ELDs are a group of diseases characterized by varying degrees of eosinophilic pulmonary infiltration or increased peripheral blood eosinophils [1]. ELDs can be classified into three categories according to whether there are clear pathogenic causes and vascular lesions [3]. The first category is ELDs with unknown pathogenic causes, including simple pulmonary eosinophilia, acute eosinophilic pneumonia, chronic eosinophilic pneumonia and idiopathic hypereosinophilic syndrome. Second category is ELDs with clear pathogenic causes, including parasitic infection, drug allergy and allergic bronchopulmonary aspergillosis. The third category is ELDs with vascular lesions, including allergic vasculitis and allergic eosinophilic granulomatous vasculitis.
CEP is a type of ELD of unknown etiology, and was first reported by Carrington in 1969 [2]. The epidemiology indicates that CEP is a rare disease with an incidence of < 1/100,000 [4], mostly reported in the form of individual case report, and there are few systematic studies on the disease. We summarized the clinical and pathological data of 20 patients pathologically diagnosed as CEP to improve the understanding of CEP, as well as to reduce misdiagnosis and mistreatment. In our study, the average age of 20 patients with CEP was 47.0 ± 10.2 years and the ratio of male to female was 1:2.3, which means that middle-aged women are more susceptible to CEP. The course of disease ranging between 2 months and 6 years, with an average course of 15.5 ± 11.5 months, which means CEP has a subacute or chronic onset. In our study, 50% patients had the history of allergic diseases, most commonly bronchial asthma, followed by allergic rhinitis and sinusitis, and CEP may be closely related to allergic diseases. 85% cases in our study were non-smokers, if smoking may play a protective role in the pathogenesis of CEP needs further investigation.
CEP has lack of specificity in the symptoms, and the main clinical manifestations were cough, dyspnea, expectoration, and shortness of breath, and often accompanied by fever, weight loss, and asthenia. CEP is mainly confined to the lung and respiratory tract, but also has mild extrapulmonary manifestations, such as pericardial effusion, arthralgia, neuropathy, nonspecific skin manifestations and abnormal liver function, which are easily confused with allergic eosinophilic granulomatous vasculitis or idiopathic hypereosinophilic syndrome [5, 6]. The symptoms of CEP are atypical and can be misdiagnosed as pneumonia, tuberculosis and lung cancer [7–9]. If there is antibiotic-refractory “pneumonia”, or “asthma” with poor therapeutic effect of inhaled hormones, or “tuberculosis” without improvement in anti-tuberculosis treatment, it is necessary to be vigilant against CEP.
In the present study, 95% patients had elevated peripheral blood eosinophils, with the proportion of eosinophils ranging from 5.3–64.7%. Therefor, the elevated peripheral blood eosinophils contribute to the diagnosis of CEP [10]. There were also a few patients with no elevation of eosinophils in peripheral blood, thus the patients with normal proportion of eosinophils in peripheral blood could not be excluded from CEP. CEP may have non-specific anemia, increased platelets, C-reactive protein and erythrocyte sedimentation rate. Elevated serum IgE level was observed in some cases, suggesting the presence of allergic factors in some CEP patients.
Hypoxemia can occur in the acute phase of CEP. Among 20 patients, 10 patients had mild hypoxemia and 2 patients had carbon dioxide retention, which indicated that the infiltration of eosinophils in the lung had an impact on the respiratory physiology of patients. The main changes of pulmonary function in CEP are restrictive ventilation disorder and diffuse hypofunction, obstructive ventilation disorder may occur in patients with asthma, and some patients develop mixed ventilation dysfunction in later stage. After treatment, pulmonary function improved rapidly. Recent studies have revealed that reduced lung CO diffusivity is a significant predictor of disease subclinical activity and recurrence in CEP patients [11].
The lesions in the pulmonary imaging of 20 cases are bilateral, non-migratory with clear boundaries, and mainly distributed in the periphery or subpleura. The most common lesions were patchy shadows, followed by consolidation and ground glass shadows. Some cases had atypical changes, such as nodular shadows, atelectasis, cavity formation, and pleural effusion. The image manifestations of CEP are diverse and can be misdiagnosed. To some extent, the peripheral and subpleural distribution of lung infiltrates may contribute to the diagnosis of CEP.
Bronchoscopic examination of the 20 patients identified that congestion and edema of bronchial mucosa were the most common manifestations. Granular or nodular protrusions could be observed in the endotracheal membrane of few patients [12], which were caused by CEP invading the airway. In our study, 90% patients had the increased proportion of eosinophils in BALF, ranging from 12–67%, with an average of 46%. The proportion of eosinophils in BALF was increased in some patients without obvious abnormal changes under bronchoscopy, which reflected the important value of bronchoscopy alveolar lavage in the diagnosis of CEP. It has been reported that it is suggestive of CEP when the proportion of eosinophils in BALF is > 25% [13]. In our study, the proportion of eosinophils in BALF was < 25% in some cases, and the pathology of pulmonary puncture indicated CEP; thus the demarcation of 25% for the diagnosis of CEP may be stringent.
If the patient is suspected of CEP and the differential diagnosis is difficult, bronchial mucosal biopsy and pulmonary biopsy are recommended. The histological examination of bronchial mucosal biopsy indicated eosinophilic infiltration in submucosal tissues and pulmonary biopsy indicated a large number of eosinophils infiltration in alveolar cavity and septum as the main pathological changes of CEP [14, 15]. Aggregation of eosinophils and necrosis form an ‘eosinophilic abscess’ [16], and Charcot-Leyden crystals also can be found in some cases. The clinical and image manifestations of CEP are complex and diverse, and the diagnosis of CEP will be confirmed by pathology.
Glucocorticoid is the most effective drug for CEP [17]. There is no unified standard for the dosage and course of glucocorticoid therapy. It has been suggested that the initial dose of glucocorticoid therapy is prednisone 0.5-1 mg kg-1 d-1. There is a possibility of recurrence of CEP during the course of hormone reduction or after withdrawal. It was also reported that when the hormone was reduced to 15 mg, it was easy for the disease to reoccur, thus the process of hormone reduction should be cautious. Previous retrospective studies demonstrated that the disease recurrence was prone to increase in < 6 months treatment. In our study, the initial dose of glucocorticoid treatment in 20 patients was methylprednisolone (dose equivalent to prednisone 1.0 mg/kg-1 d-1), intravenously used for 1–2 weeks. After chest imaging improved, oral methylprednisolone tablets (dose equivalent to prednisone 0.5 mg/kg-1 d-1) were used and gradually reduced to a minimum maintenance dose of 15 mg, and the total course of treatment was > 6 months. The overall therapeutic effect is good and can be recommended.
In recent years, there were a few case reports of successful treatment of CEP by suplatast tosilate due to intolerance of hormone therapy [18]. Suplatast tosilate is mainly used to treat asthma and allergic rhinitis, which can reduce IgE synthesis by inhibiting the production of interleukin-4 by T cells. It has also been reported that Omazu monoclonal antibody has a significant effect in the treatment of CEP [19–21]. Omazu monoclonal antibody is a new anti-IgE antibody used in asthma and other allergic diseases. The therapeutic mechanism of suplatast tosilate and Omazu in the treatment of CEP needs further study. Previous studies have reported that eosinophils play an important role in the occurrence and development of CEP and there are targeted drugs for eosinophil recruitment, eosinophil activation and eosinophil apoptosis induction [22, 23]. However, whether these drugs can be used in the treatment of CEP requires further investigation.