Chronic eosinophilic pneumonia: a review.

Abstract: Chronic eosinophilic pneumonia (CEP) is a disease of unknown cause. The hallmark of CEP is eosinophil accumulation in the lungs. While the triggering factor is unknown, eosinophil accumulation in the lungs is now believed to be secondary to the actions of eosinophil-specific chemoattractants, including eotaxin and regulated upon activation, normal T-cell expressed and secreted (RANTES), and IL-5 released from Th2 lymphocytes in the lungs. There is a female preponderance in CEP, with a peak incidence in the 5th decade; the onset is insidious with weight loss, cough, and dyspnea. An atopic history is common, but asthma is not a prerequisite for the development of CEP. Airways obstruction may develop during the course of CEP, but may also result from CEP. The chest x-ray usually shows bilateral peripheral shadows, which may be migratory. Peripheral eosinophilia is usual. Standard treatment of CEP is with oral steroids, usually with dramatic resolution of symptoms and radiographic changes; however, relapses are common when the daily steroid dose is reduced below 15 mg. Current data suggest that when treatment is stopped, relapse is common in the majority of patients (>80%) followed for a sufficiently long period of time. Some recent reports suggest that treatment with inhaled steroids may be of some value in this condition.

Key Words: chronic eosinophilic pneumonia, airway obstruction, steroids

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Chronic eosinophilic pneumonia (CEP) is a rare disorder of unknown etiology (1-4) which is frequently confused with bacterial pneumonia or other causes of pulmonary consolidation. While CEP is a relatively benign condition if treated appropriately, the diagnosis is often delayed. We review the current understanding and differential diagnosis of this condition, as well as available treatment modalities. Crofton et al (5) provided one of the earliest classifications of the pulmonary eosinophilic syndromes; they divided them into 5 groups, consisting of simple, prolonged, asthmatic and tropical pulmonary eosinophilia, and polyarteritis and related conditions. CEP in current nomenclature includes Crofton's two groups of prolonged or recurrent eosinophilia with and without asthma. (1)

Pathology

The hallmark of CEP is a massive accumulation of eosinophils in the lungs, and an increased number of eosinophils in the bronchoalveolar lavage (BAL) fluid. On histopathologic examination, there is a predominantly eosinophilic infiltrate, although other inflammatory cells are also present, including lymphocytes, plasma cells and polymorphonuclear neutrophils; some of the eosinophils may be degranulated. (6) In contrast to cryptogenic organizing pneumonia, intraluminal organization of the alveolar exudates in the distal airspace is never prominent. (4) In bronchoalveolar lavage fluid, the percentage of eosinophils is <2% in normal controls, (7) but is markedly increased in CEP. A differential cell count in BAL fluid of greater than 40% eosinophils is suggested to be diagnostic of chronic eosinophilic pneumonia. (4)

Etiology

The etiology of CEP remains unclear; the general hypothesis is that the unknown initiating stimulus/insult results in the accumulation of eosinophils in the lungs. (4,8) Because the precise initiating factor is unknown, most research has concentrated on characterizing the factors responsible for eosinophil accumulation in the lung. (4,8-12) It is known that IL-5 plays a pivotal role in the recruitment of eosinophils, as well as the inhibition of apoptosis of eosinophils; the concentration of this cytokine is increased in BAL fluid in CEP (8,9,12) and apoptosis in BAL eosinophils in CEP is significantly reduced compared with circulating eosinophils. (11) Furthermore, levels of IL-5, as well as IL-6 and IL-10, which are also eosinophil-active cytokines, have been found to be increased in BAL fluid from CEP-affected lung lobes versus BAL fluid from unaffected areas. (9) It is suggested that chronic stimulation of eosinophils in the alveolar space by IL-5 may play a major role in the development of CEP. (11) Other eosinophil-specific chemoattractants, eotaxin and RANTES, have also been found to be increased in the BAL fluid from patients with CEP. (10)

IL-5 is produced by activated T-lymphocytes, the T-helper 2 cells (Th2), and it has been suggested that an influx of Th2 cells into the lungs may be the pivotal event in CEP. (8) A thymus- and activation-regulated chemokine (TARC) is involved in the recruitment of Th2 cells, as is RANTES, and a recent study has found increased levels of TARC and IL-5 in BAL from CEP patients, but not in patients with other interstitial lung diseases. (10)

The process is summarized in Figure 1. While the triggering factor(s) for CEP are unknown, the mechanism by which eosinophils accumulate in the lung is most likely due to the selective migration of Th2 cells to the lungs, mediated by TARC and RANTES, and the chronic release of IL-5 and related cytokines in the alveolar space from Th2 cells, along with eotaxin, resulting in eosinophil accumulation in the lungs.

