Pathological and High Resolution CT Findings in Churg-Strauss Syndrome

Rui-e Feng ,Wen-bing Xu ,Ju-hong Shi ＊,Artin Mahmoudi ,Wen-bing Mu ,Wen-jie Zheng ,Yuan-jue Zhu,and Hong-rui Liu

1Department of Pathology,

2Department of Pulmonary Medicine,

3Department of Pulmonary and Critical Care Medicine,United Family Hospitals and Clinics-Beijing,Beijing 100016,China

4Department of Radiology,

5Department of Rheumatology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

CHURG-STRAUSS syndrome (CSS) is characterized by bronchial asthma,eosinophilia,and systemic necrotizing vasculitis with or without granulomas.Clinical diagnosis of CSS is not simple,and there have been a variety of definitions in the literature.Several classifications have been used including the original Churg and Strauss definition,1the Chapel Hill Consensus Conference definition,2the Lanham’s criteria,3and American College of Rheumatology’s definition.4All of these classification systems and definitions have limitations,especially in patients with mild or limited disease.5Cases have also been reported that overall features are suggestive of CSS but lack of typical features of the syndrome such as asthma,even in the absence of prior treatment.6CSS spectra of histologic changes include the combination of tissue infiltration by eosinophils,necrotizing vasculitis,and extravascular granulomas.However,experience with increasing numbers of cases indicates that this definition is too narrow and few pathologists are aware of these issues,and CSS appears to be under-diagnosed by pathologists.1,7-9These diagnostic difficulties highlight the need to better understand the characteristics of CSS in order to avoid being simply dependent on clinical manifestations or histologic changes for the purpose of diagnosis.This study was designed to review the clinicopathological features of 16 patients with CSS associated lung involvement,concentrating on clinical characteristics,pathological findings of lung involvements,response to treatment,and prognosis.

PATIENTS AND METHODS

Selection of cases

A computer-aided search was conducted to retrospectively identify all adults seen at our hospital from May 2005 to May 2009 with CSS and lung involvement.There were a total of 28 patients diagnosed as having CSS during the 4-year period.Sixteen of these CSS patients had lung biopsies performed,and they formed the final study group.All 16 patients underwent transbronchial lung biopsy(TBLB).Six of 16 patients underwent surgical lung biopsy as well.Open lung biopsy was performed in 1 patient and biopsyviavideo-assistant thorascopic surgery (VATS) was performed in 5 patients.Their clinical features,radiological pictures,and pathological findings were reviewed and analyzed.

This study was approved by the Peking Union Medical College Foundation Institutional Review Board.Patients who did not authorize the use of their medical records for research were excluded from this study.

Definitions

CSS was diagnosed on the basis of the classification criteria of the American College of Rheumatology.4Briefly,4 of the following 6 findings were required:(1) a history of asthma,(2) eosinophilia＞10%,(3) mononeuropathy or polyneuropathy,(4) nonfixed pulmonary infiltrates,(5) paranasal sinus abnormality,and (6) biopsy evidence of extravascular eosinophil infiltration.

Data analysis

Clinical data and diagnostic results were extracted from the medical records and included demographic data,clinical presentation,physical findings,laboratory results,and radiographic findings.Presenting signs and symptoms were recorded from the first encounter at our hospital that led to a diagnosis of CSS.Spirometry and carbon monoxide diffusion capacity (DLco) measurement were performed in our pulmonary function laboratory,and pulmonary function values were expressed as percentage of predicted normal values (%pred).All expressed values wereunless stated otherwise.CT scans of the lungs were reviewed by a chest radiologist with specific interest in interstitial lung disease.Lung biopsy slides were reviewed by two pulmonary pathologists.Values for the bronchoalveolar lavage cell profile were expressed as percentage of total bronchoalveolar lavage cells.

RESULTS

The diagnostic features of the 16 CSS patients are summarized in Table 1.

