Abstract
Idiopathic acute eosinophilic pneumonia (IAEP) is characterized by acute febrile respiratory failure associated with diffuse radiographic infiltrates and pulmonary eosinophilia. We conducted a multicenter retrospective study to characterize this rare clinical entity further and to improve its diagnostic criteria. A total of 13 male and 9 female patients (mean age: 29 ± 15.8 years) presented with severe hypoxemia (PaO2/fraction of inspired oxygen ratio = 156 ± 74.1) requiring mechanical ventilation in 14 cases. Bronchoalveolar lavage was performed on all patients and showed 54.4 ± 19.2% eosinophils on differential cell count, but no open-lung biopsies were done. No clinical differences were found between patients seen at less than 7 days (n = 15) or at 7 to 31 days (n = 7) from the onset of IAEP. A total of 12 patients met the clinical criteria of acute lung injury, and eight of these patients met the criteria for acute respiratory distress syndrome. All patients recovered, either spontaneously (6) or on corticosteroid treatment (16). No relapses occurred. We conclude that: (1) diagnostic criteria of IAEP are compatible with a duration of symptoms for up to 1 month, but the response to corticosteroid treatment is not diagnostic because of possible spontaneous recovery; (2) IAEP should be considered as differential diagnosis of acute lung injury or acute respiratory distress syndrome; (3) bronchoalveolar lavage eosinophilia obviates the need for lung biopsy in IAEP.
Idiopathic acute eosinophilic pneumonia (IAEP) is characterized by acute febrile respiratory failure, diffuse bilateral lung infiltrates on chest X-rays, and pulmonary eosinophilia (1–3). Because blood eosinophilia is usually not prominent at presentation, IAEP may be mistaken for acute lung injury (ALI), including its most severe form—acute respiratory distress syndrome (ARDS) (4, 5). IAEP is a rare disorder, and less than 100 cases have been reported to date, with the largest series including only 15 patients (1, 6). Some of the proposed diagnostic criteria for IAEP are debatable: the delay between first symptoms and diagnosis, the necessity for surgical lung biopsy to confirm the diagnosis, and the need for steroid therapy for recovery. We conducted a retrospective study of 22 cases of IAEP to improve our characterization of this clinical entity and, especially, to refine the relevant diagnostic criteria.
This study was undertaken by the Groupe d'Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P), a collaboration among French pulmonary physicians that was founded in 1993 and dedicated to the study of rare (so-called orphan) pulmonary diseases. By January 2001, more than 1,300 cases of orphan pulmonary diseases had been reported to the GERMOP registry.
In June 1999, we sent a letter to 5,300 physician specialists in intensive care and/or respiratory medicine in France, Belgium, and Switzerland asking them to report to the registry the cases of IAEP they had previously observed.
In November 1999, a detailed questionnaire was sent to each physician who had reported cases of IAEP to the registry. We asked the physicians to consult their medical records and report the following data: past medical history; recent occupational, environmental, and medical history; smoking history; medications; clinical and biologic data; imaging, especially computed tomography scans, pulmonary function tests, bronchoalveolar lavage (BAL) data, medical treatment, use of mechanical ventilation, and outcome.
The following criteria were required for inclusion in the study: (1) acute onset of febrile respiratory manifestations (⩽ 1 month duration before consultation); (2) bilateral diffuse infiltrates on chest radiography; (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/or oxygen saturation on room air less than 90%; (4) lung eosinophilia, with greater than 25% eosinophils on BAL differential cell count, or eosinophilic pneumonia at lung biopsy; and (5) absence of exposure to drugs known to cause pulmonary eosinophilia, of evidence of infection, or of other known causes of eosinophilic lung disease.
We received 34 completed questionnaires for analysis, but 12 cases were excluded for various reasons. In seven cases the onset of clinical symptoms occurred more than 30 days before consultation. In three cases, IAEP was related to other diseases (legionnaires' disease, Churg-Strauss syndrome, and idiopathic chronic eosinophilic pneumonia [ICEP], respectively). One case had no evidence of lung eosinophilia, and in one case there was a high probability of cocaine inhalation in a heroin-addicted patient.
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 the diagnosis of IAEP (1). But patients with duration of symptoms between 7 and 30 days may also be considered as possible cases of IAEP, as suggested by Tazelaar and coworkers (6). ALI was defined as a pulmonary disorder characterized by an acute onset, bilateral infiltrates on frontal chest radiography, pulmonary artery wedge pressure less than or equal to 18 mm Hg when measured or no evidence of left atrial hypertension, and a PaO2/FIO2 less than or equal to 300 mm Hg (4). Patients with ALI and a PaO2/FIO2 less than or equal to 200 mm Hg were defined as having ARDS (4). Numerical data are expressed as mean ± SD and compared using the unpaired t test. The number of patients in the different groups was evaluated using the chi-square test.