Clinical Features

The clinical features of CEP have continued to be defined over the last 2 decades. The male to female ratio varies widely between studies, ranging from 5:1 (13) to 4:7 (8); however overall there is a female preponderance in a ratio of 2.1:1. (3,8,13-18) The peak incidence occurs in the fifth decade, but the age range at which the disease presents is wide, ranging from 18 to 80 years. (3,8,13,14,19) The general presenting symptoms consist of an insidious development of fevers, weight loss, night sweats, nonproductive cough, dyspnea and chest pain over weeks or months. (1-3,13-15) While there is an association between preexisting asthma and CEP, an atopic history or existing asthma is not a prerequisite for the development of CEP. In the original report by Carrington et al, (1) 6 of the 9 cases had coexisting asthma and 5 had allergic rhinitis, and in a subsequent report (14) of 21 cases, asthma was noted in 8 cases, and an atopic history was present in a similar number. Marchand et al, (3) in a report of 62 patients with CEP, noted that 52% were asthmatic, and the majority (63%) had a history of atopy, including asthma, rhinitis, drug allergy, etc. Another study (15) has reported an atopic diathesis in 75% of these patients. Contrary to previous reports (1,14) the asthma was often longstanding, being present for many years before the development of CEP. (3) A recent report (13) indicates that airways obstruction may also develop during the course of CEP. Thus, patients with CEP frequently have an allergic diathesis and may have longstanding asthma. The possible reciprocal influence of asthma and chronic eosinophilic pneumonia on clinical presentation and evolution has recently been investigated. (16) Asthma was present before or was diagnosed concomitantly with chronic eosinophilic pneumonia in 64% of patients in this study, and developed several months later in 7 more patients. There were no differences in clinical presentation, but the asthma tended to be more severe. (16) On the chest x-ray, bilateral, peripheral opacities are seen (Fig. 2), described as the photographic negative of pulmonary edema. (14) In the majority of cases, the opacities are bilateral, and range from dense consolidation to ground glass migratory opacities. (3,14) Attempts to radiographically diagnose the individual eosinophilic lung diseases have met with limited success: a study of high resolution CAT scans in 81 patients was not able to distinguish between CEP and bronchiolitis obliterans in the majority of patients. (19)

[FIGURE 1 OMITTED]

Peripheral eosinophilia is usual in CEP. (1-3,13) However, since peripheral eosinophilia is one of the diagnostic tests for CEP, its true incidence in CEP is unknown. Pulmonary function tests generally show no abnormality in one third of patients, a restrictive defect in a third, and an obstructive defect in one third. (13) However, as noted above, obstructive defects may develop during the course of the disease in subjects with previously normal lung function. (13) An association of CEP with cutaneous T-cell lymphoma, (20) sarcoidosis, (21) and Churg-Strauss syndrome (22,23) has been reported.

[FIGURE 2 OMITTED]

The diagnosis of CEP is based on a history of insidious onset, with the characteristic chest radiographic appearance of peripheral infiltrates with transient opacities, and the presence of peripheral eosinophilia. (1,3,13) Most authors do not recommend lung biopsy; bronchoalveolar lavage fluid analysis, while not a prerequisite, may be helpful in the diagnosis. (3,13) If bronchoalveolar lavage is performed, it has been suggested that in the presence of the appropriate clinical features, CEP may be confidently diagnosed if there are more than 50% eosinophils in the BAL differential cell count. (3)

A large number of conditions are included under the eosinophilic lung diseases (Table 1). For a diagnosis of CEP, it is important to exclude the known causes of pulmonary eosinophilia: a careful history and examination to exclude systemic illnesses (Churg-Strauss syndrome, sarcoidosis, etc), as well as a careful review of concomitant drug intake to exclude drug-induced pulmonary eosinophilia is necessary. An examination of the stool for ova and parasites is important. Idiopathic acute eosinophilic pneumonia (AEP) should rarely cause confusion with CEP. AEP is of acute onset, with severe fever, dyspnea, chest pain and acute respiratory failure. The usual picture in AEP is of acute lung injury (ALI) which may progress to ARDS. CEP is easily misdiagnosed as a bacterial pneumonia or cryptogenic organizing pneumonia; however, the clinical and laboratory features distinguish these conditions (Table 2).