Clinical features

The median age of our 16 patients at the time of lung biopsy was 47.5 years (range,14 to 61 years),and 9 were women.Four patients had a smoking history.Clinical features at initial presentation are summarized in Table 2.The duration of respiratory symptoms ranged from 1 to 60 months (median,10 months) prior to lung biopsy.Thirteen of 16 patients had a history of asthma,and 4 patients had allergic rhinitis.Extrathoracic organs most commonly involved were the nervous system in 7 cases and skin in 5 cases.Most common respiratory symptoms were cough (12/16),exertional dyspnea (11/16),hemoptysis (4/16),and chest pain (3/16).The peak eosinophil count in peripheral blood ranged from 300 to 13 400/mL(mean,3374/mL) with the differential eosinophil count ranging from 4.6% to 52.2% (mean,23.0%) of white blood cells.

Table 1.CSS in 16 patients fulfilling feature of the American College of Rheumatology diagnostic criteria

Table 2.Presenting symptoms and laboratory results of the 16 CSS patients§

CT findings

CT scans showed bilateral patchy opacities in 12/16 patients (Fig.1C) with predominantly subpleural and lobular distribution and a lobular sparing pattern in 4/16 cases(Table 3).Six out of 16 patients had lower lung zone predilection of their infiltrates (Table 3).Ground-glass opacities (GGO) were found in 12 patients (Figs.1A,2A) with predominantly patchy and subpleural distribution (Fig.2A).Numerous nodules were present in 6 patients (Fig.3A).

Histopathologic findings

The pathologic findings of surgical lung biopsy are summarized in Table 4.

The vascular abnormalities included small vessel vasculitis and infiltration of eosinophils.Necrotizing vasculitis was observed in 4 specimens from 6 patients,characterized by intimal and medial infiltration by chronic inflammatory cells containing numerous eosinophils (Fig.3D).In 2 cases,the vasculitis only consisted of infiltration of the vascular wall by inflammatory cells without any obvious tissue necrosis.The affected capillaries and small venules were seen in 5/6 cases.Interstitial erythrocytes and/or hemosiderin and fibrinoid necrosis of capillary walls were found in these patients (Fig.2D).HE staining analysis in 2 of these cases of pulmonary capillaritis demonstrated extensive intra-alveolar hemorrhage.In these cases,erythrocytes and fibrin filled alveolar spaces (Fig.2E),whereas in chronic case,hemosiderin deposition was seen within alveolar macrophages and in the interstitium.

Eosinophilic pneumonia was found in 3/6 cases,manifested by the accumulation of large numbers of eosinophils(＞70%) and macrophages within alveolar spaces accompanied by alveolar septal expansion (Fig.2D).Tissue eosinophilia was found in 3/6 cases,manifested by a chronic inflammatory cell infiltration containing numerous eosinophils(Fig.1E,F).Granulomas were present in 2 patients (Fig.3E).

Airway abnormalities were found in 3 cases including muscle hypertrophy and eosinophilic and lymphocytic infiltration of the airway walls (Fig.1G).

Transbronchial biopsies (Table 4) demonstrated increased eosinophils in 3 cases,vasculitis in 3 cases,and interstitial pneumonia in 16 cases.No granulomas were found in TBLB specimens.

The diagnostic yield of specimens obtained by surgical lung biopsy and by transbronchial biopsy was reviewed.The correlation between TBLB and surgical lung biopsies was very poor (Table 4).

Figure 1.A.A 44-year-old female had a history of asthma for 4 years,CT scan showing multifocal ill-defined areas of ground-glass opacity in both middle and lower lung fields.Note increased vascular diameters and bronchial wall thickening.B.After 1 month of prednisone therapy ground-glass opacities have resolved.C.When prednisone was tapered and stopped for 7 months,CT scan showing focal areas of consolidation in the right middle and lower lobes.Also note small areas of ground-glass attenuation in the left lower lung.D.After the therapy with prednisone and cyclophosphamide for 12 months,areas of consolidation and ground-glass attenuation have resolved.E.Surgical lung biopsy showing idiopathic interstitial pneumonia (IIP) that is characterized by the accumulation of large numbers of chronic inflammatory cells within alveolar spaces.HE staining ×5F. High-magnification photomicrograph demonstrating alveolar spaces were filled with large numbers of macrophages,lymphocytes,and scattered eosinophils accompanied by alveolar septal expansion.HE staining ×200G.Small bronchiole with muscle hypertrophy,submucosal and submembranous inflammatory infiltrate (arrow).Replacment of ciliated columnar epithelium by goblet cell.HE staining ×100

Table 3.Distribution of lung parenchymal abnormalities at CT in 16 patients with CSS

Correlation of high-resolution CT and pathological findings

In the 6 surgical lung biopsy cases,consolidation on highresolution CT was found in 3 cases,and pathological findings were eosinophil infiltration and vasculitis.Thoracoscopic biopsy of the nodular lesions revealed granulomatous inflammation and necrotizing vasculitis with eosinophilic infiltration.Bilateral patchy ground-glass opacities coincided with capillaritis and diffuse alveolar hemorrhage.