A total of 13 of our 22 patients were male, and the mean age at diagnosis was 29 ± 15 years (range, 15–86 years). Eight patients were current smokers, and six of them had started smoking less than 3 months (but more than 1 week) before the onset of IAEP. Two patients had pre-existing atopy, but no previous history of asthma was recorded. Fourteen patients developed IAEP during summer or fall. Four patients had been involved in unusual occupational activities in the days immediately before the onset of IAEP: indoor renovation work (n = 2), gasoline tank cleaning (n = 1), and explosion of a tear gas bomb (n = 1). One patient had been taking acetylsalicylic acid because of coronary heart disease for years before the onset of IAEP. His treatment was transiently interrupted and then resumed after recovery from IAEP, which did not relapse.
The characteristics and clinical manifestations at presentation are listed in Table 1
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 |
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 |
At initial presentation, chest radiographs showed bilateral pulmonary infiltrates in all patients. Diffuse bilateral airspace opacities (50%), mixed airspace and interstitial opacities (22%), and interstitial opacities (18%) were the three most frequent radiographic patterns. Only two patients had localized bilateral airspace opacities. Pleural effusion was evident in two patients, but no migratory opacities were found. The infiltrates disappeared after an average of 27 ± 24 days after hospitalization in 21 patients for whom repeated chest X-rays were available. The questionnaire that was sent to physicians who reported cases of IAEP did not enquire about the presence of Kerley B lines on the initial chest radiographs, so their incidence cannot be evaluated.
Fourteen patients underwent chest computed tomography, 3.2 ± 3 days after their initial chest radiograph on an average. Steroid treatment had not been initiated for 10 of these patients, and 4 others had been on corticosteroids for 1 to 4 days before their computed tomography. The most common computed tomography finding was bilateral airspace opacities (93%), associated with bilateral pleural effusion in 71% of cases (Figure 1)
Figure 1. Computed tomography of the chest in a patient with IAEP, showing bilateral alveolar opacities and pleural effusion.
[More] [Minimize]Laboratory findings at the time of hospitalization are presented in Table 3
Parameter | Mean ± SD |
|---|---|
| WBC, 109/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/μL | 765.6 ± 527.7 |
| BAL eosinophils, % | 54.4 ± 19.2 |
| BAL macrophages, % | 19.4 ± 13.5 |
| BAL neutrophils, % | 13.0 ± 14.0 |
| BAL lymphocytes, % | 12.5 ± 12.7 |
Figure 2. Peripheral blood eosinophil counts on hospitalization and 6 ± 4 days later.
[More] [Minimize]All patients underwent BAL on hospitalization, and the mean percentage of eosinophils in BAL was 54 ± 19% (range, 27–81). Six patients underwent a second BAL, 2 to 44 days later, and five of them had persistent BAL eosinophilia (23 ± 13%; range, 4–37%). Two patients underwent a third BAL at 2 and 4 months, respectively, after the first procedure, and both of them then had a normal differential cell count. In one patient, the BAL eosinophilia had resolved at 6 days after the first BAL. The BAL fluid from 20 patients was sterile, as determined by routine culture, but the BAL fluid from two patients was contaminated by Nocardia otitidis, and Enterococcus fecalis and Candida albicans, respectively; both patients recovered without specific antibiotic treatment. Five patients with pleural effusion underwent diagnostic thoracocentesis; in four patients the mean percentage 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 biopsy.
A total of 16 patients were admitted to the intensive care unit and 6 other patients to a respiratory ward. At the time of hospitalization, all patients presented with severe hypoxemia: mean PaO2/FIO2 was 156 ± 74 (range, 60–238) in 21 patients, and transcutaneous oxygen saturation was 86% in 1 patient breathing room air. Among 16 patients admitted to the intensive care unit, 14 required mechanical ventilation. Eight of them were intubated on hospitalization to the intensive care unit and underwent mechanical ventilation for 9.1 ± 4.8 days. Six other patients received noninvasive mechanical ventilation with either continuous positive airway pressure (n = 5) for a mean duration of 4.2 ± 2.9 days or pressure support ventilation (n = 1) for 8 days. No failure of noninvasive mechanical ventilation leading to endotracheal intubation occurred. Two patients admitted to the intensive care unit for respiratory failure also had transient hemodynamic instability at the beginning of mechanical ventilation and needed 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 ventilation: noninvasive mechanical ventilation was given in three cases, and endotracheal mechanical ventilation was required by one patient.