Treatment and Prognosis

The standard treatment of CEP is with oral corticosteroids, although spontaneous remission may occur in 10% of patients. (3,13,18,24) The hallmark of CEP is a rapid, dramatic response to oral corticosteroids (3,13); however, the majority of patients with CEP tend to relapse once treatment is stopped. The reported incidence of relapse appears to be related to the duration of follow-up, with relapses occurring in 83% of patients followed for 10 years (Table 3).

Relapses are not related to pre-existing asthma and indeed, in some patients, the airways obstruction may not be responsive to bronchodilators. (13) It has been suggested that the likelihood of airways obstruction during the course of the disease is related to the degree of BAL fluid eosinophilia at initial presentation. (3,13)

The response to corticosteroid treatment is characterized by rapid resolution of symptoms, radiologic opacities (Fig. 2), and peripheral eosinophilia; a marked decrease in the eosinophils in BAL fluid after steroid therapy has been demonstrated. (25) However, symptoms and radiologic opacities reappear when the corticosteroid dose is lowered or stopped, and patients usually require a maintenance dose equivalent to or greater than 15 mg of prednisone per day to remain symptom free and without radiographic opacities. (24) Nevertheless, a tapered reduction and cessation of steroid treatment after several months of therapy should be tried in each patient. Evidence of relapse should be based not simply on symptoms, radiographic changes and peripheral eosinophilia, but pulmonary function should be monitored with spirometry, since it is reported that airways obstruction may occur in the absence of other symptoms. (13) As noted above, the majority of patients with CEP require long-term corticosteroid treatment, with the attendant danger of untoward side effects. Inhaled steroid treatment in CEP has not been studied prospectively; there is one brief report of the use of inhaled steroids alone in CEP. (26) However, when inhaled steroids were added to the oral corticosteroid regimen in 5 patients, Naughten et al (24) reported a reduction in the oral corticosteroid maintenance dose in three patients. Another study (16) found that patients with asthma at the time of CEP diagnosis who were treated more frequently with long-term inhaled corticosteroids had fewer relapses of CEP (56 versus 23%) and had a lower number of relapses per year of follow-up (median 0 versus 0.24). The authors conclude that the higher use of inhaled corticosteroids results in a lower incidence of relapses in CEP. (16) We have maintained a 57-year-old female with CEP on inhaled steroids with good results and no relapse for the past 8 years, since 1998. The long-term prognosis of CEP was originally felt to be excellent, (14,18) although longer term patient follow ups have tempered the prognosis somewhat. (3,13,24) There are individual reports of the development of pulmonary fibrosis. (27) CEP has also been reported in association with lymphoma, (19,20) Churg-Strauss syndrome, (22,23) and sarcoidosis, (21) but this appears to be rare, and could be fortuitous. A significant number of patients are likely to require long-term corticosteroid therapy. (3,13,24) Nevertheless, the prognosis appears to be good, so long as treatment is continued, although airways obstruction may develop during the course of the disease, in spite of corticosteroid treatment. (3,13)

References

1. Carrington CB, Addington WW, Goff AM, et al. Chronic eosinophilic pneumonia. N Engl J Med 1969;280:787-798.

2. Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med 1994;150:1423-1438.

3. Marchand E, Reynaud-Gaubert M, Lauque D, et al. Idiopathic chronic eosinophilic pneumonia. Medicine (Baltimore) 1998;77:299-312.

4. Cottin V, Cordier JF. Eosinophilic pneumonias. Allergy 2005;60:841-857.

5. Crofton JW, Livingston JL, Oswald NC, et al. Pulmonary eosinophilia. Thorax 1952;7:1-35.

6. Olopade CO, Crotty TB, Douglas WW, et al. Chronic eosinophilic pneumonia and idiopathic bronchiolitis obliterans organizing pneumonia: comparison of eosinophil number and degranulation by immunofluorescence staining for eosinophil-derived major basic protein. Mayo Clin Proc 1995;70:137-142.

7. Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups: the BAL Cooperative Group Steering Committee. Am Rev Respir Dis 1990;141:S169-S202.

8. Miyazaki E, Nurekis S, Fukami T, et al. Elevated levels of thymus- and activation-regulated chemokine in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia. Am J Respir Crit Care Med 2002;165:1125-1131.

9. Kita H, Sur S, Hunt LW, et al. Cytokine production at the site of disease in chronic eosinophilic pneumonitis. Am J Respir Crit Care Med 1996;153:1437-1441.

10. Tateno H, Nakamura H, Minematsu N, et al. Eotaxin and monocyte chemoattractant protein-1 in chronic eosinophilic pneumonia. Eur Respir J 2001;17:962-968.

11. Saita N, Yamanak T, Kohrogi H, et al. Apoptotic response of eosinophils in chronic eosinophilic pneumonia. Eur Respir J 2001;17:190-194.

12. Nakahara Y, Hayashi S, Fukuno Y, et al. Increased interleukin-5 levels in bronchoalveolar lavage fluid is a major factor for eosinophil accumulation in acute eosinophilic pneumonia. Respiration 2001;68:389-395.

13. Durieu J, Wallaert B, Tonnel AB, et al. Long-term follow-up of pulmonary function in chronic eosinophilic pneumonia. Eur Respir J 1997;10:286-291.

14. Gaensler EA, Carrington CB. Peripheral opacities in chronic eosinophilic pneumonia: The photographic negative of pulmonary edema. AJR Am J Roentgenol 1977;128:1-13.

15. Hayakawa H, Sato A, Toyoshima M, et al. A clinical study of idiopathic eosinophilic pneumonia. Chest 1994;105:1462-1466.

16. Marchand E, Etienne-Mastroianni B, Chanez P, et al. Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires. Idiopathic chronic eosinophilic pneumonia and asthma: how do they influence each other? Eur Respir J 2003;22:8-13.

17. Johkoh T, Muller NL, Akira M, et al. Eosinophilic lung diseases: diagnostic accuracy of thin section CT in 111 patients. Radiology 2000;216:773-780.

18. Pearson DJ, Rosenow EC III. Chronic eosinophilic pneumonia (Carrington's): a follow-up study. Mayo Clin Proc 1978;53:73-78.

19. Arakawa H, Kurihara Y, Niimi H, et al. Bronchiolitis obliterans with organizing pneumonia versus chronic eosinophilic pneumonia: high-resolution CT findings in 81 patients. AJR Am J Roentgenol 2001;176:1053-1058.

20. Hirshberg B, Kramer MR, Lotem M, et al. Chronic eosinophilic pneumonia associated with cutaneous T-cell lymphoma. Am J Hematol 1999;60:143-147.

21. Tani K, Kashio M, Sano N, et al. A case of sarcoidosis associated with chronic eosinophilic pneumonia. J Med Invest 1998;45:131-136.

22. Hueto-Perez-de-Heredia JJ, Dominguez-del-Valle FJ, Garcia E, et al. Chronic eosinophilic pneumonia as a presenting feature of Churg-Strauss syndrome. Eur Respir J 1994;7:1006-1008.

23. Golstein MA, Steinfeld S. Chronic eosinophilic pneumonia followed by Churg-Strauss syndrome. Rev Rheum Engl Ed 1996;63:624-628.

24. Naughton M, Fahy J, FitzGerald MX. Chronic eosinophilic pneumonia: a long-term follow-up of 12 patients. Chest 1993;103:162-165.

25. Takahashi H, Arakawa Y, Oki K, et al. Analysis of bronchoalveolar lavage cells in chronic eosinophilic pneumonia before and during corticosteroid therapy. Int Arch Allergy Immunol 1995;108 (Suppl 1):2-5.

26. Lavandier M, Carre P. Effectiveness of inhaled high-dose corticosteroid therapy in chronic eosinophilic pneumonia. Chest 1994;105:1913-1914.

27. Yoshida K, Shijubo N, Koba H, et al. Chronic eosinophilic pneumonia progressing to lung fibrosis. Eur Resp J 1994;7:1541-1544.

Mahmood Alam, MD, and Nausherwan K. Burki, MD, PhD

From the Division of Pulmonary and Critical Care Medicine, University of Connecticut Health Center, Farmington, CT.