Treatment and follow-up

At the initiation of treatment,all patients received a course of oral prednisone,starting at 0.5-1.0 mg·kg-1·d-1for 1 month which was then tapered every 3 weeks to 5.0-7.5 mg·d-1.The total length of treatment was 12 to 18 months.A rapid initial response to treatment with prednisone was observed in all cases (Figs.1B,2B).

Figure 2.A 55-year-old man presented with cough and dypsnea.

Figure 3.A 60-year-old man presented with recurred cough for 4 years.

Table 4.Comparison of pathological findings of surgical lung biopsy and TBLB

Thirteen patients also received cyclophosphamide(CTX) therapy.In 5 cases,oral CTX was administered at a dose of 100 mg·d-1for 12 months when relapse occurred after reduction of steroid dose to 15 mg·d-1(Fig.1C).In the remaining 8 patients (7 patients with neurological involvement and 1 case with gastrointestinal involvement),CTX was administered at the beginning with steroid therapy at the dose of 0.2 g administered intravenously every other day for 3 months followed by a dose of 100 mg·d-1given orally for 9 months (Fig.3A).

When CTX was given,blood cell counts were done about 7 days after starting treatment and then checked every week for 1 month,every 2 weeks for 1 month,and every 4 weeks for 10 months.If the white blood cell count fell below 3.5×109/L,CTX was temporarily stopped.Sideeffects such as myelosuppression,opportunistic infections or hemorrhagic cystitis did not develop in any of the patients after CTX therapy.

All 16 patients had follow-up data available over a median duration of 15 months (range,3 to 51 months).In all patients,symptoms and CT scans improved rapidly within 4 weeks of corticosteroid therapy.No patient died during the study period.

DISCUSSION

Clinical findings

In CSS,asthma is a disease defining feature occurring in almost all patients.10-12It precedes the onset of vasculitis in 83% of cases,with a median time of 4 years (interquartile range,2 to 11.5 years) between onset of asthma and a diagnosis of CSS.In 14% of patients the diagnosis of asthma coincides with that of vasculitis,and in rare cases vasculitis precedes the asthma by over a decade.10In our study,only 4/16 cases had a prior history of asthma.In 9/16 cases the diagnosis of CSS coincided with an acute asthmatic attack.There was no history of asthma or asthmatic attack in 3 cases.Surgical lung biopsies were performed in these 3 patients and the pathological findings showed that there were no eosinophils and lymphocytes infiltration in the bronchial walls and no chronic asthmatic inflammation.Although CSS without asthma has been thought to be extremely rare,there are several case reports detailing such occurrence.13-18In Schnabel’s study,one-third of the cases of CSS (2 out of 6) occurred in patients without the symptoms of asthma.19Silva and colleagues20found asthmatic inflammation in surgical lung biopsies in only 2/4 cases.Combined with the previous studies,we propose that asthma is present in CSS patient when there is bronchial inflammation.However,this bronchial involvement,hence the presence of asthma,may not be present in all patients.

Pathological findings

The spectrum of histologic changes described in the lung in CSS includes the combination of tissue infiltration by eosinophils,necrotizing vasculitis,and extravascular granulomas.21In our study,eosinophilic pneumonia could be seen in half of the cases (3/6) in surgical lung biopsy.Sparse eosinophilic infiltration was found in the remaining 3 cases.Among these 3 cases,steroids were given only in 1 case before the lung biopsy,so the administration of corticosteroids cannot be the only reason to make the CSS lesion to appear to have few eosinophils.22The initial study by Churg and Strauss emphasized that in the acute stage of CSS the predominant cell was the eosinophil which constituted as much as 70%-80% of the exudates.However,the number of eosinophils decreased as the acute inflammation subsided.1The composition of the cells in CSS seemed to depend on the phase of the inflammation,whether acute,subacute,or chronic.23The syndrome is frequently phasic in nature,with the pathologic findings varying not only with the anatomical site examined but also with the phase of the illness.3