Most of the patients (19 of 22) received empirical antibiotic treatment for possible severe community-acquired pneumonia, with β-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 the same PaO2/FIO2 (156 ± 69) at the time hospitalization as did the 16 steroid-treated patients (156 ± 78) (p = 0.99).
All 22 patients were discharged alive from both the intensive care unit and then from the hospital. Four patients were lost to follow-up after hospital discharge. The remaining 18 patients were followed for an average of 12.7 ± 15.8 months after diagnosis (range: 6 days to 30 months). A normal chest radiograph was eventually observed in 21 patients, with a mean delay of 27 ± 24 days after diagnosis. Patients not treated with steroids tended to normalize their chest radiograph earlier than treated patients did, at 19 ± 20 versus 33 ± 26 days, respectively (p = 0.26). No relapse occurred among the 18 patients with available follow-up. Fourteen patients had pulmonary function tests after recovery, showing a mean FEV1 of 91 ± 9% and a mean FVC of 91 ± 14% of the predicted value. No death was recorded.
This study reports a series of 22 patients with IAEP characterized by hypoxemic respiratory failure developing within 1 month after the onset of symptoms, diffuse bilateral infiltrates at imaging, pulmonary eosinophilia at BAL, rapid recovery either spontaneously or with steroid therapy, and no relapse. Because of the retrospective nature of this study on a very rare disorder, exhaustive data could not be obtained for every patient (particularly with respect to an exhaustive search for a precise cause of IAEP, the detailed pattern and distribution of abnormalities at chest imaging, and follow-up after discharge). The benefit of steroid treatment could not be evaluated precisely because the modalities of corticosteroid treatment were not established prospectively.
The causes of eosinophilic pneumonia are many (see Table E1 in the online data supplement), including infections (especially parasitic), hypersensitivity to drugs or inhaled agents, and systemic idiopathic eosinophilic disorders, all of which may have an acute presentation (1, 3, 7). No such causes were present in our patients; thus, IAEP was considered to be idiopathic. However, as reported previously (8–11), 6 of the 8 smokers in this series had started smoking less than 3 months previously. Challenge with smoking has been reported to be positive in some patients with IAEP (8–11), but tolerance may develop in some patients who resume smoking (9–11). IAEP has also been reported after exposure to smoke from fireworks (12). In some patients, IAEP has been reported to develop after exposure to dust (7, 13). Four patients in our series had engaged in potentially causative occupational activities in the days preceding the onset of IAEP, namely indoor renovation work, gasoline tank cleaning, and the explosion of a tear gas bomb. Whether inhalation of cigarette smoke or exposure to other environmental agents is the specific cause of IAEP is not known. Given the high incidence of smoking and the rarity of IAEP, it is unlikely that smoking is the simple cause of IAEP. However, exposure to smoke or other environmental agents may facilitate or contribute to the development of IAEP from another unknown cause or it may induce an eosinophilic reaction in individuals with an unexplained predisposition. Smoking was more frequent among patients in this and in other series of IAEP than in our series of ICEP, where it was distinctly rare (6.5%) (14).
In seven of our patients, symptoms had been present for more than 1 week at the time of diagnosis of IAEP. Apart from this duration of symptoms, they fulfilled the other criteria of IAEP proposed by Allen and coworkers (3). These seven patients did not differ significantly from patients with shorter onset in their clinical presentation, BAL differential cell count, severity of respiratory failure, or outcome. In the patients studied by Tazelaar and coworkers (6), IAEP was defined by histologic criteria (diffuse alveolar damage with interstitial and alveolar eosinophilia), and disease duration exceeded 1 week for some of them. It may be argued that allowing a duration of symptoms for longer than 7 days in the diagnosis of IAEP could lead to confusion between IAEP and ICEP. However, the mean time between onset of symptoms and diagnosis of ICEP is distinctly longer, with a mean of 19.7 weeks (14). IAEP also differs from ICEP by the absence of asthma, which is present in about half of the patients with ICEP, a higher proportion of smokers (only 6.5% in ICEP), a moderate male predominance contrasting with a striking female predominance in ICEP (sex ratio: 2.1), and especially respiratory failure (3, 14). In the GERMOP series of 62 cases of ICEP, no patient required mechanical ventilation (14), whereas, in the present study, 14 of 22 patients with IAEP needed endotracheal or noninvasive mechanical ventilation. Imaging features are also different, with diffuse, rather than uniquely peripheral, airspace opacities in IAEP (15, 16). Pleural effusion is a further distinctive radiologic feature of IAEP (15, 16), seen in at least 50% of our patients, in contrast to only 6.5% of patients with ICEP (14). Finally, patients with IAEP do not generally relapse, unlike about half of the patients with ICEP.