Reprint requests to Nausherwan K. Burki, MD, PhD, Division of Pulmonary Medicine, MC 1225, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1321. Email: [e-mail]

Accepted July 20, 2006.

RELATED ARTICLE: Key Points

* While the precise etiology of chronic eosinophilic pneumonia is unknown, it is now believed that IL-5 may play a pivotal role: an unknown insult/stimulus triggers the accumulation of Th2 cells and release of IL-5 and other chemoattractants from the peripheral circulation into the lungs, which results in eosinophil accumulation in the lungs.

* Pre-existing asthma and atopy are not prerequisites for the development of chronic eosinophilic pneumonia (CEP).

* There are some data to suggest that CEP may itself cause airway obstruction.

* Standard treatment is with oral steroids; anecdotal reports suggest a role for inhaled steroids.

* The majority of patients with CEP will relapse after varying periods of time; sometimes after ten years or more, unless treatment is maintained.

Table 1. Eosinophilic lung diseases

Allergic syndromes
  Allergic bronchopulmonary aspergillosis
  Allergic bronchopulmonary syndromes associated with fungi
  Bronchocentric granulomatosis
Associated with parasitic infestation
  Tropical eosinophilia (filariasis)
  Ascaris spp. infestation
  Larva migrans syndrome
  Strongyloides stercoralis infection
Associated with systemic disease
  Churg-Strauss syndrome
  Hypereosinophilic syndromes
Associated with drugs, toxic agents and radiation
Associated with miscellaneous lung diseases
  Asthma and eosinophilic bronchitis
  Idiopathic interstitial pneumonias
  Langerhans cell granulomatosis
  Sarcoidosis
  Paraneoplastic syndrome
Idiopathic eosinophilic lung disease
  Idiopathic chronic eosinophilic pneumonia
  Idiopathic acute eosinophilic pneumonia

Table 2. Differential features of chronic eosinophilic pneumonia

                       CEP                        COP

Onset                  Insidious                  Insidious
Symptoms               Mild dyspnea, low          Slowly progressive
                         grade fevers, chest        dyspnea, dry cough
                         pain, occasional
                         cough, pre-existing
                         asthma in some
                       Signs of consolidation,    Signs of
                         bilateral or unilateral    consolidation,
                                                    bilateral or
                                                    unilateral
Peripheral blood       Eosinophilia >10%          Nonspecific
Chest radiograph       Bilateral, migratory,      Unikateral or
                         peripheral opacities,      bilateral patchy
                         ("photographic negative    consolidation
                         of pulmonary edema")
BAL                    Eosinophilia >25%          Nonspecific
Lung biopsy            Eosinophilic               Granulation tissue in
                         infiltration               small airways &
                         of parenchyma              alveolar ducts
Response to treatment  No response to             No response to
                         antibiotics                antibiotics
                       Dramatic response to       Dramatic response to
                         steroids                   steroids

                       Bacterial pneumonia        AEP

Onset                  Acute                      Acute
Symptoms               Fever, cough, chest pain   Fever, cough,
                                                    dyspnea, chest pain
                       Signs of consolidation-    Cyanosis, bilateral
                         usually unilateral         crackles, acute
                                                    respiratory failure
Peripheral blood       Polymorphonuclear          Usually no
                         leukocytosis               eosinophilia
Chest radiograph       Unilateral consolidation   Diffuse, bilateral
                                                    interstitial and
                                                    alveolar opacities
BAL                    Polymorphonuclear          Eosinophilia >25%
                         leukocytosis with
                         bacteria
Lung biopsy            Inflammatory exudate in    Organizing diffuse
                         parenchyma                 alveolar damage,
                                                    edema and
                                                    eosinophilic
                                                    infiltrate
Response to treatment  Good response to           No response to
                         antibiotics                antibiotics
                       Negative response to       Dramatic response to
                         steroids                   steroids, no
                                                    relapses

CEP, chronic eosinophilic pneumonia; COP, cryptogenic organizing
pneumonia; AEP, acute eosinophilic pneumonia; BAL, bronchoalveolar
lavage.

Table 3. Relapse rates for chronic eosinophilic pneumonia

                         Mean duration  Relapse
                     N   of follow up   rate

Durieu et al (13)    19   4 years       47%
Marchand et al (3)   46   6.2 years     69%
Naughten et al (24)  12  10 years       83%