The classic histological hallmarks of the vasculitic phase are an eosinophil rich necrotizing vasculitis involving primarily small arteries,arterioles,venules,and veins and necrotizing granulomas centered on necrotic eosinophils.22In our study,capillaritis could be seen in 5/6 of surgical lung biopsies (only 1/6 was ANCA positive).The results of lavage fluid showed large numbers of hemosiderin laden macrophages in 3/6 cases and 4/6 cases presented with hemoptysis.These implying the subclinical alveolar hemorrhage is actually quite common in CSS.24,25Because of this under-recognized form of vasculitis associated with alveolar hemorrhage,26,27careful examination of lung biopsies for evidence of capillaritis should routinely be carried out in suspected CSS cases.

Although the combination of eosinophilic pneumonia,vasculitis,and granulomatous inflammation is considered diagnostic for CSS,it should be noted that the classic description of the pathologic findings is based almost exclusively on autopsy material in patients with florid disease.1In our study,eosinophilic pneumonia could be seen in half of the cases (3/6) in surgical lung biopsies,vasculitis in 6 cases (6/6) and extravascular lung granulomas in 3 of 6 cases.All three histological components coexisted in a given tissue in 50% of biopsy specimens.These observations underscore the need for carefully clinical and pathologic correlation to establish the diagnosis,especially in cases that do not show the full spectrum of histologic changes.In patients with characteristic clinical manifestations,these findings are sufficient to make a confident diagnosis.

Diagnostic valves of TBLB

The study reported by Silva showed eosinophilic pneumonia in 3 TBLB specimens;no vasculitis or granulomas were found in the same TBLB specimens.20Another study from Schnabel showed nonspecific findings in 6 of 6 biopsies.19In our study,all 6 patients who underwent surgical lung biopsies also underwent TBLB before surgery.We compared the pathologic findings of TBLB with those of surgical lung biopsies.It was clear that TBLB in our study tended to contain more nonspecific findings.None of the 6 TBLB specimens showed changes considered to be diagnostic.Pulmonary vasculitis was found in none of the TBLB specimens of the 6 patients who had definitive vasculitis demonstratedviasurgical lung biopsy.Our findings suggest that the small size of the specimens obtained by TBLB is a major impediment to the successful use of TBLB for diagnosing CSS.

CT-pathologic comparisons

The high-resolution CT findings in our study are similar to those of previous studies,3,7,20,24,28-32consolidation histologically corresponded to areas of eosinophilic pneumonia,whereas bronchial wall thickening corresponded to areas of asthmatic bronchitis.Moreover,multiple variable-sized nodules corresponded to areas of necrotizing granulomatous vasculitis with eosinophilic infiltration.In our study,the ground-glass opacities in CT scans histopathologically corresponded to mixed areas of pulmonary hemorrhage related to capillaritis,necrotizing granulomas,and surrounding eosinophilic infiltration.Bilateral thickening of the interlobular septa was not seen in our study but was described in Silva’s study corresponding to edematous septa containing numerous eosinophils and mild fibrosis in surgical lung biopsy specimen.20

Guillevinet al33recommended that CSS patients without factors indicative of poor prognosis at the time of diagnosis could be successfully treated with prednisone alone and CTX was administered only as the second-line treatment in the cases of persistent disease activity or relapse despite corticosteroid therapy.We suggest that CTX should be administered as the initial treatment because of the high relapse rate observed in patients treated with prednisone alone in our study.

Our study is limited by its retrospective nature.In addition,it includes a small number of patients.Only 6 cases underwent surgical lung biopsy so it does not provide a definite correlation between the high-resolution CT and pathologic findings.However,CSS is rare.The incidence has been estimated to be approximately 1.8 to 3.3 cases per million person-years.34,35

Based on the results of our study,we conclude that asthma may be present in CSS patient when there is bronchial involvement.Ground-glass opacities and consolidation seen on high-resolution CT reflect the presence of eosinophilic pneumonia vasculitis and pulmonary alveolar hemorrhage.TBLB tends to contain nonspecific findings and has significant limitations for the diagnosis of CSS.Early diagnosis and therapy can result in satisfactory patient outcome.

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