The presentation of IAEP closely resembles that of ALI or ARDS (4) or of acute interstitial pneumonia (17) (see Table E1 in the online data supplement). Tazelaar and coworkers (6) reported the pathologic features of acute and organizing diffuse alveolar damage, together with interstitial and alveolar eosinophilia in their patients with acute eosinophilic pneumonia. Another case of IAEP, with ARDS and diffuse alveolar damage on lung biopsy has been reported in a previously healthy adolescent (18). A total of 12 of our patients with a diagnosis of IAEP less than 7 days after onset of symptoms met the clinical criteria of ALI, and 8 of them met those of ARDS, as defined by the North American–European Consensus Committee (4). However, clinical features that distinguish IAEP from ARDS in our patients should be emphasized: (1) no organ dysfunction other than respiratory failure occurred. Thus, we did not observe multiple organ failure during the course of IAEP. Two patients had hemodynamic instability at the beginning of mechanical ventilation, but they did not develop shock. Only one case of IAEP associated with distributive shock has been reported in the literature (19). (2) The prognosis of IAEP is excellent because all our patients had a favorable outcome, contrasting with the mortality of patients with ARDS that remains between 30 and 40% (20, 21). The absence of multiple organ failure in patients with IAEP is one possible explanation for this favorable outcome. (3) Patients with IAEP have BAL eosinophilia, whereas patients with ARDS have a high percentage of neutrophils on BAL (22). (4) We found no clinical disorder associated with IAEP that could have led to direct or indirect lung injury, such causes are usually observed in ALI or ARDS (20).
Some authors consider that surgical lung biopsy is a necessary diagnostic tool for IAEP, particularly for ruling out a diagnosis of infection (18, 19). IAEP was recognized by BAL in all our patients, and no surgical lung biopsy was performed. In this series, BAL fluid culture and staining for fungi and other infectious agents were systematically performed and were considered negative in most cases. All patients recovered, and none of them had a clinical course evocative of infectious, especially fungal, pneumonia. Pope-Harman and coworkers (1) suggested that lung biopsy may be considered in immunocompromised patients developing IAEP and especially in patients with potential fungal exposure. We consider that in nonimmunocompromised patients, BAL fluid analysis associated with a careful screening of medical history may provide a reliable diagnosis of IAEP, thereby avoiding lung biopsy, which is not devoid of risk in patients with acute respiratory failure.
Steroid therapy has been used in most of the reported cases of IAEP. The treatment modalities varied in our patients as well as in the literature, but all our treated patients received steroids, first intravenous and orally thereafter (1, 19). Interestingly, six of our patients (27%) recovered spontaneously without steroids, as has been reported previously (23, 24). As a consequence, a complete response to steroid therapy may not be considered to be a reliable diagnostic criterion for IAEP, as has been proposed previously (6). Nevertheless, although the efficacy of steroid therapy has not been demonstrated, the presence of life-threatening hypoxemia with a possible fatal evolution (25) leads us to maintain the recommendation of using steroid treatment as soon as possible.
In conclusion, in addition to further clarifying the major clinical characteristics of IAEP among the heterogeneous group of eosinophilic lung diseases, this study suggests that the diagnostic criteria may include a duration of respiratory symptoms for up to 1 month. However, the possible recovery without corticosteroid treatment suggests that the response to corticosteroid therapy should not be taken as a diagnostic criterion. BAL eosinophilia obviates the need for surgical lung biopsy in most nonimmunocompromised patients. We emphasize that IAEP should be considered as a differential diagnosis of ALI or ARDS, especially because of its excellent prognosis. Given the heterogeneity of ALI and ARDS and the resulting difficulties in their clinical epidemiology (5), we propose that BAL eosinophilia greater than 25% on differential count may be added as an exclusion criterion for the diagnosis of ALI and ARDS.
The following physicians participated in this study by including one or more cases: P. Beuret (Roanne), O. Brenet (Cholet), J.-F.C. (Lyon), J. C. Dalphin (Besançon), J. L. Delacour (Vesoul), B. Langevin (Lyon), P. Leclerc (Sartrouville), A.P. (Paris), and F.P. (Lyon), France; P. Bulpa (Yvoir), I. Mairesse (Bouge), and T. Pieters (Bruxelles), Belgium; and J. P. Janssen (Rolle) and P. Jolliet (Genève), Switzerland. The authors thank T. Greenland for linguistic review of the manuscript.
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