and coworkers (3). These seven patients did exposure. We consider that in nonimmunocompromised pa- not differ signiﬁcantly from patients with shorter onset in their tients, BAL ﬂuid analysis associated with a careful screening of clinical presentation, BAL differential cell count, severity of medical history may provide a reliable diagnosis of IAEP, respiratory failure, or outcome. In the patients studied by Tazel- thereby avoiding lung biopsy, which is not devoid of risk in aar and coworkers (6), IAEP was deﬁned by histologic criteria patients with acute respiratory failure. (diffuse alveolar damage with interstitial and alveolar eosino- Steroid therapy has been used in most of the reported cases philia), and disease duration exceeded 1 week for some of them. of IAEP. The treatment modalities varied in our patients as well Philit, Etienne-Mastroıanni, Parrot, et al.: Acute Eosinophilic Pneumonia ¨ 1239 as in the literature, but all our treated patients received steroids, 7. Cordier JF. Eosinophilic pneumonias. In: Schwarz MI, King TE, editors. ﬁrst intravenous and orally thereafter (1, 19). Interestingly, six Interstitial lung disease. Hamilton: BC Decker Inc.; 1998. p. 559–595. 8. Nakajima M, Manabe T, Niki Y, Matsushima T. Cigarette smoke–induced of our patients (27%) recovered spontaneously without steroids, acute eosinophilic pneumonia. Radiology 1998;207:829–831. as has been reported previously (23, 24). As a consequence, a 9. Shintani H, Fujimura M, Yasui M, Ueda K, Kameda S, Noto M, Matsuda complete response to steroid therapy may not be considered to T, Kobayashi M. Acute eosinophilic pneumonia caused by cigarette be a reliable diagnostic criterion for IAEP, as has been proposed smoking. Intern Med 2000;39:66–68. previously (6). Nevertheless, although the efﬁcacy of steroid 10. Nakajima M, Manabe T, Niki Y, Matsushima T, Takashi S. A case therapy has not been demonstrated, the presence of life-threat- of cigarette smoking–induced acute eosinophilic pneumonia showing tolerance. Chest 2000;118:1517–1518. ening hypoxemia with a possible fatal evolution (25) leads us to 11. Shintani H, Fujimura M, Ishiura Y, Noto M. A case of cigarette smoking– maintain the recommendation of using steroid treatment as soon induced acute eosinophilic pneumonia showing tolerance. Chest 2000; as possible. 117:277–279. In conclusion, in addition to further clarifying the major clini- 12. 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